AU2013203748C1 - Antigen Binding Proteins to Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) - Google Patents

Antigen Binding Proteins to Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Download PDF

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AU2013203748C1
AU2013203748C1 AU2013203748A AU2013203748A AU2013203748C1 AU 2013203748 C1 AU2013203748 C1 AU 2013203748C1 AU 2013203748 A AU2013203748 A AU 2013203748A AU 2013203748 A AU2013203748 A AU 2013203748A AU 2013203748 C1 AU2013203748 C1 AU 2013203748C1
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pcsk9
antigen binding
seq
amino acid
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Qiong CAO
Teresa Arazas Carabeo
Joyce Chi Yee Chan
Simon Mark Jackson
Randal Robert Ketchem
Chadwick Terence King
Christopher Mehlin
Derek Evan Piper
Bei Shan
Wenyan Shen
Nigel Pelham Clinton Walker
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Amgen Inc
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Amgen Inc
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Priority claimed from PCT/US2008/074097 external-priority patent/WO2009026558A1/en
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Abstract

Antigen binding proteins that interact with Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) are described. Methods of treating hypercholesterolemia and other disorders by administering a pharmaceutically effective amount of an 5 antigen binding protein to PCSK9 are described. Methods of detecting the amount of PCSK9 in a sample using an antigen binding protein to PCSK9 are described. WO 2009/026558 PCT/US2008/074097 1-----------------------------------------------50 PCSK9parent (1) OZUNUGOYEiMIIAj '5EdGLAAP$1k5G5A~'iFRIKdPWESPG3YVV PCSK9mutants (1) R _1iRRRR RR FiliRdl lPWfi PdlYVV 51--- pro domain ------------------------------ 100 PCSK9parent (51) VNIIiIT LN NiTKII~if9FINGLLPGFLVf§fd PCSK9mutants (51) V-'Lj lKS! S TgF LKlIAil E-li TKIIAlFiGLLPGFLMEliF L 101-------------------=======50 PCSK9parent (101) ILELAILf LMNiUdYIEEDSSVFISIFINIlEItIPPRYRAf0EidPidGGI4V PCSK9mutants (101) EIL L YEI 1 IlPPRYR lIPIGGV 151================================ -------=== 200 PCSK9parent (151) E EAS CDSI-GTHL PCSK9mutants (151) EVYLLD'II|RRRH|EEEIDGRVRRRERRRERRRRRRERRR CDRqGTHL 201===---=============---=----------= = -====250 PCSK9parent (201) AGVVSG fAGVAINgfMRSI NVLNdGNGtVSGTLIGLEINI!NZ5~QvdB~9 PCSK9mutants (201) AGVVSGFPAGVA lidNlMRSlVLNClG1GlVSGTLIGLElR S P 251================= catalytic domain =========300 PCSK9parent (251) 7PLVVLLPLAGYSIVLtACQ RLIN GVVLVTAAGNF1 DDAC YSPA2A PCSK9mutants (251) 'PLVVLLPLAdlYSEVL lAdARLAEGVVLVTAAGNEEDDACRYSPARA 301============================================------350 PCSK9parent (301) PEVITVGATNQDQP TIGTI4GTNFGRCVDLFAPGEdIIGAS8CSC5' PCSK9mut ants (301) PEVI TVGA TNIRNRP(PMiiliGPGTNFGRCVDLFAPGl 9I I GAS$1 CSI Cli 351-= = = = = = = = = = == = = = = = = = = = = 400 PCSK9parent (351) 5 GSAAVGAIMjA5ILiAIL~ SK9IEEF PCSK9mutants (351) |PSGTAHAI I 401===------------------------------------------450 PCSK9parent (401) INININTPI LVA LPP5TN SG LFCRTVWSS WSRIbAl CAB PCSK9mutants (401) '__RRTALVALPPRRRRRRLFCRTWIS RRRECB 451--------------------------------------------500 PCSK9parent (451) EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGP2GVYAIARCCLLP PCSK9mutants (451) EELLSCSSFSRSGKRRGERMERQGGKLVCRAHNR9GRCGVYAIARCCLLP 501-------------- v domain ------------------------ 550 PCSK9parent (501) QANCSVHdAPPZEAIN GTI-iViSfdQHQ GHVLTGCSSHVEfldG'IKPPIMLR PCSK9mutants (501) QACSViiAPPA lIiGII Cl liGHVLTGCSSHailIlGi KPFliLR 551---------------------------------------------------600 PCSK9parent (551) PINGdNQCVGHREASIHASCCHAPGLECkVKEIIPAVQEidVTPfCIZGW PCSK9mutants (551) PFIPlQCVGHREASIHASCCHAPGLEC(RRR IPAi ElVT\lCfGW 601--------------------------------------------650 PCSK9parent (601) TLTGCSALPGTSHVLGAYAIMDNTCVVR$NDVSTTGSTSEIEAVTAVAICCN PCSK9mutants (601) TLTGCSALPGTSHVLGAYAliDNTCVVRD ER _ V A 651 --------- 680 PCSK9parent (651) SPHLAQASQELQGSSDYKDDDKHHHHHHHH (SEQ ID NO:303) PCSK9mutants (651) S&HLAQASQELQGSSDYKDDDKHHHHHHHH (SEQ ID NO:304)

Description

ANTIGEN BINDING PROTEINS TO PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 (PCSK9) 2013203748 12 Dec 2014
RELATED APPLICATIONS
[0001]
FIELD OF THE INVENTION
[0002] The present invention relates to antigen binding proteins that bind to proprotein convertase subtilisin kexin type 9 (PCSK9) and methods of using and making the antigen binding proteins.
BACKGROUND OF VARIOUS EMBODIMENTS
[0003] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al., 2007; Seidah and Prat, 2007). In vitro experiments have shown that adding PCSK9 to HepG2 cells lowers the levels of cell surface LDLR (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al., 2005; Park et al., 2004). Experiments with mice have shown that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver (Benjannet et al., 2004; Lagace et al., 2006; Maxwell et al., 2005; Park et al., 2004), while PCSK9 knockout mice have increased levels of LDLR in the liver (Rashid et al., 2005). Additionally, various human PCSK9 mutations that result in either increased or decreased levels of plasma LDL have been identified (Kotowski et al., 2006; Zhao et al., 2006). PCSK9 has been shown to directly interact with the LDLR protein, be endocytosed along with the LDLR, and co-immunofluoresce with the LDLR throughout the endosomal pathway (Lagace et al., 2006). Degradation of the LDLR by PCSK9 has not been observed and the mechanism through which it lowers extracellular LDLR protein levels is uncertain.
[0004] PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). Humans have nine prohormone-proprotein convertases 1 PCT/US2008/074097 WO 2009/026558 that can be divided between the S8A and S8B subfamilies (Rawlings et al., 2006). Furin, PC1/PC3, PC2, PACE4, PC4, PC5/PC6 and PC7/PC8/LPC/SPC7 are classified in subfamily S8B. Crystal and NMR structures of different domains from mouse furin and PCI reveal subtilisin-like pro- and catalytic domains, and a P domain directly C-terminal to the catalytic domain (Henrich et al., 2003; Tangrea et al., 2002). Based on the amino acid sequence similarity within this subfamily, all seven members are predicted to have similar structures (Henrich et al., 2005). SKI-1/S1P and PCSK9 are classified in subfamily S8A. Sequence comparisons with these proteins also suggest the presence of subtilisin-like pro- and catalytic domains (Sakai et al., 1998; Seidah et al., 2003; Seidah et al., 1999). In these proteins the amino acid sequence C-terminal to the catalytic domain is more variable and does not suggest the presence of a P domain.
[0005] Prohormone-proprotein convertases are expressed as zymogens and they mature through a multi step process. The function of the pro-domain in this process is two-fold. The pro-domain first acts as a chaperone and is required for proper folding of the catalytic domain (Ikemura et al., 1987). Once the catalytic domain is folded, autocatalysis occurs between the pro-domain and catalytic domain. Following this initial cleavage reaction, the prodomain remains bound to the catalytic domain where it then acts as an inhibitor of catalytic activity (Fu et al., 2000). When conditions are correct, maturation proceeds with a second autocatalytic event at a site within the pro-domain (Anderson et al., 1997). After this second cleavage event occurs the pro-domain and catalytic domain dissociate, giving rise to an active protease.
[0006] Autocatalysis of the PCSK9 zymogen occurs between Gin 152 and Seri 53 (VFAQ|SIP) (Naureckiene et al., 2003), and has been shown to be required for its secretion from cells (Seidah et al., 2003). A second autocatalytic event at a site within PCSK9’s pro-domain has not been observed. Purified PCSK9 is made up of two species that can be separated by nonreducing SDS-PAGE; the pro-domain at 17 Kd, and the catalytic plus C-terminal domains at 65 Kd. PCSK9 has not been isolated without its inhibitory pro-domain, and measurements of PCSK9’s catalytic activity have been variable (Naureckiene et al., 2003; Seidah et al., 2003). 2
SUMMARY OF VARIOUS EMBODIMENTS 2013203748 01 Dec 2016 [0007a] In some embodiments, the invention comprises an antigen binding protein to PCSK9.
[007b] In one aspect of the present invention, there is provided an isolated monoclonal antibody that binds to human PCSK9 and reduces binding between human PCSK9 and an EGFa domain of LDLR, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: (a) a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEQ ID NO: 23; or (b) a heavy chain variable region of the amino acid sequence in SEQ ID NO: 67; and a light chain variable region of the amino acid sequence in SEQ ID NO: 12; or (c) a heavy chain variable region of the amino acid sequence in SEQ ID NO: 467; and a light chain variable region of the amino acid sequence in SEQ ID NO: 469; or (d) a heavy chain variable region of the amino acid sequence in SEQ ID NO: 87; and a light chain variable region of the amino acid sequence in SEQ ID NO: 13.
[0007c] In another aspect of the present invention, there is provided an isolated monoclonal antibody that binds to human PCSK9 and reduces binding between human PCSK9 and an EGFa domain of LDLR, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEQ ID NO: 23.
[0007d] In another aspect of the present invention, there is provided an isolated monoclonal antibody that binds to human PCSK9 and is neutralizing in that an excess of said antibody reduces the quantity of human PCSK9 bound to LDLR in an in vitro competitive binding assay, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEQ ID NO: 23. 3a [0008] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9 comprising: A) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of: (i) a CDRH1 from a CDRH1 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (ii) a CDRH2 from a CDRH2 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (iii) a CDRH3 from a CDRH3 in a sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; and (iv) a CDRH of (i), (ii), and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids; B) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of: (i) a CDRL1 from a CDRL1 in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (ii) a CDRL2 from a CDRL2 in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (iii) a CDRL3 from a CDRL3 in a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 4 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the isolated antigen binding protein comprises at least one CDRH of A) and at least one CDRL of B). In some embodiments, the isolated antigen binding protein comprises at least two CDRH of A) and at least two CDRL of B). In some embodiments, the isolated antigen binding protein comprises said CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3. In some embodiments, the CDRH of A) is selected from at least one of the group consisting of: (i) a CDRH1 amino acid sequence selected from the CDRH1 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; (ii) a CDRH2 amino acid 2013203748 01 Dec 2016 [text continued on page 4] 3b PCT/US2008/074097 WO 2009/026558 sequence selected from the CDRH2 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; (iii) a CDRH3 amino acid sequence selected from the CDRH3 in a sequence selected from the group consisting of SEQ ID NO: 67, 79, 89, and 49; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids. In addition, the CDRL of B) is selected from at least one of the group consisting of: (i) a CDRL1 amino acid sequence selected from the CDRL1 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (ii) a CDRL2 amino acid sequence selected from the CDRL2 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; (iii) a CDRL3 amino acid sequence selected from the CDRL3 in a sequence selected from the group consisting of SEQ ID NO: 12, 35, 32, and 23; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B. In some embodiments, the CDRH of A) is selected from at least one of the group consisting of: (i) a CDRH1 amino acid sequence of the CDRH1 amino acid sequence in SEQ ID NO: 67; (ii) a CDRH2 amino acid sequence of the CDRH2 amino acid sequence in SEQ ID NO: 67; (iii) a CDRH3 amino acid sequence of the CDRH3 amino acid sequence in SEQ ID NO: 67; and (iv) a CDRH of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; said CDRL of B) is selected from at least one of the group consisting of: (i) a CDRL1 amino acid sequence of the CDRL1 amino acid sequence in SEQ ID NO: 12; (ii) a CDRL2 amino acid sequence of the CDRL2 amino acid sequence in SEQ ID NO: 12; (iii) a CDRL3 amino acid sequence of the CDRL3 amino acid sequence in SEQ ID NO: 12; and (iv) a CDRL of (i), (ii) and (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than 2 amino acids; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the antigen binding protein comprises A) a CDRHl of the CDRHl sequence in SEQ ID NO: 67, a CDRH2 of the CDRH2 sequence in SEQ ID NO: 67, and a CDRH3 of the CDRH3 sequence in SEQ ID NO: 67, and B) a CDRL1 of the CDRL1 sequence in SEQ ID NO: 12, a CDRL2 of the CDRL2 sequence in SEQ ID NO: 12, and a CDRL3 of the CDRL3 sequence in SEQ ID NO: 12. In some embodiments, the antigen binding protein comprises a heavy chain variable region (VH) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 4 PCT/U S2008/074097 WO 2009/026558
58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or a light chain variable region (VL) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, the VH has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or the VL has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, the VH is selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60, and/or the VL is selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46.
[0009] In some aspects, the invention comprises an isolated antigen binding protein that specifically binds to an epitope that is bound by any of the ABPs disclosed herein.
[0010] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, wherein the antigen binding protein comprises: A) one or more heavy chain CDRs (CDRHs) selected from at least one of the group consisting of: (i) a CDRH1 with at least 80% sequence identity to a CDRH1 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (ii) a CDRH2 with at least 80% sequence identity to a CDRH2 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; and (iii) a CDRH3 with at least 80% sequence identity to a CDRH3 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; B) one or more light chain CDRs (CDRLs) selected from at least one of the group consisting of: (i) a CDRL1 with at least 80% sequence identity to a CDRL1 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (ii)a CDRL2 with at least 80% sequence 5 PCT/US2008/074097 WO 2009/026558 identity to a CDRL2 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; and (iii) a CDRL3 with at least 80% sequence identity to a CDRL3 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B). In some embodiments, the antigen binding protein comprises: A) one or more CDRHs selected from at least one of the group consisting of: (i) a CDRH1 with at least 90% sequence identity to a CDRH1 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; (ii) a CDRH2 with at least 90% sequence identity to a CDRH2 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; and (iii) a CDRH3 with at least 90% sequence identity to a CDRH3 in one of the sequences selected from the group consisting of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60; B) one or more CDRLs selected from at least one of the group consisting of: (i) a CDRL1 with at least 90% sequence identity to a CDRL1 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; (ii) a CDRL2 with at least 90% sequence identity to a CDRL2 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; and (iii) a CDRL3 with at least 90% sequence identity to a CDRL3 in one of the sequences selected from the group consisting of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46; or C) one or more heavy chain CDRHs of A) and one or more light chain CDRLs of B).
[0011] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprises: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of: (i) a CDRH3 selected from the CDRH3 within the sequences selected from the group consisting of SEQ ID NOs: 67, 79, and 49, (ii) a CDRH3 that differs in amino acid sequence from the CDRH3 of (i) by 6 PCT/US2008/074097 WO 2009/026558 an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) X,X2X3X4X5X6X7X8X9XioXi 1X12X13X14 (SEQ ID NO: 404), wherein X, is selected from the group consisting of D, A, R, and not amino acid, X2 is selected from the group consisting of Y, I, G, and no amino acid, X3 is selected from the group consisting of D, A, G, and no amino acid, X4 is selected from the group consisting of F, A, L, and no amino acid, X5 is selected from the group consisting of W, L, A, and no amino acid, X6 is selected from the group consisting of S, Y, A, and no amino acid, X7 is selected from the group consisting of A, Y, R, and no amino acid, Xg is selected from the group consisting of Y, P, and no amino acid, X9 is selected from the group consisting of Y, G, and no amino acid, Xio is selected from the group consisting of D, G, and no amino acid, Xu is selected from the group consisting of A, M, and no amino acid, Xi2 is selected from the group consisting of F, D, and no amino acid, Xi3 is selected from the group consisting of D, V, and no amino acid, X14 is selected from the group consisting of V and no amino acid; B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of: (i) a CDRL3 selected from the CDRL3 within the sequences selected from the group consisting of SEQ ID NOs: 12, 35, and 23, (ii) a CDRL3 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL3 amino acid sequence selected from the group consisting of: X1X2X3X4X5X6X7X8X9X10X11 (SEQ ID NO: 405), wherein X] is selected from the group consisting of Q and G, X2 is selected from the group consisting of S, T, A, and no amino acid, X3 is selected from the group consisting of Y, no amino acid, and W, X4 is selected from the group consisting of D and no amino acid, X5 is selected from the group consisting of S and no amino acid, X(, is selected from the group consisting of S and no amino acid, X7 is selected from the group consisting of L, T, and no amino acid, Xg is selected from the group consisting of no amino acid, A, and S, X9 is selected from the group consisting of no amino acid, G, A, and V, Xio is selected from the group consisting of no amino acid, S, Y, and V, Xu is selected from the group consisting of no amino acid and V.
[0012] In some aspects, the invention comprises an isolated antigen binding protein comprising a light chain having the amino acid sequence selected from the group consisting of: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, 46, and some combination thereof. 7 PCT/US2008/074097 WO 2009/026558 [0013] In some embodiments, the antigen binding protein specifically binds to an epitope that is bound by at least one of the antigen binding proteins disclosed herein. In some embodiments, the isolated antigen binding protein further comprises a heavy chain having the amino acid sequence selected from the group consisting of: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, 60, and some combination thereof. In some embodiments, the amino acid sequence of the ABP is selected from the group consisting of SEQ ID NO: 12, 35, 23, and some combination thereof. In some embodiments, the heavy chain of the ABP comprises a CDRH3 of SEQ ID NO: 67, a CDRH2 of SEQ ID NO: 67, and a CDRH1 of SEQ ID NO:67, and said light chain comprises a CDRL3 of SEQ ID NO: 12, a CDRL2 of SEQ ID NO: 12, and a CDRL1 of SEQ ID NO: 12. In some embodiments, the isolated antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof. In some embodiments, the isolated antigen binding protein is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule. In some embodiments, the isolated antigen binding protein is a human antibody. In some embodiments, the isolated antigen binding protein is a monoclonal antibody. In some embodiments, the isolated antigen binding protein is of the IgGl-, IgG2- IgG3- or IgG4-type. In some embodiments, the isolated antigen binding protein is of the IgG4- or IgG2-type. In some embodiments, the isolated antigen binding protein is coupled to a labeling group. In some embodiments, the isolated antigen binding protein competes for binding to PCSK9 with an antigen binding protein described herein. In some embodiments, the isolated antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof. In some embodiments, the isolated antigen binding protein is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule. In some embodiments, the isolated antigen binding protein is coupled to a labeling group. In some embodiments, the isolated antigen binding protein reduces binding of PCSK9 to LDLR. In some embodiments, the isolated antigen binding protein the antigen binding protein decreases an amount of LDL present in a subject when administered to the subject. In some embodiments, the isolated antigen binding protein decreases an amount of serum cholesterol present in a subject when administered to the subject. In some embodiments, the isolated antigen 8 PCT/US2008/074097 WO 2009/026558 binding protein increases an amount of LDLR present in a subject when administered to the subject.
[0014] In some aspects, the invention comprises a vector comprising a nucleic acid molecule as described herein. In some embodiments, the invention comprises a host cell comprising a nucleic acid molecule as described herein.
[0015] In some aspects, the invention comprises an isolated antigen binding protein that competes for binding to PCSK9 with an antigen binding protein disclosed herein.
[0016] In some aspects, the invention comprises a nucleic acid molecule encoding the antigen binding protein according disclosed herein.
[0017] In some aspects, the invention comprises a pharmaceutical composition comprising at least one antigen binding protein described herein.
[0018] In some aspects, the invention comprises a method for treating or preventing a condition associated with elevated serum cholesterol levels in a patient, comprising administering to a patient in need thereof an effective amount of at least one isolated antigen binding protein disclosed herein.
[0019] In some aspects, the invention comprises a method of inhibiting binding of PCSK9 to LDLR in a subject comprising administering an effective amount of at least one antigen binding protein disclosed herein.
[0020] In some aspects, the invention comprises an antigen binding protein that selectively binds to PCSK9, wherein the antigen binding protein binds to PCSK9 with a K<j that is smaller than 100 pM.
[0021] In some aspects, the invention comprises a method for treating or preventing a condition associated with elevated serum cholesterol levels in a subject, the method comprising administering to a subject in need thereof an effective amount of at least one isolated antigen binding protein disclosed herein simultaneously or sequentially with an agent that elevates the availability of LDLR protein.
[0022] In some aspects, the invention comprises a method of lowering serum cholesterol level in a subject, the method comprising administering to a subject an effective amount of at least one isolated antigen binding protein as disclosed herein.
[0023] In some aspects, the invention comprises a method of lowering serum cholesterol level in a subject, the method comprising administering to a subject an effective 9 PCT/US2008/074097 WO 2009/026558 amount of at least one isolated antigen binding protein as disclosed herein, simultaneously or sequentially with an agent that elevates the availability of LDLR protein.
[0024] In some aspects, the invention comprises a method of increasing LDLR protein level in a subject, the method comprising administering to a subject an effective amount of at least one isolated antigen binding protein as disclosed herein.
[0025] In some aspects, the invention comprises a method of increasing LDLR protein levels in a subject, the method comprising administering to a subject an effective amount of at least one isolated antigen binding protein as disclosed herein simultaneously or sequentially with an agent that elevates the availability of LDLR protein.
[0026] In some aspects, the invention comprises a pharmaceutical composition comprising an ABP as disclosed herein and an agent that elevates the availability of LDLR protein levels. In some embodiments, the agent that elevates the availability of LDLR protein comprises a statin. In some embodiments, the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and some combination thereof.
[0027] In some aspect, the invention comprises a method of making the antigen binding protein as described herein, comprising the step of preparing said antigen binding protein from a host cell that secretes said antigen binding protein.
[0028] In some aspect, the invention comprises a pharmaceutical composition comprising at least one antigen binding protein as described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises an additional active agent. In some embodiments, said additional active agent is selected from the group consisting of a radioisotope, radionuclide, a toxin, or a therapeutic and a chemotherapeutic group.
[0029] In some aspects, the invention comprises a method for treating or preventing a condition associated with an elevated serum cholesterol level in a patient. The method comprises administering to a patient in need thereof an effective amount of at least one isolated antigen binding protein as disclosed herein. In some embodiments, the condition is hypercholesterolemia.
[0030] In some aspects, the invention comprises a method of inhibiting binding of PCSK9 to LDLR in a patient comprising administering an effective amount of at least one antigen binding protein according as described herein. 10 PCT/US2008/074097 WO 2009/026558 [0031) In some aspect, the invention comprises an antigen binding protein that binds to PCSK9 with a K<j that is smaller than 100 pM. In some embodiments, the antigen binding protein binds with a K<j that is smaller than 10 pM. In some embodiments, the antigen binding protein binds with a K<j that is less than 5 pM.
[0032) In some aspects, the invention comprises a method for treating or preventing a condition associated with elevated serum cholesterol levels in a subject, said method comprising administering to a subject in need thereof an effective amount of at least one isolated antigen binding protein described herein simultaneously or sequentially with an agent that elevates the availability of LDLR protein. In some embodiments, the agent that elevates the availability of LDLR protein comprises a statin. In some embodiments, the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and some combination thereof.
[0033) In some aspects, the invention comprises a method of lowering the serum cholesterol level in a subject. The method comprises administering to a subject an effective amount of at least one isolated antigen binding protein as described herein.
[0034] In some aspects, the invention comprises a method of lowering serum cholesterol levels in a subject comprising administering to a subject an effective amount of at least one isolated antigen binding protein, as described herein, simultaneously or sequentially with an agent that elevates the availability of LDLR protein. In some embodiments, the agent that elevates the availability of LDLR protein comprises a statin. In some embodiments, the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and some combination thereof.
[0035] In some aspects, the invention comprises a method of increasing LDLR protein levels in a subject by administering to a subject an effective amount of at least one isolated antigen binding protein as provided herein.
[0036] In some aspects, the invention comprises a method of increasing LDLR protein levels in a subject by administering to a subject an effective amount of at least one isolated antigen binding protein, as described herein, simultaneously or sequentially with an agent that elevates the availability of LDLR protein. In some embodiments, the agent that elevates the availability of LDLR protein levels comprises a statin. In some embodiments, the 11 PCT/US2008/074097 WO 2009/026558 statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and some combination thereof.
[0037] In some aspects, the invention comprises a neutralizing antibody that binds to PCSK9 and reduces a low density lipoprotein receptor (LDLR) lowering effect of PCSK9 on LDLR. In some embodiments, the antibody specifically binds to PCSK9. In some embodiments, the antibody binds to the catalytic domain of PCSK9. In some embodiments, the antibody binds to an epitope within residues 31-447 of SEQ ID NO: 3. In some embodiments, the antibody binds to PCSK9 having an amino acid sequence that is at least 90% identical to SEQ ID NO: 3.
[0038] In some aspects, the invention comprises a neutralizing antigen binding protein that binds to PCSK9, wherein the antigen binding protein binds to PCSK9 at a location within residues 31-447 of SEQ ID NO: 3. In some embodiments, when the antigen binding protein is bound to PCSK9, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, 1368, G370, A371, S373, S376, Q382, W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, 1368, 1369, S372, S373, C378, F379, T385, S386, Q387, S153, S188,1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, HI93, El95, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247, 1369, S372, C375, or C378. In some embodiments, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153,1154, P155, R194, D238, A239,1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367,1368, G370, A371, S373, S376, or Q382. In some embodiments, the antibody is positioned 5 angstroms or less from at least one of the following residues of PCSK9: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381. In some embodiments, the antibody is positioned 5 angstroms or less from at least two of the following residues of PCSK9: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, 12 PCT/U S2008/074097 WO 2009/026558 C375, T377, C378, F379, V380, or S381. In some embodiments, the antibody is 5 angstroms or less from at least four of the following residues of PCSK9: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, or S381. In some embodiments, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: W72, FI 50, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365,1368, 1369, S372, S373, C378, F379, T385, S386, or Q387. In some embodiments, the antibody is positioned 5 angstroms or less from at least one of the following residues of PCSK9: W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, or G384. In some embodiments, the antibody is positioned 5 angstroms or less from at least two of the following residues of PCSK9: W72, FI 50, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, or G384. In some embodiments, the antibody is positioned 5 angstroms or less from at least four of the following residues of PCSK9: W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, or G384. In some embodiments, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, H193, E195, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247, 1369, S372, C375, or C378. In some embodiments, the antibody is positioned 5 angstroms or less from at least one of the following residues of PCSK9: SI53, SI88, 1189, Q190, S191, D192, R194, El97, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, or F379. In some embodiments, the antibody is positioned 5 angstroms or less from at least two of the following residues of PCSK9: S153, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, or F379. In some embodiments, the antibody is positioned 5 angstroms or less from at least four of the following residues of PCSK9: SI53, SI88, 1189, 13 PCT/US2008/074097 WO 2009/026558 Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, or F379 .
[0039] In some aspects, the invention comprises a neutralizing antibody that binds to PCSK9, wherein the antibody binds to PCSK9 and reduces the likelihood that PCSK9 binds to LDLR.
[0040] In some embodiments, an antibody or antigen binding molecule that binds to PCSK9 is contemplated. The antibody binds to PCSK9 at a location within residues 31-447 of SEQ ID NO: 3. In some embodiments, the antibody or antigen binding molecule, when bound to PCSK9, is positioned 8 angstroms or less from at least one of the following residues of PCSK9: S153,1154, P155, R194, D238, A239,1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, 1368, G370, A371, S373, S376, Q382, W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365,1368,1369, S372, S373, C378, F379, T385, S386, Q387, SI53, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, HI93, El95, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247,1369, S372, C375, or C378.
[0041] In some embodiments, an isolated antibody or antigen binding molecule that blocks an antibody to PCSK9 from binding within 8 angstroms of a residue of PCSK9 is provided. In some embodiments the residue of PCSK9 is selected from at least one of the following PCSK9 residues: S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, 1368, G370, A371, S373, S376, Q382, W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, SI48, VI49, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, 1368, 1369, S372, S373, C378, F379, T385, S386, Q387, S153, S188,1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, 14 PCT/U S2008/074097 WO 2009/026558 HI93, E195, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247, 1369, S372, C375, or C378.
[0042] In some embodiments, an isolated antibody or antigen binding molecule that binds to PCSK9 at a location that overlaps with a location that LDLR binds to PCSK9 is provided. In some embodiments, the location that LDLR binds to PCSK9 includes at least one amino acid residue selected from the group consisting of: S153,1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, and S381.
[0043] In some embodiments, an isolated antibody or antigen binding molecule that binds to PCSK9 is provided. In some embodiments, the antibody or antigen binding molecule reduces the likelihood that EGFa will bind to PCSK9 within 8 angstroms of at least one of the following residues on PCSK9: SI53, 1154, PI55, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367,1368, G370, A371, S373, S376, or Q382.
[0044] In some embodiments, an antibody, antigen binding protein, or antigen binding molecule that binds to a surface of PCSK9 that overlaps with a surface that EGFa binds, Ab 2IB 12 binds, and/or 31H4 binds is provided. In some embodiments, an antibody, antigen binding protein, or antigen binding molecule that binds to PCSK9 in a manner that is similar to that depicted in the figures is provided.
[0045] In some embodiments, the above embodiments are neutralizing antibodies or antigen binding proteins. In some embodiments, the antigen binding protein is not LDLR or a fragment thereof (such as EGFa).
[0046] In some aspects, the invention comprises an isolated neutralizing antibody, wherein when the antibody is bound to PCSK9, the antibody is positioned 8 angstroms or less from at least one of the following residues of PCSK9: T468, R469, M470, A471, T472, R496, R499, E501, A502, Q503, R510, H512, F515, P540, P541, A542, E543, H565, W566, E567, V568, E569, R592, E593, S465, G466, P467, A473, 1474, R476, G497, E498, M500, G504, K506, L507, V508, A511, N513, A514, G516, V536, T538, A539, A544, T548, D570, L571, H591, A594, S595, and H597 of SEQ ID NO: 3. In some embodiments, the antibody is positioned 5 angstroms or less from at least one of the following residues of PCSK9: T468, R469, M470, A471, T472, R496, R499, E501, A502, Q503, R510, H512, F515, P540, P541, A542, E543, H565, W566, E567, V568, E569, R592, and E593 of SEQ ID NO: 3. 15 PCT/US2008/074097 WO 2009/026558 [0047] In some aspects, the invention comprises an isolated antigen binding protein. The antigen binding protein comprises: A) a CDRH1 of the CDRH1 sequence in SEQ ID NO: 89, a CDRH2 of the CDRH2 sequence in SEQ ID NO: 89, and a CDRH3 of the CDRH3 sequence in SEQ ID NO: 89, and B) a CDRL1 of the CDRL1 sequence in SEQ ID NO:32, a CDRL2 of the CDRL2 sequence in SEQ ID NO:32, and a CDRL3 of the CDRL3 sequence in SEQ ID NO:32.
[0048] In some aspects, the invention comprises an isolated antigen binding protein that binds to a PCSK9 protein of SEQ ID NO: 1 where the binding between said isolated antigen binding protein and a variant PCSK9 protein is less than 50% of the binding between the isolated antigen binding protein and the PCSK9 protein of SEQ ID NO: 1 and/or SEQ ID NO: 303. In some embodiments, the variant PCSK9 protein comprises at least one mutation of a residue at a position selected from the group consisting or comprising 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554, as shown in SEQ ID NO: 1. In some embodiments, the at least one mutation selected from the group comprising or consisting of R207E, D208R, E181R, R185E, R439E, E513R, V538R, E539R, T132R, S351R, A390R, A413R, and E582R. In some embodiments, the at least one mutation is selected from the group consisting of D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R,and Q554R.
[0049] In some aspects, the invention comprises an antigen binding protein that binds to a PCSK-9 protein of SEQ ID NO: 303 in a first manner and binds to a variant of PCSK9 in a second manner. The PCSK9 variant has at least one point mutation at a position selected from the group comprising or consisting of: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554 of SEQ ID NO: 303 and/or SEQ ID NO: 1. In some embodiments, the first manner comprises a first EC50, a first Bmax, or a first EC50 and a first Bmax. In some embodiments, the second manner comprises a second EC50, a second Bmax, or a second EC50 and a second Bmax. The value for the first manner is different from the value for the second manner. In some embodiments, the first manner comprises a first EC50, wherein the second manner involves a second EC50, and wherein the point mutation is selected from the group consisting or comprising: R207E, D208R, E181R, R185E, R439E, E513R, V538R, E539R, T132R, S351R, A390R, A413R, and E582R. In some embodiments, the first EC50 is at least 20% different from the second EC50. In some 16 PCT/US2008/074097 WO 2009/026558 embodiments, the first EC50 is at least 50% different from the second EC50. In some embodiments, the second EC50 is a larger numerical value than the first EC50. In some embodiments, the first EC50 is determined by a multiplex bead binding assay. In some embodiments, the second EC50 is greater than 1 um. In some embodiments, the antigen binding protein is a neutralizing antigen binding protein. In some embodiments, the neutralizing antigen binding protein is a competitive neutralizing antigen binding protein. In some embodiments, the neutralizing antigen binding protein is a non-competitive neutralizing antigen binding protein. In some embodiments, the first manner comprises a first Bmax and the second manner comprises a second Bmax that is different from the first Bmax. The PCSK9 variant has at least one point mutation selected from the group consisting or comprising: D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R,and Q554R. In some embodiments, the second Bmax is about 10% of the first Bmax. In some embodiments, the first Bmax is at least 20% different from the second Bmax. In some embodiments, the first Bmax is at least 50% different from the second Bmax.
[0050] In some aspects, the invention comprises an isolated antigen binding protein that binds to a PCSK9 protein of SEQ ID NO: 3, wherein the epitope of the antigen binding protein includes at least one of the following amino acids of SEQ ID NO: 1: 207, 208, 181, 185, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554.
[0051] In some aspects, the invention comprises an isolated neutralizing antigen binding protein that binds to a PCSK9 protein comprising the amino acid sequence of SEQ ID NO: 1, wherein the neutralizing antigen binding protein decreases the LDLR lowering effect of PCSK9 on LDLR. In some embodiments, the antigen binding protein is a LDLR noncompetitive neutralizing antigen binding protein. In some embodiments, the antigen binding protein is a LDLR competitive neutralizing antigen binding protein.
[0052] In some aspects, the invention comprises an isolated antigen binding protein, wherein said antigen binding protein comprises: A) a CDRH1 of the CDRH1 sequence in SEQ ID NO: 49, a CDRH2 of the CDRH2 sequence in SEQ ID NO: 49, and a CDRH3 of the CDRH3 sequence in SEQ ID NO: 49, and B) a CDRL1 of the CDRL1 sequence in SEQ ID NO:23, a CDRL2 of the CDRL2 sequence in SEQ ID NO:23, and a CDRL3 of the CDRL3 sequence in SEQ ID NO:23. 17 PCT/U S2008/074097 WO 2009/026558 [0053] In some aspects, the invention comprises a composition comprising a crystallized PCSK9 protein and an antigen binding protein that binds to PCSK9. The composition comprises the crystallized PCSK9 protein is such that the three dimensional structure of the PCSK9 protein can be determined to a resolution of about 2.2 angstroms or better. In some embodiments, the antigen binding protein is an antibody or a fragment thereof.
[0054] In some aspects, the invention comprises a crystallized PCSK9 protein and at least an EGFa section of a LDLR protein, wherein the EGFa section of the LDLR protein is bound by a PCSK9 protein, wherein said crystallized PCSK9 protein is such that the three dimensional structure of the PCSK9 protein can be determined to a resolution of about 2.2 angstroms or better. In some embodiments, the molecular model is on a computer readable medium.
[0055] In some aspects, the invention comprises the use of an antigen binding protein as described herein, in the preparation of a medicament for the lowering of serum cholesterol.
[0056] In some aspects, the invention comprises the use of an antigen binding protein as described herein, in the preparation of a medicament for treating or preventing a condition associated with elevated serum cholesterol levels in a subject.
[0057] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprising: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of: (i) a CDRH1 selected from the CDRH1 within the sequences selected from the group consisting of SEQ ID NOs: 67, 79, 89, and 49, (ii) a CDRH1 that differs in amino acid sequence from the CDRH1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH1 amino acid sequence selected from the group consisting of X1X2X3X4X5X0X7X8X9X10 (SEQ ID NO: 406), wherein Xj is selected from the group consisting of G, X2 is selected from the group consisting of Y, F, and G, X3 is selected from the group consisting of T and S, X4 is selected from the group consisting of L and F, X5 is selected from the group consisting of T, S, and N, X6 is selected from the group consisting of S and A, X7 is selected from the group consisting of Y and F, is selected from the group consisting of G, S, and Y, X9 is selected from the group consisting of I, M, and W, Xi0 is selected from the group consisting of S, N and Η, B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of: (i) a CDRL1 selected from the CDRL1 within the sequences selected from 18 PCT/U S2008/074097 WO 2009/026558 the group consisting of SEQ ID NOs: 12, 32, 35, and 23, (ii) a CDRL1 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL1 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13X14 (SEQ ID NO: 407), wherein Xi is selected from the group consisting of T and no amino acid, X2 is selected from the group consisting of G and S, X3 is selected from the group consisting of S, T, and G, X4 is selected from the group consisting of S, X5 is selected from the group consisting of S, X6 is selected from the group consisting of N, D, and S, X7 is selected from the group consisting of I, V, and N, Xg is selected from the group consisting of G and I, X9 is selected from the group consisting of A and G, X10 is selected from the group consisting of G, Y, S, and N, Xu is selected from the group consisting of Y and N, X)2 is selected from the group consisting of D, S, T, and F, X13 is selected from the group consisting of V, X]4 is selected from the group consisting of S, N, and H. One of skill in the art will appreciate that a single ABP or antibody can meet one or more of the above options and still fall within the described invention for this embodiment.
[0058] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprising: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of the following: (i) a CDRH2 selected from the CDRH2 within the sequences selected from the group consisting of SEQ ID NOs: 67, 79, 89, and 49, (ii) a CDRH2 that differs in amino acid sequence from the CDRH2 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH2 amino acid sequence selected from the group consisting of X,X2X3X4X5X6X7X8X9XioXi 1X12X13X14 X15X16X17 (SEQ ID NO: 408), wherein Xi is selected from the group consisting of W, S, L and no amino acid, X2 is selected from the group consisting of V, I, and E, X3 is selected from the group consisting of S, W, and I, X4 is selected from the group consisting of F, S, and N, X5 is selected from the group consisting of Y, S, D, and Η, X6 is selected from the group consisting of N, S, and G, X7 is selected from the group consisting of S and G, Xg is selected from the group consisting of N, Y, D, and R, X9 is selected from the group consisting of T, I, and E, Xi0 is selected from the group consisting of N, S, Y, and D, Xu is selected from the group consisting of Y, Xj2 is selected from the group consisting of A and N, X13 is selected from the group consisting of Q, D, and P, Xm is selected from the group consisting of K and S, X15 is selected from the group consisting of L, and V, Xj6 is selected from 19 PCT/U S2008/074097 WO 2009/026558 the group consisting of Q and K, X|7 is selected from the group consisting of G and S, B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of the following: (i) a CDRL2 selected from the CDRL3 within the sequences selected from the group consisting of SEQ ID NOs: 12, 32, 35, and 23, (ii) a CDRL2 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL2 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7 (SEQ ID NO: 409), wherein Xj is selected from the group consisting of G, E, S, and D, X2 is selected from the group consisting of N, V, and Y, X3 is selected from the group consisting of S and N, X4 is selected from the group consisting of N, Q, and K, X5 is selected from the group consisting of R, Xe is selected from the group consisting of P, X7 is selected from the group consisting of S.
[0059] In some aspects, the invention comprises An isolated antigen binding protein that binds PCSK9, the antigen binding protein comprising: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of the following: (i) a CDRH3 selected from the CDRH3 within the sequences selected from the group consisting of SEQ ID NOs: 67, 79, 89, and 49, (ii) a CDRH3 that differs in amino acid sequence from the CDRH3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH3 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13X14 (SEQ ID NO: 410), wherein X| is selected from the group consisting of D, and no amino acid, X2 is selected from the group consisting of Y, A, and no amino acid, X3 is selected from the group consisting of D, I, and no amino acid, X4 is selected from the group consisting of F, A, and no amino acid, X5 is selected from the group consisting of W, A, and no amino acid, X6 is selected from the group consisting of S, L, and no amino acid, X7 is selected from the group consisting of A, Y, G, and no amino acid, Xg is selected from the group consisting of Y, Q, and no amino acid, X9 is selected from the group consisting of G, Y, and L, X10 is selected from the group consisting of Y, D, and V, Xu is selected from the group consisting of G, A, and P, X12 is selected from the group consisting of M and F, X13 is selected from the group consisting of D, X14 is selected from the group consisting of V and Y, and B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of the following: (i) a CDRL3 selected from the CDRL3 within the sequences selected from the group consisting of SEQ ID NOs: 12, 32, 35, and 23, (ii) a CDRL3 that differs in amino 20 PCT/U S2008/074097 WO 2009/026558 acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL3 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7X8X9X10X11 (SEQ ID NO: 411), wherein Xi is selected from the group consisting of Q, A, G, and no amino acid, X2 is selected from the group consisting of S, V, T, and no amino acid, X3 is selected from the group consisting of Y, N, and W, X4 is selected from the group consisting of S and D, X5 is selected from the group consisting of S, Y, and D, X(, is selected from the group consisting of S and T, X7 is selected from the group consisting of L and S, Xg is selected from the group consisting of S, T, and N, X9 is selected from the group consisting of G, S, and A, X10 is selected from the group consisting of S, M, W, and Y, and Xu is selected from the group consisting of V. In some embodiments, any of the above amino acids can be replaced by a conservative amino acid substitution.
[0060] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprises A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of (i) a CDRH1 selected from the CDRH 1 within the sequences selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, and 58, (ii) a CDRH1 that differs in amino acid sequence from the CDRH1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH1 amino acid sequence selected from the group consisting of X1X2X3X4X5X5X7X8X9X10 (SEQ ID NO: 412), wherein Xi is selected from the group consisting of G, P, and A, X2 is selected from the group consisting of Y, W, F, T, and S, X3 is selected from the group consisting of T, P, S and A, C, V, L, and I, X» is selected from the group consisting of L, F, I, V, M, A, and Y, X5 is selected from the group consisting of T, P, S, and A, X6 is selected from the group consisting of S, T, A, and C, X7 is selected from the group consisting of Y, W, F, T, and S, Xs is selected from the group consisting of G, P, and A, X9 is selected from the group consisting of I, L, V, M, A, and F, Xjo is selected from the group consisting of S, T, A, and C, B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of: (i) a CDRL1 selected from the CDRL1 within the sequences selected from the group consisting of SEQ ID NOs: 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, (ii) a CDRL1 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL1 amino acid sequence selected from the group consisting of 21 PCT/US2008/074097 WO 2009/026558 X1X2X3X4X5X0X7X8X9X10X11X12X13X14 (SEQ ID NO: 413), wherein, Xi is selected from the group consisting of T and S, X2 is selected from the group consisting of G, P, and A, X3 is selected from the group consisting of T, and S, X4 is selected from the group consisting of S N, T, A, C, and Q, X5 is selected from the group consisting of S, T, A, and C, X6 is selected from the group consisting of D, and E, X7 is selected from the group consisting of V, I, M, L, F, and A, Xg is selected from the group consisting of G, P, and A, X9 is selected from the group consisting of G, A, R, P, V, L, I, K, Q, and N, X10 is selected from the group consisting of Y, W, F, T, and S, Xu is selected from the group consisting of N, and Q, X12 is selected from the group consisting of Y, S, W, F, T, A, and C, X13 is selected from the group consisting of V, I, M, L, F, and A, X14 is selected from the group consisting of S, T, A, and C.
[0061] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprising: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of: (i) a CDRH2 selected from the CDRH2 within the sequences selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, and 58, (ii) a CDRH2 that differs in amino acid sequence from the CDRH2 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH2 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7X8X9X10X11X12X13X14 XisXieXn, (SEQ ID NO: 414), wherein Xi is selected from the group consisting of W, Y, and F, X2 is selected from the group consisting of V, I, M, L, F, and A, X3 is selected from the group consisting of S, T, A, and C, X4 is selected from the group consisting of A, F, V, L, I, Y, and Μ, X5 is selected from the group consisting of Y, W, F, T, and S, X6 is selected from the group consisting of N and Q, X7 is selected from the group consisting of G, P, and A, X8 is selected from the group consisting of N, and Q, X9 is selected from the group consisting of T, and S, Xi0 is selected from the group consisting of N, and Q, Xu is selected from the group consisting of Y, W, F, T, and S, X12 is selected from the group consisting of A, V, L, and I, X13 is selected from the group consisting of Q, E, N, and D, X]4 is selected from the group consisting of K, R, Q, and N, X15 is selected from the group consisting of L, F, V, I, M, A, and Y, X16 is selected from the group consisting of Q, and N, X]7 is selected from the group consisting of G, P, and A, B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of: (i) a CDRL2 selected from the CDRL3 within the sequences selected from the group consisting of SEQ ID NOs: 14, 15, 16, 22 PCT/US2008/074097 WO 2009/026558 17, 18, 19, 20, 21, 22, 23, and 24, (ii) a CDRL2 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL2 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7 (SEQ ID NO: 415), wherein X] is selected from the group consisting of E, and D, X2 is selected from the group consisting of V, I, M, L, F, and A, X3 is selected from the group consisting of S, T, A, and C, X4 is selected from the group consisting of N, and Q, X5 is selected from the group consisting of R, K, Q, and N, X6 is selected from the group consisting of P, and A, X7 is selected from the group consisting of S, T, A, and C.
[0062] In some aspects, the invention comprises an isolated antigen binding protein that binds PCSK9, the antigen binding protein comprising: A) a heavy chain complementary determining region (CDRH) selected from at least one of the group consisting of (i) a CDRH3 selected from the CDRH3 within the sequences selected from the group consisting of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, and 58, (ii) a CDRH3 that differs in amino acid sequence from the CDRH3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRH3 amino acid sequence selected from the group consisting of X1X2X3X4X5X6 (SEQ ID NO: 416), wherein Xi is selected from the group consisting of G, P, A and no amino acid, X2 is selected from the group consisting of Y, W, F, T, and S, X3 is selected from the group consisting of G, V, P, A, I, M, L, and F, X4 is selected from the group consisting of M, L, F, and I, X5 is selected from the group consisting of D, and E, X6 is selected from the group consisting of V, I, M, L, F, and A, B) a light chain complementary determining region (CDRL) selected from at least one of the group consisting of: (i) a CDRL3 selected from the CDRL3 within the sequences selected from the group consisting of SEQ ID NOs: 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24, (ii) a CDRL3 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and (iii) a CDRL3 amino acid sequence selected from the group consisting of X1X2X3X4X5X6X7X8X9 (SEQ ID NO: 417), wherein Xi is selected from the group consisting of S, N, T, A, C, and Q, X2 is selected from the group consisting of S, T, A, and C, X3 is selected from the group consisting of Y, W, F, T, and S, X4 is selected from the group consisting of T, and S, X5 is selected from the group consisting of S, T, A, and C, X6 is selected from the group consisting of S, T, A, and C, X7 is selected from the group consisting of N, S, Q, T, A, and C, Xg 23 PCT/US2008/074097 WO 2009/026558 is selected from the group consisting of Μ, V, L, F, I, and A, X9 is selected from the group consisting of V, I, M, L, F, and A.
BRIEF DESCRIPTION OF THE FIGURES
[0063] FIG. 1A depicts an amino acid sequence of the mature form of the PCSK9 with the pro-domain underlined.
[0064] FIGs. IB1-IB4 depict amino acid and nucleic acid sequences of PCSK9 with the pro-domain underlined and the signal sequence in bold.
[0065] FIGs. 2A-2D are sequence comparison tables of various light chains of various antigen binding proteins. FIG. 2C continues the sequence started in FIG. 2A. FIG. 2D continues the sequence started on FIG. 2B.
[0066] FIGs. 3A-3D are sequence comparison tables of various heavy chains of various antigen binding proteins. FIG. 3C continues the sequence started in FIG. 3A. FIG. 3D continues the sequence started on FIG. 3B.
[0067] FIGs. 3E-3JJ depict the amino acid and nucleic acid sequences for the variable domains of some embodiments of the antigen binding proteins.
[0068] FIG. 3KK depicts the amino acid sequences for various constant domains.
[0069] FIGs. 3LL-3BBB depict the amino acid and nucleic acid sequences for the variable domains of some embodiments of the antigen binding proteins.
[0070] FIGs. 3CCC-3JJJ are sequence comparison tables of various heavy and light chains of some embodiments of the antigen binding proteins.
[0071] FIG. 4A is a binding curve of an antigen bindng protein to human PCSK9.
[0072] FIG. 4B is a binding curve of an antigen bindng protein to human PCSK9.
[0073] FIG. 4C is a binding curve of an antigen bindng protein to cynomolgus PCSK9.
[0074] FIG. 4D is a binding curve of an antigen bindng protein to cynomolgus PCSK9.
[0075] FIG. 4E is a binding curve of an antigen bindng protein to mouse PCSK9.
[0076] FIG. 4F is a binding curve of an antigen bindng protein to mouse PCSK9. 24 PCT/US2008/074097 WO 2009/026558 [0077] FIG. 5A depicts the results of an SDS PAGE experiement involving PCSK9 and various antigen binding proteins demonstrating the relative purity and concentration of the proteins.
[0078] FIG. 5B and 5C depict graphs from biacore solution equilibrium assays for 21B12.
[0079] FIG. 5D depicts the graph of the kinetics from a biacore capture assay.
[0080] FIG. 5E depicts a bar graph depicting binning results for three ABPs.
[0081] FIG. 6A is an inhibition curve of antigen binding protein 31H4 IgG2 to PCSK9 in an in vitro PCSK9:LDLR binding assay [0082] FIG. 6B is an inhibition curve of antigen binding protein 31H4 IgG4 to PCSK9 in an in vitro PCSK9:LDLR binding assay.
[0083] FIG. 6C is an inhibition curve of antigen binding protein 2IB 12 IgG2 to PCSK9 in an in vitro PCSK9:LDLR binding assay.
[0084] FIG. 6D is an inhibition curve of antigen binding protein 21B12 IgG4 to PCSK9 in an in vitro PCSK9:LDLR binding assay.
[0085] FIG. 7A is an inhibition curve of antigen binding protein 31H4 IgG2 in the cell LDL uptake assay showing the effect of the ABP to reduce the LDL uptake blocking effects of PCSK9 [0086] FIG. 7B is an inhibition curve of antigen binding protein 31H4 IgG4 in the cell LDL uptake assay showing the effect of the ABP to reduce the LDL uptake blocking effects of PCSK9 [0087] FIG. 7C is an inhibition curve of antigen binding protein 21B12 IgG2 in the cell LDL uptake assay showing the effect of the ABP to reduce the LDL uptake blocking effects of PCSK9 [0088] FIG. 7D is an inhibition curve of antigen binding protein 2IB 12 IgG4 in the cell LDL uptake assay showing the effect of the ABP to reduce the LDL uptake blocking effects ofPCSK9 [0089] FIG. 8A is a graph depicting the serum cholesterol lowering ability in mice of ABP 31H4, changes relative to the IgG control treated mice (* p< 0.01).
[0090] FIG. 8B is a graph depicting the serum cholesterol lowering ability in mice of ABP 31H4, changes relative to time = zero hours (# p, 0.05). 25 PCT/U S2008/074097 WO 2009/026558 [0091] FIG. 8C is a graph depicting the effect of ΑΒΡ 31H4 on HDL cholesterol levels in C57B1/6 mice (* p< 0.01).
[0092] FIG. 8D is a graph depicting the effect of ΑΒΡ 31H4 on HDL cholesterol levels in C57B1/6 mice (# p< 0.05).
[0093] FIG. 9 depicts a western blot analysis of the ability of ΑΒΡ 31H4 to enhance the amount of liver LDLR protein present after various time points.
[0094] FIG. 10A is a graph depicting the ability of an antigen binding protein 31H4 to lower total serum cholesterol in wild type mice, relative.
[0095] FIG. 10B is a graph depicting the ability of an antigen binding protein 31H4 to lower HDL in wild type mice.
[0096] FIG. 10C is a graph depicting the serum cholesterol lowering ability of various antigen binding proteins 31H4 and 16F12.
[0097] FIG. 11A depicts an injection protocol for testing the duration and ability of antigen binding proteins to lower serum cholesterol.
[0098] FIG. 1 IB is a graph depicting the results of the protocol in FIG. 11 A.
[0099] FIG. 12A depicts LDLR levels in response to the combination of a statin and ABP 2IB 12 in HepG2 cells.
[0100] FIG. 12B depicts LDLR levels in response to the combination of a statin and ABP31H4 in HepG2 cells.
[0101] FIG. 12C depicts LDLR levels in response to the combination of a statin and ΑΒΡ 25A7.1, a nonneutralizing antibody, (in contrast the “25A7” a neutralizing antibody) in HepG2 cells.
[0102] FIG. 12D depicts LDLR levels in response to the combination of a statin and ABP 2 IB 12 in HepG2 cells overexpressing PCSK9.
[0103] FIG. 12E depicts LDLR levels in response to the combination of a statin and ABP 31H4 in HepG2 cells overexpressing PCSK9.
[0104] FIG. 12F depicts LDLR levels in response to the combination of a statin and ABP 25A7.1, a nonneutralizing antibody, (in contrast the “25A7” a neutralizing antibody) in HepG2 cells overexpressing PCSK9.
[0105] FIG. 13A depicts the various light chain amino acid sequences of various ABPs to PCSK9. The dots (.) indicate no amino acid. 26 PCT/US2008/074097 WO 2009/026558 [0106] FIG. 13B depicts a light chain cladogram for various ABPs to PCSK9.
[0107] FIG. 13C depicts the various heavy chain amino acid sequences of various ABPs to PCSK9. The dots (.) indicate no amino acid.
[0108] FIG. 13D depicts a heavy chain dendrogram for various ABPs to PCSK9.
[0109] FIG. 13E depicts a comparison of light and heavy CDRs and designation of groups from which to derive consensus.
[0110] FIG. 13F depicts the consensus sequences for Groups 1 and 2.
[0111] FIG. 13G depicts the consensus sequences for Groups 3 and 4.
[0112] FIG. 13H depicts the consensus sequences for Groups 1 and 2. The dots (.) indicated identical residues.
[0113] FIG. 131 depicts the consensus sequences for Group 2. The dots (.) indicated identical residues.
[0114] FIG. 13J depicts the consensus sequences for Groups 3 and 4. The dots (.) indicated identical residues.
[0115] FIG. 14A is a graph depicting in vivo LDL lowering ability of various ABPs (at 10 mg/kg).
[0116] FIG. 14B is a graph depicting in vivo LDL lowering ability of various ABPs (at 30 mg/kg).
[0117] FIG. 15A and FIG. 15B are sequence comparison tables of various light chains of various embodiments of antigen binding proteins. FIG. 15B continues the sequence started in FIG. 15A.
[0118] FIG. 15C and FIG. 15D are sequence comparison tables of various light chains of various embodiments of antigen binding proteins. FIG. 15D continues the sequence started in FIG. 15C.
[0119] FIG. 16A is a depiction of a gel used to test the ability of Ab 2 IB 12 to bind to the ProCat or VD sections of PCSK9.
[0120] FIG. 16B is a depiction of a gel used to test the ability of Ab 31H4 to bind to the ProCat or VD sections of PCSK9.
[0121] FIG. 17 is a depiction of the structure of PCSK9 and the EGFa section of LDLR.
[0122] FIG. 18 A is a depiction of the structure of PCSK9 and the 31H4 Ab. 27 PCT/US2008/074097 WO 2009/026558 [0123] FIG. 18B is a depiction of the structure of PCSK9 and the 31H4 Ab.
[0124] FIG. 19A is a depiction of the structure of PCSK9, the 31H4 Ab, and the 21B12 Ab.
[0125] FIG. 19B is a depiction of the structure of PCSK9 and the 21B12 Ab.
[0126] FIG. 20A is a depiction of the structure of PCSK9 and EGFa from the LDLR superimposed with the structure of antibodies 31H4 and 21B12 bound to PCSK9.
[0127] FIG. 20B is a depiction of the structural model of PCSK9 and LDLR.
[0128] FIG. 20C is a depiction of the structural model of PCSK9 and LDLR from an alternative perspective.
[0129] FIG. 20D is a depiction of the structural model of PCSK9 and LDLR with structural representations of31H4 and 2IB 12 included.
[0130] FIG. 20E is a depiction of the structural model in FIG. 20D, rotated 90 degrees about the noted axis.
[0131] FIG. 20F is a depiction of the structural model in FIG. 20D rotated 180 degrees about the noted axis.
[0132] FIG. 21A is a depiction of the structure of PCSK9 and 31A4.
[0133] FIG. 21B is a depiction of the structure of PCSK9 and 31A4.
[0134] FIG. 21C is a depiction of the structure of PCSK9 and 31A4.
[0135] FIG. 2ID is a depiction of the structural model of full length PCSK9 and 31A4.
[0136] FIG. 22 is a set of ABP sequences identifying various differences between the human ABP sequences and the ABP sequences that were raised in E. coli and used for the crystal structures.
[0137] FIG. 23 is a table of the various binning results.
[0138] FIG. 23A is a first part of a table depicting the various binning results.
[0139] FIG. 23B is a second part of a table depicting the various binning results.
[0140] FIG. 23C is a third part of a table depicting the various binning results.
[0141] FIG. 23D is a fourth part of a table depicting the various binning results.
[0142] FIG. 24A is a depiction of a western blot under non-reduced conditions.
[0143] FIG. 24B is a depiction of a western blot under reduced conditions.
[0144] FIG. 25A is a depiction of the surface coverage of PCSK9. 28 PCT/US2008/074097 WO 2009/026558 [0145] FIG. 25B is a depiction of the surface coverage of PCSK9.
[0146] FIG. 25C is a depiction of the surface coverage of PCSK9.
[0147] FIG. 25D is a depiction of the surface coverage of PCSK9.
[0148] FIG. 25E is a depiction of the surface coverage of PCSK9.
[0149] FIG. 25F is a depiction of the surface coverage of PCSK9.
[0150] FIG. 26 is a sequence comparison of the PCSK9 amino acid sequence and all of the residues that were mutated in PCSK9 variants to examine the epitopes of the various antibodies.
[0151] FIG. 27A depicts the 21B12 epitope hits, as mapped onto a crystal structure of PCSK9 with the 21B12.
[0152] FIG. 27B depicts the 31H4 epitope hits, as mapped ont a crystal structure of PCSK9 with 31H4 and 21B1.
[0153] FIG. 27C depicts the 31A4 epitope hits, as mapped onto a crystal structure of PCSK9 with 31H4 and21B12.
[0154] FIG. 27D depicts the 12H11 epitope hits, as mapped onto the crystal structure ofPCSK9 with 31H4 and 21B12.
[0155] FIG. 27E depicts the 3C4 epitope hits, as mapped onto the crystal structure of PCSK9 with 31H4 and 21B12.
[0156] FIG. 28A is a graph demonstrating the binding ability of the various ABPs to various parts of PCSK9.
[0157] FIG. 28B is a graph demonstrating the binding ability of the various ABPs to various parts of PCSK9.
[0158] FIG. 28C is a graph comparing the LDLR binding ability of two ABPs.
[0159] FIG. 28D is a graph comparing the cell LDL uptake activity of two ABPs.
DETAILED DESCRIPTION OF CERTAIN EXEMPLARY EMBODIMENTS
[0160] Antigen binding proteins (such as antibodies and functional binding fragments thereof) that bind to PCSK9 are disclosed herein. In some embodiments, the antigen binding proteins bind to PCSK9 and prevent PCSK9 from functioning in various ways. In some embodiments, the antigen binding proteins block or reduce the ability of PCSK9 to interact with other substances. For example, in some embodiments, the antigen binding protein binds to 29 PCT/U S2008/074097 WO 2009/026558 PCSK9 in a manner that prevents or reduces the likelihood that PCSK9 will bind to LDLR. In other embodiments, antigen binding proteins bind to PCSK9 but do not block PCSK9’s ability to interact with LDLR. In some embodiments, the antigen binding proteins are human monoclonal antibodies.
[0161] As will be appreciated by one of skill in the art, in light of the present disclosure, altering the interactions between PCSK9 and LDLR can increase the amount of LDLR available for binding to LDL, which in turn decreases the amount of serum LDL in a subject, resulting in a reduction in the subject’s serum cholesterol level. As such, antigen binding proteins to PCSK9 can be used in various methods and compositions for treating subjects with elevated serum cholesterol levels, at risk of elevated serum cholesterol levels, or which could benefit from a reduction in their serum cholesterol levels. Thus, various methods and techniques for lowering, maintaining, or preventing an increase in serum cholesterol are also described herein. In some embodiments, the antigen binding protein allows for binding between PCSK9 and LDLR, but the antigen binding protein prevents or reduces the adverse activity of PCSK9 on LDLR. In some embodiments, the antigen binding protein prevents or reduces the binding of PCSK9 to LDLR.
[0162] For convenience, the following sections generally outline the various meanings of the terms used herein. Following this discussion, general aspects regarding antigen binding proteins are discussed, followed by specific examples demonstrating the properties of various embodiments of the antigen binding proteins and how they can be employed.
Definitions and Embodiments [0163] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including”, as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise. Also, the use of the term “portion” can include part of a moiety or the entire moiety. 30 PCT/US2008/074097 WO 2009/026558 [0164] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: [0165] The term “proprotein convertase subtilisin kexin type 9” or “PCSK9” refers to a polypeptide as set forth in SEQ ID NO: 1 and/or 3 or fragments thereof, as well as related polypeptides, which include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, and/or insertion variants including the addition of an N-terminal methionine, fusion polypeptides, and interspecies homologs. In certain embodiments, a PCSK9 polypeptide includes terminal residues, such as, but not limited to, leader sequence residues, targeting residues, amino terminal methionine residues, lysine residues, tag residues and/or fusion protein residues. “PCSK9” has also been referred to as FH3, NARC1, HCHOLA3, proprotein convertase subtilisin/kexin type 9, and neural apoptosis regulated convertase 1. The PCSK9 gene encodes a proprotein convertase protein that belongs to the proteinase K subfamily of the secretory subtilase family. The term “PCSK9” denotes both the proprotein and the product generated following autocatalysis of the proprotein. When only the autocatalyzed product is being referred to (such as for an antigen binding protein that selectively binds to the cleaved PCSK9), the protein can be referred to as the “mature,” “cleaved”, “processed” or “active” PCSK9. When only the inactive form is being referred to, the protein can be referred to as the “inactive”, “pro-form”, or “unprocessed” form of PCSK9. The term PCSK9 as used herein also includes naturally occurring alleles, such as the mutations D374Y, S127R and F216L. The term PCSK9 also encompasses PCSK9 molecules incorporating post-translational modifications of the PCSK9 amino acid sequence, such as PCSK9 sequences that have been glycosylated, PEGylated, PCSK9 sequences from which its signal sequence has been cleaved, PCSK9 sequence from which its pro domain has been cleaved from the catalytic domain but not separated from the catalytic domain (e.g., FIGs. 1A and IB).
[0166] The term “PCSK9 activity” includes any biological effect of PCSK9. In certain embodiments, PCSK9 activity includes the ability of PCSK9 to interact or bind to a substrate or receptor. In some embodiments, PCSK9 activity is represented by the ability of 31 PCT/US2008/074097 WO 2009/026558 PCSK9 to bind to a LDL receptor (LDLR). In some embodiments, PCSK9 binds to and catalyzes a reaction involving LDLR. In some embodiments, PCSK9 activity includes the ability of PCSK9 to alter (e.g., reduce) the availability of LDLR. In some embodiments, PCSK9 activity includes the ability of PCSK9 to increase the amount of LDL in a subject. In some embodiments, PCSK9 activity includes the ability of PCSK9 to decrease the amount of LDLR that is available to bind to LDL. In some embodiments, “PCSK9 activity” includes any biological activity resulting from PCSK9 signaling. Exemplary activities include, but are not limited to, PCSK9 binding to LDLR, PCSK9 enzyme activity that cleaves LDLR or other proteins, PCSK9 binding to proteins other than LDLR that facilitate PCSK9 action, PCSK9 altering APOB secretion (Sun X-M et al, “Evidence for effect of mutant PCSK9 on apoliprotein B secretion as the cause of unusually severe dominant hypercholesterolemia, Human Molecular Genetics 14: 1161-1169, 2005 and Ouguerram K et al, “Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9, Arterioscler thromb Vase Biol. 24: 1448-1453, 2004), PCSK9’s role in liver regeneration and neuronal cell differentiation (Seidah NG et al, ‘The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation” PNAS 100: 928-933, 2003), and PCSK9s role in hepatic glucose metabolism (Costet et al., “Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein lc” J. Biol. Chem. 281(10):6211-18, 2006).
[0167] The term “hypercholesterolemia,” as used herein, refers to a condition in which cholesterol levels are elevated above a desired level. In some embodiments, this denotes that serum cholesterol levels are elevated. In some embodiments, the desired level takes into account various “risk factors” that are known to one of skill in the art (and are described or referenced herein).
[0168] The term “polynucleotide” or “nucleic acid” includes both single-stranded and double-stranded nucleotide polymers. The nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Said modifications include base modifications such as bromouridine and inosine derivatives, ribose modifications such as 2’,3’-dideoxyribose, and intemucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. 32 PCT/US2008/074097 WO 2009/026558 [0169] The term “oligonucleotide” means a polynucleotide comprising 200 or fewer nucleotides. In some embodiments, oligonucleotides are 10 to 60 bases in length. In other embodiments, oligonucleotides are 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 nucleotides in length. Oligonucleotides can be single stranded or double stranded, e.g., for use in the construction of a mutant gene. Oligonucleotides can be sense or antisense oligonucleotides. An oligonucleotide can include a label, including a radiolabel, a fluorescent label, a hapten or an antigenic label, for detection assays. Oligonucleotides can be used, for example, as PCR primers, cloning primers or hybridization probes.
[0170] An “isolated nucleic acid molecule” means a DNA or RNA of genomic, mRNA, cDNA, or synthetic origin or some combination thereof which is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, or is linked to a polynucleotide to which it is not linked in nature. For purposes of this disclosure, it should be understood that “a nucleic acid molecule comprising” a particular nucleotide sequence does not encompass intact chromosomes. Isolated nucleic acid molecules “comprising” specified nucleic acid sequences can include, in addition to the specified sequences, coding sequences for up to ten or even up to twenty other proteins or portions thereof, or can include operably linked regulatory sequences that control expression of the coding region of the recited nucleic acid sequences, and/or can include vector sequences.
[0171] Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence discussed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA transcript that are 5’ to the 5’ end of the RNA transcript are referred to as “upstream sequences;” sequence regions on the DNA strand having the same sequence as the RNA transcript that are 3’ to the 3’ end of the RNA transcript are referred to as “downstream sequences.” [0172] The term “control sequence” refers to a polynucleotide sequence that can affect the expression and processing of coding sequences to which it is ligated. The nature of such control sequences can depend upon the host organism. In particular embodiments, control sequences for prokaryotes can include a promoter, a ribosomal binding site, and a transcription termination sequence. For example, control sequences for eukaryotes can include promoters 33 PCT/US2008/074097 WO 2009/026558 comprising one or a plurality of recognition sites for transcription factors, transcription enhancer sequences, and transcription termination sequence. “Control sequences” can include leader sequences and/or fusion partner sequences.
[0173] The term “vector” means any molecule or entity (e.g., nucleic acid, plasmid, bacteriophage or virus) used to transfer protein coding information into a host cell.
[0174] The term “expression vector” or “expression construct” refers to a vector that is suitable for transformation of a host cell and contains nucleic acid sequences that direct and/or control (in conjunction with the host cell) expression of one or more heterologous coding regions operatively linked thereto. An expression construct can include, but is not limited to, sequences that affect or control transcription, translation, and, if introns are present, affect RNA splicing of a coding region operably linked thereto.
[0175] As used herein, “operably linked” means that the components to which the term is applied are in a relationship that allows them to carry out their inherent functions under suitable conditions. For example, a control sequence in a vector that is “operably linked” to a protein coding sequence is ligated thereto so that expression of the protein coding sequence is achieved under conditions compatible with the transcriptional activity of the control sequences.
[0176] The term “host cell” means a cell that has been transformed, or is capable of being transformed, with a nucleic acid sequence and thereby expresses a gene of interest. The term includes the progeny of the parent cell, whether or not the progeny is identical in moiphology or in genetic make-up to the original parent cell, so long as the gene of interest is present.
[0177] The term “transfection” means the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham et al., 1973, Virology 52:456; Sambrook et al., 2001, Molecular Cloning: A Laboratory Manual, supra', Davis et al., 1986, Basic Methods in Molecular Biology, Elsevier; Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host cells.
[0178] The term “transformation” refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain new DNA or RNA. For example, a cell is transformed where it is genetically modified from its native state by 34 PCT/U S2008/074097 WO 2009/026558 introducing new genetic material via transfection, transduction, or other techniques. Following transfection or transduction, the transforming DNA can recombine with that of the cell by physically integrating into a chromosome of the cell, or can be maintained transiently as an episomal element without being replicated, or can replicate independently as a plasmid. A cell is considered to have been “stably transformed” when the transforming DNA is replicated with the division of the cell.
[0179] The terms “polypeptide” or “protein” means a macromolecule having the amino acid sequence of a native protein, that is, a protein produced by a naturally-occurring and non-recombinant cell; or it is produced by a genetically-engineered or recombinant cell, and comprise molecules having the amino acid sequence of the native protein, or molecules having deletions from, additions to, and/or substitutions of one or more amino acids of the native sequence. The term also includes amino acid polymers in which one or more amino acids are chemical analogs of a corresponding naturally-occurring amino acid and polymers. The terms “polypeptide” and “protein” specifically encompass PCSK9 antigen binding proteins, antibodies, or sequences that have deletions from, additions to, and/or substitutions of one or more amino acid of antigen-binding protein. The term “polypeptide fragment” refers to a polypeptide that has an amino-terminal deletion, a carboxyl-terminal deletion, and/or an internal deletion as compared with the full-length native protein. Such fragments can also contain modified amino acids as compared with the native protein. In certain embodiments, fragments are about five to 500 amino acids long. For example, fragments can be at least 5, 6, 8, 10, 14, 20, 50, 70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Useful polypeptide fragments include immunologically functional fragments of antibodies, including binding domains. In the case of a PCSK9-binding antibody, useful fragments include but are not limited to a CDR region, a variable domain of a heavy and/or light chain, a portion of an antibody chain or just its variable region including two CDRs, and the like.
[0180] The term “isolated protein” referred means that a subject protein (1) is free of at least some other proteins with which it would normally be found, (2) is essentially free of other proteins from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in 35 PCT/US2008/074097 WO 2009/026558 nature, or (6) does not occur in nature. Typically, an “isolated protein” constitutes at least about 5%, at least about 10%, at least about 25%, or at least about 50% of a given sample. Genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof can encode such an isolated protein. Preferably, the isolated protein is substantially free from proteins or polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic, research or other use.
[0181] The term “amino acid” includes its normal meaning in the art.
[0182] A “variant” of a polypeptide (e.g., an antigen binding protein, or an antibody) comprises an amino acid sequence wherein one or more amino acid residues are inserted into, deleted from and/or substituted into the amino acid sequence relative to another polypeptide sequence. Variants include fusion proteins.
[0183] The term “identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent identity” means the percent of identical residues between the amino acids or nucleotides in the compared molecules and is calculated based on the size of the smallest of the molecules being compared. For these calculations, gaps in alignments (if any) are preferably addressed by a particular mathematical model or computer program (/. e., an “algorithm”). Methods that can be used to calculate the identity of the aligned nucleic acids or polypeptides include those described in Computational Molecular Biology, (Lesk, A. M., ed.), 1988, New York: Oxford University Press; Biocomputing Informatics and Genome Projects, (Smith, D. W., ed.), 1993, New York: Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A. M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; von Heinje, G., 1987, Sequence Analysis in Molecular Biology, New York: Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux, J., eds.), 1991, New York: M. Stockton Press; and Carillo et al., 1988, SIAMJ. Applied Math. 48:1073.
[0184] In calculating percent identity, the sequences being compared are typically aligned in a way that gives the largest match between the sequences. One example of a computer program that can be used to determine percent identity is the GCG program package, which includes GAP (Devereux et al., 1984, Nucl. Acid Res. .12:387; Genetics Computer Group, University of Wisconsin, Madison, WI). The computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined. The 36 PCT/US2008/074097 WO 2009/026558 sequences are aligned for optimal matching of their respective amino acid or nucleotide (the “matched span”, as determined by the algorithm). A gap opening penalty (which is calculated as 3x the average diagonal, wherein the “average diagonal” is the average of the diagonal of the comparison matrix being used; the “diagonal” is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (which is usually 1/10 times the gap opening penalty), as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used in conjunction with the algorithm. In certain embodiments, a standard comparison matrix (see, Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff et al., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919 for the BLOSUM 62 comparison matrix) is also used by the algorithm.
[0185] Examples of parameters that can be employed in determining percent identity for polypeptides or nucleotide sequences using the GAP program are the following: • Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-453 • Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, supra • Gap Penalty: 12 (but with no penalty for end gaps) • Gap Length Penalty: 4 • Threshold of Similarity: 0 [0186] Certain alignment schemes for aligning two amino acid sequences may result in matching of only a short region of the two sequences, and this small aligned region may have very high sequence identity even though there is no significant relationship between the two full-length sequences. Accordingly, the selected alignment method (GAP program) can be adjusted if so desired to result in an alignment that spans at least 50 or other number of contiguous amino acids of the target polypeptide.
[0187] As used herein, the twenty conventional (e.g., naturally occurring) amino acids and their abbreviations follow conventional usage. See Immunology—A Synthesis (2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference for any purpose. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-, α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids can also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-Ν,Ν,Ν-trimethyllysine, ε-Ν-acetyllysine, O-37 PCT/U S2008/074097 WO 2009/026558 phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-Ν-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.
[0188] Similarly, unless specified otherwise, the left-hand end of single-stranded polynucleotide sequences is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction; sequence regions on the DNA strand having the same sequence as the RNA and which are 5’ to the 5’ end of the RNA transcript are referred to as “upstream sequences”; sequence regions on the DNA strand having the same sequence as the RNA and which are 3’ to the 3’ end of the RNA transcript are referred to as “downstream sequences.” [0189] Conservative amino acid substitutions can encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties.
[0190] Naturally occurring residues can be divided into classes based on common side chain properties: 1) hydrophobic: norleucine, Met, Ala, Val, Leu, lie; 2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; 3) acidic: Asp, Glu; 4) basic: His, Lys, Arg; 5) residues that influence chain orientation: Gly, Pro; and 6) aromatic: Trp, Tyr, Phe.
For example, non-conservative substitutions can involve the exchange of a member of one of these classes for a member from another class. Such substituted residues can be introduced, for example, into regions of a human antibody that are homologous with non-human antibodies, or into the non-homologous regions of the molecule.
[0191] In making changes to the antigen binding protein or the PCSK9 protein, according to certain embodiments, the hydropathic index of amino acids can be considered. 38 PCT/US2008/074097 WO 2009/026558
Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
[0192] The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is understood in the art. Kyte et al., J. Mol. Biol., 157:105-131 (1982). It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, in certain embodiments, the substitution of amino acids whose hydropathic indices are within ±2 is included. In certain embodiments, those which are within ±1 are included, and in certain embodiments, those within ±0.5 are included.
[0193] It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functional protein or peptide thereby created is intended for use in immunological embodiments, as in the present case. In certain embodiments, the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein.
[0194] The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0 ± 1); glutamate (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ± 1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). In making changes based upon similar hydrophilicity values, in certain embodiments, the substitution of amino acids whose hydrophilicity values are within ±2 is included, in certain embodiments, those which are within ±1 are included, and in certain embodiments, those within ±0.5 are included. One can also identify epitopes from primary amino acid sequences on the basis of hydrophilicity. These regions are also referred to as "epitopic core regions." [0195] Exemplary amino acid substitutions are set forth in Table 1. TABLE 1
Amino Acid Substitutions 39 PCT/US2008/074097
Original Residues Exemplary Substitutions Preferred Substitutions Ala Val, Leu, lie Val Arg Lys, Gin, Asn Lys Asn Gin Gin Asp Glu Glu Cys Ser, Ala Ser Gin Asn Asn Glu Asp Asp Gly Pro, Ala Ala His Asn, Gin, Lys, Arg Arg lie Leu, Val, Met, Ala, Phe, Norleucine Leu Leu Norleucine, He, Val, Met, Ala, Phe He Lys Arg, 1,4 Diamino-butyric Acid, Gin, Asn Arg Met Leu, Phe, He Leu Phe Leu, Val, He, Ala, Tyr Leu Pro Ala Gly Ser Thr, Ala, Cys Thr Thr Ser Ser Trp Tyr, Phe Tyr Tyr Trp, Phe, Thr, Ser Phe Val He, Met, Leu, Phe, Ala, Norleucine Leu WO 2009/026558 [0196] The term “derivative” refers to a molecule that includes a chemical modification other than an insertion, deletion, or substitution of amino acids (or nucleic acids). In certain embodiments, derivatives comprise covalent modifications, including, but not limited 40 PCT/US2008/074097 WO 2009/026558 to, chemical bonding with polymers, lipids, or other organic or inorganic moieties. In certain embodiments, a chemically modified antigen binding protein can have a greater circulating half-life than an antigen binding protein that is not chemically modified. In certain embodiments, a chemically modified antigen binding protein can have improved targeting capacity for desired cells, tissues, and/or organs. In some embodiments, a derivative antigen binding protein is covalently modified to include one or more water soluble polymer attachments, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. See, e.g., U.S. Patent Nos: 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. In certain embodiments, a derivative antigen binding protein comprises one or more polymer, including, but not limited to, monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers.
[0197] In certain embodiments, a derivative is covalently modified with polyethylene glycol (PEG) subunits. In certain embodiments, one or more water-soluble polymer is bonded at one or more specific position, for example at the amino terminus, of a derivative. In certain embodiments, one or more water-soluble polymer is randomly attached to one or more side chains of a derivative. In certain embodiments, PEG is used to improve the therapeutic capacity for an antigen binding protein. In certain embodiments, PEG is used to improve the therapeutic capacity for a humanized antibody. Certain such methods are discussed, for example, in U.S. Patent No. 6,133,426, which is hereby incorporated by reference for any purpose.
[0198] Peptide analogs are commonly used in the pharmaceutical industry as nonpeptide drugs with properties analogous to those of the template peptide. These types of nonpeptide compound are termed “peptide mimetics” or “peptidomimetics.” Fauchere, J., Adv. Drug Res., 15:29 (1986); Veber &amp; Freidinger, TINS, p.392 (1985); and Evans et al., J. Med. Chem., 30:1229 (1987), which are incorporated herein by reference for any purpose. Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to therapeutically useful peptides can be used to produce a similar therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biochemical property or pharmacological activity), such as human antibody, but have one or more peptide linkages optionally replaced by 41 PCT/US2008/074097 WO 2009/026558 a linkage selected from: —CH2 NH—, —CH2 S—, —CH2 -CH2 —, — CH=CH-(cis and trans), --COCH2 —, —CH(OH)CH2 —, and — (¾ SO—, by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) can be used in certain embodiments to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation can be generated by methods known in the art (Rizo and Gierasch, Ann. Rev. Biochem., 61:387 (1992), incorporated herein by reference for any purpose); for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.
[0199] The term “naturally occurring” as used throughout the specification in connection with biological materials such as polypeptides, nucleic acids, host cells, and the like, refers to materials which are found in nature or a form of the materials that is found in nature.
[0200] An “antigen binding protein” (“ABP”) as used herein means any protein that binds a specified target antigen. In the instant application, the specified target antigen is the PCSK9 protein or fragment thereof. “Antigen binding protein” includes but is not limited to antibodies and binding parts thereof, such as immunologically functional fragments. Peptibodies are another example of antigen binding proteins. The term “immunologically functional fragment” (or simply “fragment”) of an antibody or immunoglobulin chain (heavy or light chain) antigen binding protein, as used herein, is a species of antigen binding protein comprising a portion (regardless of how that portion is obtained or synthesized) of an antibody that lacks at least some of the amino acids present in a full-length chain but which is still capable of specifically binding to an antigen. Such fragments are biologically active in that they bind to the target antigen and can compete with other antigen binding proteins, including intact antibodies, for binding to a given epitope. In some embodiments, the fragments are neutralizing fragments. In some embodiments, the fragments can block or reduce the likelihood of the interaction between LDLR and PCSK9. In one aspect, such a fragment will retain at least one CDR present in the full-length light or heavy chain, and in some embodiments will comprise a single heavy chain and/or light chain or portion thereof. These biologically active fragments can be produced by recombinant DNA techniques, or can be produced by enzymatic or chemical cleavage of antigen binding proteins, including intact antibodies. Immunologically functional immunoglobulin fragments include, but are not limited to, Fab, a diabody (heavy chain variable 42 PCT/U S2008/074097 WO 2009/026558 domain on the same polypeptide as a light chain variable domain, connected via a short peptide linker that is too short to permit pairing between the two domains on the same chain), Fab’, F(ab’)2, Fv, domain antibodies and single-chain antibodies, and can be derived from any mammalian source, including but not limited to human, mouse, rat, camelid or rabbit. It is further contemplated that a functional portion of the antigen binding proteins disclosed herein, for example, one or more CDRs, could be covalently bound to a second protein or to a small molecule to create a therapeutic agent directed to a particular target in the body, possessing bifunctional therapeutic properties, or having a prolonged serum half-life. As will be appreciated by one of skill in the art, an antigen bindng protein can include nonprotein components. In some sections of the present disclosure, examples of ABPs are described herein in terms of “number/letter/number” (e.g., 25A7). In these cases, the exact name denotes a specific antibody. That is, an ABP named 25A7 is not necessarily the same as an antibody named 25A7.1, (unless they are explicitly taught as the same in the specification, e.g., 25A7 and 25A7.3). As will be appreciated by one of skill in the art, in some embodiments LDLR is not an antigen binding protein. In some embodiments, binding subsections of LDLR are not antigen binding proteins, e.g., EGFa. In some embodiments, other molecules through which PCSK9 signals in vivo are not antigen binding proteins. Such embodiments will be explicitly identified as such.
[0201] Certain antigen binding proteins described herein are antibodies or are derived from antibodies. In certain embodiments, the polypeptide structure of the antigen binding proteins is based on antibodies, including, but not limited to, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), and fragments thereof, respectively. In some embodiments, the ABP comprises or consists of avimers (tightly binding peptide). These various antigen binding proteins are further described herein.
[0202] An “Fc” region comprises two heavy chain fragments comprising the Ch 1 and Ch2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the Ch3 domains.
[0203] A “Fab fragment” comprises one light chain and the ChI and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. 43 PCT/US2008/074097 WO 2009/026558 [0204] A “Fab’ fragment” comprises one light chain and a portion of one heavy chain that contains the VH domain and the CH1 domain and also the region between the ChI and Ch2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab’ fragments to form an F(ab’)2 molecule.
[0205] A “F(ab’)2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the ChI and Ch2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab’)2 fragment thus is composed of two Fab’ fragments that are held together by a disulfide bond between the two heavy chains.
[0206] The “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
[0207] “Single-chain antibodies” are Fv molecules in which the heavy and light chain variable regions have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen binding region. Single chain antibodies are discussed in detail in International Patent Application Publication No. WO 88/01649 and United States Patent Nos. 4,946,778 and No. 5,260,203, the disclosures of which are incorporated by reference.
[0208] A “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more Vh regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two Vh regions of a bivalent domain antibody can target the same or different antigens.
[0209] A “bivalent antigen binding protein” or “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. Bivalent antigen binding proteins and bivalent antibodies can be bispecific, see, infra. A bivalent antibody other than a “multispecific” or “multifunctional” antibody, in certain embodiments, typically is understood to have each of its binding sites identical.
[0210] A “multispecific antigen binding protein” or “multispecific antibody” is one that targets more than one antigen or epitope.
[0211] A “bispecific,” “dual-specific” or “bifunctional” antigen binding protein or antibody is a hybrid antigen binding protein or antibody, respectively, having two different antigen binding sites. Bispecific antigen binding proteins and antibodies are a species of 44 PCT/U S2008/074097 WO 2009/026558 multispecific antigen binding protein antibody and can be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab’ fragments. See, e.g., Songsivilai and Lachmann, 1990, Clin. Exp. Immunol. 79:315-321; Kostelny et al., 1992, J. Immunol. 148:1547-1553. The two binding sites of a bispecific antigen binding protein or antibody will bind to two different epitopes, which can reside on the same or different protein targets.
[0212] An antigen binding protein is said to “specifically bind” its target antigen when the dissociation constant (K<j) is <10'7 M. The ABP specifically binds antigen with “high affinity” when the K<j is <5 x 10'9 M, and with “very high affinity” when the Ka is <5x 10'10 M. In one embodiment, the ABP has a K<j of <10'9 M. In one embodiment, the off-rate is <1 x 10'5. In other embodiments, the ABPs will bind to human PCSK9 with a K<j of between about 10‘9 M and 10'13 M, and in yet another embodiment the ABPs will bind with a Ka <5 x 1010. As will be appreciated by one of skill in the art, in some embodiments, any or all of the antigen binding fragments can specifically bind to PCSK9.
[0213] An antigen binding protein is “selective” when it binds to one target more tightly than it binds to a second target.
[0214] “Antigen binding region” means a protein, or a portion of a protein, that specifically binds a specified antigen (e.g., a paratope). For example, that portion of an antigen binding protein that contains the amino acid residues that interact with an antigen and confer on the antigen binding protein its specificity and affinity for the antigen is referred to as “antigen binding region.” An antigen binding region typically includes one or more “complementary binding regions” (“CDRs”). Certain antigen binding regions also include one or more “framework” regions. A “CDR” is an amino acid sequence that contributes to antigen binding specificity and affinity. “Framework” regions can aid in maintaining the proper conformation of the CDRs to promote binding between the antigen binding region and an antigen. Structurally, framework regions can be located in antibodies between CDRs. Examples of framework and CDR regions are shown in FIGs. 2A-3D, 3CCC-3JJJ, and 15A-15D. In some embodiments, the sequences for CDRs for the light chain of antibody 3B6 are as follows: CDR1 TLSSGYSSYEVD (SEQ ID NO: 279); CDR2 VDTGGIVGSKGE (SEQ ID NO: 280); CDR3 GADHGSGTNFWV (SEQ ID NO: 281), and the FRs are as follows: FR1 QPVLTQPLFASASLGASVTLTC (SEQ ID NO: 282); FR2 WYQQRPGKGPRFVMR (SEQ 45 PCT/US2008/074097 WO 2009/026558 ID NO: 283); FR3 GIPDRFSVLGSGLNRYLTIKNIQEEDESDYHC (SEQ ID NO: 284); and FR4 FGGGTKLTVL (SEQ ID NO: 285).
[0215] In certain aspects, recombinant antigen binding proteins that bind PCSK9, for example human PCSK9, are provided. In this context, a “recombinant antigen binding protein” is a protein made using recombinant techniques, i.e., through the expression of a recombinant nucleic acid as described herein. Methods and techniques for the production of recombinant proteins are well known in the art.
[0216] The term “antibody” refers to an intact immunoglobulin of any isotype, or a fragment thereof that can compete with the intact antibody for specific binding to the target antigen, and includes, for instance, chimeric, humanized, fully human, and bispecific antibodies. An “antibody” is a species of an antigen binding protein. An intact antibody will generally comprise at least two full-length heavy chains and two full-length light chains, but in some instances can include fewer chains such as antibodies naturally occurring in camelids which can comprise only heavy chains. Antibodies can be derived solely from a single source, or can be “chimeric,” that is, different portions of the antibody can be derived from two different antibodies as described further below. The antigen binding proteins, antibodies, or binding fragments can be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term “antibody” includes, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, derivatives, variants, fragments, and muteins thereof, examples of which are described below. Furthermore, unless explicitly excluded, antibodies include monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as “antibody conjugates”), and fragments thereof, respectively. In some embodiments, the term also encompasses peptibodies.
[0217] Naturally occurring antibody structural units typically comprise a tetramer. Each such tetramer typically is composed of two identical pairs of polypeptide chains, each pair having one full-length “fight” (in certain embodiments, about 25 kDa) and one full-length “heavy” chain (in certain embodiments, about 50-70 kDa). The amino-terminal portion of each chain typically includes a variable region of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically 46 PCT/US2008/074097 WO 2009/026558 defines a constant region that can be responsible for effector function. Human light chains are typically classified as kappa and lambda light chains. Heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgGl, IgG2, IgG3, and IgG4. IgM has subclasses including, but not limited to, IgMl and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgAl and IgA2. Within full-length light and heavy chains, typically, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See, e.g., Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety for all purposes). The variable regions of each light/heavy chain pair typically form the antigen binding site.
[0218] The variable regions typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hyper variable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which can enable binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chain variable regions typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is typically in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia &amp; Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:878-883 (1989).
[0219] In certain embodiments, an antibody heavy chain binds to an antigen in the absence of an antibody light chain. In certain embodiments, an antibody light chain binds to an antigen in the absence of an antibody heavy chain. In certain embodiments, an antibody binding region binds to an antigen in the absence of an antibody light chain. In certain embodiments, an antibody binding region binds to an antigen in the absence of an antibody heavy chain. In certain embodiments, an individual variable region specifically binds to an antigen in the absence of other variable regions.
[0220] In certain embodiments, definitive delineation of a CDR and identification of residues comprising the binding site of an antibody is accomplished by solving the structure of the antibody and/or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled 47 PCT/US2008/074097 WO 2009/026558 in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition and the contact definition.
[0221] The Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson &amp; Wu, Nucleic Acids Res., 28: 214-8 (2000). The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g, Chothia et al., J. Mol. Biol., 196: 901-17 (1986); Chothia et al., Nature, 342: 877-83 (1989). The AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure. See, e.g., Martin et al., Proc Natl Acad Sci (USA), 86:9268-9272 (1989); “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from primary sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198 (1999). The contact definition is based on an analysis of the available complex crystal structures. See, e.g., MacCallum et al., J. Mol. Biol., 5:732-45 (1996).
[0222] By convention, the CDR regions in the heavy chain are typically referred to as HI, H2, and H3 and are numbered sequentially in the direction from the amino terminus to the carboxy terminus. The CDR regions in the light chain are typically referred to as LI, L2, and L3 and are numbered sequentially in the direction from the amino terminus to the carboxy terminus.
[0223] The term “light chain” includes a full-length light chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length light chain includes a variable region domain, VL, and a constant region domain, CL. The variable region domain of the light chain is at the amino-terminus of the polypeptide. Light chains include kappa chains and lambda chains.
[0224] The term “heavy chain” includes a full-length heavy chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length heavy chain includes a variable region domain, Vh, and three constant region domains, ChI, Ch2, and Ch3. The Vh domain is at the amino-terminus of the polypeptide, and the (¾ domains 48 PCT/US2008/074097 WO 2009/026558 are at the carboxyl-terminus, with the Ch3 being closest to the carboxy-terminus of the polypeptide. Heavy chains can be of any isotype, including IgG (including IgGl, IgG2, IgG3 and IgG4 subtypes), IgA (including IgAl and IgA2 subtypes), IgM and IgE.
[0225] A bispecific or bifunctional antibody typically is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai et al., Clin. Exp. Immunol., 79: 315-321 (1990); Kostelny et al., J. Immunol., 148:1547-1553 (1992).
[0226] Some species of mammals also produce antibodies having only a single heavy chain.
[0227] Each individual immunoglobulin chain is typically composed of several “immunoglobulin domains,” each consisting of roughly 90 to 110 amino acids and having a characteristic folding pattern. These domains are the basic units of which antibody polypeptides are composed. In humans, the IgA and IgD isotypes contain four heavy chains and four light chains; the IgG and IgE isotypes contain two heavy chains and two light chains; and the IgM isotype contains five heavy chains and five light chains. The heavy chain C region typically comprises one or more domains that can be responsible for effector function. The number of heavy chain constant region domains will depend on the isotype. IgG heavy chains, for example, contain three C region domains known as ChI, Ch2 and Ch3. The antibodies that are provided can have any of these isotypes and subtypes. In certain embodiments of the present invention, an anti-PCSK9 antibody is of the IgG2 or IgG4 subtype.
[0228] The term “variable region” or “variable domain” refers to a portion of the light and/or heavy chains of an antibody, typically including approximately the amino-terminal 120 to 130 amino acids in the heavy chain and about 100 to 110 amino terminal amino acids in the light chain. In certain embodiments, variable regions of different antibodies differ extensively in amino acid sequence even among antibodies of the same species. The variable region of an antibody typically determines specificity of a particular antibody for its target [0229] The term “neutralizing antigen binding protein” or “neutralizing antibody” refers to an antigen binding protein or antibody, respectively, that binds to a ligand and prevents or reduces the biological effect of that ligand. This can be done, for example, by directly blocking a binding site on the ligand or by binding to the ligand and altering the ligand’s ability 49 PCT/US2008/074097 WO 2009/026558 to bind through indirect means (such as structural or energetic alterations in the ligand). In some embodiments, the term can also denote an antigen binding protein that prevents the protein to which it is bound from performing a biological function. In assessing the binding and/or specificity of an antigen binding protein, e.g., an antibody or immunologically functional fragment thereof, an antibody or fragment can substantially inhibit binding of a ligand to its binding partner when an excess of antibody reduces the quantity of binding partner bound to the ligand by at least about 1-20, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-85%, 85-90%, 90-95%, 95-97%, 97-98%, 98-99% or more (as measured in an in vitro competitive binding assay). In some embodiments, in the case of PCSK9 antigen binding proteins, such a neutralizing molecule can diminish the ability of PCSK9 to bind the LDLR. In some embodiments, the neutralizing ability is characterized and/or described via a competition assay. In some embodiments, the neutralizing ability is described in terms of an IC5o or EC5o value. In some embodiments, ABPs 27B2, 13H1, 13B5 and 3C4 are non-neutralizing ABPs, 3B6, 9C9 and 31A4 are weak neutralizers, and the remaining ABPs in Table 2 are strong neutralizers. In some embodiments, the antibodies or antigen binding proteins neutralize by binding to PCSK9 and preventing PCSK9 from binding to LDLR (or reducing the ability of PCSK9 to bind to LDLR). In some embodiments, the antibodies or ABPs neutralize by binding to PCSK9, and while still allowing PCSK9 to bind to LDLR, preventing or reducing the PCSK9 mediated degradation of LDLR. Thus, in some embodiments, a neutralizing ABP or antibody can still permit PCSK9/LDLR binding, but will prevent (or reduce) subsequent PCSK9 involved degradation of LDLR.
[0230] The term “target” refers to a molecule or a portion of a molecule capable of being bound by an antigen binding protein. In certain embodiments, a target can have one or more epitopes. In certain embodiments, a target is an antigen. The use of “antigen” in the phrase “antigen binding protein” simply denotes that the protein sequence that comprises the antigen can be bound by an antibody. In this context, it does not require that the protein be foreign or that it be capable of inducing an immune response.
[0231] The term “compete” when used in the context of antigen binding proteins (e.g., neutralizing antigen binding proteins or neutralizing antibodies) that compete for the same epitope means competition between antigen binding proteins as determined by an assay in which the antigen binding protein (e.g., antibody or immunologically functional fragment thereof) 50 PCT/US2008/074097 WO 2009/026558 being tested prevents or inhibits (e.g., reduces) specific binding of a reference antigen binding protein (e.g., a ligand, or a reference antibody) to a common antigen (e.g., PCSK9 or a fragment thereof). Numerous types of competitive binding assays can be used to determine if one antigen binding protein competes with another, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619) solid phase direct labeled assay, solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (see, e.g., Morel et al., 1988, Molec. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990, Virology 176:546-552): and direct labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82). Typically, such an assay involves the use of purified antigen bound to a solid surface or cells bearing either of these, an unlabelled test antigen binding protein and a labeled reference antigen binding protein. Competitive inhibition is measured by determining the amount of label bound to the solid surface or cells in the presence of the test antigen binding protein. Usually the test antigen binding protein is present in excess. Antigen binding proteins identified by competition assay (competing antigen binding proteins) include antigen binding proteins binding to the same epitope as the reference antigen binding proteins and antigen binding proteins binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antigen binding protein for steric hindrance to occur. Additional details regarding methods for determining competitive binding are provided in the examples herein. Usually, when a competing antigen binding protein is present in excess, it will inhibit (e.g, reduce) specific binding of a reference antigen binding protein to a common antigen by at least 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75% or 75% or more. In some instances, binding is inhibited by at least 80-85%, 85-90%, 90-95%, 95-97%, or 97% or more.
[0232] The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antigen binding protein (including, e.g., an antibody or immunological functional fragment thereof). In some embodiments, the antigen is capable of being used in an animal to produce antibodies capable of binding to that antigen. An 51 PCT/US2008/074097 WO 2009/026558 antigen can possess one or more epitopes that are capable of interacting with different antigen binding proteins, e.g., antibodies.
[0233] The term “epitope” includes any determinant capable being bound by an antigen binding protein, such as an antibody or to a T-cell receptor. An epitope is a region of an antigen that is bound by an antigen binding protein that targets that antigen, and when the antigen is a protein, includes specific amino acids that directly contact the antigen binding protein. Most often, epitopes reside on proteins, but in some instances can reside on other kinds of molecules, such as nucleic acids. Epitope determinants can include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three dimensional structural characteristics, and/or specific charge characteristics. Generally, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and/or macromolecules.
[0234] As used herein, “substantially pure” means that the described species of molecule is the predominant species present, that is, on a molar basis it is more abundant than any other individual species in the same mixture. In certain embodiments, a substantially pure molecule is a composition wherein the object species comprises at least 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise at least 80%, 85%, 90%, 95%, or 99% of all macromolecular species present in the composition. In other embodiments, the object species is purified to essential homogeneity wherein contaminating species cannot be detected in the composition by conventional detection methods and thus the composition consists of a single detectable macromolecular species.
[0235] The term “agent” is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials.
[0236] As used herein, the terms “label” or “labeled” refers to incorporation of a detectable marker, e.g., by incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotin moieties that can be detected by marked avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). In certain embodiments, the label or marker can also be therapeutic. Various methods of labeling polypeptides and glycoproteins are known in the art and can be used. Examples of labels for polypeptides include, but are not limited to, the following: 52 PCT/US2008/074097 WO 2009/026558 radioisotopes or radionuclides (e.g., 3H, 14C, 15N, 35S, 90Y, 99Tc, 11'in, 125I, 131I), fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic labels (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent, biotinyl groups, predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags). In certain embodiments, labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
[0237] The term “biological sample”, as used herein, includes, but is not limited to, any quantity of a substance from a living thing or formerly living thing. Such living things include, but are not limited to, humans, mice, monkeys, rats, rabbits, and other animals. Such substances include, but are not limited to, blood, serum, urine, cells, organs, tissues, bone, bone marrow, lymph nodes, and skin.
[0238] The term “pharmaceutical agent composition” (or agent or drug) as used herein refers to a chemical compound, composition, agent or drug capable of inducing a desired therapeutic effect when properly administered to a patient. It does not necessarily require more than one type of ingredient.
[0239] The term “therapeutically effective amount” refers to the amount of a PCSK9 antigen binding protein determined to produce a therapeutic response in a mammal. Such therapeutically effective amounts are readily ascertained by one of ordinary skill in the art.
[0240] The term “modulator,” as used herein, is a compound that changes or alters the activity or function of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity or function of a molecule compared to the magnitude of the activity or function observed in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of at least one activity or function of a molecule. Certain exemplary activities and functions of a molecule include, but are not limited to, binding affinity, enzymatic activity, and signal transduction. Certain exemplary inhibitors include, but are not limited to, proteins, peptides, antibodies, peptibodies, carbohydrates or small organic molecules. Peptibodies are described in, e.g., U.S. Patent No. 6,660,843 (corresponding to PCT Application No. WO 01/83525).
[0241] The terms “patient” and “subject” are used interchangeably and include human and non-human animal subjects as well as those with formally diagnosed disorders, those 53 PCT/US2008/074097 WO 2009/026558 without formally recognized disorders, those receiving medical attention, those at risk of developing the disorders, etc.
[0242] The term “treat” and “treatment” includes therapeutic treatments, prophylactic treatments, and applications in which one reduces the risk that a subject will develop a disorder or other risk factor. Treatment does not require the complete curing of a disorder and encompasses embodiments in which one reduces symptoms or underlying risk factors.
[0243] The term “prevent” does not require the 100% elimination of the possibility of an event. Rather, it denotes that the likelihood of the occurrence of the event has been reduced in the presence of the compound or method.
[0244] Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques can be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose. Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
Antigen Binding Proteins to PCSK9 [0245] Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein (Horton et al., 2007; Seidah and Prat, 2007). PCSK9 is a prohormone-proprotein convertase in the subtilisin (S8) family of serine proteases (Seidah et al., 2003). An exemplary human PCSK9 amino acid sequence is presented as SEQ ID NOs: 1 and 3. in FIG. 1A (depicting the “pro” domain of the protein as underlined) and FIG. IB (depicting the signal sequence in bold and the 54 PCT/US2008/074097 WO 2009/026558 pro domain underlined). An exemplary human PCSK9 coding sequence is presented as SEQ ID NO: 2 (FIG. IB). As described herein, PCSK9 proteins can also include fragments of the full length PCSK9 protein. The structure of the PCSK9 protein has recently been solved by two groups (Cunningham et al., Nature Structural &amp; Molecular Biology, 2007, and Piper et al., Structure, 15:1-8, 2007), the entireties of both of which are herein incorporated by reference. PCSK9 includes a signal sequence, a N-terminal prodomain, a subtilisin-like catalytic domain and a C-terminal domain.
[0246] Antigen binding proteins (ABPs) that bind PCSK9, including human PCSK9, are provided herein. In some embodiments, the antigen binding proteins provided are polypeptides which comprise one or more complementary determining regions (CDRs), as described herein. In some antigen binding proteins, the CDRs are embedded into a “framework” region, which orients the CDR(s) such that the proper antigen binding properties of the CDR(s) is achieved. In some embodiments, antigen binding proteins provided herein can interfere with, block, reduce or modulate the interaction between PCSK9 and LDLR. Such antigen binding proteins are denoted as “neutralizing.” In some embodiments, binding between PCSK9 and LDLR can still occur, even though the antigen binding protein is neutralizing and bound to PCSK9. For example, in some embodiments, the ABP prevents or reduces the adverse influence of PCSK9 on LDLR without blocking the LDLR binding site on PCSK9. Thus, in some embodiments, the ABP modulates or alters PCSK9’s ability to result in the degradation of LDLR, without having to prevent the binding interaction between PCSK9 and LDLR. Such ABPs can be specifically described as “non-competitively neutralizing” ABPs. In some embodiments, the neutralizing ABP binds to PCSK9 in a location and/or manner that prevents PCSK9 from binding to LDLR. Such ABPs can be specifically described as “competitively neutralizing” ABPs. Both of the above neutralizers can result in a greater amount of free LDLR being present in a subject, which results in more LDLR binding to LDL (thereby reducing the amount of LDL in the subject). In turn, this results in a reduction in the amount of serum cholesterol present in a subject.
[0247] In some embodiments, the antigen binding proteins provided herein are capable of inhibiting PCSK9-mediated activity (including binding). In some embodiments, antigen binding proteins binding to these epitopes inhibit, inter alia, interactions between PCSK9 55 PCT/US2008/074097 WO 2009/026558 and LDLR and other physiological effects mediated by PCSK9. In some embodiments, the antigen binding proteins are human, such as fully human antibodies to PCSK9.
[0248] In some embodiments, the ABP binds to the catalytic domain of PCSK9. In some embodiments, the ABP binds to the mature form of PCSK9. In some embodiments the ABP binds in the prodomain of PCSK9. In some embodiments, the ABP selectively binds to the mature form of PCSK9. In some embodiments, the ABP binds to the catalytic domain in a manner such that PCSK9 cannot bind or bind as efficiently to LDLR. In some embodiments, the antigen binding protein does not bind to the c-terminus of the cataylytic domain. In some embodiments, the antigen binding protein does not bind to the n-terminus of the catalytic domain. In some embodiments, the ABP does not bind to the n- or c-terminus of the PCSK9 protein. In some embodiments, the ABP binds to any one of the epitopes bound by the antibodies discussed herein. In some embodiments, this can be determined by competition assays between the antibodies disclosed herein and other antibodes. In some embodiments, the ABP binds to an epitope bound by one of the antibodies described in Table 2. In some embodiments, the antigen binding proteins bind to a specific conformational state of PCSK9 so as to prevent PCSK9 from interacting with LDLR. In some embodiments, the ABP binds to the V domain of PCSK9. In some embodiments, the ABP binds to the V domain of PCSK9 and prevents (or reduces) PCSK9 from binding to LDLR. In some embodiments, the ABP binds to the V domain of PCSK9, and while it does not prevent (or reduce) the binding of PCSK9 to LDLR, the ABP prevents or reduces the adverse activities mediated through PCSK9 on LDLR.
[0249] The antigen binding proteins that are disclosed herein have a variety of utilities. Some of the antigen binding proteins, for instance, are useful in specific binding assays, affinity purification of PCSK9, in particular human PCSK9 or its ligands and in screening assays to identify other antagonists of PCSK9 activity. Some of the antigen binding proteins are useful for inhibiting binding of PCSK9 to LDLR, or inhibiting PCSK9-mediated activities.
[0250] The antigen binding proteins can be used in a variety of therapeutic applications, as explained herein. For example, in some embodiments the PCSK9 antigen binding proteins are useful for treating conditions associated with PCSK9, such as cholesterol related disorders (or “serum cholesterol related disorders”) such as hypercholesterolemia, as further described herein. Other uses for the antigen binding proteins include, for example, diagnosis of PCSK9-associated diseases or conditions and screening assays to determine the 56 PCT/U S2008/074097 WO 2009/026558 presence or absence of PCSK9. Some of the antigen binding proteins described herein are useful in treating consequences, symptoms, and/or the pathology associated with PCSK9 activity.
[0251] In some embodiments, the antigen binding proteins that are provided comprise one or more CDRs (e.g., 1, 2, 3, 4, 5 or 6 CDRs). In some embodiments, the antigen binding protein comprises (a) a polypeptide structure and (b) one or more CDRs that are inserted into and/or joined to the polypeptide structure. The polypeptide structure can take a variety of different forms. For example, it can be, or comprise, the framework of a naturally occurring antibody, or fragment or variant thereof, or can be completely synthetic in nature. Examples of various polypeptide structures are further described below.
[0252] In certain embodiments, the polypeptide structure of the antigen binding proteins is an antibody or is derived from an antibody, including, but not limited to, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as “antibody mimetics”), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as “antibody conjugates”), and portions or fragments of each, respectively. In some instances, the antigen binding protein is an immunological fragment of an antibody (e.g., a Fab, a Fab’, a F(ab’)2, or a scFv). The various structures are further described and defined herein.
[0253] Certain of the antigen binding proteins as provided herein specifically and/or selectively bind to human PCSK9. In some embodiments, the antigen binding protein specifically and/or selectively binds to human PCSK9 protein having and/or consisting of residues 153-692 of SEQ ID NO: 3. In some embodiments the ABP specifically and/or selectively binds to human PCSK9 having and/or consiting of residues 31-152 of SEQ ID NO: 3. In some embodiments, the ABP selectively binds to a human PCSK9 protein as depicted in FIG. 1A (SEQ ID NO: 1). In some embodiments, the antigen binding protein specifically binds to at least a fragment of the PCSK9 protein and/or a full length PCSK9 protein, with or without a signal sequence.
[0254] In embodiments where the antigen binding protein is used for therapeutic applications, an antigen binding protein can inhibit, interfere with or modulate one or more biological activities of PCSK9. In one embodiment, an antigen binding protein binds specifically to human PCSK9 and/or substantially inhibits binding of human PCSK9 to LDLR by at least about 20%-40%, 40-60%, 60-80%, 80-85%, or more (for example, by measuring binding 57 PCT/U S2008/074097 WO 2009/026558 in an in vitro competitive binding assay). Some of the antigen binding proteins that are provided herein are antibodies. In some embodiments, the ABP has a K<j of less (binding more tightly) than 1 O'7, 1 O'8, 10'9, ΙΟ'10, 10'11, ΙΟ'12, 10'13 M. In some embodiments, the ABP has an IC50 for blocking the binding of LDLR to PCSK9 (D374Y, high affinity variant) of less than 1 microM, 1000 nM to 100 nM, lOOnM to 10 nM, lOnM to 1 nM, lOOOpM to 500pM, 500 pM to 200 pM, less than 200 pM, 200 pM to 150 pM, 200 pM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM.
[0255] One example of an IgG2 heavy chain constant domain of an anti-PCSK9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 154, FIG. 3KK.
[0256] One example of an IgG4 heavy chain constant domain of an anti-PCSK9 antibody of the present invention has the amino acid sequence as shown in SEQ ID NO: 155, FIG. 3KK.
[0257] One example of a kappa light chain constant domain of an anti-PCSK9 antibody has the amino acid sequence as shown in SEQ ID NO: 157, FIG. 3KK.
[0258] One example of a lambda light chain constant domain of an anti-PCSK9 antibody has the amino acid sequence as shown in SEQ ID NO: 156, FIG. 3KK.
[0259] Variable regions of immunoglobulin chains generally exhibit the same overall structure, comprising relatively conserved framework regions (FR) joined by three hypervariable regions, more often called “complementarity determining regions” or CDRs. The CDRs from the two chains of each heavy chain/light chain pair mentioned above typically are aligned by the framework regions to form a structure that binds specifically with a specific epitope on the target protein (e.g., PCSK9). From N-terminal to C-terminal, naturally-occurring light and heavy chain variable regions both typically conform with the following order of these elements: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. A numbering system has been devised for assigning numbers to amino acids that occupy positions in each of these domains. This numbering system is defined in Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, MD), or Chothia &amp; Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:878-883.
[0260] Various heavy chain and light chain variable regions are provided herein and are depicted in FIGs. 2A-3JJ and 3LL-3BBB. In some embodiments, each of these variable regions can be attached to the above heavy and light chain constant regions to form a complete 58 2013203748 12 Dec 2014 antibody heavy and light chain, respectively. Further» each of the so generated heavy and light chain aet|uences can be combined to form a complete antibody structure. |02i6|| Specific examples of some Of the variable regions of the light and heavy chains of the antibodies that am provided and their corresponding amino acid sequences are summarized in TABLE 2. TABLE 2
Exemplary Heavy and Light: Chain Variable Regions
Antibody lEighi/Reavyb SEQID MO 30A4 5/74 3C4 7/85 23BS S/71 25G4 10/72 3 1H4 1*7 27B2 13/87 25A7 15/58 27BS 16/52 26H5 17/51 31Dt 18/53 20D'sn : 19/48- 27m mm 30B9 21/55 » 22 m mm 23/49 2iB12 23/49 17C2 24/57 23G1 26/50 13ΒΊ 28/01 9ca mm 9136 dim 31Λ4 32/89 ΙΛ12 33/65 I 16F12 35/79 22E2 38/80 27Λ6 37/76 2SB12 38/7? 28P6 39/78 310 tl 40/83 13B5 42/69 3 IB 12 j 44/81 3B6 1 46/80 [0262] Again, each of the exemplary variable heathy chains listed in Table 2 can be combined with any of the exemplary variable light chains shown in Table 2 to form an antibody. Table 2 shows exemplary light and heavy chain pairings found in several: of the antibodies 59 PCT/U S2008/074097 WO 2009/026558 disclosed herein. In some instances, the antibodies include at least one variable heavy chain and one variable light chain from those listed in Table 2. In other instances, the antibodies contain two identical light chains and two identical heavy chains. As an example, an antibody or antigen binding protein can include a heavy chain and a light chain, two heavy chains, or two light chains. In some embodiments the antigen binding protein comprises (and/or consists) of 1, 2, and/or 3 heavy and/or light CDRs from at least one of the sequences listed in Table 2 (CDRs for the sequences are outlined in FIGs. 2A-3D, and other embodiments in FIGs. 3CCC-3JJJ and 15A-15D). In some embodiments, all 6 CDRs (CDR1-3 from the light (CDRL1, CDRL2, CDRL3) and CDR1-3 from the heavy (CDRH1, CDRH2, and CDRH3)) are part of the ABP. In some embodiments, 1, 2, 3, 4, 5, or more CDRs are included in the ABP. In some embodiments, one heavy and one light CDR from the CDRs in the sequences in Table 2 is included in the ABP (CDRs for the sequences in table 2 are outlined in FIGs. 2A-3D). In some embodiments, additional sections (e.g., as depicted in FIG. 2A-2D, 3A-3D, and other embodiments in 3CCC-3JJJ and 15A-15D) are also included in the ABP. Examples of CDRs and FRs for the heavy and light chains noted in Table 2 are outlined in FIGs. 2A-3D (and other embodiments in FIGs. 3CCC-3JJJ and 15A-15D). Optional light chain variable sequences (including CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4) can be selected from the following: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. Optional heavy chain variable sequences (including CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4) can be selected from the following: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In some of the entries in FIG. 2A-3D, variations of the sequences or alternative boundaries of the CDRs and FRs are identified. These alternatives are identified with a “vl” following the ABP name. As most of these alternatives are minor in nature, only sections with differences are displayed in the table. It is understood that the remaining section of the light or heavy chain is the same as shown for the base ABP in the other panels. Thus, for example, 19H9vl in FIG. 2C has the same FR1, CDR1, and FR2 as 19H9 in FIG. 2A as the only difference is noted in FIG. 2C. For three of the nucleic acid sequences (ABPs 26E10, 30B9, and 31B12), additional alternative nucleic acid sequences are provided in the figures. As will be appreciated by one of skill in the art, no more than one such sequence need actually be used in the creation of an antibody or ABP. Indeed, in some 60 PCT/US2008/074097 WO 2009/026558 embodiments, only one or neither of the specific heavy or light chain nucleic acids need be present.
[0263] In some embodiments, the ABP is encoded by a nucleic acid sequence that can encode any of the protein sequences in Table 2.
[0264] In some embodiments, the ABP binds selectively to the form of PCSK9 that binds to LDLR (e.g., the autocatalyzed form of the molecule). In some embodiments, the antigen binding protein does not bind to the c-terminus of the cataylytic domain (e.g., the 5. 5-10, 10-15, 15-20, 20-25, 25-30, 30-40 most amino acids in the c-terminus). In some embodiments, the antigen binding protein does not bind to the n-terminus of the catalytic domain (e.g., the 5. 5-10, 10-15, 15-20, 20-25, 25-30, 30-40 most amino acids in the n-terminus). In some embodiments, the ABP binds to amino acids within amino acids 1-100 of the mature form of PCSK9. In some embodiments, the ABP binds to amino acids within (and/or amino acid sequences consisting of) amino acids 31-100, 100-200, 31-152, 153-692, 200-300, 300-400, 452-683, 400-500, 500-600, 31-692, 31-449, and/or 600-692. In some embodiments, the ABP binds to the catalytic domain. In some embodiments, the neutralizing and/or non-neutralizing ABP binds to the prodomain. In some embodiments, the ABP binds to both the catalytic and pro domains. In some embodiments, the ABP binds to the catalytic domain so as to obstruct an area on the catalytic domain that interacts with the pro domain. In some embodiments, the ABP binds to the catalytic domain at a location or surface that the pro-domain interacts with as outlined in Piper et al. (Structure 15:1-8 (2007), the entirety of which is hereby incorporated by reference, including the structural representations therein). In some embodiments, the ABP binds to the catalytic domain and restricts the mobility of the prodomain. In some embodiments, the ABP binds to the catalytic domain without binding to the pro-domain. In some embodiments, the ABP binds to the catalytic domain, without binding to the pro-domain, while preventing the prodomain from reorienting to allow PCSK9 to bind to LDLR. In some embodiments, the ABP binds in the same epitope as those surrounding residues 149-152 of the pro-domain in Piper et al. In some embodiments, the ABPs bind to the groove (as outlined in Piper et al.) on the V domain. In some embodiments, the ABPs bind to the histidine-rich patch proximal to the groove on the V domain. In some embodiments, such antibodies (that bind to the V domain) are not neutralizing. In some embodiments, antibodies that bind to the V domain are neutralizing. In some embodiments, the neutralizing ABPs prevent the binding of PCSK9 to LDLR. In some 61 PCT/US2008/074097 WO 2009/026558 embodiments, the neturalizing ABPs, while preventing the PCSK9 degradation of LDLR, do not prevent the binding of PCSK9 to LDLR (for example ΑΒΡ 31A4). In some embodiments, the ABP binds to or blocks at least one of the histidines depicted in Figure 4 of the Piper et al. paper. In some embodiments, the ABP blocks the catalytic triad in PCSK9.
[0265] In some embodiments, the antibody binds selectively to variant PCSK9 proteins, e.g., D374Y over wild type PCSK9. In some embodiments, these antibodies bind to the variant at least twice as strongly as the wild type, and preferably 2-5, 5-10, 10-100, 100-1000, 1000-10,000 fold or more to the mutant than the wild type (as measured via a K<j). In some embodiments, the antibody selectively inhibits variant D374Y PCSK9 from interacting with LDLR over wild type PCSK9’s ability to interact with LDLR. In some embodiments, these antibodies block the variant’s ability to bind to LDLR more strongly than the wild type’s ability, e.g., at least twice as strongly as the wild type, and preferably 2-5, 5-10, 10-100, 100-1000 fold or more to the mutant than the wild type (as measured via an IC50). In some embodiments, the antibody binds to and neutralizes both wild type PCSK9 and variant forms of PCSK9, such as D374Y at similar levels. In some embodiments, the antibody binds to PCSK9 to prevent variants of LDLR from binding to PCSK9. In some embodiments, the variants of LDLR are at least 50% identical to human LDLR. It is noted that variants of LDLR are known to those of skill in the art (e.g., Brown MS et al, “Calcium cages, acid baths and recycling receptors” Nature 388: 629-630, 1997). In some embodiments, the ABP can raise the level of effective LDLR in heterozygote familial hypercholesterolemia (where a loss-of function variant of LDLR is present).
[0266] In some embodiments, the ABP binds to (but does not block) variants of PCSK9 that are at least 50%, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, or greater percent identity to the form of PCSK9 depicted in FIG. 1A and/or FIG. IB. In some embodiments, the ABP binds to (but does not block) variants of PCSK9 that are at least 50%, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, or greater percent identity to the mature form of PCSK9 depicted in FIG. 1A and/or FIG. IB. In some embodiments, the ABP binds to and prevents variants of PCSK9 that are at least 50%, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, or greater percent identity to the form of PCSK9 depicted in FIG. 1A and/or FIG. IB from interacting with LDLR. In some embodiments, the ABP binds to and prevents variants of PCSK9 that are at least 50, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, or greater percent identity to the mature form of PCSK9 depicted in FIG. IB from interacting with LDLR. In some embodiments, the variant of PCSK9 is a 62 PCT/US2008/074097 WO 2009/026558 human variant, such as variants at position 474, E620G, and/or E670G. In some embodiments, the amino acid at position 474 is valine (as in other humans) or threonine (as in cyno and mouse). Given the cross-reactivity data presented herein, it is believed that the present antibodies will readily bind to the above variants.
[0267] In some embodiments, the ABP binds to an epitope bound by one of the antibodies described in Table 2. In some embodiments, the antigen binding proteins bind to a specific conformational state of PCSK9 so as to prevent PCSK9 from interacting with LDLR.
Humanized Antigen Binding Proteins (e.g.. Antibodies! [0268] As described herein, an antigen binding protein to PCSK9 can comprise a humanized antibody and/or part thereof. An important practical application of such a strategy is the “humanization” of the mouse humoral immune system.
[0269] In certain embodiments, a humanized antibody is substantially non-immunogenic in humans. In certain embodiments, a humanized antibody has substantially the same affinity for a target as an antibody from another species from which the humanized antibody is derived. See, e.g., U.S. Patent 5,530,101, U.S. Patent 5,693,761; U.S. Patent 5,693,762; U.S. Patent 5,585,089.
[0270] In certain embodiments, amino acids of an antibody variable domain that can be modified without diminishing the native affinity of the antigen binding domain while reducing its immunogenicity are identified. See, e.g., U.S. Patent Nos. 5,766,886 and 5,869,619.
[0271] In certain embodiments, modification of an antibody by methods known in the art is typically designed to achieve increased binding affinity for a target and/or to reduce immunogenicity of the antibody in the recipient. In certain embodiments, humanized antibodies are modified to eliminate glycosylation sites in order to increase affinity of the antibody for its cognate antigen. See, e.g., Co et al., Mol. Immunol., 30:1361-1367 (1993). In certain embodiments, techniques such as “reshaping,” “hyperchimerization,” or “veneering/resurfacing” are used to produce humanized antibodies. See, e.g., Vaswami et al., Annals of Allergy, Asthma, &amp; Immunol. 81:105 (1998); Roguska et al., Prot. Engineer., 9:895-904 (1996); and U.S. Patent No. 6,072,035. In certain such embodiments, such techniques typically reduce antibody immunogenicity by reducing the number of foreign residues, but do not prevent anti-idiotypic and anti-allotypic responses following repeated administration of the antibodies. Certain other 63 PCT/US2008/074097 WO 2009/026558 methods for reducing immunogenicity are described, e.g., in Gilliland et al., J. Immunol., 62(6): 3663-71 (1999).
[0272] In certain instances, humanizing antibodies results in a loss of antigen binding capacity. In certain embodiments, humanized antibodies are “back mutated.” In certain such embodiments, the humanized antibody is mutated to include one or more of the amino acid residues found in the donor antibody. See, e.g., Saldanha et al., Mol Immunol 36:709-19 (1999).
[0273] In certain embodiments the complementarity determining regions (CDRs) of the light and heavy chain variable regions of an antibody to PCSK9 can be grafted to framework regions (FRs) from the same, or another, species. In certain embodiments, the CDRs of the light and heavy chain variable regions of an antibody to PCSK9 can be grafted to consensus human FRs. To create consensus human FRs, in certain embodiments, FRs from several human heavy chain or light chain amino acid sequences are aligned to identify a consensus amino acid sequence. In certain embodiments, the FRs of an antibody to PCSK9 heavy chain or light chain are replaced with the FRs from a different heavy chain or light chain. In certain embodiments, rare amino acids in the FRs of the heavy and light chains of an antibody to PCSK9 are not replaced, while the rest of the FR amino acids are replaced. Rare amino acids are specific amino acids that are in positions in which they are not usually found in FRs. In certain embodiments, the grafted variable regions from an antibody to PCSK9 can be used with a constant region that is different from the constant region of an antibody to PCSK9. In certain embodiments, the grafted variable regions are part of a single chain Fv antibody. CDR grafting is described, e.g., in U.S. Patent Nos. 6,180,370, 6,054,297, 5,693,762, 5,859,205, 5,693,761, 5,565,332, 5,585,089, and 5,530,101, and in Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988), Winter, FEBS Letts., 430:92-94 (1998), which are hereby incorporated by reference for any purpose.
Human Antigen Binding Proteins (e.g.. Antibodies') [0274] As described herein, an antigen binding protein that binds to PCSK9 can comprise a human (i.e., fully human) antibody and/or part thereof. In certain embodiments, nucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to the variable regions are provided. In certain embodiments, sequences corresponding to complementarity determining 64 PCT/US2008/074097 WO 2009/026558 regions (CDR's), specifically from CDR1 through CDR3, are provided. According to certain embodiments, a hybridoma cell line expressing such an immunoglobulin molecule is provided. According to certain embodiments, a hybridoma cell line expressing such a monoclonal antibody is provided. In certain embodiments a hybridoma cell line is selected from at least one of the cell lines described in Table 2, e.g., 2IB 12, 16F12 and 31H4. In certain embodiments, a purified human monoclonal antibody to human PCSK9 is provided.
[0275] One can engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci in anticipation that such mice would produce human antibodies in the absence of mouse antibodies. Large human Ig fragments can preserve the large variable gene diversity as well as the proper regulation of antibody production and expression. By exploiting the mouse machinery for antibody diversification and selection and the lack of immunological tolerance to human proteins, the reproduced human antibody repertoire in these mouse strains can yield high affinity fully human antibodies against any antigen of interest, including human antigens. Using the hybridoma technology, antigen-specific human MAbs with the desired specificity can be produced and selected. Certain exemplary methods are described in WO 98/24893, U.S. Patent No. 5,545,807, EP 546073, and EP 546073.
[0276] In certain embodiments, one can use constant regions from species other than human along with the human variable region(s).
[0277] The ability to clone and reconstruct megabase sized human loci in yeast artificial chromosomes (YACs) and to introduce them into the mouse germline provides an approach to elucidating the functional components of very large or crudely mapped loci as well as generating useful models of human disease. Furthermore, the utilization of such technology for substitution of mouse loci with their human equivalents could provide insights into the expression and regulation of human gene products during development, their communication with other systems, and their involvement in disease induction and progression.
[0278] Human antibodies avoid some of the problems associated with antibodies that possess murine or rat variable and/or constant regions. The presence of such murine or rat derived proteins can lead to the rapid clearance of the antibodies or can lead to the generation of an immune response against the antibody by a patient. In order to avoid the utilization of murine or rat derived antibodies, fully human antibodies can be generated through the introduction of 65 PCT/US2008/074097 WO 2009/026558 functional human antibody loci into a rodent, other mammal or animal so that the rodent, other mammal or animal produces fully human antibodies.
[0279] Humanized antibodies are those antibodies that, while initially starting off containing antibody amino acid sequences that are not human, have had at least some of these nonhuman antibody amino acid sequences replaced with human antibody sequences. This is in contrast with human antibodies, in which the antibody is encoded (or capable of being encoded) by genes possessed a human.
Antigen Binding Protein Variants [0280] Other antibodies that are provided are variants of the ABPs listed above formed by combination or subparts of the variable heavy and variable light chains shown in Table 2 and comprise variable light and/or variable heavy chains that each have at least 50%, 50-60, 60-70, 70-80%, 80-85%, 85-90%, 90-95%, 95-97%, 97-99%, or above 99% identity to the amino acid sequences of the sequences in Table 2 (either the entire sequence or a subpart of the sequence, e.g., one or more CDR). In some instances, such antibodies include at least one heavy chain and one light chain, whereas in other instances the variant forms contain two identical light chains and two identical heavy chains (or subparts thereof). In some embodiments, the sequence comparison in FIG. 2A-3D (and 13A-13J and other embodiments in 15A-15D) can be used in order to identify sections of the antibodies that can be modified by observing those variations that impact binding and those variations that do not appear to impact binding. For example, by comparing similar sequences, one can identify those sections (e.g., particular amino acids) that can be modified and how they can be modified while still retaining (or improving) the functionality of the ABP. In some embodiments, variants of ABPs include those consensus groups and sequences depicted in FIGs. 13A, 13C, 13F, 13G, 13H, 131 and/or 13J and variations are allowed in the positions identified as variable in the figures. The CDRs shown in FIGs. 13A, 13C, 13F, and 13G were defined based upon a hybrid combination of the Chothia method (based on the location of the structural loop regions, see, e.g., “Standard conformations for the canonical structures of immunoglobulins,” Bissan Al-Lazikani, Arthur M. Lesk and Cyrus Chothia, Journal of Molecular Biology, 273(4): 927-948, 7 November (1997)) and the Kabat method (based on sequence variability, see, e.g., Sequences of Proteins of Immunological Interest, Fifth 66 PCT/US2008/074097 WO 2009/026558
Edition. NIH Publication No. 91-3242, Kabat et al., (1991)). Each residue determined by either method, was included in the final list of CDR residues (and are presented in FIGs. 13A, 13C, 13F, and 13G). The CDRs in FIGs. 13H, 131, and 13J were obtained by the Kabat method alone. Unless specified otherwise, the defined consensus sequences, CDRs, and FRs in FIGs. 13H-13J will define and control the noted CDRs and FRs for the referenced ABPs in FIG. 13.
[0281] In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In certain embodiments, an antigen binding protein comprises a heavy chain comprising a variable region comprising an amino acid sequence at least 99% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60.
[0282] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more CDRs from the CDRs in at least one of sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In some embodiments, 1,2, 3, 4, 5, or 6 CDR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.
[0283] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more FRs from the FRs in at least one of sequences of SEQ ID NO: 74, 85, 71, 72, 67, 87, 58, 52, 51, 53, 48, 54, 55, 56, 49, 57, 50, 91, 64, 62, 89, 65, 79, 80, 76, 77, 78, 83, 69, 81, and 60. In some embodiments, 1, 2, 3, or 4 FR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.
[0284] In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 5, 7, 9, 10, 12, 67 PCT/US2008/074097 WO 2009/026558 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In certain embodiments, an antigen binding protein comprises a light chain comprising a variable region comprising an amino acid sequence at least 99% identical to an amino acid sequence selected from at least one of the sequences of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46.
[0285] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more CDRs from the CDRs in at least one of sequences of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20,21,22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, 1, 2, 3, 4, 5, or 6 CDR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.
[0286] In some embodiments, the antigen binding protein comprises a sequence that is at least 90%, 90-95%, and/or 95-99% identical to one or more FRs from the FRs in at least one of sequences of SEQ ID NO: 5, 7, 9, 10, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 32, 33, 35, 36, 37, 38, 39, 40, 42, 44, and 46. In some embodiments, 1, 2, 3, or 4 FR (each being at least 90%, 90-95%, and/or 95-99% identical to the above sequences) is present.
[0287] In light of the present disclosure, a skilled artisan will be able to determine suitable variants of the ABPs as set forth herein using well-known techniques. In certain embodiments, one skilled in the art can identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. In certain embodiments, one can identify residues and portions of the molecules that are conserved among similar polypeptides. In certain embodiments, even areas that can be important for biological activity or for structure can be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.
[0288] Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view 68 PCT/US2008/074097 WO 2009/026558 of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues which are important for activity or structure in similar proteins. One skilled in the art can opt for chemically similar amino acid substitutions for such predicted important amino acid residues.
[0289] One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar ABPs. In view of such information, one skilled in the art can predict the alignment of amino acid residues of an antibody with respect to its three dimensional structure. In certain embodiments, one skilled in the art can choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues can be involved in important interactions with other molecules. Moreover, one skilled in the art can generate test variants containing a single amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skilled in the art. Such variants can be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change can be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations.
[0290] A number of scientific publications have been devoted to the prediction of secondary structure. See Moult J., Curr. Op. in Biotech., 7(4):422-427 (1996), Chou et al., Biochemistry, 13(2):222-245 (1974); Chou et al., Biochemistry, 113(2):211-222 (1974); Chou et al., Adv. Enzymol. Relat. Areas Mol. Biol., 47:45-148 (1978); Chou et al., Ann. Rev. Biochem., 47:251-276 and Chou et al., Biophys. J., 26:367-384 (1979). Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins which have a sequence identity of greater than 30%, or similarity greater than 40% often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within a polypeptide’s or protein’s structure. See Holm et al., Nucl. Acid. Res., 27(1):244-247 (1999). It has been suggested (Brenner et al., Curr. Op. Struct. Biol., 7(3):369-376 (1997)) that there are a limited number of folds in a given polypeptide or protein and that once a critical 69 PCT/US2008/074097 WO 2009/026558 number of structures have been resolved, structural prediction will become dramatically more accurate.
[0291] Additional methods of predicting secondary structure include “threading” (Jones, D., Curr. Opin. Struct. Biol., 7(3):377-87 (1997); Sippl et al., Structure, 4(1):15-19 (1996)), “profile analysis” (Bowie et al., Science, 253:164-170 (1991); Gribskov et al., Meth. Enzym., 183:146-159 (1990); Gribskov et al., Proc. Nat. Acad. Sci. USA, 84(13):4355-4358 (1987)), and “evolutionary linkage” (See Holm, supra (1999), and Brenner, supra (1997)).
[0292] In certain embodiments, antigen binding protein variants include glycosylation variants wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a parent polypeptide. In certain embodiments, protein variants comprise a greater or a lesser number of N-linked glycosylation sites than the native protein. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X can be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence. Cysteine variants can be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines.
[0293] According to certain embodiments, amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and/or (4) confer or modify other physiocochemical or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) can be made in the naturally-occurring sequence (in certain 70 PCT/US2008/074097 WO 2009/026558 embodiments, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts). In certain embodiments, a conservative amino acid substitution typically may not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden &amp; J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al., Nature, 354:105 (1991), which are each incorporated herein by reference.
[0294] In some embodiments, the variants are variants of the nucleic acid sequences of the ABPs disclosed herein. One of skill in the art will appreciate that the above discussion can be used for identifying, evaluating, and/creating ABP protein variants and also for nucleic acid sequences that can encode for those protein variants. Thus, nucleic acid sequences encoding for those protein variants (as well as nucleic acid sequences that encode for the ABPs in Table 2, but are different from those explicitly disclosed herein) are contemplated. For example, an ABP variant can have at least 80, 80-85, 85-90, 90-95, 95-97, 97-99 or greater identity to at least one nucleic acid sequence described in SEQ ID NOs: 152, 153, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151 or at least one to six (and various combinations thereof) of the CDR(s) encoded by the nucleic acid sequences in SEQ ID NOs: 152, 153, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, and 151.
[0295] In some embodiments, the antibody (or nucleic acid sequence encoding it) is a variant if the nucleic acid sequence that encodes the particular ABP (or the nucleic acid sequence itself) can selectively hybridize to any of the nucleic acid sequences that encode the proteins in Table 2 (such as, but not limited to SEQ ID NO: 152, 153, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 71 PCT/US2008/074097 WO 2009/026558 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, and 151) under stringent conditions. In one embodiment, suitable moderately stringent conditions include prewashing in a solution of 5XSSC; 0.5% SDS, 1.0 mM EDTA (pH 8:0); hybridizing at 50° C, -65° C, 5xSSC, overnight or, in the event of cross-species homology, at 45° C with 0.5xSSC; followed by washing twice at 65° C for 20 minutes with each of 2x, 0.5x and 0.2xSSC containing 0.1% SDS. Such hybridizing DNA sequences are also within the scope of this invention, as are nucleotide sequences that, due to code degeneracy, encode an antibody polypeptide that is encoded by a hybridizing DNA sequence and the amino acid sequences that are encoded by these nucleic acid sequences. In some embodiments, variants of CDRs include nucleic acid sequences and the amino acid sequences encoded by those sequences, that hybridize to one or more of the CDRs within the sequences noted above (individual CDRs can readily be determined in light of FIGs. 2A-3D, and other embodiments in FIGs. 3CCC-3JJJ and 15A-15D). The phrase "selectively hybridize" referred to in this context means to detectably and selectively bind. Polynucleotides, oligonucleotides and fragments thereof in accordance with the invention selectively hybridize to nucleic acid strands under hybridization and wash conditions that minimize appreciable amounts of detectable binding to nonspecific nucleic acids. High stringency conditions can be used to achieve selective hybridization conditions as known in the art and discussed herein. Generally, the nucleic acid sequence homology between the polynucleotides, oligonucleotides, and fragments of the invention and a nucleic acid sequence of interest will be at least 80%, and more typically with preferably increasing homologies of at least 85%, 90%, 95%, 99%, and 100%. Two amino acid sequences are homologous if there is a partial or complete identity between their sequences. For example, 85% homology means that 85% of the amino acids are identical when the two sequences are aligned for maximum matching. Gaps (in either of the two sequences being matched) are allowed in maximizing matching; gap lengths of 5 or less are preferred with 2 or less being more preferred. Alternatively and preferably, two protein sequences (or polypeptide sequences derived from them of at least 30 amino acids in length) are homologous, as this term is used herein, if they have an alignment score of at more than 5 (in standard deviation units) using the program ALIGN with the mutation data matrix and a gap penalty of 6 or greater. See Dayhoff, M. O., in Atlas of Protein Sequence and Structure, pp. 101-110 (Volume 5, National Biomedical Research Foundation (1972)) and Supplement 2 to this volume, pp. 1-10. The two sequences or parts thereof are more preferably homologous if their amino acids are 72 PCT/US2008/074097 WO 2009/026558 greater than or equal to 50% identical when optimally aligned using the ALIGN program. The term "corresponds to" is used herein to mean that a polynucleotide sequence is homologous (i.e., is identical, not strictly evolutionarily related) to all or a portion of a reference polynucleotide sequence, or that a polypeptide sequence is identical to a reference polypeptide sequence. In contradistinction, the term "complementary to" is used herein to mean that the complementary sequence is homologous to all or a portion of a reference polynucleotide sequence. For illustration, the nucleotide sequence "TATAC" corresponds to a reference sequence "TATAC" and is complementary to a reference sequence "GTATA".
Preparation of Antigen Binding Proteins (e.g., Antibodies) [0296] In certain embodiments, antigen binding proteins (such as antibodies) are produced by immunization with an antigen (e.g., PCSK9). In certain embodiments, antibodies can be produced by immunization with full-length PCSK9, a soluble form of PCSK9, the catalytic domain alone, the mature form of PCSK9 shown in FIG. 1A, a splice variant form of PCSK9, or a fragment thereof. In certain embodiments, the antibodies of the invention can be polyclonal or monoclonal, and/or can be recombinant antibodies. In certain embodiments, antibodies of the invention are human antibodies prepared, for example, by immunization of transgenic animals capable of producing human antibodies (see, for example, PCT Published Application No. W0 93/12227).
[0297] In certain embodiments, certain strategies can be employed to manipulate inherent properties of an antibody, such as the affinity of an antibody for its target. Such strategies include, but are not limited to, the use of site-specific or random mutagenesis of the polynucleotide molecule encoding an antibody to generate an antibody variant. In certain embodiments, such generation is followed by screening for antibody variants that exhibit the desired change, e.g. increased or decreased affinity.
[0298] In certain embodiments, the amino acid residues targeted in mutagenic strategies are those in the CDRs. In certain embodiments, amino acids in the framework regions of the variable domains are targeted. In certain embodiments, such framework regions have been shown to contribute to the target binding properties of certain antibodies. See, e.g., Hudson, Curr. Opin. Biotech., 9:395-402 (1999) and references therein. 73 PCT/U S2008/074097 WO 2009/026558 [0299] In certain embodiments, smaller and more effectively screened libraries of antibody variants are produced by restricting random or site-directed mutagenesis to hypermutation sites in the CDRs, which are sites that correspond to areas prone to mutation during the somatic affinity maturation process. See, e.g., Chowdhury &amp; Pastan, Nature Biotech., 17: 568-572 (1999) and references therein. In certain embodiments, certain types of DNA elements can be used to identify hyper-mutation sites including, but not limited to, certain direct and inverted repeats, certain consensus sequences, certain secondary structures, and certain palindromes. For example, such DNA elements that can be used to identify hyper-mutation sites include, but are not limited to, a tetrabase sequence comprising a purine (A or G), followed by guainine (G), followed by a pyrimidine (C or T), followed by either adenosine or thymidine (A or T) (i.e., A/G-G-C/T-A/T). Another example of a DNA element that can be used to identify hypermutation sites is the serine codon, A-G-C/T.
Preparation of Fully Human ABPs (e.g. Antibodies) [0300] In certain embodiments, a phage display technique is used to generate monoclonal antibodies. In certain embodiments, such techniques produce fully human monoclonal antibodies. In certain embodiments, a polynucleotide encoding a single Fab or Fv antibody fragment is expressed on the surface of a phage particle. See, e.g., Hoogenboom et al., J. Mol. Biol., 227: 381 (1991); Marks et al., J Mol Biol 222: 581 (1991); U.S. Patent No. 5,885,793. In certain embodiments, phage are “screened” to identify those antibody fragments having affinity for target. Thus, certain such processes mimic immune selection through the display of antibody fragment repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to target. In certain such procedures, high affinity functional neutralizing antibody fragments are isolated. In certain such embodiments (discussed in more detail below), a complete repertoire of human antibody genes is created by cloning naturally rearranged human V genes from peripheral blood lymphocytes. See, e.g., Mullinax et al., Proc Natl Acad Sci (USA), 87: 8095-8099 (1990).
[0301] According to certain embodiments, antibodies of the invention are prepared through the utilization of a transgenic mouse that has a substantial portion of the human antibody producing genome inserted but that is rendered deficient in the production of endogenous, murine antibodies. Such mice, then, are capable of producing human immunoglobulin molecules 74 PCT/US2008/074097 WO 2009/026558 and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilized for achieving this result are disclosed in the patents, applications and references disclosed in the specification, herein. In certain embodiments, one can employ methods such as those disclosed in PCT Published Application No. WO 98/24893 or in Mendez et al., Nature Genetics, 15:146-156 (1997), which are hereby incorporated by reference for any purpose.
[0302] Generally, fully human monoclonal ABPs (e.g., antibodies) specific for PCSK9 can be produced as follows. Transgenic mice containing human immunoglobulin genes are immunized with the antigen of interest, e.g. PCSK9, lymphatic cells (such as B-cells) from the mice that express antibodies are obtained. Such recovered cells are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. In certain embodiments, the production of a hybridoma cell line that produces antibodies specific to PCSK9 is provided.
[0303] In certain embodiments, fully human antibodies are produced by exposing human splenocytes (B or T cells) to an antigen in vitro, and then reconstituting the exposed cells in an immunocompromised mouse, e.g. SCID or nod/SCID. See, e.g., Brams et al., J.Immunol. 160: 2051-2058 (1998); Carballido et al., Nat. Med., 6: 103-106 (2000). In certain such approaches, engraftment of human fetal tissue into SCID mice (SCID-hu) results in long-term hematopoiesis and human T-cell development. See, e.g., McCune et al., Science, 241:1532-1639 (1988); Ifversen et al., Sem. Immunol., 8:243-248 (1996). In certain instances, humoral immune response in such chimeric mice is dependent on co-development of human T-cells in the animals. See, e.g., Martensson et al., Immunol., 83:1271-179 (1994). In certain approaches, human peripheral blood lymphocytes are transplanted into SCID mice. See, e.g., Mosier et al., Nature, 335:256-259 (1988). In certain such embodiments, when such transplanted cells are treated either with a priming agent, such as Staphylococcal Enterotoxin A (SEA), or with anti-human CD40 monoclonal antibodies, higher levels of B cell production is detected. See, e.g., Martensson et al., Immunol., 84: 224-230 (1995); Murphy et al., Blood, 86:1946-1953 (1995).
[0304] Thus, in certain embodiments, fully human antibodies can be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells. In other embodiments, antibodies can be produced using the phage display techniques described herein. 75 PCT/U S2008/074097 WO 2009/026558 [0305] The antibodies described herein were prepared through the utilization of the XenoMouse® technology, as described herein. Such mice, then, are capable of producing human immunoglobulin molecules and antibodies and are deficient in the production of murine immunoglobulin molecules and antibodies. Technologies utilized for achieving the same are disclosed in the patents, applications, and references disclosed in the background section herein. In particular, however, a preferred embodiment of transgenic production of mice and antibodies therefrom is disclosed in U.S. Patent Application Serial No. 08/759,620, filed December 3, 1996 and International Patent Application Nos. WO 98/24893, published June 11, 1998 and WO 00/76310, published December 21, 2000, the disclosures of which are hereby incorporated by reference. See also Mendez et al., Nature Genetics, 15:146-156 (1997), the disclosure of which is hereby incorporated by reference.
[0306] Through the use of such technology, fully human monoclonal antibodies to a variety of antigens have been produced. Essentially, XenoMouse® lines of mice are immunized with an antigen of interest (e.g. PCSK9), lymphatic cells (such as B-cells) are recovered from the hyper-immunized mice, and the recovered lymphocytes are fused with a myeloid-type cell line to prepare immortal hybridoma cell lines. These hybridoma cell lines are screened and selected to identify hybridoma cell lines that produced antibodies specific to the antigen of interest. Provided herein are methods for the production of multiple hybridoma cell lines that produce antibodies specific to PCSK? Further, provided herein are characterization of the antibodies produced by such cell lines, including nucleotide and amino acid sequence analyses of the heavy and light chains of such antibodies.
[0307] The production of the XenoMouse® strains of mice is further discussed and delineated in U.S. Patent Application Serial Nos. 07/466,008, filed January 12, 1990, 07/610,515, filed November 8, 1990, 07/919,297, filed July 24, 1992, 07/922,649, filed July 30, 1992, 08/031,801, filed March 15, 1993, 08/112,848, filed August 27, 1993, 08/234,145, filed April 28, 1994, 08/376,279, filed January 20, 1995, 08/430, 938, filed April 27, 1995, 08/464,584, filed June 5, 1995, 08/464,582, filed June 5, 1995, 08/463,191, filed June 5, 1995, 08/462,837, filed June 5, 1995, 08/486,853, filed June 5, 1995, 08/486,857, filed June 5, 1995, 08/486,859, filed June 5, 1995, 08/462,513, filed June 5, 1995, 08/724,752, filed October 2, 1996, 08/759,620, filed December 3, 1996, U.S. Publication 2003/0093820, filed November 30, 2001 and U.S. Patent Nos. 6,162,963, 6,150,584, 6,114,598, 6,075,181, and 5,939,598 and 76 PCT/US2008/074097 WO 2009/026558
Japanese Patent Nos. 3 068 180 B2, 3 068 506 B2, and 3 068 507 B2. See also European Patent No., EP 0 463 151 Bl, grant published June 12, 1996, International Patent Application No., WO 94/02602, published February 3, 1994, International Patent Application No., WO 96/34096, published October 31, 1996, WO 98/24893, published June 11, 1998, WO 00/76310, published December 21, 2000. The disclosures of each of the above-cited patents, applications, and references are hereby incorporated by reference in their entirety.
[0308] In an alternative approach, others, including GenPharm International, Inc., have utilized a “minilocus” approach. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more Vh genes, one or more Dh genes, one or more Jh genes, a mu constant region, and usually a second constant region (preferably a gamma constant region) are formed into a construct for insertion into an animal. This approach is described in U.S. Patent No. 5,545,807 to Surani et al. and U.S. Patent Nos. 5,545,806, 5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650, 5,814,318, 5,877,397, 5,874,299, and 6,255,458 each to Lonberg &amp; Kay, U.S. Patent No. 5,591,669 and 6,023.010 to Krimpenfort &amp; Bems, U.S. Patent Nos. 5,612,205, 5,721,367, and 5,789,215 to Bems et al., and U.S. Patent No. 5,643,763 to Choi &amp; Dunn, and GenPharm International U.S. Patent Application Serial Nos. 07/574,748, filed August 29, 1990, 07/575,962, filed August 31, 1990, 07/810,279, filed December 17, 1991, 07/853,408, filed March 18, 1992, 07/904,068, filed June 23, 1992, 07/990,860, filed December 16, 1992, 08/053,131, filed April 26, 1993, 08/096,762, filed July 22, 1993, 08/155,301, filed November 18, 1993, 08/161,739, filed December 3, 1993, 08/165,699, filed December 10, 1993, 08/209,741, filed March 9, 1994, the disclosures of which are hereby incorporated by reference. See also European Patent No. 0 546 073 Bl, International Patent Application Nos. WO 92/03918, WO 92/22645, WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO 96/14436, WO 97/13852, and WO 98/24884 and U.S. Patent No. 5,981,175, the disclosures of which are hereby incorporated by reference in their entirety. See further Taylor et al., 1992, Chen et al., 1993, Tuaillon et al., 1993, Choi et al., 1993, Lonberg et al., (1994), Taylor et al., (1994), and Tuaillon et al., (1995), Fishwild et al., (1996), the disclosures of which are hereby incorporated by reference in their entirety.
[0309] Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have 77 PCT/U S2008/074097 WO 2009/026558 been introduced. See European Patent Application Nos. 773 288 and 843 961, the disclosures of which are hereby incorporated by reference. Additionally, KM™ mice, which are the result of cross-breeding of Kirin’s Tc mice with Medarex’s minilocus (Humab) mice have been generated. These mice possess the human IgH transchromosome of the Kirin mice and the kappa chain transgene of the Genpharm mice (Ishida et ai, Cloning Stem Cells, (2002) 4:91-102).
[0310] Human antibodies can also be derived by in vitro methods. Suitable examples include but are not limited to phage display (CAT, Morphosys, Dyax, Biosite/Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed) ribosome display (CAT), yeast display, and the like.
[0311] In some embodiments, the antibodies described herein possess human IgG4 heavy chains as well as IgG2 heavy chains. Antibodies can also be of other human isotypes, including IgGl. The antibodies possessed high affinities, typically possessing a Kd of from about 10'6 through about 10"13 M or below, when measured by various techniques.
[0312] As will be appreciated, antibodies can be expressed in cell lines other than hybridoma cell lines. Sequences encoding particular antibodies can be used to transform a suitable mammalian host cell. Transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Patent Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference). The transformation procedure used depends upon the host to be transformed. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
[0313] Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC), including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), human epithelial kidney 293 cells, and a number of other cell lines. Cell 78 PCT/U S2008/074097 WO 2009/026558 lines of particular preference are selected through determining which cell lines have high expression levels and produce antibodies with constitutive PCSK9 binding properties.
[0314] In certain embodiments, antibodies and/or ABP are produced by at least one of the following hybridomas: 21B12, 31H4, 16F12, any the other hybridomas listed in Table 2 or disclosed in the examples. In certain embodiments, antigen binding proteins bind to PCSK9 with a dissociation constant (Kq) of less than approximately 1 nM, e.g., lOOOpM to 100 pM, 100 pM to 10 pM, 10 pM to 1 pM, and/or 1 pM to 0.1 pM or less.
[0315] In certain embodiments, antigen binding proteins comprise an immunoglobulin molecule of at least one of the IgGl, IgG2, IgG3, IgG4, Ig E, IgA, IgD, and IgM isotype. In certain embodiments, antigen binding proteins comprise a human kappa light chain and/or a human heavy chain. In certain embodiments, the heavy chain is of the IgGl, IgG2, IgG3, IgG4, IgE, IgA, IgD, or IgM isotype. In certain embodiments, antigen binding proteins have been cloned for expression in mammalian cells. In certain embodiments, antigen binding proteins comprise a constant region other than any of the constant regions of the IgGl, IgG2, IgG3, IgG4, IgE, IgA, IgD, and IgM isotype.
[0316] In certain embodiments, antigen binding proteins comprise a human lambda light chain and a human IgG2 heavy chain. In certain embodiments, antigen binding proteins comprise a human lambda light chain and a human IgG4 heavy chain. In certain embodiments, antigen binding proteins comprise a human lambda light chain and a human IgGl, IgG3, IgE, IgA, IgD or IgM heavy chain. In other embodiments, antigen binding proteins comprise a human kappa light chain and a human IgG2 heavy chain. In certain embodiments, antigen binding proteins comprise a human kappa light chain and a human IgG4 heavy chain. In certain embodiments, antigen binding proteins comprise a human kappa light chain and a human IgGl, IgG3, IgE, IgA, IgD or IgM heavy chain. In certain embodiments, antigen binding proteins comprise variable regions of antibodies ligated to a constant region that is neither the constant region for the IgG2 isotype, nor the constant region for the IgG4 isotype. In certain embodiments, antigen binding proteins have been cloned for expression in mammalian cells.
[0317] In certain embodiments, conservative modifications to the heavy and light chains of antibodies from at least one of the hybridoma lines: 21B12, 31H4 and 16F12 (and corresponding modifications to the encoding nucleotides) will produce antibodies to PCSK9 having functional and chemical characteristics similar to those of the antibodies from the 79 PCT/US2008/074097 WO 2009/026558 hybridoma lines: 2IB 12, 31H4 and 16F12. In contrast, in certain embodiments, substantial modifications in the functional and/or chemical characteristics of antibodies to PCSK9 can be accomplished by selecting substitutions in the amino acid sequence of the heavy and light chains that differ significantly in their effect on maintaining (a) the structure of the molecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
[0318] For example, a “conservative amino acid substitution” can involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position. Furthermore, any native residue in the polypeptide can also be substituted with alanine, as has been previously described for “alanine scanning mutagenesis.” [0319] Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of antibodies to PCSK9, or to increase or decrease the affinity of the antibodies to PCSK9 as described herein.
[0320] In certain embodiments, antibodies of the present invention can be expressed in cell lines other than hybridoma cell lines. In certain embodiments, sequences encoding particular antibodies can be used for transformation of a suitable mammalian host cell. According to certain embodiments, transformation can be by any known method for introducing polynucleotides into a host cell, including, for example packaging the polynucleotide in a virus (or into a viral vector) and transducing a host cell with the virus (or vector) or by transfection procedures known in the art, as exemplified by U.S. Pat. Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents are hereby incorporated herein by reference for any purpose). In certain embodiments, the transformation procedure used can depend upon the host to be transformed. Methods for introduction of heterologous polynucleotides into mammalian cells are well known in the art and include, but are not limited to, dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei.
[0321] Mammalian cell lines available as hosts for expression are well known in the art and include, but are not limited to, many immortalized cell lines available from the American 80 PCT/US2008/074097 WO 2009/026558
Type Culture Collection (ATCC), including but not limited to Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and a number of other cell lines. In certain embodiments, cell lines can be selected through determining which cell lines have high expression levels and produce antibodies with constitutive HGF binding properties. Appropriate expression vectors for mammalian host cells are well known.
[0322] In certain embodiments, antigen binding proteins comprise one or more polypeptides. In certain embodiments, any of a variety of expression vector/host systems can be utilized to express polynucleotide molecules encoding polypeptides comprising one or more ABP components or the ABP itself. Such systems include, but are not limited to, microorganisms, such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with virus expression vectors (e.g., baculovirus); plant cell systems transfected with virus expression vectors (e.g., cauliflower mosaic virus, CaMV, tobacco mosaic virus, TMV) or transformed with bacterial expression vectors (e.g., Ti or pBR322 plasmid); or animal cell systems.
[0323] In certain embodiments, a polypeptide comprising one or more ABP components or the ABP itself is recombinantly expressed in yeast. Certain such embodiments use commercially available expression systems, e.g., the Pichia Expression System (Invitrogen, San Diego, CA), following the manufacturer's instructions. In certain embodiments, such a system relies on the pre-pro-alpha sequence to direct secretion. In certain embodiments, transcription of the insert is driven by the alcohol oxidase (AOX1) promoter upon induction by methanol.
[0324] In certain embodiments, a secreted polypeptide comprising one or more ABP components or the ABP itself is purified from yeast growth medium. In certain embodiments, the methods used to purify a polypeptide from yeast growth medium is the same as those used to purify the polypeptide from bacterial and mammalian cell supernatants.
[0325] In certain embodiments, a nucleic acid encoding a polypeptide comprising one or more ABP components or the ABP itself is cloned into a baculovirus expression vector, such as pVL1393 (PharMingen, San Diego, CA). In certain embodiments, such a vector can be used according to the manufacturer's directions (PharMingen) to infect Spodoptera frugiperda cells in 81 PCT/US2008/074097 WO 2009/026558 sF9 protein-free media and to produce recombinant polypeptide. In certain embodiments, a polypeptide is purified and concentrated from such media using a heparin-Sepharose column (Pharmacia).
[0326] In certain embodiments, a polypeptide comprising one or more ABP components or the ABP itself is expressed in an insect system. Certain insect systems for polypeptide expression are well known to those of skill in the art. In one such system, Autographa califomica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes in Spodoptera frugiperda cells or in Trichoplusia larvae. In certain embodiments, a nucleic acid molecule encoding a polypeptide can be inserted into a nonessential gene of the virus, for example, within the polyhedrin gene, and placed under control of the promoter for that gene. In certain embodiments, successful insertion of a nucleic acid molecule will render the nonessential gene inactive. In certain embodiments, that inactivation results in a detectable characteristic. For example, inactivation of the polyhedrin gene results in the production of virus lacking coat protein.
[0327] In certain embodiments, recombinant viruses can be used to infect S. frugiperda cells or Trichoplusia larvae. See, e.g., Smith et ah, J. Virol., 46: 584 (1983); Engelhard et al., Proc. Nat. Acad. Sci. (USA), 91: 3224-7 (1994).
[0328] In certain embodiments, polypeptides comprising one or more ABP components or the ABP itself made in bacterial cells are produced as insoluble inclusion bodies in the bacteria. In certain embodiments, host cells comprising such inclusion bodies are collected by centrifugation; washed in 0.15 M NaCl, 10 mM Tris, pH 8, 1 mM EDTA; and treated with 0.1 mg/ml lysozyme (Sigma, St. Louis, MO) for 15 minutes at room temperature. In certain embodiments, the lysate is cleared by sonication, and cell debris is pelleted by centrifugation for 10 minutes at 12,000 X g. In certain embodiments, the polypeptide-containing pellet is resuspended in 50 mM Tris, pH 8, and 10 mM EDTA; layered over 50% glycerol; and centrifuged for 30 minutes at 6000 X g. In certain embodiments, that pellet can be resuspended in standard phosphate buffered saline solution (PBS) free of Mg** and Ca++. In certain embodiments, the polypeptide is further purified by fractionating the resuspended pellet in a denaturing SDS polyacrylamide gel {See, e.g., Sambrook et al., supra). In certain embodiments, such a gel can be soaked in 0.4 M KC1 to visualize the protein, which can be excised and electroeluted in gel-running buffer lacking SDS. According to certain embodiments, a 82 PCT/US2008/074097 WO 2009/026558
Glutathione-S-Transferase (GST) fusion protein is produced in bacteria as a soluble protein. In certain embodiments, such GST fusion protein is purified using a GST Purification Module (Pharmacia).
[0329] In certain embodiments, it is desirable to “refold” certain polypeptides, e.g., polypeptides comprising one or more ABP components or the ABP itself. In certain embodiments, such polypeptides are produced using certain recombinant systems discussed herein. In certain embodiments, polypeptides are “refolded” and/or oxidized to form desired tertiary structure and/or to generate disulfide linkages. In certain embodiments, such structure and/or linkages are related to certain biological activity of a polypeptide. In certain embodiments, refolding is accomplished using any of a number of procedures known in the art. Exemplary methods include, but are not limited to, exposing the solubilized polypeptide agent to a pH typically above 7 in the presence of a chaotropic agent. An exemplary chaotropic agent is guanidine. In certain embodiments, the refolding/oxidation solution also contains a reducing agent and the oxidized form of that reducing agent. In certain embodiments, the reducing agent and its oxidized form are present in a ratio that will generate a particular redox potential that allows disulfide shuffling to occur. In certain embodiments, such shuffling allows the formation of cysteine bridges. Exemplary redox couples include, but are not limited to, cysteine/cystamine, glutathione/dithiobisGSH, cupric chloride, dithiothreitol DTT/dithiane DTT, and 2-mercaptoethanol (bME)/dithio-bME. In certain embodiments, a co-solvent is used to increase the efficiency of refolding. Exemplary cosolvents include, but are not limited to, glycerol, polyethylene glycol of various molecular weights, and arginine.
[0330] In certain embodiments, one substantially purifies a polypeptide comprising one or more ABP components or the ABP itself. Certain protein purification techniques are known to those of skill in the art. In certain embodiments, protein purification involves crude fractionation of polypeptide fractionations from non-polypeptide fractions. In certain embodiments, polypeptides are purified using chromatographic and/or electrophoretic techniques. Exemplary purification methods include, but are not limited to, precipitation with ammonium sulphate; precipitation with PEG; immunoprecipitation; heat denaturation followed by centrifugation; chromatography, including, but not limited to, affinity chromatography (e.g., Protein-A-Sepharose), ion exchange chromatography, exclusion chromatography, and reverse phase chromatography; gel filtration; hydroxyapatite chromatography; isoelectric focusing; 83 PCT/US2008/074097 WO 2009/026558 polyacrylamide gel electrophoresis; and combinations of such and other techniques. In certain embodiments, a polypeptide is purified by fast protein liquid chromatography or by high pressure liquid chromotography (HPLC). In certain embodiments, purification steps can be changed or certain steps can be omitted, and still result in a suitable method for the preparation of a substantially purified polypeptide.
[0331] In certain embodiments, one quantitates the degree of purification of a polypeptide preparation. Certain methods for quantifying the degree of purification are known to those of skill in the art. Certain exemplary methods include, but are not limited to, determining the specific binding activity of the preparation and assessing the amount of a polypeptide within a preparation by SDS/PAGE analysis. Certain exemplary methods for assessing the amount of purification of a polypeptide preparation comprise calculating the binding activity of a preparation and comparing it to the binding activity of an initial extract. In certain embodiments, the results of such a calculation are expressed as “fold purification.” The units used to represent the amount of binding activity depend upon the particular assay performed.
[0332] In certain embodiments, a polypeptide comprising one or more ABP components or the ABP itself is partially purified. In certain embodiments, partial purification can be accomplished by using fewer purification steps or by utilizing different forms of the same general purification scheme. For example, in certain embodiments, cation-exchange column chromatography performed utilizing an HPLC apparatus will generally result in a greater “fold purification” than the same technique utilizing a low-pressure chromatography system. In certain embodiments, methods resulting in a lower degree of purification can have advantages in total recovery of polypeptide, or in maintaining binding activity of a polypeptide.
[0333] In certain instances, the electrophoretic migration of a polypeptide can vary, sometimes significantly, with different conditions of SDS/PAGE. See, e.g., Capaldi et al., Biochem. Biophys. Res. Comm., 76: 425 (1977). It will be appreciated that under different electrophoresis conditions, the apparent molecular weights of purified or partially purified polypeptide can be different.
Exemplary Epitopes [0334] Epitopes to which anti-PCSK9 antibodies bind are provided. In some embodiments, epitopes that are bound by the presently disclosed antibodies are particularly 84 PCT/US2008/074097 WO 2009/026558 useful. In some embodiments, antigen binding proteins that bind to any of the epitopes that are bound by the antibodies described herein are useful. In some embodiments, the epitopes bound by any of the antibodies listed in Table 2 and FIGs. 2 and 3 are especially useful. In some embodiments, the epitope is on the catalytic domain PCSK9.
[0335] In certain embodiments, a PCSK9 epitope can be utilized to prevent (e.g., reduce) binding of an anti-PCSK9 antibody or antigen binding protein to PCSK9. In certain embodiments, a PCSK9 epitope can be utilized to decrease binding of an anti-PCSK9 antibody or antigen binding protein to PCSK9. In certain embodiments, a PCSK9 epitope can be utilized to substantially inhibit binding of an anti-PCSK9 antibody or antigen binding protein to PCSK9.
[0336] In certain embodiments, a PCSK9 epitope can be utilized to isolate antibodies or antigen binding proteins that bind to PCSK9. In certain embodiments, a PCSK9 epitope can be utilized to generate antibodies or antigen binding proteins which bind to PCSK9. In certain embodiments, a PCSK9 epitope or a sequence comprising a PCSK9 epitope can be utilized as an immunogen to generate antibodies or antigen binding proteins that bind to PCSK9. In certain embodiments, a PCSK9 epitope can be administered to an animal, and antibodies that bind to PCSK9 can subsequently be obtained from the animal. In certain embodiments, a PCSK9 epitope or a sequence comprising a PCSK9 epitope can be utilized to interfere with normal PCSK9-mediated activity, such as association of PCSK9 with the LDLR.
[0337] In some embodiments, antigen binding proteins disclosed herein bind specifically to N-terminal prodomain, a subtilisin-like catalytic domain and/or a C-terminal domain. In some embodiments, the antigen binding protein binds to the substrate-binding groove of PCSK-9 (described in Cunningham et al., incorporated herein in its entirety by reference).
[0338] In some embodiments, the domain(s)/region(s) containing residues that are in contact with or are buried by an antibody can be identified by mutating specific residues in PCSK9 (e.g., a wild-type antigen) and determining whether the antigen binding protein can bind the mutated or variant PCSK9 protein. By making a number of individual mutations, residues that play a direct role in binding or that are in sufficiently close proximity to the antibody such that a mutation can affect binding between the antigen binding protein and antigen can be identified. From a knowledge of these amino acids, the domain(s) or region(s) of the antigen that contain residues in contact with the antigen binding protein or covered by the antibody can be 85 PCT/US2008/074097 WO 2009/026558 elucidated. Such a domain can include the binding epitope of an antigen binding protein. One specific example of this general approach utilizes an arginine/glutamic acid scanning protocol (see, e.g., Nanevicz, T., et al., 1995, J. Biol. Chem., 270:37. 21619-21625 and Zupnick, A., et al., 2006, J. Biol. Chem., 281:29. 20464-20473). In general, arginine and glutamic acids are substituted (typically individually) for an amino acid in the wild-type polypeptide because these amino acids are charged and bulky and thus have the potential to disrupt binding between an antigen binding protein and an antigen in the region of the antigen where the mutation is introduced. Arginines that exist in the wild-type antigen are replaced with glutamic acid. A variety of such individual mutants are obtained and the collected binding results analyzed to determine what residues affect binding.
[0339] Example 39 describes one such arginine/glutamic acid scanning of PCSK9 for PCSK9 antigen binding proteins provided herein. A series of mutant PCSK9 antigens were created, with each mutant antigen having a single mutation. Binding of each mutant PCSK9 antigen with various PCSK9 ABPs was measured and compared to the ability of the selected ABPs to bind wild-type PCSK9 (SEQ ID NO: 303).
[0340] An alteration (for example a reduction or increase) in binding between an antigen binding protein and a variant PCSK9 as used herein means that there is a change in binding affinity (e.g., as measured by known methods such as Biacore testing or the bead based assay described below in the examples), ECso, and/or a change (for example a reduction) in the total binding capacity of the antigen binding protein (for example, as evidenced by a decrease in Bmax in a plot of antigen binding protein concentration versus antigen concentration). A significant alteration in binding indicates that the mutated residue is directly involved in binding to the antigen binding protein or is in close proximity to the binding protein when the binding protein is bound to antigen.
[0341] In some embodiments, a significant reduction in binding means that the binding affinity, EC50, and/or capacity between an antigen binding protein and a mutant PCSK9 antigen is reduced by greater than 10%, greater than 20%, greater than 40 %, greater than 50 %, greater than 55 %, greater than 60 %, greater than 65 %, greater than 70 %, greater than75 %, greater than 80 %, greater than 85 %, greater than 90% or greater than 95% relative to binding between the antigen binding protein and a wild type PCSK9 (e.g., shown in SEQ ID NO: 1 and/or SEQ ID NO: (303). In certain embodiments, binding is reduced below detectable limits. 86 PCT/US2008/074097 WO 2009/026558
In some embodiments, a significant reduction in binding is evidenced when binding of an antigen binding protein to a variant PCSK9 protein is less than 50% (for example, less than 40%, 35%, 30%, 25%, 20%, 15% or 10%) of the binding observed between the antigen binding protein and a wild-type PCSK9 protein (for example, the protein of SEQ ID NO: 1 and/or SEQ ID NO: (303). Such binding measurements can be made using a variety of binding assays known in the art. A specific example of one such assay is described in Example 39. (0342) In some embodiments, antigen binding proteins are provided that exhibit significantly lower binding for a variant PCSK9 protein in which a residue in a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303 is substituted with arginine or glutamic acid. In some embodiments, binding of an antigen binding protein is significantly reduced or increased for a variant PCSK9 protein having any one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 244) of the following mutations: R207E, D208R, R185E, R439E, E513R, V538R, E539R, T132R, S351R, A390R, A413R, E582R, D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R, and Q554R as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303. In the shorthand notation used here, the format is: Wild type residue: Position in polypeptide: Mutant residue, with the numbering of the residues as indicated in SEQ ID NO: lor SEQ ID NO: 303.
[0343] In some embodiments, binding of an antigen binding protein is significantly reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, or more) mutations at the following positions: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554, as shown in SEQ ID NO: 1 as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, binding of an antigen binding protein is reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, or more) mutations at the following positions: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554, as shown in SEQ ID NO: 1 as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, binding of an antigen binding protein is substantially reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, or more) mutations at the following positions: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554, 87 PCT/U S2008/074097 WO 2009/026558 within SEQ ID NO: 1 as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303.
[0344] In some embodiments, binding of an ABP is significantly reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, etc.) of the following mutations: R207E, D208R, R185E, R439E, E513R, V538R, E539R, T132R, S351R, A390R, A413R, E582R, D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R, and Q554R within SEQ ID NO: 1 or SEQ ID NO: 303, as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303).
[0345] In some embodiments, binding of an ABP is significantly reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, etc.) of the following mutations: R207E, D208R, R185E, R439E, E513R, V538R, E539R, T132R, S351R, A390R, A413R, and E582R within SEQ ID NO: 1 or SEQ ID NO: 303, as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303). In some embodiments, the binding is reduced. In some embodiments, the reduction in binding is observed as a change in EC50. In some embodiments, the change in EC50 is an increase in the numerical value of the EC50 (and thus is a decrease in binding).
[0346] In some embodiments, binding of an ABP is significantly reduced or increased for a mutant PCSK9 protein having one or more (e.g., 1, 2, 3, 4, 5, etc.) of the following mutations: D162R, R164E, E167R, S123R, E129R, A311R, D313R, D337R, R519E, H521R, and Q554R within SEQ ID NO: 1, as compared to a wild-type PCSK9 protein (e.g., SEQ ID NO: 1 or SEQ ID NO: 303). In some embodiments, the binding is reduced. In some embodiments, the reduction in binding is observed as a change in Bmax. In some embodiments, the shift in Bmax is a reduction of the maximum signal generated by the ABP. In some embodiments, for an amino acid to be part of an epitope, the Bmax is reduced by at least 10%, for example, reductions of at least any of the following amounts: 20, 30, 40, 50, 60, 70, 80, 90, 95, 98, 99, or 100 percent can, in some embodiments, indicate that the residue is part of the epitope. .[0308] Although the variant forms just listed are referenced with respect to the wild-type sequence shown in SEQ ID NO: 1 or SEQ ID NO: 303, it will be appreciated that in an allelic variant of PCSK9 the amino acid at the indicated position could differ. Antigen binding proteins showing significantly lower binding for such allelic forms of PCSK9 are also 88 PCT/US2008/074097 WO 2009/026558
contemplated. Accordingly, in some embodiments, any of the above embodiments can be compared to an allelic sequence, rather than purely the wild-type sequence shown in FIG. 1A
[0347] In some embodiments, binding of an antigen binding protein is significantly reduced for a variant PCSK9 protein in which the residue at a selected position in the wild-type PCSK9 protein is mutated to any other residue. In some embodiments, the herein described arginine/glutamic acid replacements are used for the identified positions. In some embodiments, alanine is used for the identified positions.
[0348] As noted above, residues directly involved in binding or covered by an antigen binding protein can be identified from scanning results. These residues can thus provide an indication of the domains or regions of SEQ ID NO: 1 (or SEQ ID NO: 303 or SEQ ID NO: 3) that contain the binding region(s) to which antigen binding proteins bind. As can be seen from the results summarized in Example 39, in some embodiments an antigen binding protein binds to a domain containing at least one of amino acids: 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129, 311, 313, 337, 519, 521, and 554 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, the antigen binding protein binds to a region containing at least one of amino acids 207, 208, 185, 181, 439, 513, 538, 539, 132, 351, 390, 413, 582, 162, 164, 167, 123, 129,311,313,337,519, 521, and 554 of SEQ ID NO: 1 or SEQ ID NO: 303.
[0349] In some embodiments, the antigen binding protein binds to a region containing at least one of amino acids 162, 164, 167, 207 and/or 208 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, more than one (e.g., 2, 3, 4, or 5) of the identified residues are part of the region that is bound by the ABP. In some embodiments, the ABP competes with ABP21B12.
[0350] In some embodiments, the antigen binding protein binds to a region containing at least one of amino acid 185 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, the ABP competes with ABP 31H4.
[0351] In some embodiments, the antigen binding protein binds to a region containing at least one of amino acids 439, 513, 538, and/or 539 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, more than one (e.g., 2, 3, or 4) of the identified residues are part of the region that is bound by the ABP. In some embodiments, the ABP competes with ABP 31A4. 89 PCT/US2008/074097 WO 2009/026558 [0352] In some embodiments, the antigen binding protein binds to a region containing at least one of amino acids 123, 129, 311,313, 337, 132, 351, 390, and/or 413 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, more than one (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) of the identified residues are part of the region that is bound by the ABP. In some embodiments, the ABP competes with ABP 12H11.
[0353] In some embodiments, the antigen binding protein binds to a region containing at least one of amino acid 582, 519, 521, and/or 554 of SEQ ID NO: 1 or SEQ ID NO: 303. In some embodiments, more than one (e.g., 2, 3, or 4) of the identified residues are part of the region that is bound by the ABP. In some embodiments, the ABP competes with ABP 3C4.
[0354] In some embodiments, the antigen binding proteins binds to the foregoing regions within a fragment or the full length sequence of SEQ ID NO: 1 or SEQ ID NO: 303. In other embodiments, antigen binding proteins bind to polypeptides consisting of these regions. The reference to “SEQ ID NO: 1 or SEQ ID NO: 303” denotes that one or both of these sequences can be employed or relevant. The phrase does not denote that only one should be employed.
[0355] As noted above, the above description references specific amino acid positions with reference to SEQ ID NO: 1. However, throughout the specification generally, reference is made to a Pro/Cat domain that commences at position 31, which is provided in SEQ ID NO: 3. As noted below, SEQ ID NO: 1 and SEQ ID NO: 303 lack the signal sequence of PCSK9. As such, any comparison between these various disclosures should take this difference in numbering into account. In particular, any amino acid position in SEQ ID NO: 1, will correspond to an amino acid position 30 amino acids further into the protein in SEQ ID NO: 3. For example, position 207 of SEQ ID NO: 1, corresponds to position 237 of SEQ ID NO: 3 (the full length sequence, and the numbering system used in the present specification generally). Table 39.6 outlines how the above noted positions, which reference SEQ ID NO: 1 (and/or SEQ ID NO: 303) correspond to SEQ ID NO: 3 (which includes the signal sequence). Thus, any of the above noted embodiments that are described in regard to SEQ ID NO: 1 (and/or SEQ ID NO: 303), are described in reference to SEQ ID NO: 3, by the noted corresponding positions.
[0356] In some embodiments, ABP 2IB 12 binds to an epitope including residues 162-167 (e.g., residues D162-E167 of SEQ ID NO: 1). In some embodiments, ABP 12H11 90 PCT/US2008/074097 WO 2009/026558 binds to an epitope that includes residues 123-132 (e.g., S123-T132 of SEQ ID NO: 1). In some embodiments, ΑΒΡ 12H11 binds to an epitope that includes residues 311-313 (e.g., A311-D313 of SEQ ID NO: 1). In some embodiments, ABPs can bind to an epitope that includes any one of these strands of sequences.
Competing Antigen Binding Proteins [0357] In another aspect, antigen binding proteins are provided that compete with one of the exemplified antibodies or functional fragments binding to the epitope described herein for specific binding to PCSK9. Such antigen binding proteins can also bind to the same epitope as one of the herein exemplified antigen binding proteins, or an overlapping epitope. Antigen binding proteins and fragments that compete with or bind to the same epitope as the exemplified antigen binding proteins are expected to show similar functional properties. The exemplified antigen binding proteins and fragments include those described above, including those with the heavy and light chains, variable region domains and CDRs included in TABLE 2 And/or FIGs. 2-3 and 15 . Thus, as a specific example, the antigen binding proteins that are provided include those that compete with an antibody or antigen binding protein having: (a) all 6 of the CDRs listed for an antibody listed in FIGs. 2-3 and 15; (b) a VH and a VL listed for an antibody listed in Table 2; or (c) two light chains and two heavy chains as specified for an antibody listed in Table 2.
Certain Therapeutic Uses and Pharmaceutical Compositions [0358] In certain instances, PCSK9 activity correlates with a number of human disease states. For example, in certain instances, too much or too little PCSK9 activity correlates with certain conditions, such as hypercholesterolemia. Therefore, in certain instances, modulating PCSK9 activity can be therapeutically useful. In certain embodiments, a neutralizing antigen binding protein to PCSK9 is used to modulate at least one PCSK9 activity (e.g., binding to LDLR). Such methods can treat and/or prevent and/or reduce the risk of disorders that relate to elevated serum cholesterol levels or in which elevated cholesterol levels are relevant.
[0359] As will be appreciated by one of skill in the art, in light of the present disclosure, disorders that relate to, involve, or can be influenced by varied cholesterol, LDL, or LDLR levels can be addressed by various embodiments of the antigen binding proteins. In some 91 PCT/U S2008/074097 WO 2009/026558 embodiments, a “cholesterol related disorder” (which includes “serum cholesterol related disorders”) includes any one or more of the following: hypercholesterolemia, heart disease, metabolic syndrome, diabetes, coronary heart disease, stroke, cardiovascular diseases, Alzheimers disease and generally dyslipidemias, which can be manifested, for example, by an elevated total serum cholesterol, elevated LDL, elevated triglycerides, elevated VLDL, and/or low HDL. Some non-limiting examples of primary and secondary dyslipidemias that can be treated using an ABP, either alone, or in combination with one or more other agents include the metabolic syndrome, diabetes mellitus, familial combined hyperlipidemia, familial hypertriglyceridemia, familial hypercholesterolemias, including heterozygous hypercholesterolemia, homozygous hypercholesterolemia, familial defective apoplipoprotein B-100; polygenic hypercholesterolemia; remnant removal disease, hepatic lipase deficiency; dyslipidemia secondary to any of the following: dietary indiscretion, hypothyroidism, drugs including estrogen and progestin therapy, beta-blockers, and thiazide diuretics; nephrotic syndrome, chronic renal failure, Cushing's syndrome, primary biliary cirrhosis, glycogen storage diseases, hepatoma, cholestasis, acromegaly, insulinoma, isolated growth hormone deficiency, and alcohol-induced hypertriglyceridemia. ABP can also be useful in preventing or treating atherosclerotic diseases, such as, for example, coronary heart disease, coronary artery disease, peripheral arterial disease, stroke (ischaemic and hemorrhagic), angina pectoris, or cerebrovascular disease and acute coronary syndrome, myocardial infarction. In some embodiments, the ABP is useful in reducing the risk of: nonfatal heart attacks, fatal and non-fatal strokes, certain types of heart surgery, hospitalization for heart failure, chest pain in patients with heart disease, and/or cardiovascular events because of established heart disease such as prior heart attack, prior heart surgery, and/or chest pain with evidence of clogged arteries. In some embodiments, the ABP and methods can be used to reduce the risk of recurrent cardiovascular events.
[0360] As will be appreciated by one of skill in the art, diseases or disorders that are generally addressable (either treatable or preventable) through the use of statins can also benefit from the the application of the instant antigen binding proteins. In addition, in some embodiments, disorders or disease that can benefit from the prevention of cholesterol synthesis or increased LDLR expression can also be treated by various embodiments of the antigen binding proteins. In addition, as will be appreciated by one of skill in the art, the use of the anti-92 PCT/U S2008/074097 WO 2009/026558 PCSK9 antibodies can be especially useful in the treatment of Diabetes. Not only is Diabetes a risk factor for coronary heart disease, but insulin increases the expression of PCSK9. That is, people with Diabetes have elevated plasma lipid levels (which can be related to high PCSK9 levels) and can benefit from lowering those levels. This is generally discussed in more detail in Costet et al. (“Hepatic PCSK9 Expression is Regulated by Nutirtional Status via Insulin and Sterol Regulatiory Element-binding Protein 1C”, J. Biol. Chem., 281: 6211-6218, 2006), the entirety of which is incorporated herein by reference.
[0361] In some embodiments, the antigen binding protein is administered to those who have diabetes mellitus, abdominal aortic aneurysm, atherosclerosis and/or peripheral vascular disease in order to decrease their serum cholesterol levels to a safer range. In some embodiments, the antigen binding protein is administered to patients at risk of developing any of the herein described disorders. In some embodiments, the ABPs are administered to subjects that smoke, have hypertension or a familial history of early heart attacks.
[0362] In some embodiments, a subject is administered an ABP if they are at a moderate risk or higher on the 2004 NCEP treatment goals. In some embodiments, the ABP is admininstered to a subject if the subject’s LDL cholesterol level is greater than 160 mg/dl. In some embodiments, the ABP is administered if the subjects LDL cholesterol level is greater than 130 (and they have a moderate or moderately high risk according to the 2004 NCEP treatment goals). In some embodiments, the ABP is administered if the subjects LDL cholesterol level is greater than 100 (and they have a high or very high risk according to the 2004 NCEP treatment goals).
[0363] A physician will be able to select an appropriate treatment indications and target lipid levels depending on the individual profile of a particular patient. One well-accepted standard for guiding treatment of hyperlipidemia is the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of the High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, National Institutes of Health, NIH Publication No. 02-5215 (2002), the printed publication of which is hereby incorporated by reference in its entirety.
[0364] In some embodiments, antigen binding proteins to PCSK9 are used to decrease the amount of PCSK9 activity from an abnormally high level or even a normal level. In some embodiments, antigen binding proteins to PCSK9 are used to treat or prevent 93 PCT/US2008/074097 WO 2009/026558 hypercholesterolemia and/or in the preparation of medicaments therefore and/or for other cholesterol related disorders (such as those noted herein). In certain embodiments, an antigen binding protein to PCSK9 is used to treat or prevent conditions such as hypercholesterolemia in which PCSK9 activity is normal. In such conditions, for example, reduction of PCSK9 activity to below normal can provide a therapeutic effect.
[0365] In some embodiments, more than one antigen binding protein to PCSK9 is used to modulate PCSK9 activity.
[0366] In certain embodiments, methods are provided of treating a cholesterol related disorder, such as hypercholesterolemia comprising administering a therapeutically effective amount of one or more antigen binding proteins to PCSK9 and another therapeutic agent.
[0367] In certain embodiments, an antigen binding protein to PCSK9 is administered alone. In certain embodiments, an antigen binding protein to PCSK9 is administered prior to the administration of at least one other therapeutic agent. In certain embodiments, an antigen binding protein to PCSK9 is administered concurrent with the administration of at least one other therapeutic agent. In certain embodiments, an antigen binding protein to PCSK9 is administered subsequent to the administration of at least one other therapeutic agent. In other embodiments, an antigen binding protein to PCSK9 is administered prior to the administration of at least one other therapeutic agent. Therapeutic agents (apart from the antigen binding protein), include, but are not limited to, at least one other cholesterol-lowering (serum and/or total body cholesterol) agent or an agent. In some embodiments, the agent increases the expression of LDLR, have been observed to increase serum HDL levels, lower LDL levels or lower triglyceride levels. Exemplary agents include, but are not limited to, statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), Nicotinic acid (Niacin) (NIACOR, NIASPAN (slow release niacin), SLO-NLACIN (slow release niacin)), Fibric acid (LOPID (Gemfibrozil), TRICOR (fenofibrate), Bile acid sequestrants (QUESTRAN (cholestyramine), colesevelam (WELCHOL), COLESTID (colestipol)), Cholesterol absorption inhibitors (ZETIA (ezetimibe)), Combining nicotinic acid with statin (ADVICOR (LOVASTATIN and NIASPAN), Combining a statin with an absorption inhibitor (VYTORIN (ZOCOR and ZETIA) and/or lipid modifying agents. In some embodiments, the ABP is combined with PPAR gamma agonsits, PPAR alpha/gamma agonists, squalene synthase inhibitors, CETP inhibitors, anti-hypertensives, anti-diabetic agents (such as sulphonyl ureas, 94 PCT/US2008/074097 WO 2009/026558 insulin, GLP-1 analogs, DDPIV inhibitors), ApoB modulators, MTP inhibitoris and /or arteriosclerosis obliterans treatments. In some embodiments, the ABP is combined with an agent that increases the level of LDLR protein in a subject, such as statins, certain cytokines like oncostatin M, estrogen, and/or certain herbal ingredients such as berberine. In some embodiments, the ABP is combined with an agent that increases serum cholesterol levels in a subject (such as certain anti-psycotic agents, certain HIV protease inhibitors, dietary factors such as high fructose, sucrose, cholesterol or certain fatty acids and certain nuclear receptor agonists and antagonists for RXR, RAR, LXR, FXR). In some embodiments, the ABP is combined with an agent that increases the level of PCSK9 in a subject, such as statins and/or insulin. The combination of the two can allow for the undesireable side-effects of other agents to be mitigated by the ABP. As will be appreciated by one of skill in the art, in some embodiments, the ABP is combined with the other agent/compound. In some embodiments, the ABP and other agent are administered concurrently. In some embodiments, the ABP and other agent are not administered simultaneously, with the ABP being administered before or after the agent is administered. In some embodiments, the subject receives both the ABP and the other agent (that increases the level of LDLR) during a same period of prevention, occurrence of a disorder, and/or period of treatment.
[0368] Pharmaceutical compositions of the invention can be administered in combination therapy, i.e., combined with other agents. In certain embodiments, the combination therapy comprises an antigen binding protein capable of binding PCSK9, in combination with at least one anti-cholesterol agent. Agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, and combinations and conjugates thereof. In certain embodiments, an agent can act as an agonist, antagonist, alllosteric modulator, or toxin. In certain embodiments, an agent can act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote increased expression of LDLR or decrease serum cholesterol levels.
[0369] In certain embodiments, an antigen binding protein to PCSK9 can be administered prior to, concurrent with, and subsequent to treatment with a cholesterol-lowering (serum and/or total cholesterol) agent. In certain embodiments, an antigen binding protein to PCSK9 can be administered prophylactially to prevent or mitigate the onset of hypercholesterolemia, heart disease, diabetes, and/or any of the cholesterol related disorder. In 95 PCT/US2008/074097 WO 2009/026558 certain embodiments, an antigen binding protein to PCSK9 can be administered for the treatment of an existing hypercholesterolemia condition. In some embodiments, the ABP delays the onset of the disorder and/or symptoms associated with the disorder. In some embodiments, the ABP is provided to a subject lacking any sympotoms of any one of the cholesterol related disorders or a subset thereof.
[0370] In certain embodiments, an antigen binding protein to PCSK9 is used with particular therapeutic agents to treat various cholesterol related disorders, such as hypercholesterolemia. In certain embodiments, in view of the condition and the desired level of treatment, two, three, or more agents can be administered. In certain embodiments, such agents can be provided together by inclusion in the same formulation. In certain embodiments, such agent(s) and an antigen binding protein to PCSK9 can be provided together by inclusion in the same formulation. In certain embodiments, such agents can be formulated separately and provided together by inclusion in a treatment kit. In certain embodiments, such agents and an antigen binding protein to PCSK9 can be formulated separately and provided together by inclusion in a treatment kit. In certain embodiments, such agents can be provided separately. In certain embodiments, when administered by gene therapy, the genes encoding protein agents and/or an antigen binding protein to PCSK9 can be included in the same vector. In certain embodiments, the genes encoding protein agents and/or an antigen binding protein to PCSK9 can be under the control of the same promoter region. In certain embodiments, the genes encoding protein agents and/or an antigen binding protein to PCSK9 can be in separate vectors.
[0371] In certain embodiments, the invention provides for pharmaceutical compositions comprising an antigen binding protein to PCSK9 together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and/or adjuvant.
[0372] In certain embodiments, the invention provides for pharmaceutical compositions comprising an antigen binding protein to PCSK9 and a therapeutically effective amount of at least one additional therapeutic agent, together with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative and/or adjuvant.
[0373] In certain embodiments, an antigen binding protein to PCSK9 can be used with at least one therapeutic agent for inflammation. In certain embodiments, an antigen binding protein to PCSK9 can be used with at least one therapeutic agent for an immune disorder. Exemplary therapeutic agents for inflammation and immune disorders include, but are not 96 PCT/U S2008/074097 WO 2009/026558 limited to cyclooxygenase type 1 (COX-1) and cyclooxygenase type 2 (COX-2 ) inhibitors small molecule modulators of 38 kDa mitogen-activated protein kinase (p38-MAPK); small molecule modulators of intracellular molecules involved in inflammation pathways, wherein such intracellular molecules include, but are not limited to, jnk, IKK, NF-κΒ, ZAP70, and lck. Certain exemplary therapeutic agents for inflammation are described, e.g., in C.A. Dinarello &amp; L.L. Moldawer Proinflammatory and Anti-Inflammatory Cytokines in Rheumatoid Arthritis: A Primer for Clinicians Third Edition (2001) Amgen Inc. Thousand Oaks, CA.
[0374] In certain embodiments, pharmaceutical compositions will include more than one different antigen binding protein to PCSK9. In certain embodiments, pharmaceutical compositions will include more than one antigen binding protein to PCSK9 wherein the antigen binding proteins to PCSK9 bind more than one epitope. In some embodiments, the various antigen binding proteins will not compete with one another for binding to PCSK9. In some embodiments, any of the antigen binding proteins depicted in Table 2 and FIGs. 2 and/or 3 can be combined together in a pharmaceutical composition.
[0375] In certain embodiments, acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed. In some embodiments, the formulation material(s) are for s.c. and/or I.V. administration. In certain embodiments, the pharmaceutical composition can contain formulation materials for modifying, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In certain embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, 97 PCT/US2008/074097 WO 2009/026558
methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin, propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such as sucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); delivery vehicles; diluents; excipients and/or pharmaceutical adjuvants. {Remington's Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, ed., Mack Publishing Company (1995). In some embodiments, the formulation comprises PBS; 20mM NaOAC, pH 5.2, 50mM NaCl; and/or lOmM NAOAC, pH 5.2, 9% Sucrose.
[0376] In certain embodiments, an antigen binding protein to PCSK9 and/or a therapeutic molecule is linked to a half-life extending vehicle known in the art. Such vehicles include, but are not limited to, polyethylene glycol, glycogen (e.g., glycosylation of the ABP), and dextran. Such vehicles are described, e.g., in U.S. Application Serial No. 09/428,082, now US Patent No. 6,660,843 and published PCT Application No. WO 99/25044, which are hereby incorporated by reference for any purpose.
[0377] In certain embodiments, the optimal pharmaceutical composition will be determined by one skilled in the art depending upon, for example, the intended route of administration, delivery format and desired dosage. See, for example, Remington's Pharmaceutical Sciences, supra. In certain embodiments, such compositions may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the antibodies of the invention.
[0378] In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, in certain embodiments, a suitable vehicle or carrier can be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. In some embodiments, the saline comprises isotonic phosphate-buffered saline. In certain embodiments, neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. In certain embodiments, pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute therefore. In certain embodiments, a 98 PCT/U S2008/074097 WO 2009/026558 composition comprising an antigen binding protein to PCSK9, with or without at least one additional therapeutic agents, can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents {Remington's Pharmaceutical Sciences, supra) in the form of a lyophilized cake or an aqueous solution. Further, in certain embodiments, a composition comprising an antigen binding protein to PCSK9, with or without at least one additional therapeutic agents, can be formulated as a lyophilizate using appropriate excipients such as sucrose.
[0379] In certain embodiments, the pharmaceutical composition can be selected for parenteral delivery. In certain embodiments, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the ability of one skilled in the art.
[0380] In certain embodiments, the formulation components are present in concentrations that are acceptable to the site of administration. In certain embodiments, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
[0381] In certain embodiments, when parenteral administration is contemplated, a therapeutic composition can be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising a desired antigen binding protein to PCSK9, with or without additional therapeutic agents, in a pharmaceutically acceptable vehicle. In certain embodiments, a vehicle for parenteral injection is sterile distilled water in which an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, is formulated as a sterile, isotonic solution, properly preserved. In certain embodiments, the preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that can provide for the controlled or sustained release of the product which can then be delivered via a depot injection. In certain embodiments, hyaluronic acid can also be used, and can have the effect of promoting sustained duration in the circulation. In certain embodiments, implantable drug delivery devices can be used to introduce the desired molecule.
[0382] In certain embodiments, a pharmaceutical composition can be formulated for inhalation. In certain embodiments, an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, can be formulated as a dry powder for inhalation. In 99 PCT/US2008/074097 WO 2009/026558 certain embodiments, an inhalation solution comprising an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, can be formulated with a propellant for aerosol delivery. In certain embodiments, solutions can be nebulized. Pulmonary administration is further described in PCT application no. PCT/US94/001875, which describes pulmonary delivery of chemically modified proteins.
[0383] In certain embodiments, it is contemplated that formulations can be administered orally. In certain embodiments, an antigen binding protein to PCSK9, with or without at least one additional therapeutic agents, that is administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. In certain embodiments, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. In certain embodiments, at least one additional agent can be included to facilitate absorption of an antigen binding protein to PCSK9 and/or any additional therapeutic agents. In certain embodiments, diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.
[0384] In certain embodiments, a pharmaceutical composition can involve an effective quantity of an antigen binding protein to PCSK9, with or without at least one additional therapeutic agents, in a mixture with non-toxic excipients which are suitable for the manufacture of tablets. In certain embodiments, by dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. In certain embodiments, suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
[0385] Additional pharmaceutical compositions will be evident to those skilled in the art, including formulations involving antigen binding proteins to PCSK9, with or without at least one additional therapeutic agent(s), in sustained- or controlled-delivery formulations. In certain embodiments, techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. See for example, PCT Application No. PCT/US93/00829 which describes the controlled release of porous polymeric microparticles for 100 PCT/US2008/074097 WO 2009/026558 the delivery of pharmaceutical compositions. In certain embodiments, sustained-release preparations can include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides (U.S. 3,773,919 and EP 058,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., Biopolymers, 22:547-556 (1983)), poly (2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed. Mater. Res., 15:167-277 (1981) and Langer, Chem. Tech., 12:98-105 (1982)), ethylene vinyl acetate (Langer et al., supra) or poly-D(-)-3-hydroxybutyric acid (EP 133,988). In certain embodiments, sustained release compositions can also include liposomes, which can be prepared by any of several methods known in the art. See, e.g., Eppstein et al., Proc. Natl. Acad. Sci. USA, 82:3688-3692 (1985); EP 036,676; EP 088,046 and EP 143,949.
[0386] The pharmaceutical composition to be used for in vivo administration typically is sterile. In certain embodiments, this can be accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method can be conducted either prior to or following lyophilization and reconstitution. In certain embodiments, the composition for parenteral administration can be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
[0387] In certain embodiments, once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. In certain embodiments, such formulations can be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.
[0388] In certain embodiments, kits are provided for producing a single-dose administration unit. In certain embodiments, the kit can contain both a first container having a dried protein and a second container having an aqueous formulation. In certain embodiments, kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes) are included.
[0389] In certain embodiments, the effective amount of a pharmaceutical composition comprising an antigen binding protein to PCSK9, with or without at least one additional 101 PCT/U S2008/074097 WO 2009/026558 therapeutic agent, to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment, according to certain embodiments, will thus vary depending, in part, upon the molecule delivered, the indication for which an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient. In certain embodiments, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect. In certain embodiments, a typical dosage can range from about 0.1 pg/kg to up to about 100 mg/kg or more, depending on the factors mentioned above. In certain embodiments, the dosage can range from 0.1 pg/kg up to about 100 mg/kg; or 1 pg/kg up to about 100 mg/kg; or 5 pg/kg up to about 100 mg/kg.
[0390] In certain embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of an antigen binding protein to PCSK9and/or any additional therapeutic agents in the formulation used. In certain embodiments, a clinician will administer the composition until a dosage is reached that achieves the desired effect. In certain embodiments, the composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. In certain embodiments, appropriate dosages can be ascertained through use of appropriate dose-response data. In some embodiments, the amount and frequency of administration can take into account the desired cholesterol level (serum and/or total) to be obtained and the subject’s present cholesterol level, LDL level, and/or LDLR levels, all of which can be obtained by methods that are well known to those of skill in the art.
[0391] In certain embodiments, the route of administration of the pharmaceutical composition is in accord with known methods, e.g. orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, subcutaneously, intra-ocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices. In certain embodiments, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device. 102 PCT/US2008/074097 WO 2009/026558 [0392] In certain embodiments, the composition can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. In certain embodiments, where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.
[0393] In certain embodiments, it can be desirable to use a pharmaceutical composition comprising an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, in an ex vivo manner. In such instances, cells, tissues and/or organs that have been removed from the patient are exposed to a pharmaceutical composition comprising an antigen binding protein to PCSK9, with or without at least one additional therapeutic agent, after which the cells, tissues and/or organs are subsequently implanted back into the patient.
[0394] In certain embodiments, an antigen binding protein to PCSK9 and/or any additional therapeutic agents can be delivered by implanting certain cells that have been genetically engineered, using methods such as those described herein, to express and secrete the polypeptides. In certain embodiments, such cells can be animal or human cells, and can be autologous, heterologous, or xenogeneic. In certain embodiments, the cells can be immortalized. In certain embodiments, in order to decrease the chance of an immunological response, the cells can be encapsulated to avoid infiltration of surrounding tissues. In certain embodiments, the encapsulation materials are typically biocompatible, semi-permeable polymeric enclosures or membranes that allow the release of the protein product(s) but prevent the destruction of the cells by the patient’s immune system or by other detrimental factors from the surrounding tissues.
[0395] Based on the ability of ABPs to significantly neutralize PCSK9 activity (as demonstrated in the Examples below), these ABPs will have therapeutic effects in treating and preventing symptoms and conditions resulting from PCSK9-mediated activity, such as hypercholesterolemia.
Diagnostic Applications [0396] In some embodiments, the ABP is used as a diagnostic tool. The ABP can be used to assay the amount of PCSK9 present in a sample and/or subject. As will be appreciated by one of skill in the art, such ABPs need not be neutralizing ABPs. In some embodiments, the 103 PCT/U S2008/074097 WO 2009/026558 diagnostic ABP is not a neutralizing ABP. In some embodiments, the diagnostic ABP binds to a different epitope than the neutralizing ABP binds to. In some embodiments, the two ABPs do not compete with one another.
[0397] In some embodiments, the ABPs disclosed herein are used or provided in an assay kit and/or method for the detection of PCSK9 in mammalian tissues or cells in order to screen/diagnose for a disease or disorder associated with changes in levels of PCSK9. The kit comprises an ABP that binds PCSK9 and means for indicating the binding of the ABP with PCSK9, if present, and optionally PCSK9 protein levels. Various means for indicating the presence of an ABP can be used. For example, fluorophores, other molecular probes, or enzymes can be linked to the ABP and the presence of the ABP can be observed in a variety of ways. The method for screening for such disorders can involve the use of the kit, or simply the use of one of the disclosed ABPs and the determination of whether the ABP binds to PCSK9 in a sample. As will be appreciated by one of skill in the art, high or elevated levels of PCSK9 will result in larger amounts of the ABP binding to PCSK9 in the sample. Thus, degree of ABP binding can be used to determine how much PCSK9 is in a sample. Subjects or samples with an amount of PCSK9 that is greater than a predetermined amount (e.g., an amount or range that a person without a PCSK9 related disorder would have) can be characterized as having a PCSK9 mediated disorder. In some embodiments, the ABP is administered to a subject taking a statin, in order to determine if the statin has increased the amount of PCSK9 in the subject.
[0398] In some embodiments, the ABP is a non-neutralizing ABP and is used to determine the amount of PCSK9 in a subject receiving an ABP and/or statin treatment.
EXAMPLES
[0399] The following examples, including the experiments conducted and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention. EXAMPLE 1
Immunization and Titering 104 PCT/US2008/074097 WO 2009/026558
Generation of Anti-PC SK9 Antibodies and Hvbridomas [0400] Antibodies to the mature form of PCSK9 (depicted as the sequence in FIG. 1A, with the pro-domain underlined), were raised in XenoMouse® mice (Abgenix, Fremont, CA), which are mice containing human immunoglobulin genes. Two groups of XenoMouse® mice, group 1 and 2, were used to produce antibodies to PCSK9. Group 1 included mice of the XenoMouse® strain XMG2-KL, which produces fully human IgG2K and IgG2X antibodies. Group 1 mice were immunized with human PCSK9. PCSK9 was prepared using standard recombinant techniques using the GenBank sequence as reference (NM_174936). Group 2 involved mice of the XenoMouse® strain XMG4-KL, which produce fully human IgG4K and IgG4X antibodies. Group 2 mice were also immunized with human PCSK9.
[0401] The mice of both groups were injected with antigen eleven times, according to the schedule in Table 3. In the initial immunizations, each mouse was injected with a total of 10 pg of antigen delivered intraperitoneally into the abdomen. Subsequent boosts are 5ug doses and injection method is staggered between intraperitoneal injections into the abdomen and subcutaneous injections at the base of the tail. For intraperitoneal injections antigen is prepared as an emulsion with TiterMax Gold (Sigma, Cat # T2684) and for subcutaneous injections antigen is mixed with Alum (aluminum phosphate) and CpG oligos. In injections 2 through 8 and 10, each mouse was injected with a total of 5 pg of antigen in the adjuvant alum gel. A final injection of 5 pg of antigen per mouse is delivered in Phospho buffered saline and delivered into 2 sites 50% IP into the abdomen and 50% SQ at the base of tail. The immunization programs are summarized in Table 3, shown below. TABLE 3 mouse strain XMG2/kl XMG4/kl # of animals 10 10 immunogen PCSK9-V5/His IP injection 10ug each PCSK9-V5/His IP injection 10ug each 1 st boost Titermax Gold Titermax Gold 2nd boost tail injection 5ug each tail injection 5ug each Alum/CpG ODN Alum/CpG ODN 3rd boost IP injection 5ug each IP injection 5ug each 105 PCT/US2008/074097
Titermax Gold Titermax Gold 4th boost tail injection tail injection 5ug each 5ug each Alum/CpG ODN Alum/CpG ODN 5th boost IP injection IP injection 5ug each 5ug each Titermax Gold Titermax Gold 6th boost tail injection tail injection 5ug each 5ug each Alum/CpG ODN Alum/CpG ODN 7th boost IP injection IP injection 5ug each 5ug each Titermax Gold Titermax Gold 8th boost tail injection tail injection 5ug each 5ug each Alum/CpG ODN Alum/CpG ODN bleed 9th boost IP injection IP injection 5ug each 5ug each Titermax Gold Titermax Gold 10th boost tail injection tail injection 5ug each 5ug each Alum/CpG ODN Alum/CpG ODN 11 th boost BIP BIP 5ug each 5ug each PBS PBS harvest WO 2009/026558 [0402] The protocol used to titer the XenoMouse animals was as follows: Costar 3368 medium binding plates were coated with neutravadin @ 8ug/ml (50ul/well) and incubated at 4°C in lXPBS/0.05% azide overnight. They were washed using TiterTek 3-cycle wash with RO water. Plates were blocked using 250ul of 1XPBS/I%milk and incubated for at least 30 minutes at RT. Block was washed off using TiterTek 3-cycle wash with RO water. One then captured b-human PCSK9 @ 2ug/ml in lXPBS/l%milk/10mM Ca2+ (assay diluent) 50ul/well and incubated for lhr at RT. One then washed using TiterTek 3-cycle wash with RO water. For the primary antibody, sera was titrated 1:3 in duplicate from 1:100. This was done in assay diluent 50ul/well and incubated for lhr at RT. One then washed using TiterTek 3-cycle wash with RO water. The secondary antibody was goat anti Human IgG Fc HRP @ 400 ng/ml in assay diluent at 50ul/well. This was incubated for lhr at RT. This was then washed using TiterTek 3-cycle wash with RO water and patted dry on paper towels. For the substrate, one-step 106 PCT/US2008/074097 WO 2009/026558 TMB solution (Neogen, Lexington, Kentucky) was used (50ul/well) and it was allowed to develop for 30 min at RT.
[0403] The protocols followed in the ELISA assays was as follows: For samples comprising b-PCSK9 with no V5His tag the following protocol was employed: Costar 3368 medium binding plates (Coming Life Sciences) were employed. The plates were coated with neutravadin at 8 pg/ml in lXPBS/0.05%Azide, (50 μΐ/well). The plates were incubated at 4°C overnight. The plates were then washed using a Titertek M384 plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 250 μΐ of 1XPBS/1% milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the M384 plate washer. A 3-cycle wash was perfomed. The capture was b-hu PCSK9, without a V5 tag, and was added at 2 pg/ml in lXPBS/l%milk/10mM Ca2+ (40 μΐ/well). The plates were then incubated for 1 hour at room temperature. A 3-cycle wash was perfomed. Sera were titrated 1:3 in duplicate from 1:100, and row H was blank for sera. The titration was done in assay diluent, at a volume of 50 μΐ/well. The plates were incubated for 1 hour at room temperature. Next, a 3-cycle wash was perfomed. Goat anti Human IgG Fc HRP at 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ (50 μΐ/well) was added to the plate and was incubated 1 hour at room temperature. The plates were washed once again, using a 3-cycle wash. The plates were then patted dry with paper towel. Finally, 1 step TMB (Neogen, Lexington, Kentucky) (50 μΐ/well) was added to the plate and was quenched with IN hydrochloric acid (50 μΐ/well) after 30 minutes at room temperature. OD's were read immediately at 450 nm using a Titertek plate reader.
[0404] Positive controls to detect plate bound PCSK9 were soluble LDL receptor (R&amp;D Systems, Cat #2148LD/CF) and a polyclonal rabbit anti-PCSK9 antibody (Caymen Chemical #10007185) titrated 1:3 in duplicate from 3 pg/ml in assay diluent. LDLR was detected with goat anti LDLR (R&amp;D Systems, Cat #AF2148) and rabbit anti goat IgGFc HRP at a concentration of 400 ng/ml; the rabbit polyclonal was detected with goat anti-rabbit IgG Fc at a concentration of 400 ng/ml in assay diluent. Negative control was naive XMG2-KL and XMG4-KL sera titrated 1:3 in duplicate from 1:100 in assay diluent.
[0405] For samples comprising b-PCSK9 with a V5His tag the following protocol was employed: Costar 3368 medium binding plates (Coming Life Sciences) were employed. The plates were coated with neutravadin at 8 pg/ml in lXPBS/0.05%Azide, (50 μΐ/well). The 107 PCT/U S2008/074097 WO 2009/026558 plates were incubated at 4°C overnight. The plates were then washed using a Titertek M384 plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 250 μΐ of 1XPBS/1% milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the M3 84 plate washer. A 3-cycle wash was perfomed. The capture was b-hu PCSK9, with a V5 tag, and was added at 2 pg/ml in lXPBS/l%milk/10mM Ca2+ (40 μΐ/well). The plates were then incubated for 1 hour at room temperature. A 3-cycle wash was perfomed. Sera were titrated 1:3 in duplicate from 1:100, and row H was blank for sera. The titration was done in assay diluent, at a volume of 50 μΐ/well. The plates were incubated for 1 hour at room temperature. Next, the plates were washed using the M384 plate washer operated using a 3-cycle wash. Goat anti Human IgG Fc HRP at 400 ng/ml in lXPBS/l%milk/10mM Ca2+ was added at 50 μΐ/well to the plate and the plate was incubated 1 hour at room temperature. The plates were washed once again, using a 3-cycle wash. The plates were then patted dry with paper towel. Finally, 1 step TMB (Neogen, Lexington, Kentucky) (50 μΐ/well) was added to the plate and the plate was quenched with IN hydrochloric acid (50 μΐ/well) after 30 minutes at room temperature. OD's were read immediately at 450 nm using a Titertek plate reader.
[0406] Positive control was LDLR, rabbit anti-PCSK9 titrated 1:3 in duplicate from 3 pg/ml in assay diluent. LDLR detect with goat anti-LDLR (R&amp;D Systems, Cat #AF2148) and rabbit anti-goat IgG Fc HRP at a concentration of 400 ng/ml; rabbit poly detected with goat antirabbit IgG Fc at a concentration of 400 ng/ml in assay diluent. Human anti-His 1.2,3 and anti-V5 1.7.1 titrated 1:3 in duplicate from 1 pg/ml in assay diluent; both detected with goat anti-human IgG Fc HRP at a concentration of 400 ng/ml in assay diluent. Negative control was naive XMG2-KL and XMG4-KL sera titrated 1:3 in duplicate from 1:100 in assay diluent. (0407) Titers of the antibody against human PCSK9 were tested by ELISA assay for mice immunized with soluble antigen as described. Table 4 summarizes the ELISA data and indicates that there were some mice which appeared to be specific for PCSK9. See, e.g., Table 4. Therefore, at the end of the immunization program, 10 mice (in bold in Table 4) were selected for harvest, and splenocytes and lymphocytes were isolated from the spleens and lymph nodes respectively, as described herein. TABLE 4
Summary of ELISA Results 108 PCT/US2008/074097
Titer Titer Animal ID b-hu PCSK9 (V5His) @ 2ug/ml b-hu PCSK9 @ 2ug/ml P175807 >72900 @ OD 2.2 68359 P175808 >72900 @ OD 2.3 >72900 @ OD 2.5 P175818 >72900 @ OD 3.2 >72900 @ OD 3.0 P175819 >72900 @ OD 3.4 >72900 @ OD 3.2 Group 1 - P175820 >72900 @ OD 2.4 >72900 @ OD 2.5 lgG2k/l P175821 >72900 @ OD 3.4 >72900 @ OD 3.0 P175830 >72900 @ OD 2.6 >72900 @ OD 2.5 P175831 >72900 @ OD 3.1 >72900 @ OD 3.1 P175832 >72900 @ OD 3.8 >72900 @ OD 3.6 P175833 >72900 <® OD 2.6 >72900 @ OD 2.3 P174501 19369 17109 P174503 31616 23548 P174508 48472 30996 P174509 23380 21628 Group 2 - P174510 15120 9673 lgG4k/l P175773 19407 15973 P175774 54580 44424 P175775 60713 55667 P175776 30871 22899 P175777 16068 12532 Naive G2 < 100 @OD 0.54 < 100 @ OD 0.48 Naive G4 < 100 ® OD 1.57 < 100 @ OD 1.32 WO 2009/026558 EXAMPLE 2
Recovery of Lymphocytes, B-cell Isolations, Fusions and Generation of Hybridomas [0408] This example outlines how the immune cells were recovered and the hybridomas were generated. Selected immunized mice were sacrificed by cervical dislocation and the draining lymph nodes were harvested and pooled from each cohort. The B cells were dissociated from lymphoid tissue by grinding in DMEM to release the cells from the tissues, and the cells were suspended in DMEM. The cells were counted, and 0.9 ml DMEM per 100 million lymphocytes was added to the cell pellet to resuspend the cells gently but completely.
[0409] Lymphocytes were mixed with nonsecretory myeloma P3X63Ag8.653 cells purchased from ATCC, cat.# CRL 1580 (Kearney et al., (1979) J. Immunol. 123, 1548-1550) at a ratio of 1:4. The cell mixture was gently pelleted by centrifugation at 400 x g 4 min. After decanting of the supernatant, the cells were gently mixed using a 1 ml pipette. Preheated 109 PCT/U S2008/074097 WO 2009/026558 PEG/DMSO solution from Sigma (cat# P7306) (1 ml per million of B-cells) was slowly added with gentle agitation over 1 min followed by 1 min of mixing. Preheated IDMEM (2 ml per million of B cells) (DMEM without glutamine, L-glutamine, pen/strep, MEM non-essential amino acids (all from Invitrogen), was then added over 2 minutes with gentle agitation. Finally preheated IDMEM (8 ml per 106 B-cells) was added over 3 minutes.
[0410] The fused cells were spun down 400 x g 6 min and resuspended in 20 ml selection media (DMEM (Invitrogen), 15 % FBS (Hyclone), supplemented with L-glutamine, pen/strep, MEM Non-essential amino acids, Sodium Pyruvate, 2-Mercaptoethanol (all from Invitrogen), HA-Azaserine Hypoxanthine and OPI (oxaloacetate, pyruvate, bovine insulin) (both from Sigma) and IL-6 (Boehringer Mannheim)) per million B-cells. Cells were incubated for 20-30 min at 37C and then resuspended in 200 ml selection media and cultured for 3-4 days in T175 flask prior to 96 well plating. Thus, hybridomas that produced antigen binding proteins to PCSK9 were produced. EXAMPLE 3
Selection of PCSK9 Antibodies [0411] The present example outlines how the various PCSK9 antigen binding proteins were characterized and selected. The binding of secreted antibodies (produced from the hybridomas produced in Examples 1 and 2) to PCSK9 was assessed. Selection of antibodies was based on binding data and inhibition of PCSK9 binding to LDLR and affinity. Binding to soluble PCSK9 was analyzed by ELISA, as described below. BIAcore® (surface plasmon resonance) was used to quantify binding affinity.
Primary Screen [0412] A primary screen for antibodies which bind to wild-type PCSK9 was performed. The primary screen was performed on two harvests. The primary screen comprised an ELISA assay and was performed using the following protocol: [0413] Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed. The plates were coated with neutravadin at a concentration of 4 pg/ml in lXPBS/0.05%Azide, at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 90 μΐ of 1XPBS/I%milk and incubated 110 PCT/US2008/074097 WO 2009/026558 approximately 30 minutes at room temperature. The plates were then washed. Again, a 3-cycle wash was perfomed. The capture sample was biotinylated-PCSK9, without a V5 tag, and was added at 0.9 pg/ml in lXPBS/l%milk/10mM Ca2+ at a volume of 40 μΐ/well. The plates were then incubated for 1 hour at room temperature. Next, the plates were washed using the Titertek plate washer operated using a 3-cycle wash. 10 μΐ of supernatant was transferred into 40 μΐ of lXPBS/l%milk/10mM Ca2+ and incubated 1.5 hours at room temperature. Again the plates were washed using the Titertek plate washer operated using a 3-cycle wash. 40 μΐ/well of Goat anti-Human IgG Fc POD at a concentration of 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ was added to the plate and was incubated 1 hour at room temperature. The plates were washed once again, using a 3-cycle wash. Finally, 40 μΐ/well of One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and quenching with 40 μΐ/well of IN hydrochloric acid was performed after 30 minutes at room temperature. OD’s were read immediately at 450 nm using a Titertek plate reader.
[0414] The primary screen resulted in a total of 3104 antigen specific hybridomas being identified from the two harvests. Based on highest ELISA OD, 1500 hybridomas per harvest were advanced for a total of 3000 positives.
Confirmatory Screen [0415] The 3000 positives were then rescreened for binding to wild-type PCSK9 to confirm stable hybridomas were established. The screen was performed as follows: Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed. The plates were coated with neutravadin at 3 pg/ml in lXPBS/0.05%Azide at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 90 μΐ of 1XPBS/I%milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the M3 84 plate washer. A 3-cycle wash was perfomed. The capture sample was b-PCSK9, without a V5 tag, and was added at 0.9 pg/ml in lXPBS/l%milk/10mM Ca2+ at a volume of 40 μΐ/well. The plates were then incubated for 1 hour at room temperature. Next, the plates were washed using a 3-cycle wash. 10 μΐ of supernatant was transferred into 40 μΐ of lXPBS/l%milk/10mM Ca2+ and incubated 1.5 hours at room temperature. Again the 111 PCT/US2008/074097 WO 2009/026558 plates were washed using the Titertek plate washer operated using a 3-cycle wash. 40 μΐ/well of Goat anti-Human IgG Fc POD at a concentration of 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ was added to the plate, and the plate was incubated 1 hour at room temperature. The plates were washed once again, using the Titertek plate washer operated using a 3-cycle wash. Finally, 40 μΐ/well of One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and was quenched with 40 μΐ/well of IN hydrochloric acid after 30 minutes at room temperature. OD’s were read immediately at 450 nm using a Titertek plate reader. A total of 2441 positives repeated in the second screen. These antibodies were then used in the subsequent screenings.
Mouse Cross-reactivitv Screen [0416] The panel of hybridomas was then screened for cross-reactivity to mouse PCSK9 to make certain that the antibodies could bind to both human and mouse PCSK9. The following protocol was employed in the cross-reactivity screen: Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed. The plates were coated with neutravadin at 3 pg/ml in lXPBS/0.05%Azide at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 90 μΐ of 1XPBS/I%milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the Titertek plate washer. A 3-cycle wash was perfomed. The capture sample was biotinylated-mouse PCSK9, and was added at 1 pg/ml in lXPBS/l%milk/10mM Ca2+ at a volume of 40 μΐ/well. The plates were then incubated for 1 hour at room temperature. Next, the plates were washed using the Titertek plate washer operated using a 3-cycle wash. 50 μΐ of supernatant was transferred to the plates and incubated 1 hour at room temperature. Again the plates were washed using a 3-cycle wash. 40 μΐ/well of Goat anti-Human IgG Fc POD at a concentration of 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ was added to the plate and the plate was incubated 1 hour at room temperature. The plates were washed once again, using a 3-cycle wash. Finally, 40 μΐ/well One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and was quenched with 40 μΐ/well of IN hydrochloric acid after 30 minutes at room temperature. OD’s were read immediately at 450 nm using a Titertek plate reader. 579 112 PCT/U S2008/074097 WO 2009/026558 antibodies were observed to cross-react with mouse PCSK9. These antibodies were then used in the subsequent screenings. D374Y Mutant Binding Screen [0417] The D374Y mutation in PCSK9 has been documented in the human population (e.g., Timms KM et al, “A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree”, Hum. Genet. 114: 349-353, 2004). In order to determine if the antibodies were specific for the wild type or also bound to the D374Y form of PCSK9, the samples were then screened for binding to the mutant PCSK9 sequence comprising the mutation D374Y. The protocol for the screen was as follows: Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed in the screen. The plates were coated with neutravadin at 4 pg/ml in lXPBS/0.05% Azide at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 90 μΐ of 1XPBS/I%milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the Titertek plate washer. A 3-cycle wash was perfomed. The plates were coated with biotinylated human PCSK9 D374Y at a concentration of 1 pg/ml in lXPBS/l%milk/10mMCa2+ and incubated for 1 hour at room temperature. The plates were then washed using a Titertek plate washer. A 3-cycle wash was perfomed. Late exhaust hybridoma culture supernatant was diluted 1:5 in PBS/milk/Ca2+ (10 ml plus 40 ml) and incubated for 1 hour at room temperature. Next, 40 μΐ/well of rabbit anti-human PCSK9 (Cayman Chemical) and human anti-His 1.2.3 1:2 at lug/ml in lXPBS/l%milk/10mMCa2+ was titrated onto the plates, which were then incubated for 1 hour at room temperature. The plates were then washed using a Titertek plate washer. A 3-cycle wash was perfomed. 40 μΐ/well of Goat anti-Human IgG Fc HRP at a concentration of 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ was added to the plate and the plate was incubated 1 hour at room temperature. 40 μΐ/well of Goat antirabbit IgG Fc HRP at a concentration of 100 ng/ml (1:4000) in lXPBS/l%milk/10mM Ca2+ was added to the plate and the plate was incubated 1 hour at room temperature. The plates were then washed using a Titertek plate washer. A 3-cycle wash was perfomed. Finally, 40 μΐ/well of One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and was quenched with 40 μΐ/well of IN hydrochloric acid after 30 minutes at room temperature. OD’s were read 113 PCT/U S2008/074097 WO 2009/026558 immediately at 450 nm using a Titertek plate reader. Over 96% of the positive hits on the wild-type PCSK9 also bound mutant PCSK9.
Large Scale Receptor Ligand Blocking Screen [0418] To screen for the antibodies that block PCSK9 binding to LDLR an assay was developed using the D374Y PCSK9 mutant. The mutant was used for this assay because it has a higher binding affinity to LDLR allowing a more sensitive receptor ligand blocking assay to be developed. The following protocol was employed in the receptor ligand blocking screen: Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed in the screen. The plates were coated with goat anti-LDLR (R&amp;D Cat #AF2148) at 2 pg/ml in lXPBS/0.05%Azide at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was performed. The plates were blocked with 90 μΐ of 1XPBS/1% milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the Titertek plate washer. A 3-cycle wash was performed. The capture sample was LDLR (R&amp;D, Cat #2148LD/CF), and was added at 0.4 pg/ml in lXPBS/l%milk/10mM Ca2+ at a volume of 40 μΐ/well. The plates were then incubated for 1 hour and 10 minutes at room temperature. Contemporaneously, 20 ng/ml of biotinylated human D374Y PCSK9 was incubated with 15 microliters of hybridoma exhaust supernatant in Nunc polypropylene plates and the exhaust supernatant concentration was diluted 1:5. The plates were then pre-incubated for about 1 hour and 30 minutes at room temperature. Next, the plates were washed using the Titertek plate washer operated using a 3-cycle wash. 50 μΐ/well of the pre-incubated mixture was transferred onto the LDLR coated ELISA plates and incubated for 1 hour at room temperature. To detect LDLR-bound b-PCSK9, 40 μΐ/well streptavidin HRP at 500 ng/ml in assay diluent was added to the plates. The plates were incubated for 1 hour at room temperature. The plates were again washed using a Titertek plate washer. A 3-cycle wash was performed. Finally, 40 μΐ/well of One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and was quenched with 40 μΐ/well of IN hydrochloric acid after 30 minutes at room temperature. OD’s were read immediately at 450 nm using a Titertek plate reader. The screen identified 384 antibodies that blocked the interaction between PCSK9 and the LDLR well, 100 antibodies blocked the interaction strongly (OD < 0.3). 114 PCT/US2008/074097 WO 2009/026558
These antibodies inhibited the binding interaction of PCSK9 and LDLR greater than 90% (greater than 90% inhibition).
Receptor Ligand Binding Assay on Blocker Subset [0419] The receptor ligand assay was then repeated using the mutant enzyme on the 384 member subset of neutralizers identified in the first large scale receptor ligand inhibition assay. The same protocol was employed in the screen of the 384 member blocker subset assay as was done in the large scale receptor ligand blocking screen. This repeat screen confirmed the initial screening data.
[0420] This screen of the 384 member subset identified 85 antibodies that blocked interaction between the PCSK9 mutant enzyme and the LDLR greater than 90%.
Receptor Ligand Binding Assay of Blockers that Bind the Wild Type PCSK9 but not the D374Y Mutant [0421] In the initial panel of 3000 sups there were 86 antibodies shown to specifically bind to the wild-type PCSK9 and not to the huPCSK9(D374Y) mutant. These 86 sups were tested for the ability to block wild-type PCSK9 binding to the LDLR receptor. The following protocol was employed: Costar 3702 medium binding 384 well plates (Coming Life Sciences) were employed in the screen. The plates were coated with anti-His 1.2.3 at 10 pg/ml in lXPBS/0.05% Azide at a volume of 40 μΐ/well. The plates were incubated at 4°C overnight. The plates were then washed using a Titertek plate washer (Titertek, Huntsville, AL). A 3-cycle wash was perfomed. The plates were blocked with 90 μΐ of 1XPBS/I%milk and incubated approximately 30 minutes at room temperature. The plates were then washed using the Titertek plate washer. A 3-cycle wash was perfomed. LDLR (R&amp;D Systems, #2148LD/CF or R&amp;D Systems, #2148LD) was added at 5 pg/ml in lXPBS/l%milk/10mM Ca2+ at a volume of 40 μΐ/well. The plates were then incubated for 1 hour at room temperature. Next, the plates were washed using the Titertek plate washer operated using a 3-cycle wash. Contemporaneously, biotinylated human wild-type PCSK9 was pre-incubated with hybridoma exhaust supernatant in Nunc polypropylene plates. 22 μΐ of hybridoma sup was transferred into 33ul of b-PCSK9 at a concentration of 583 ng/ml in lXPBS/l%milk/10mMCa2+, giving a final b-PCSK9 concentration = 350 ng/ml and the exhaust supernatant at a final dilution of 1:2.5. The plates 115 PCT/US2008/074097 WO 2009/026558 were pre-incubated for approximately 1 hour and 30 minutes at room temperature. 50 μΐ/well of the preincubated mixture was transferred onto LDLR captured ELISA plates and incubated for 1 hour at room temperature. The plates were then washed using the Titertek plate washer. A 3-cycle wash was perfomed. 40 μΐ/well streptavidin HRP at 500 ng/ml in assay diluent was added to the plates. The plates were incubated for 1 hour at room temperature. The plates were then washed using a Titertek plate washer. A 3-cycle wash was perfomed. Finally, 40 μΐ/well of One-step TMB (Neogen, Lexington, Kentucky) was added to the plate and was quenched with 40 μΐ/well of IN hydrochloric acid after 30 minutes at room temperature. OD’s were read immediately at 450 nm using a Titertek plate reader.
Screening Results [0422] Based on the results of the assays described, several hybridoma lines were identified as producing antibodies with desired interactions with PCSK9. Limiting dilution was used to isolate a manageable number of clones from each line. The clones were designated by hybridoma line number (e.g. 21B12) and clone number (e.g. 21B12.1). In general, no difference among the different clones of a particular line were detected by the functional assays described herein. In a few cases, clones were identified from a particular line that behaved differently in the functional assays, for example, 25A7.1 was found not to block PCSK9/LDLR but 25A7.3 (referred to herein as 25 A7) was neutralizing. The isolated clones were each expanded in 50-100 ml of hybridoma media and allowed to grow to exhaustion, (i.e., less than about 10% cell viability). The concentration and potency of the antibodies to PCSK9 in the supernatants of those cultures were determined by ELISA and by in vitro functional testing, as described herein. As a result of the screening described herein, the hybridomas with the highest titer of antibodies to PCSK9 were identified. The selected hybridomas are shown in FIGS 2A-3D and Table 2. EXAMPLE 4.1
Production of Human 31H4 IgG4 Antibodies from Hybridomas [0423] This example generally describes how one of the antigen binding proteins was produced from a hybridoma line. The production work used 50ml exhaust supernatant generation followed by protein A purification. Integra production was for scale up and was performed later. Hybridoma line 31H4 was grown in T75 flasks in 20 ml of media (Integra 116 PCT/US2008/074097 WO 2009/026558
Media, Table 5). When the hybridoma was nearly confluent in the T75 flasks, it was transferred to an Integra flask (Integra Biosciences, Integra CL1000, cat# 90 005).
[0424] The Integra flask is a cell culture flask that is divided by a membrane into two chambers, a small chamber and a large chamber. A volume of 20-30 ml hybridoma cells at a minimum cell density of lxl06 cells per ml from the 31H4 hybridoma line was placed into the small chamber of an Integra flask in Integra media (see Table 5 for components of Integra media). Integra media alone (1L) was placed in the large chambers of the Integra flasks. The membrane separating the two chambers is permeable to small molecular weight nutrients but is impermeable to hybridoma cells and to antibodies produced by those cells. Thus, the hybridoma cells and the antibodies produced by those hybridoma cells were retained in the small chamber.
[0425] After one week, media was removed from both chambers of the Integra flask and was replaced with fresh Integra media. The collected media from the small chambers was separately retained. After a second week of growth, the media from the small chamber was again collected. The collected media from week 1 from the hybridoma line was combined with the collected media from week 2 from the hybridoma line. The resulting collected media sample from the hybridoma line was spun to remove cells and debris (15 minutes at 3000rpm) and the resulting supernatant was filtered (0.22um). Clarified conditioned media was loaded onto a Protein A-Sepharose column. Optionally, the media can be first concentrated and then loaded onto a Protein A Sepharose column. Non-specific bindings were removed by an extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (such as 50 mM Citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on anion exchanger resin such as Q Sepharose resin. The specific IEX conditions for the 31H4 proteins are Q-Sepharose HP at pH 7.8-8.0. Antibody was eluted with a NaCl gradient of 10 mM-500 mM in 25 column volumes. TABLE 5
Composition of Media
INTEGRA MEDIA
HSFM 10% Ultra Low IgG serum 2mmol/L L-glutamine 117 PCT/US2008/074097 WO 2009/026558 1% NEAA 4g/L glucose EXAMPLE 4.2
Production of Recombinant 31H4 Human IgG2 Antibodies From Transfected Cells [0426] The present example outlines how 31H4 IgG2 antibodies were produced from transfected cells. 293 cells for transient expression and CHO cells for stable expression were transfected with plasmids that encode 31H4 heavy and light chains. Conditioned media from transfected cells was recovered by removing cells and cell debris. Clarified conditioned media was loaded onto a Protein A-Sepharose column. Optionally, the media can first be concentrated and then loaded onto a Protein A Sepharose column. Non-specific bindings were removed by extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (such as 50 mM citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on anion exchanger resin such as Q Sepharose resin. The specific IEX conditions for the 31H4 proteins are Q-Sepharose HP at pH 7.8-8.0. The antibody was eluted with a NaCl gradient of 10 mM-500 mM in 25 column volumes. EXAMPLE 5
Production of Human 21B12 IgG4 Antibodies from Hybridomas [0427] The present example outlines how antibody 2IB 12 IgG4 was produced from hybridomas. Hybridoma line 21B12 was grown in T75 flasks in media (Integra Media, Table 5). When the hybridomas were nearly confluent in the T75 flasks, they were transferred to Integra flasks (Integra Biosciences, Integra CL1000, cat# 90 005).
[0428] The Integra flask is a cell culture flask that is divided by a membrane into two chambers, a small chamber and a large chamber. A volume of 20-30 ml hybridoma cells at a minimum cell density of lx 106 cells per ml from the 31H4 hybridoma line was placed into the small chamber of an Integra flask in Integra media (see Table 5 for components of Integra media). Integra media alone (1L) was placed in the large chambers of the Integra flasks. The membrane separating the two chambers is permeable to small molecular weight nutrients but is 118 PCT/US2008/074097 WO 2009/026558 impermeable to hybridoma cells and to antibodies produced by those cells. Thus, the hybridoma cells and the antibodies produced by those hybridoma cells were retained in the small chamber. After one week, media was removed from both chambers of the Integra flask and was replaced with fresh Integra media. The collected media from the small chambers was separately retained. After a second week of growth, the media from the small chamber was again collected. The collected media from week 1 from the hybridoma line was combined with the collected media from week 2 from the hybridoma line. The resulting collected media sample from the hybridoma line was spun to remove cells and debris (15 minutes at 3000 rpm) and the resulting supernatant was filtered (0.22 pm). Clarified conditioned media were loaded onto a Protein A Sepharose column. Optionally, the media are first concentrated and then loaded onto a Protein A Sepharose column. Non-specific bindings were removed by an extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (such as 50 mM Citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on anion exchanger resin such as Q Sepharose resin. The specific IEX conditions for the 21B12 proteins are Q-Sepharose HP at pH 7.8-8.0. The antibody was eluted with a NaCl gradient of 10 mM-500 mM in 25 column volumes. EXAMPLE 6
Production of Human 2 IB 12 IgG2 Antibodies From Transfected Cells [0429] The present example outlines how 21B12 IgG2 antibodies were produced from transfected cells. Cells (293 cells for transient expression and CHO cells for stable expression) were transfected with plasmids that encode 2IB 12 heavy and light chains. Conditioned media from hybridoma cells were recovered by removing cells and cell debris. Clarified conditioned media were loaded onto a Protein A-Sepharose column. Optionally, the media can first be concentrated and then loaded onto a Protein A Sepharose column. Nonspecific bindings were removed by extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (50 mM Citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on cation exchanger 119 PCT/U S2008/074097 WO 2009/026558 resin such as SP-Sepharose resin. The specific IEX conditions for the 21B12 proteins were SP-Sepharose HP at pH 5.2. Antibodies were eluted with 25 column volumes of buffer that contains a NaCl gradient of 10 mM-500 mM in 20 mM sodium acetate buffer. EXAMPLE 7
Production of Human 16F12 IgG4 Antibodies from Hybridomas [0430] The present example outlines how antibody 16F12 IgG4 was produced from hybridomas. Hybridoma line 16F12 was grown in T75 flasks in media (see Table 5). When the hybridomas were nearly confluent in the T75 flasks, they were transferred to Integra flasks (Integra Biosciences, Integra CL1000, cat# 90 005).
[0431] The Integra flask is a cell culture flask that is divided by a membrane into two chambers, a small chamber and a large chamber. A volume of 20-30 ml Hybridoma cells at a minimum cell density of lxlO6 cells per ml from the 31H4 hybridoma line was placed into the small chamber of an Integra flask in Integra media (see Table 5 for components of Integra media). Integra media alone (1L) was placed in the large chambers of the Integra flasks. The membrane separating the two chambers is permeable to small molecular weight nutrients but is impermeable to hybridoma cells and to antibodies produced by those cells. Thus, the hybridoma cells and the antibodies produced by those hybridoma cells were retained in the small chamber.
[0432] After one week, media was removed from both chambers of the Integra flask and was replaced with fresh Integra media. The collected media from the small chambers was separately retained. After a second week of growth, the media from the small chamber was again collected. The collected media from week 1 from the hybridoma line was combined with the collected media from week 2 from the hybridoma line. The resulting collected media sample from the hybridoma line were spun to remove cells and debris (15 minutes at 3000 rpm) and the resulting supernatants were filtered (0.22 pm). Clarified conditioned media were loaded onto a Protein A Sepharose column. Optionally, the media can be first concentrated and then loaded onto a Protein A Sepharose column. Non-specific bindings were removed by extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (50 mM Citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on anion exchanger resin such as Q Sepharose resin. The 120 PCT/US2008/074097 WO 2009/026558 specific IEX conditions for the 16F12 proteins are Q Sepharose HP at pH 7.8-8.0. Antibody was eluted with a NaCl gradient of 10 mM-500 mM in 25 column volumes. EXAMPLE 8
Production of Human 16F12 IgG2 Antibodies From Transfected Cells
[0433] The present example outlines how 16F12 IgG2 antibodies were produced from transfected cells. Cells (293 cells for transient expression and CHO cells for stable expression) were transfected with plasmids that encode 16F12 heavy and light chains. Conditioned media from hybridoma cells were recovered by removing cells and cell debris. Clarified conditioned media were loaded onto a Protein A-Sepharose. Optionally, the media can be first concentrated and then loaded onto a Protein A Sepharose column. Non-specific bindings were removed by extensive PBS wash. Bound antibody proteins on the Protein A column were recovered by standard acidic antibody elution from Protein A columns (50 mM Citrate, pH 3.0). Aggregated antibody proteins in the Protein A Sepharose pool were removed by size exclusion chromatography or binding ion exchange chromatography on cation exchanger resin such as SP Sepharose resin. The specific IEX conditions for the 16F12 proteins are SP Sepharose HP at pH 5.2. Antibody is eluted with 25 column volumes of buffer that contains a NaCl gradient of 10 mM-500 mM in 20 mM sodium acetate buffer. EXAMPLE 9
Sequence Analysis of Antibody Heavy and Light Chains [0434] The nucleic acid and amino acid sequences for the light and heavy chains of the above antibodies were then deteremined by Sanger (dideoxy) nucleotide sequencing. Amino acid sequences were then deduced for the nucleic acid sequences. The nucleic acid sequences for the variable domains are depicted in FIG.s 3E-3JJ.
[0435] The cDNA sequences for the lambda light chain variable regions of 31H4, 2IB 12, and 16F12 were determined and are disclosed as SEQ ID NOs: 153, 95, and 105 respectively.
[0436] The cDNA sequences for the heavy chain variable regions of 31H4, 2IB 12, and 16F12 were determined and are disclosed as SEQ ID NOs: 152, 94, and 104 respectively. 121 PCT/U S2008/074097 WO 2009/026558 [0437] The lambda light chain constant region (SEQ ID NO: 156), and the IgG2 and IgG4 heavy chain constant regions (SEQ ID NOs: 154 and 155) are shown in FIG. 3KK.
[0438) The polypeptide sequences predicted from each of those cDNA sequences were determined. The predicted polypeptide sequences for the lambda light chain variable regions of 31H4, 21B12, and 16F12 were predicted and are disclosed as SEQ ID NOs: 12, 23, and 35 respectively, the lambda light chain constant region (SEQ ID NO: 156), the heavy chain variable regions of 31H4, 21B12, and 16F12 were predicted and are disclosed as (SEQ. ID NOs. 67, 49, and 79 respectively. The IgG2 and IgG4 heavy chain constant regions (SEQ ID NOs: 154 and 155).
[0439J The FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 divisions are shown in FIG 2A-3D.
[0440] Based on the sequence data, the germline genes from which each heavy chain or light chain variable region was derived was determined. The identity of the germline genes are indicated next to the corresponding hybridoma line in FIGs. 2A-3D and each is represented by a unique SEQ ID NO. FIGs. 2A-3D also depict the determined amino acid sequences for additional antibodies that were characterized. EXAMPLE 8
Determination of Isoelectric Points of Three Antibodies [0441] The theoretical pis of the antibodies based on amino acid sequence were determined to be 7.36 for 16F12; 8.47 for 21B12; and 6.84 for 31H4. EXAMPLE 9
Characterization of Binding of Antibodies to PCSK9 [0442] Having identified a number of antibodies that bind to PCSK9, several approaches were employed to quantify and further characterize the nature of the binding. In one aspect of the study, a Biacore affinity analysis was performed. In another aspect of the study a KinExA® affinity analysis was performed. The samples and buffers employed in these studies are presented in Table 6 below. 122 PCT/US2008/074097 TABLE 6 sample [sample] mg/ml Buffer [sample] uM hPCSK9 1.26 PBS 16.6 mPCSK9-8xHIS 1.44 PBS 18.9 cPCSK9-V5-6xHIS 0.22 PBS 2.9 16F12, anti-PCSK9 huIgG4 4.6 20m M NaOAC, pH 5.2, 50mM NaCl 31.9 21B12, anti-PCSK9 huIgG4 3.84 10mM NAOAC, pH 5.2, 9% Sucrose 27.0 31H4, anti-PCSK9 hu!gG4 3.3 10mM NAOAC, pH 5.2, 9% Sucrose 22.9 WO 2009/026558 BIAcore® Affinity Measurements [0443] A BIAcore® (surface plasmon resonance device, Biacore, Inc., Piscataway, NJ) affinity analysis of the 21B12 antibodies to PCSK9 described in this Example was performed according to the manufacturer’s instructions.
[0444] Briefly, the surface plasmon resonance experiments were performed using Biacore 2000 optical biosensors (Biacore, GE Healthcare, Piscataway, NJ). Each individual anti-PCSK9 antibody was immobilized to a research-grade CM5 biosensor chip by amine-coupling at levels that gave a maximum analyte binding response (Rmax) of no more than 200 resonance units (RU). The concentration of PCSK9 protein was varied at 2 fold intervals (the analyte) and was injected over the immobilized antibody surface (at a flow rate of 100 μΐ/min for 1.5 minutes). Fresh HBS-P buffer (pH 7.4, 0.01 M Hepes, 0.15 M NaCl, 0.005% surfactant P-20, Biacore) supplemented with 0.01% BSA was used as binding buffer. Binding affinities of each anti-PCSK9 antibody were measured in separate experiments against each of the human, mouse, and cynomolgus monkey PCSK9 proteins at pH 7.4 (the concentrations used were 100, 50, 25, 12.5, 6.25, 3.125, and OnM).
[0445] In addition, the binding affinities of antibody to human PCSK9 were also measured at pH 6.0 with the pH 6.0 HBS-P buffer (pH 6.0, 0.01 M Hepes, 0.15 M NaCl, 0.005% surfactant P-20, Biacore) supplemented with 0.01% BSA. The binding signal obtained was 123 PCT/US2008/074097 WO 2009/026558 proportional to the free PCSK9 in solution. The dissociation equilibrium constant (Kd) was obtained from nonlinear regression analysis of the competition curves using a dual-curve one-site homogeneous binding model (KinExA® software, Sapidyne Instruments Inc., Boise, ID) (n=l for the 6.0 pH runs). Interestingly, the antibodies appeared to display a tighter binding affinity at the lower pH (where the Kd was 12.5, 7.3, and 29 pM for 31H4, 21B12, and 16F12 respectively).
[0446] Antibody binding kinetic parameters including ka (association rate constant), kd (dissociation rate constant), and Kp (dissociation equilibrium constant) were determined using the BIA evaluation 3.1 computer program (BIAcore, Inc. Piscataway, NJ). Lower dissociation equilibrium constants indicate greater affinity of the antibody for PCSK9. The Kp values determined by the BIAcore® affinity analysis are presented in Table 7.1, shown below. TABLE 7.1
Antibody hPCSK9 CynoPCSK9 mPCSK9 31H4 210 pM 190 pM 6nM 21B12 190 pM 360 pM 460 nM 16F12 470 pM 870 pM 6.4 nM
Table 7.2 depicts the kon and kofl- rates. TABLE 7.2
- K™ (M-l s-n K,ff fs-1) Κρ 31H4.1, pH 7.4 2.45 e+5 5.348 e-5 210 pM 31H4.1, pH 6 5.536 e+6 6.936 e-5 12.5 pM 21B12.1, pH 7.4 3.4918 e+4 6.634 e-6 190 pM 21B12.1, pH 6 2.291 e+6 1.676 e-5 7.3 pM 16F12.1, pH 7.4 1.064 of 5 4.983 e-5 470 pM 16F12.1, pH 6 2.392 e+6 7.007 e-5 29 pM 124 PCT/US2008/074097 WO 2009/026558
KinExA® Affinity Measurements [0447] A KinExA® (Sapidyne Instruments, Inc., Boise, ID) affinity analysis of 16F12 and 31H4 was performed according to the manufacturer’s instructions. Briefly, Reacti-Gel™ (6x) (Pierce) was pre-coated with one of human, V5-tagged cyno or His-tagged mouse PCSK9 proteins and blocked with BSA. 10 or 100 pM of either antibody 16F12 or antibody 31H4 and one of the PCSK9 proteins was then incubated with various concentrations (0.1 pM — 25 nM) of PCSK9 proteins at room temperature for 8 hours before being passed through the PCSK9-coated beads. The amount of the bead-bound 16F12 or 31H4 was quantified by fluorescently (Cy5) labeled goat anti-human IgG (H+L) antibody (Jackson Immuno Research). The binding signal is proportional to the concentration of free 16F12 or 31H4 at binding equilibrium. Equilibrium dissociation constant (KD) were obtained from nonlinear regression of the two sets of competition curves using a one-site homogeneous binding model. The KinExA® Pro software was employed in the analysis. Binding curves generated in this analysis are presented as FIGs. 4A-4F.
[0448] Both the 16F12 and 31H4 antibodies showed similar affinity to human and cyno PCSK9, but approximately 10-250 fold lower affinity to mouse PCSK9. Of the two antibodies tested using the KinExA® system, antibody 31H4 showed higher affinity to both human and cyno PCSK9 with 3 and 2 pM KDj respectively. 16F12 showed slightly weaker affinity at 15pM Kd to human PCSK9 and 16 pM Kd to cyno PCSK9.
[0449] The results of the KinExA® affinity analysis are summarized in Table 8.1, shown below. TABLE 8.1 hPCSK9 cPCSK mPCSK Sample Ko(pM) 95% Cl Kd (pM) 95% Cl Kd (pM) 95% Cl 16F12 15 11 ~22 16 14-19 223 106-410 31H4.1 3 1~5 2 1-3 500 400-620 [0450] In addition, a SDS PAGE was run to check the quality and quantity of the samples and is shown in FIG. 5A. cPCSK9 showed around 50% less on the gel and also from the active binding concentration calculated from KinExA® assay. Therefore, the KD of the mAbs to cPCSK9 was adjusted as 50% of the active cPCSK9 in the present. 125 PCT/US2008/074097 WO 2009/026558 [0451] A BIAcore solution equilibrium binding assay was used to measure the Kd values for ABP 2IB 12. 2IB 12.1 showed little signal using KinExA assay, therefore, biacore solution equilibrium assay was applied. Since no significant binding was observed on binding of antibodies to immobilized PCSK9 surface, 2IB 12 antibody was immobilized on the flow cell 4 of a CM5 chip using amine coupling with density around 7000 RU. Flow cell 3 was used as a background control. 0.3, 1, and 3 nM of human PCSK9 or cyno PCSK9 were mixed with a serial dilutions of 2IB 12.1 antibody samples (ranged from 0.001 ~ 25 nM) in PBS plus O.lmg/ml BSA, 0.005% P20. Binding of the free PCSK9 in the mixed solutions were measured by injecting over the 21B12.1 antibody surface. 100% PCSK9 binding signal on 21B12.1 surface was determined in the absence of mAb in the solution. A decreased PCSK9 binding response with increasing concentrations of mAb indicated that PCSK9 binding to mAb in solution, which blocked PCSK9 from binding to the immobilized peptibody surface. Plotting the PCSK9 binding signal versus mAb concentrations, KD was calculated from three sets of curves (0.3, 1 and 3nM fixed PCSK9 concentration) using a one-site homogeneous binding model in KinExA Pro™ software. Although cPCSK9 has lower protein concentration observed from KinExA assay and SDS-gel, its concentration was not adjusted here since the concentration of cPCSK9 was not used for calculation of KD. The results are displayed in Table 8.2 below and in FIGs. 5B-5D. FIG. 5B depicts the results from the solution equilibrium assay at three different hPCSK9 concentrations for hPCSK9. FIG. 5C depicts a similar set of results for mPCSK9. FIG. 5D depicts the results from the above biacore capture assay. TABLE 8.2 HPCSK9 cPCSK mPCSK Sample Kd (pM) 95% Cl Kd (pM) 95% Cl Kd (pM) 95% Cl 21B12.1 15 9~23 11 7-16 17000 - EXAMPLE 10 Epitope Binning [0452] Competition ELISA was used for anti-PCSK9 antibody binning. Briefly, to determine if two antibodies belong to the same epitope bin, one of the antibodies (mAbl) was first coated onto an ELISA plate (NUNC) at 2 pg/ml by overnight incubation. The plate was 126 PCT/US2008/074097 WO 2009/026558 then washed and blocked with 3% BSA. Meanwhile, 30 ng/ml of biotinylated hPCSK9 was incubated with the second antibody (mAb2) for 2 hours at room temperature. The mixture was applied to coated mAbl and incubated for 1 hour at room temperature. The ELISA plate was then washed and incubated with Neutravidin-HRP (Pierce) at 1:5000 dilutions for 1 hour. After another wash, the plate was incubated with TMB substrate and signal was detected at 650 nm using a Titertek plate reader. Antibodies with the same binding profiles were grouped together into the same epitope bin. The results of the antibody binning studies are presented in Table 8.3. TABLE 8.3
Clone Bin 21B12.2 1 31H4 3 20D10 1 25A7.1 2 25A7.3 1 23G1 1 26H5 1 31D1 1 16F12 3 28D6 3 27A6 3 31G11 3 27B2 ND 28B12 3 22E2 3 1A12.2 1 3B6 1 3C4 4 9C9 1 9H6 1 13B5 6 13H1 7 17C2 1 19H9.2 1 23B5 1 25G4 1 26E10 1 27E7 1 27H5 1 30A4 1 30B9 1 127
Clone Bin 31A4 5 31B12 5 WO 2009/026558 PCT/US2008/074097 [0453] Additional examination of the epitope binning was performed using BIAcore. Three mAbs, 16F12, 21B12 and 31H4, were immobilized on flow cells 2, 3 and 4 with density around 8000 RU. 5 nM PCSK9 from human, mouse and cyno were injected over the mAb surfaces to reach around 100 to 500 RU. lOnM mAbs were then injected over the PCSK9 surface. Binding of three mAbs to three different PCSK9 proteins over the three mAbs were then recorded.
[0454] If the two mAbs had a similar epitope on the antigen, mAb 1 will not show the binding to the antigen already bound to the mAb 2. If the two mAbs have the different epitope on the antigen, mAbl will show the binding to the antigen bound to the mAb2. FIG. 5E depicts these epitope binning results in graph form for three mAbs on human PCSk9. A similar pattern was observed for mPCSK9 and cPCSK9. As shown in the graph, 16F12 and 31H4 appear to share a similar epitope, while 2 IB 12 appears to have a different epitope. EXAMPLE 11
Efficacy of 31H4 and 2 IB 12 for Blocking D374Y PCSK9/LDLR Binding [0455] This example provides the IC50 values for two of the antibodies in blocking PCSK9 D374Y’s ability to bind to LDLR. Clear 384 well plates (Costar) were coated with 2 micrograms/ml of goat anti-LDL receptor antibody (R&amp;D Systems) diluted in buffer A (100 mM sodium cacodylate, pH 7.4). Plates were washed thoroughly with buffer A and then blocked for 2 hours with buffer B (1% milk in buffer A). After washing, plates were incubated for 1.5 hours with 0.4 micrograms/ml of LDL receptor (R&amp;D Systems) diluted in buffer C (buffer B supplemented with 10 mM CaC12). Concurrent with this incubation, 20 ng/ml of biotinylated D374Y PCSK9 was incubated with various concentrations of the 31H4 IgG2, 31H4 IgG4, 21B12 IgG2 or 21B12 IgG4 antibody, which was diluted in buffer A, or buffer A alone (control). The LDL receptor containing plates were washed and the biotinylated D374Y PCSK9/antibody mixture was transferred to them and incubated for 1 hour at room temperature. Binding of the biotinylated D374Y to the LDL receptor was detected by incubation with streptavidin-HRP (Biosource) at 500 ng/ml in buffer C followed by TMB substrate (KJPL). The signal was quenched with IN HC1 and the absorbance read at 450 nm. 128 PCT/US2008/074097 WO 2009/026558 [0456] The results of this binding study are shown in FIGs. 6A-6D. Summarily, IC5o values were determined for each antibody and found to be 199 pM for 31H4 IgG2 (FIG. 6A), 156 pM for 31H4 IgG4 (FIG. 6B), 170 pM for 2IB 12 IgG2 (FIG. 6C), and 169 pM for 21B12 IgG4 (FIG. 6D).
[0457] The antibodies also blocked the binding of wild-type PCSK9 to the LDLR in this assay. EXAMPLE 12 Cell LDL Uptake Assay [0458] This example demonstrates the ability of various antigen binding proteins to reduce LDL uptake by cells. Human HepG2 cells were seeded in black, clear bottom 96-well plates (Costar) at a concentration of 5x10s cells per well in DMEM medium (Mediatech, Inc) supplemented with 10% FBS and incubated at 37°C (5% C02) overnight. To form the PCSK9 and antibody complex, 2 pg/ml of D374Y human PCSK9 was incubated with various concentrations of antibody diluted in uptake buffer (DMEM with 1% FBS) or uptake buffer alone (control) for 1 hour at room temperature. After washing the cells with PBS, the D374Y PCSK9/antibody mixture was transferred to the cells, followed by LDL-BODIPY (Invitrogen) diluted in uptake buffer at a final concentration of 6 pg/ml. After incubation for 3 hours at 37°C (5% C02), cells were washed thoroughly with PBS and the cell fluorescence signal was detected by Satire™ (TECAN) at 480-520nm (excitation) and 520-600nm (emission).
[0459] The results of the cellular uptake assay are shown in FIGs. 7A-7D. Summarily, IC50 values were determined for each antibody and found to be 16.7 nM for 31H4 IgG2 (FIG. 7A), 13.3 nM for 31H4 IgG4 (FIG. 7B), 13.3 nM for 2IB 12 IgG2 (FIG. 7C), and 18 nM for 21B12 IgG4 (FIG. 7D). These results demonstrate that the applied antigen binding proteins can reduce the effect of PCSK9 (D374Y) to block LDL updtake by cells The antibodies also blocked the effect of wild-type PCSK9 in this assay. EXAMPLE 13
Serum cholesterol Lowering Effect of the 31H4 Antibody in 6 Day Study [0460] In order to assess total serum cholesterol (TC) lowering in wild type (WT) mice via antibody therapy against PCSK9 protein, the following procedure was performed. 129 PCT/U S2008/074097 WO 2009/026558 [0461] Male WT mice (C57BL/6 strain, aged 9-10 weeks, 17-27 g) obtained from Jackson Laboratory (Bar Harbor, ME) were fed a normal chow (Harland-Teklad, Diet 2918) through out the duration of the experiment. Mice were administered either anti-PCSK9 antibody 31H4 (2 mg/ml in PBS) or control IgG (2 mg/ml in PBS) at a level of lOmg/kg through the mouse’s tail vein at T=0. Naive mice were also set aside as a naive control group. Dosing groups and time of sacrifice are shown in Table 9. TABLE 9
Group Treatment Time point after dosing Number 1 IgG 8 hr 7 2 31H4 8 hr 7 3 IgG 24 hr 7 4 31H4 24 hr 7 5 IgG 72 hr 7 6 31H4 72 hr 7 7 IgG 144 hr 7 8 31H4 144 hr 7 9 Naive n/a 7 [0462] Mice were sacrificed with C02 asphyxiation at the pre-determined time points shown in Table 9. Blood was collected via vena cava into eppendorf tubes and was allowed to clot at room temperature for 30 minutes. The samples were then spun down in a table top centrifuge at 12,000xg for 10 minutes to separate the serum. Serum total cholesterol and HDL-C were measured using Hitachi 912 clinical analyzer and Roche/Hitachi TC and HDL-C kits.
[0463] The results of the experiment are shown in FIGs. 8A-8D. Summarily, mice to which antibody 31H4 was administered showed decreased serum cholesterol levels over the course of the experiment (FIG. 8A and FIG. 8B). In addition, it is noted that the mice also showed decreased HDL levels (FIG. 8C and FIG. 8D). For FIG. 8A and FIG. 8C, the percentage change is in relation to the control IgG at the same time point (*P<0.01, # P<0.05). For FIG. 8B and FIG 8D, the percentage change is in relation to total serum cholesterol and HDL levels measured in naive animals at t=0 hrs (*P<0.01, # P<0.05). 130 PCT/U S2008/074097 WO 2009/026558 [0464] In respect to the lowered HDL levels, it is noted that one of skill in the art will appreciate that the decrease in HDL in mice is not indicative that an HDL decrease will occur in humans and merely further reflects that the serum cholesterol level in the organism has decreased. It is noted that mice transport the majority of serum cholesterol in high density lipoprotein (HDL) particles which is different to humans who carry most serum cholesterol on LDL particles. In mice the measurement of total serum cholesterol most closely resembles the level of serum HDL-C. Mouse HDL contains apolipoprotein E (apoE) which is a ligand for the LDL receptor (LDLR) and allows it to be cleared by the LDLR. Thus, examining HDL is an appropriate indicator for the present example, in mice (with the understanding that a decrease in HDL is not expected for humans). For example, human HDL, in contrast, does not contain apoE and is not a ligand for the LDLR. As PCSK9 antibodies increase LDLR expression in mouse, the liver can clear more HDL and therefore lowers serum HDL-C levels. EXAMPLE 14
Effect of Antibody 31H4 on LDLR Levels in a 6 Day Study [0465] The present example demonstrates that an antigen binding protein alters the level of LDLR in a subject, as predicted, over time. A Western blot analysis was performed in order to ascertain the effect of antibody 31H4 on LDLR levels. 50-100 mg of liver tissue obtained from the sacrified mice described in Example 13 was homogenized in 0.3 ml of RIPA buffer (Santa Cruz Biotechnology Inc.) containing complete protease inhibitor (Roche). The homogenate was incubated on ice for 30 minutes and centrifuged to pellet cellular debris. Protein concentration in the supernatant was measured using BioRad protein assay reagents (BioRad laboratories). 100pg of protein was denatured at 70°C for 10 minutes and separated on 4-12% Bis-Tris SDS gradient gel (Invitrogen). Proteins were transferred to a 0.45 pm PVDF membrane (Invitrogen) and blocked in washing buffer (50mM Tris PH7.5, 150mM NaCL, 2mM CaCl2 and 0.05% Tween 20) containing 5% non-fat milk for 1 hour at room temperature. The blot was then probed with goat anti-mouse LDLR antibody (R&amp;D system) 1:2000 or anti-B actin (sigma) 1:2000 for 1 hour at room temperature. The blot was washed briefly and incubated with bovine anti-goat IgG-HRP (Santa Cruz Biotechnology Inc.) 1:2000 or goat anti-mouse IgG-HRP (Upstate) 1:2000. After a 1 hour incubation at room temperature, the blot was washed thoroughly and immunoreactive bands were detected using ECL plus kit (Amersham 131 PCT/US2008/074097 WO 2009/026558 biosciences). The Western blot showed an increase in LDLR protein levels in the presence of antibody 31H4, as depicted in FIG. 9. EXAMPLE 15
Serum cholesterol Lowering Effect of Antibody 31H4 in a 13 Day Study [0466] In order to assess total serum cholesterol (TC) lowering in wild type (WT) mice via antibody therapy against PCSK9 protein in a 13 day study, the following procedure was performed.
[0467] Male WT mice (C57BL/6 strain, aged 9-10 weeks, 17-27 g) obtained from Jackson Laboratory (Bar Harbor, ME) were fed a normal chow (Harland-Teklad, Diet 2918) through out the duration of the experiment. Mice were administered either anti-PCSK9 antibody 31H4 (2 mg/ml in PBS) or control IgG (2 mg/ml in PBS) at a level of 10 mg/kg through the mouse’s tail vein at T=0. Naive mice were also set aside as naive control group.
[0468] Dosing groups and time of sacrifice are shown in Table 10. Animals were sacrificed and livers were extracted and prepared as in Example 13. TABLE 10
Group Treatment Time point after dosing Number Dose 1 IgG 72 hr 6 lOmg/kg 2 31H4 72 hr 6 lOmg/kg 3 31H4 72 hr 6 1 mg/kg 4 IgG 144 hr 6 lOmg/kg 5 31H4 144 hr 6 lOmg/kg 6 31H4 144 hr 6 1 mg/kg 7 IgG 192 hr 6 lOmg/kg 8 31H4 192 hr 6 lOmg/kg 9 31H4 192 hr 6 1 mg/kg 10 IgG 240 hr 6 lOmg/kg 11 31H4 240hr 6 lOmg/kg 12 31H4 240hr 6 1 mg/kg 13 IgG 312 hr 6 lOmg/kg 132 PCT/US2008/074097
Group Treatment Time point after dosing Number Dose 14 31H4 312 hr 6 lOmg/kg 15 31H4 312 hr 6 1 mg/kg 16 Naive n/a 6 n/a WO 2009/026558 [0469] When the 6 day experiment was extended to a 13 day study, the same serum cholesterol lowering effect observed in the 6 day study was also observed in the 13 day study. More specifically, animals dosed at 10 mg/kg demonstrated a 31% decrease in serum cholesterol on day 3, which gradually returned to pre-dosing levels by day 13. FIG. 10A depicts the results of this experiment. FIG. 10C depicts the results of repeating the above procedure with the lOmg/kg dose of 31H4, and with another antibody, 16F12, also at lOmg/kg. Dosing groups and time of sacrifice are shown in Table 11. TABLE 11
Group Treatment Time point after dosing Number Dose 1 IgG 24 hr 6 lOmg/kg 2 16F12 24 hr 6 lOmg/kg 3 31H4 24 hr 6 lOmg/kg 4 IgG 72 hr 6 lOmg/kg 5 16F12 72 hr 6 lOmg/kg 6 31H4 72 hr 6 lOmg/kg 7 IgG 144 hr 6 lOmg/kg 8 16F12 144 hr 6 lOmg/kg 9 31H4 144 hr 6 lOmg/kg 10 IgG 192 hr 6 lOmg/kg 11 16F12 192 hr 6 lOmg/kg 12 31H4 192 hr 6 lOmg/kg 13 IgG2 240 hr 6 lOmg/kg 14 16F12 240hr 6 lOmg/kg 133 PCT/US2008/074097
Group Treatment Time point after dosing Number Dose 15 31H4 240hr 6 lOmg/kg 16 IgG2 312 hr 6 lOmg/kg 17 16F12 312 hr 6 lOmg/kg 18 31H4 312 hr 6 lOmg/kg 19 Naive n/a 6 lOmg/kg WO 2009/026558 [0470] As shown in FIG. 10C both 16F12 and 31H4 resulted in significant and substantial decreases in total serum cholesterol after just a single dose and provided benefits for over a week (10 days or more). The results of the repeated 13 day study were consistent with the results of the first 13 day study, with a decrease in serum cholesterol levels of 26% on day 3 being observed. For FIG. 10A and FIG. 10B, the percentage change is in relation to the control IgG at the same time point (*P<0.01). For FIG. 10C, the percentage change is in relation to the control IgG at the same time point (*P<0.05). EXAMPLE 16
Effect of Antibody 31H4 on HDL Levels in a 13 Day Study [0471] The HDL levels for the animals in Example 15 were also examined. HDL levels decreased in the mice. More specifically, animals dosed at 10 mg/kg demonstrated a 33% decrease in HDL levels on day 3, which gradually returned to pre-dosing levels by day 13. FIG. 10B depicts the results of the experiment. There was a decrease in HDL levels of 34% on day 3. FIG. 10B depicts the results of the repeated 13 day experiment.
[0472] As will be appreciated by one of skill in the art, while the antibodies will lower mouse HDL, this is not expected to occur in humans because of the differences in HDL in humans and other organisms (such as mice). Thus, the decrease in mouse HDL is not indicative of a decrease in human HDL. EXAMPLE 17
Repeated Administration of Antibodies Produce Continued Benefits of Antigen Binding Peptides 134 PCT/US2008/074097 WO 2009/026558 (0473] In order to verify that the results obtained in the Examples above can be prolonged for further benefits with additional doses, the Experiments in Examples 15 and 16 were repeated with the dosing schedule depicted in FIG. 11A. The results are displayed in FIG. 1 IB. As can be seen in the graph in FIG. 1 IB, while both sets of mice displayed a significant decrease in total serum cholesterol because all of the mice received an initial injection of the 31H4 antigen binding protein, the mice that received additional injections of the 31H4 ABP displayed a continued reduction in total serum cholesterol, while those mice that only received the control injection eventually displayed an increase in their total serum cholesterol. For FIG. 11, the percentage change is in relation to the naive animals at t=0 hours (*P<0.01, **P<0.001).
[0474] The results from this example demonstrate that, unlike other cholesterol treatment methods, in which repeated applications lead to a reduction in efficacy because of biological adjustments in the subject, the present approach does not seem to suffer from this issue over the time period examined. Moreover, this suggests that the return of total serum cholesterol or HDL cholesterol levels to baseline, observed in the previous exampless is not due to some resistance to the treatment being developed by the subject, but rather the depletion of the antibody availability in the subject. EXAMPLE 18
Epitope Mapping of Human Anti PCSK9 Antibodies [0475] This example outlines methods for determining which residues in PCSK9 are involved in forming or part of the epitope for the antigen binding proteins disclosed herein to PCSK9.
[0476] In order to determine the epitopes to which certain of the ABPs of the present invention bind, the epitopes of the ABPs can be mapped using synthetic peptides derived from the specific PCSK9 peptide sequence.
[0477] A SPOTs peptide array (Sigma Genosys) can be used to study the molecular interaction of the human anti-PCSK9 antibodies with their peptide epitope. SPOTs technology is based on the solid-phase synthesis of peptides in a format suitable for the systematic analysis of antibody epitopes. Synthesis of custom arrayed oligopeptides is commerically available from Sigma-Genosys. A peptide array of overlapping oligopeptides derived from the amino-acid sequence of the PCSK9 peptide can be obtained. The array can comprise a series of 12-mer 135 PCT/US2008/074097 WO 2009/026558 peptides as spots on a polypropylene membrane sheets. The peptide array can span the entire length of the PCSK9 mature sequence. Each consecutive peptide can be offset by 1 residue from the previous one, yielding a nested, overlapping library of arrayed oligopeptides. The membrane carrying the peptides can be reacted with different anti-PCSK9 antibodies (1 micrograms/ml). The binding of the mAbs to the membrane-bound peptides can be assessed by an enzyme-linked immunosorbent assay using HRP-conjugated secondary antibody followed by enhanced chemiluminescence (ECL).
[0478] In addition, functional epitopes can be mapped by combinatorial alanine scanning. In this process, a combinatorial alanine-scanning strategy can be used to identify amino acids in the PCSK9 protein that are necessary for interaction with anti-PCSK9 ABPs. To accomplish this, a second set of SPOTs arrays can be used for alanine scanning. A panel of variant peptides with alanine substitutions in each of the 12 residues can be scanned as above. This will allow for the epitopes for the ABPs to the human PCSK9 to be mapped and identified.
[0479] In the alternative, given that it is possible that the epitope is conformational, a combination of alanine scanning and/or arginine scanning, antibody FAB/PCSK9 co-crystalization, and limited proteolysis/LC-MS (liquid chromatography mass spec.) can be employed to indentify the epitopes.
Example 19
Uses of PCSK9 Antibodies for the Treatment of Cholesterol Related Disorders [0480] A human patient exhibiting a Cholesterol Related Disorder (in which a reduction in cholesterol (such as serum cholesterol) can be beneficial) is administered a therapeutically effective amount of PCSK9 antibody, 31H4 (or, for example, 2IB 12 or 16F12). At periodic times during the treatment, the patient is monitored to determine whether the symptoms of the disorder has subsided. Following treatment, it is found that patients undergoing treatment with the PCSK9 antibody have reduced serum cholesterol levels, in comparison to patients that are not treated. EXAMPLE 20
Uses of PCSK9 Antibodies for the Treatment of Hypercholesterolemia 136 PCT/US2008/074097 WO 2009/026558 [0481] A human patient exhibiting symptoms of hypercholesterolemia is administered a therapeutcially effective amount of PCSK9 antibody, such as 31H4 (or, for example, 21B12 or 16F12). At periodic times during the treatment, the human patient is monitored to determine whether the serum cholesterol level has declined. Following treatment, it is found that the patient receiving the treatment with the PCSK9 antibodies has reduced serum cholesterol levels in comparison to arthritis patients not receiving the treatment. EXAMPLE 21
Uses of PCSK9 Antibodies for the Prevention of Coronary Heart Disease and/or Recurrent Cardiovascular Events [0482] A human patient at risk of developing coronary haeart disease is identified. The patient is administered a therapeutically effective amount of PCSK9 antibody, such as 31H4 (or, for example, 2IB 12 or 16F12), either alone, concurrently or sequentially with a statin, e.g., simvastatin. At periodic times during the treatment, the human patient is monitored to determine whether the patient’s total serum cholesterol level changes. Throughout the preventative treatment, it is found that the patient receiving the treatment with the PCSK9 antibodies has reduced serum cholesterol thereby reducing their risk to coronary heart disases or recurrent cardiovascular events in comparison to patients not receiving the treatment. EXAMPLE 22
Use of PCSK9 Antibodies as a Diagnostic Agent [0483] An Enzyme-Linked Immunosorbent Assay (ELISA) for the detection of PCSK9 antigen in a sample can used to diagnose patients exhibiting high levels of PCSK9 production. In the assay, wells of a microtiter plate, such as a 96-well microtiter plate or a 384-well microtiter plate, are adsorbed for several hours with a first fully human monoclonal antibody directed against PCSK9. The immobilized antibody serves as a capture antibody for any of the PCSK9 that may be present in a test sample. The wells are rinsed and treated with a blocking agent such as milk protein or albumin to prevent nonspecific adsorption of the analyte.
[0484] Subsequently the wells are treated with a test sample suspected of containing the PCSK9, or with a solution containing a standard amount of the antigen. Such a sample may be, for example, a serum sample from a subject suspected of having levels of circulating antigen considered to be diagnostic of a pathology. 137 PCT/US2008/074097 WO 2009/026558 [0485] After rinsing away the test sample or standard, the wells are treated with a second fully human monoclonal PCSK9 antibody that is labeled by conjugation with biotin. A monoclonal or mouse or other species origin can also be used. The labeled PCSK9 antibody serves as a detecting antibody. After rinsing away excess second antibody, the wells are treated with avidin-conjugated horseradish peroxidase (HRP) and a suitable chromogenic substrate. The concentration of the antigen in the test samples is determined by comparison with a standard curve developed from the standard samples.
[0486] This ELISA assay provides a highly specific and very sensitive assay for the detection of the PCSK9 antigen in a test sample.
Determination of PCSK9 Protein Concentration in Subjects [0487] A sandwich ELISA can quantify PCSK9 levels in human serum. Two fully human monoclonal PCSK9 antibodies from the sandwich ELISA, recognize different epitopes on the PCSK9 molecule. Alternatively, monoclonal antibodies of mouse or other species origin may be used. The ELISA is performed as follows: 50 pL of capture PCSK9 antibody in coating buffer (0.1 M NaHCC>3, pH 9.6) at a concentration of 2 pg/mL is coated on ELISA plates (Fisher). After incubation at 4° C. overnight, the plates are treated with 200 pL of blocking buffer (0.5% BSA, 0.1% Tween 20, 0.01% Thimerosal in PBS) for 1 hour at 25° C. The plates are washed (3x) using 0.05% Tween 20 in PBS (washing buffer, WB). Normal or patient sera (Clinomics, Bioreclaimation) are diluted in blocking buffer containing 50% human serum. The plates are incubated with serum samples overnight at 4° C, washed with WB, and then incubated with 100 pL/well of biotinylated detection PCSK9 antibody for 1 hour at 25° C After washing, the plates are incubated with HRP-Streptavidin for 15 minutes, washed as before, and then treated with 100 pL/well of o-phenylenediamine in H2O2 (Sigma developing solution) for color generation. The reaction is stopped with 50 pL/well of H2SO4 (2M) and analyzed using an ELISA plate reader at 492 nm. Concentration of PCSK9 antigen in serum samples is calculated by comparison to dilutions of purified PCSK9 antigen using a four parameter curve fitting program.
Determination of PCSK9 Variant Protein Concentration in Subjects [0488] The steps outlined above can be performed using antibodies noted herein that bind to both the wild type PCSK9 and the variant PCSK9 (D374Y). Next, antibodies that bind to 138 PCT/US2008/074097 WO 2009/026558 the wild type but not the mutant can be used (again using a similar protocol as outlined above) to determine if the PCSK9 present in the subject is wild type or the D374Y variant. As will be appreciatedy by one of skill in the art, results that are positive for both rounds will be wild-type, while those that are positive for the first round, but not the second round of antibodies, will include the D374Y mutation. There are high frequency mutations in the population that are known and the could benefit particularly from an agent such as the ABPs disclosed herein. EXAMPLE 23
Use of PCSK9 Antigen Binding Protein for the Prevention of Hypercholesterolemia [0489] A human patient exhibiting a risk of developing hypercholesterolemia is identified via family history analysis and/or lifestyle, and/or current cholesterol levels. The subject is regularly administered (e.g., one time weekly) a therapeutically effective amount of PCSK9 antibody, 31H4 (or, for example, 21B12 or 16F12). At periodic times during the treatment, the patient is monitored to determine whether serum cholesterol levels have decreased. Following treatment, it is found that subjects undergoing preventative treatment with the PCSK9 antibody have lowered serum cholesterol levels, in comparison to subjects that are not treated. EXAMPLE 24 PCSK9 ABPs Further Upregulated LDLR in the Presence of Statins [0490] This example demonstrates that ABPs to PCSK9 produced further increases in LDLR availability when used in the presence of statins, demonstrating that further benefits can be achieved by the combined use of the two.
[0491] HepG2 cells were seeded in DMEM with 10% fetal bovine serum (FBS) and grown to -90% confluence. The cells were treated with indicated amounts of mevinolin (a statin, Sigma) and PCSK9 ABPs (FIGs. 12A-12C) in DMEM with 3% FBS for 48 hours. Total cell lysates were prepared. 50 mg of total proteins were separated by gel electrophoresis and transferred to PVDF membrane. Immunoblots were performed using rabbit anti-human LDL receptor antibody (Fitzgerald) or rabbit anti-human b-actin antibody. The enhanced chemiluminescent results are shown in the top panels of FIGs. 12A-12C. The intensity of the bands were quantified by ImageJ software and normalized by b-actin. The relative levels of 139 PCT/US2008/074097 WO 2009/026558 LDLR are shown in the lower panels of FIGs. 12A-12C. ABPs 2IB 12 and 31H4 are PCSK9 neutralizing antibodies, while 25A7.1 is a non-neutralizing antibody.
[0492] HepG2-PCSK9 cells were also created. These were stable HepG2 cell line transfected with human PCSK9. The cells were seeded in DMEM with 10% fetal bovine serum (FBS) and grew to ~90% confluence. The cells were treated with indicated amounts of mevinolin (Sigma) and PCSK9 ABPs (FIGs. 12D-12F) in DMEM with 3% FBS for 48 hours. Total cell lysates were prepared. 50 mg of total proteins were separated by gel electrophoresis and transferred to PVDF membrane. Immunoblots were performed using rabbit anti-human LDL receptor antibody (Fitzgerald) or rabbit anti-human b-actin antibody. The enhanced chemiluminescent results are shown in the top panels. The intensity of the bands were quantified by ImageJ software and normalized by b-actin.
[0493] As can be seen in the results depicted in FIGs. 12A-12F, increasing amounts of the neutralizing antibody and increasing amounts of the statin generally resulted in increases in the level of LDLR. This increase in effectiveness for increasing levels of the ABP is especially evident in FIGs. 12D-12F, in which the cells were also transfected with PCSK9, allowing the ABPs to demonstrate their effectiveness to a greater extent.
[0494] Interestingly, as demonstrated by the results in the comparison of FIGs. 12D-12F to 12A-12C, the influcence of the ABP concentrations on LDLR levels increased dramatically when PCSK9 was being produced by the cells. In addition, it is clear that the neutralizing ABPs (21B12 and 31H4) resulted in a greater increase in LDLR levels, even in the presence of statins, than the 25A7.1 ABP (a non-neutralizer), demonstrating that additional benefits can be achieved by the use of both statins and ABPs to PCSK9. EXAMPLE 25 Consensus Sequences [0495] Consensus sequences were determined using standard phylogenic analyses of the CDRs corresponding to the Vh and Vl of anti-PCSK9 ABPs. The consensus sequences were determined by keeping the CDRs contiguous within the same sequence corresponding to a Vh or VL. Briefly, amino acid sequences corresponding to the entire variable domains of either Vh or VL were converted to FASTA formatting for ease in processing comparative alignments and inferring phylogenies. Next, framework regions of these sequences were replaced with an 140 PCT/US2008/074097 WO 2009/026558 artificial linker sequence (“bbbbbbbbbb” placeholders, non-specific nucleic acid construct) so that examination of the CDRs alone could be performed without introducing any amino acid position weighting bias due to coincident events (e.g., such as unrelated antibodies that serendipitously share a common germline framework heritage) while still keeping CDRs contiguous within the same sequence corresponding to a Vh or Vl. Vh or Vl sequences of this format were then subjected to sequence similarity alignment interrogation using a program that employs a standard ClutalW-like algorithm (see, Thompson et al., 1994, Nucleic Acids Res. 22:4673-4680). A gap creation penalty of 8.0 was employed along with a gap extension penalty of 2.0. This program likewise generated phylograms (phylogenic tree illustrations) based on sequence similarity alignments using either UPGMA (unweighted pair group method using arithmetic averages) or Neighbor-Joining methods (see, Saitou and Nei, 1987, Molecular Biology and Evolution 4:406-425) to construct and illustrate similarity and distinction of sequence groups via branch length comparison and grouping. Both methods produced similar results but UPGMA-derived trees were ultimately used as the method employs a simpler and more conservative set of assumptions. UPGMA-derived trees were generated where similar groups of sequences were defined as having fewer than 15 substitutions per 100 residues (see, legend in tree illustrations for scale) amongst individual sequences within the group and were used to define consensus sequence collections. The results of the comparisons are depicted in FIGs. 13A-13J. In FIG. 13E, the groups were chosen so that sequences in the light chain that clade are also a clade in the heavy chain and have fewer than 15 substitutions. (0496) As will be appreciated by one of skill in the art, the results presented in FIGs. 13A-13J present a large amount of guidance as to the importance of particular amino acids (for example, those amino acids that are conserved) and which amino acid positions can likely be altered (for example, those positions that have different amino acids for different ABPs). EXAMPLE 26
Mouse Model for PCSK9 and ABP ability to lower LDL in vivo [0497] To generate mice which over-expressed human PCSK9, three week old WT C57B1/6 mice were injected via tail vein administration with various concentrations of adenoassociated virus (AAV), recombinantly modified to express human PCSK9, to determine the correct titer which would provide a measurable increase of LDL-cholesterol in the 141 PCT/US2008/074097 WO 2009/026558 mice. Using this particular virus that expressed human PCSK9, it was determined that 4.5 x 10E12 pfu of virus would result in an LDL-cholesterol level of approximately 40mg/dL in circulating blood (normal levels of LDL in a WT mice are approximately lOmg/dL). The human PCSK9 levels in these animals was found to be approximately 13ug/mL. A colony of mice were generated using this injection criteria.
[0498] One week after injection, mice were assessed for LDL-cholesterol levels, and randomized into different treatment groups. Animals were then administered, via tail vein injection, a single bolus injection of either lOmg/kg or 30mg/kg of 16F12, 21B12, or 31H4 antigen binding proteins. IgG2 ABP was administered in a separate group of animals as a dosing control. Subgroups of animals (n=6-7) were then euthanized at 24 and 48 hours after ABP administration. There were no effects on LDL-cholesterol levels following IgG2 administration at either dose. Both31H4 and 2IB 12 demonstrated significant LDL-cholesterol lowering up to and including 48 hours post-administration, as compared to IgG2 control (shown in FIG. 14A and 14B at two different doses). 16F12 shows an intermediary LDL-cholesterol lowering response, with levels returning to baseline of approximately 40mg/dL by the 48 hour time point. This data is consistent with in vitro binding data (Biacore and Kinexa), which shows near equivalent binding affinity between 31H4 and 21B12, and a lesser affinity of 16F12 to human PCSK9.
[0499] As can be seen in the results, total cholesterol and HDL-cholesterol were reduced by the PCSK9 ABPs in the model (both total and HDL-C are elevated above WT mice due to the overexpression of PCSK9). While cholesterol lowering in this model appears to occur over a relatively short period of time, this is believed to be due to the levels of human PCSK9 that are present, which are supraphysiologically high in this model. In addition, given that the expression is governed by AAV, there is no regulation of PCSK9 expression. In these figures, (*) denotes a P<0.05, and (**) denotes a P<0.005 as compared to LDL-cholesterol levels observed in IgG2 control injected animals at the same time point. The 13 microgram/ml level of serum human PCSK9 in the mice corresponds to an approximately 520-fold increase above the endogenous mouse PCSK9 levels (~ 25 ng/ml), and an approximately 75-fold increase above average human serum levels (~ 175 ng/ml). Thus, the antigen binding proteins should be even more effective in humans. 142 PCT/US2008/074097 WO 2009/026558 [0500] As will be appreciated by one of skill in the art, the above results demonstrate that appropriateness of the mouse model for testing the antigen binding protein’s ability to alter serum cholesterol in a subject. One of skill in the art will also recognize that the use of mouse HDL to monitor serum cholesterol levels in a mouse, while useful for monitoring mouse serum cholesterol levels, is not indicative of the ABPs impact on human HDL in humans. For example, Cohen et al. (“Sequence variations in PCSK9, low LDL, and protection against coronary heart disease”, N Engl J Med, 354:1264-1272, 2006) demonstrated the lack of any effect of the PCSK9 loss-of-function mutations on human HDL levels (the entirety of which is incorporated by reference). Thus, one of skill in the art will appreciate that the ability of the ABP to lower mouse HDL (which lack LDL) is not indicative of the ABP’s ability to lower human HDL. Indeed, as shown by Cohen, this is unlikely to occur for neutralizing antibodies in humans. EXAMPLE 27 31H4 and 2IB 12 bind to the ProCat region of PCSK9 [0501] The present example describes one method for determining where various antibodies bind to PCSK9.
[0502] The ProCat (31 -449 of SEQ ID NO: 3) or V domain (450-692 of SEQ ID NO: 3) of the PCSK9 protein was combined with either antibody 31H4 or 21B12. The samples were analyzed by Native PAGE for complex formation. As can be seen in FIG. 16A and FIG. 16B, gel shifts were present for the ProCat / 31H4 and ProCat / 21B12 samples, demonstrating that the antibodies bound to the ProCat domain. EXAMPLE 28
The LDLR EGFa domain binds to the catalytic domain of PCSK9 [0503] The present example presents the solved crystal structure of PCSK9 ProCat (31-454 of SEQ ID NO: 3) bound to the LDLR EGFa domain (293-334) at 2.9 A resolution (the conditions for which are described in the below Examples).
[0504] A representation of the structure of PCSK9 bound to EGFa is shown in FIG. 17. The crystal structure (and its depiction in FIG. 17) reveals that the EGFa domain of LDLR binds to the catalytic domain of PCSK9. In addition, the interaction of PCSK9 and EGFa 143 PCT/US2008/074097 WO 2009/026558 appears to occur across a surface of PCSK9 that is between residues D374 and SI53 in the structure depicted in FIG. 17.
[0505] Specific core PCSK9 amino acid residues of the interaction interface with the LDLR EGFa domain were defined as PCSK9 residues that are within 5 A of the EGFa domain. The core residues are as follows: S153,1154, P155, R194, D238, A239,1369, S372, D374, C375, T377, C378, F379, V380, and S381.
[0506] Boundary PCSK9 amino acid residues of the interaction interface with the LDLR EGFa domain were defined as PCSK9 residues that are 5-8 A from the EGFa domain. The boundary residues are as follows: W156, N157. L158, E159, H193, E195, H229. R237, G240, K243, D367,1368, G370. A371, S373, S376, and Q382. Residues that are underlined are nearly or completely buried within PCSK9.
[0507] As will be appreciated by one of skill in the art, the results from this example demonstrate where PCSK9 and EGFa interact. Thus, antibodies that interact with or block any of these residues can be useful as antibodies that inhibit the interaction between PCSK9 and the EGFa domain of LDLR (and/or LDLR generally). In some embodiments, antibodies that, when bound to PCSK9, interact with or block any of the above residues or are within 15-8, 8, 8-5, or 5 angstroms of the above residues are contemplated to provide useful inhibition of PCSK9 binding to LDLR. EXAMPLE 29 31H4 interacts with amino acid residues from both the pro- and catalytic domains of PCSK9 [0508] The present example presents the crystal structure of full length PCSK9 (N533A mutant of SEQ ID NO: 3) bound to the Fab fragment of 31H4, determined to 2.3 A resolution (the conditions for which are described in the below Examples). This structure, depicted in FIG. 18A and 18B, shows that 31H4 binds to PCSK9 in the region of the catalytic site and makes contacts with amino acid residues from both the prodomain and catalytic domain.
[0509] The depicted structure also allows one to identify specific core PCSK9 amino acid residues for the interaction interface of 31H4 with PCSK9. This was defined as residues that are within 5 A of the 31H4 protein. The core residues are as follows: W72, FI50, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, 144 PCT/US2008/074097 WO 2009/026558 N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, and G384.
[0510] The structures were also used to identify boundary PCSK9 amino acid residues for the interaction interface with 31H4. These residues were PCSK9 residues that were 5-8 A from the 31H4 protein. The boundary residues are as follows: K69, D70, P71, SI48, VI49. D186. T187, E211, D212, G213, R218, Q219, C223, D224, G227. H229. L253, N254, G259, P288. A290. G291. G316. R319, Y325, V346, G352. T353. G365. 1368, 1369, S372, S373, C378, F379, T385. S386. and Q387. Amino acid residues completely buried within the PCSK9 protein are underlined.
[0511] As will be appreciated by one of skill in the art, FIG. 18B depicts the interaction between the CDRs on the antigen binding protein and PCSK9. As such, the model allows one of skill in the art to identify the residues and/or CDRs that are especially important in the paratope, and which residues are less critical to the paratope. As can be seen in FIG. 18B, the heavy chain CDR1, CDR2, and CDR3 are most directly involved in the antigen binding protein’s binding to the epitope, with the CDRs from the light chain being relatively far away from the epitope. As such, it is probable that larger variations in the light chain CDRs are possible, without unduly interfering with the binding of the antigen binding protein to PCSK9. In some embodiments, residues in the structures that directly interact are conserved (or alternatively conservatively replaced) while residues that are not directly interacting with one another can be altered to a greater extent. As such, one of skill in the art, given the present teachings, can predict which residues and areas of the antigen binding proteins can be varied without unduly interfering with the antigen binding protein’s ability to bind to PCSK9. For example, those residues that are located closest to PCSK9 when the antigen binding protein is bound to PCSK9 are those that likely play a more important role in the binding of the antigen binding protein to PCSK9. As above, these residues can be divided into those that are within 5 angstroms of PCSK9 and those that are between 5 and 8 angstroms. Specific core 31H4 amino acid residues of the interaction interface with PCSK9 were defined as 31H4 residues that are within 5 A of the PCSK9 protein. For the heavy chain, the residues that are within 5 angstroms include the following: T28, S30, S31, Y32, S54, S55, S56, Y57,158, S59, Y60, N74, A75, R98, Y100, FI02, W103, S104, A105, Y106, Y107, D108, A109, and Dill. For the light chain, 145 PCT/US2008/074097 WO 2009/026558 those residues that are within 5 angstroms include the following: L48, S51, Y93, and S98. For the heavy chain, those residues that are 5-8 A from the PCSK9 protein include the following: G26, F27, F29, W47, S50, 151, S52, S53, K65, F68, T69, 170, S71, R72, D73, K76, N77, D99, D101, FI 10, and VI12. For the light chain, those residues that are within 5-8 angstroms of PCSK9 include A31, G32, Y33, D34, H36, Y38,150, G52, N55, R56, P57, S58, D94, S95, S96, L97, G99, and SI00.
[0512] As will be appreciated by one of skill in the art, the results from Example 29 demonstrate where antibodies to PCSK9 can interact on PCSK9 and still block PCSK9 from interacting with EGFa (and thus LDLR). Thus, antigen binding proteins that interact with any of these PCSK9 residues, or that block any of these residues (e.g., from other antigen binding proteins that bind to these residues), can be useful as antibodies that inhibit the interaction of PCSK9 and EGFa (and LDLR accordingly). Thus, in some embodiments, antigen binding proteins that interact with any of the above residues or interact with residues that are within 5 A of the above residues are contemplated to provide useful inhibition PCSK9 binding to LDLR. Similarly, antigen binding proteins that block any of the above residues (which can be determined, for example, via a competition assay) can also be useful for inhibition of the PCSK9/LDLR interaction. EXAMPLE 30 21B12 binds to the catalytic domain of PCSK9, has a distinct binding site from 31H4 and can bind to PCSK9 simultaneously with 31H4 [0513] The present example presents the crystal structure of PCSK9 ProCat (31-449 of SEQ ID NO: 3) bound to the Fab fragments of 31H4 and 21B12, determined at 2.8 A resolution (the conditions for which are described in the below Examples). This crystal structure, depicted in FIG. 19A and FIG. 19B, shows that 31H4 and 21B12 have distinct binding sites on PCSK9 and that both antigen binding proteins can bind to PCSK9 simultaneously. The structure shows that 2IB 12 interacts with amino acid residues from PCSK9’s catalytic domain. In this structure, the interaction between PCSK9 and 31H4 is similar to what was observed above.
[0514] Specific core PCSK9 amino acid residues of the interaction interface with 2 IB 12 were defined as PCSK9 residues that are within 5 A of the 2IB 12 protein. The core 146 PCT/US2008/074097 WO 2009/026558 residues are as follows: S153, S188, 1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, and F379.
[0515] Boundary PCSK9 amino acid residues of the interaction interface with 21B12 were defined as PCSK9 residues that were 5-8 A from the 21B12 protein. The boundary residues are as follows: 1154, T187, H193, E195,1196, M201, V202, C223, T228. S235. G236. A239, G244, M247, 1369, S372, C375, and C378. Amino acid residues nearly or completely buried within the PCSK9 protein are underlined.
[0516] As will be appreciated by one of skill in the art, FIG. 19B depicts the interaction between the CDRs on the antigen binding protein and PCSK9. As such, the model allows one of skill in the art to identify the residues and/or CDRs which are especially important for the paratope and which residues are less critical to the paratope. As can be seen in the structure, heavy chain CDR2 and light chain CDR1 appear to closely interact with the epitope. Next, heavy chain CDR1, heavy chain CDR3 and light chain CDR3, appear to be close to the epitope, but not as close as the first set of CDRs. Finally, light chain CDR2 appears to be some distance from the epitope. As such, it is probable that larger variations in the more distant CDRs are possible without unduly interfering with the binding of the antigen binding protein to PCSK9. In some embodiments, residues in the structures that directly interact are conserved (or alternatively conservatively replaced) while residues that are not directly interacting with one another can be altered to a greater extent. As such, one of skill in the art, given the present teachings, can predict which residues and areas of the antigen binding proteins can be varied without unduly interfering with the antigen binding protein’s ability to bind to PCSK9. For example, those residues that are located closest to PCSK9 when the antigen binding protein is bound to PCSK9 are those that likely play a more important role in the binding of the antigen binding protein to PCSK9. As above, these residues can be divided into those that are within 5 angstroms of PCSK9 and those that are between 5 and 8 angstroms. Specific core 21B12 amino acid residues of the interaction interface with PCSK9 were defined as 2IB 12 residues that are within 5 A of the PCSK9 protein. For the heavy chain, the residues that are within 5 angstroms include the following: T30, S31, Y32, G33, W50, S52, F53, Y54, N55, N57, N59, R98, G99, Y100, and G101. For the light chain, those residues that are within 5 angstroms include the following: G30, G31, Y32, N33, S34, E52, Y93, T94, S95, T96, and S97. For the heavy chain, 147 PCT/US2008/074097 WO 2009/026558 those residues that are 5-8 A from the PCSK9 protein include the following: T28, L29,134, S35, W47, V51, G56, T58, Y60, T72, M102, and D103. For the light chain, those residues that are within 5-8 angstroms of PCSK9 include the following: S26, V29, V35, Y51, N55, S92, M98, and V99.
[0517] As will be appreciated by one of skill in the art, the results from Example 30 demonstrate where antigen binding proteins to PCSK9 can interact on PCSK9 and still block PCSK9 from interacting with EGFa (and thus LDLR). Thus, antigen binding proteins that interact with any of these PCSK9 residues or that block any of these residues can be useful as antibodies that inhibit the interaction of PCSK9 and EGFa (and LDLR accordingly). Thus, in some embodiments, antibodies that interact with any of the above residues or interact with residues that are within 5 A of the above residues are contemplated to provide useful inhibition PCSK9 binding to LDLR. Similarly, antigen binding proteins that block any of the above residues (which can be determined, for example, via a competition assay) can also be useful for inhibition of PCSK9/LDLR interaction. EXAMPLE 31
Interaction between EGFa, PCSK9, and the Antibodies [0518] The structure of the ternary complex (PCSK9 / 31H4 / 21B12) from the above example was overlaid on the PCSK9 / EGFa structure (determined as described in Example 28) and the result of this combination is depicted in FIG. 20A. This figure demonstrates areas on PCSK9 which can be usefully targeted to inhibit PCSK9 interaction with EGFa. The figure shows that both 31H4 and 2IB 12 partially overlap with the position of the EGFa domain of LDLR and sterically interfere with its binding to PCSK9. In addition, as can be seen in the structures, 2IB 12 directly interacts with a subset of amino acid residues that are specifically involved in binding to the LDLR EGFa domain.
[0519] As noted above, analysis of the crystal structures identified specific amino acids involved in the interaction between PCSK9 and the partner proteins (the core and boundary regions of the interface on the PCSK9 surface) and the spatial requirements of these partner proteins to interact with PCSK9. The structures suggest ways to inhibit the interaction between PCSK9 and the LDLR. First, as noted above, binding an agent to PCSK9 where it shares residues in common with the binding site of the EGFa domain of the LDLR would inhibit the 148 PCT/U S2008/074097 WO 2009/026558 interaction between PCSK9 and the LDLR. Second, an agent that binds outside of the residues in common can sterically interfere with the EGFa domain or regions of the LDLR that are either N- or C-terminal to the EGFa domain to prevent the interaction between PCSK9 and the LDLR.
[0520] In some embodiments, the residues that are involved in both EGFa binding and are close to the areas where the above noted antigen binding proteins bind are especially useful for manipulating PCSK9 binding to LDLR. For example, amino acid residues from interfaces in common in both the core region and boundary region for the different binding partners are listed in Table 12 below. Amino acid residues completely buried within the PCSK9 protein are underlined.
Table 12
Parameters Amino acid position(s) 31H4 / EGFa both under 5 A D374, V380, S381 31H4 under 5 A / EGFa 5-8 A D367, Q382 31H4 at 5-8 A / EGFa under 5 A 1369, S372, C378, F379 31H4/EGFa both at 5-8 A H229, S373 2IB 12 / EGFa both under 5 A SI53, R194, D238, D374, T377, F379 21B12 under 5 A / EGFa 5-8 A R237, K243, S373, S376 21B12 at 5-8 A / EGFa under 5 A 1154, A239, 1369, S372, C375, C378 21B12 / EGFa both at 5-8 A H193, E195 [0521] As will be appreciated by one of skill in the art, in some embodiments, the antigen binding proteins bind to and/or block at least one of the above noted residues. EXAMPLE 32
Structural interaction of LDLR and PCSK9 [0522] A model of full length PCSK9 bound to a full length representation of the LDLR was made using the PCSK9 ProCat (31-454 of SEQ ID NO: 3)/EGFa complex structure. 149 PCT/U S2008/074097 WO 2009/026558
The structure of full length PCSK91 (Piper, D.E. et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 15, 545-52 (2007)) was overlaid onto the PCSK9 ProCat 31-454 from the complex and the structure of the LDLR in its low pH conformation (Rudenko, G. et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 298, 2353-8 (2002)) was overlaid onto the EGFa domain from the complex. Depictions of the model are shown in FIGs. 20B and 20C. The EGFa domain is indicated by the box in the figure. The figures show regions of the LDLR outside of the immediate EGFa binding domain that lie in close proximity to PCSK9. FIGs. 20D-20F show the above interaction, along with mesh surface representations of antibody 31H4 and 21B12 from three different angles. As is clear from the depictions, not only can the antibody interact and/or interfere with LDLR’s interaction with PCSK9 at the actual binding site, but other steric interactions appear to occur as well.
[0523] In light of the above results, it is clear that antigen binding proteins that bind to PCSK9 can also inhibit the interaction between PCSK9 and the LDLR by clashing with various regions of the LDLR (not just the site at which LDLR and PCSK9 interact). For example, it can clash with repeat 7 (R7), the EGFb domain, and/or the β-propeller domain.
Embodiments of Antigen Binding Molecules that bind to or block EGFa interaction with PCSK9 [0524] As will be appreciated by one of skill in the art, Examples 28-32, and their accompanying figures, provide a detailed description of how and where EGFa interacts with PCSK9 and how two representative neutralizing antigen binding proteins, 21B12 and 31H4 interact with PCSK9 and produce their neutralizing effect. As such, one of skill in the art will readily be able to identify antigen binding molecules that can similarly reduce the binding between EGFa (including LDLR) and PCSK9 by identifying other antigen binding molecules that bind at or near at least one of the same locations on PCSK9. While the relevant locations (or epitopes) on PCSK9 are identified in the figures and the present description, it can also be advantageous to describe these sites as being within a set distance from residues that have been identified as close to the EGFa binding site. In some embodiments, an antigen binding molecule will bind to or within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): S153, 1154, P155, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, 150 PCT/US2008/074097 WO 2009/026558 K243, D367, 1368, G370, A371, S373, S376, Q382, W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, SI48, VI49, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, 1368, 1369, S372, S373, C378, F379, T385, S386, Q387, S153, S188,1189, Q190, S191, D192, R194, E197, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, HI93, El95, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247, 1369, S372, C375, or C378. In some embodiments, the antigen binding molecule binds within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): SI 53,1154, PI 55, R194, D238, A239, 1369, S372, D374, C375, T377, C378, F379, V380, S381, W156, N157, L158, E159, H193, E195, H229, R237, G240, K243, D367, 1368, G370, A371, S373, S376, or Q382. In some embodiments, the antigen binding molecule binds within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): W72, F150, A151, Q152, T214, R215, F216, H217, A220, S221, K222, S225, H226, C255, Q256, G257, K258, N317, F318, T347, L348, G349, T350, L351, E366, D367, D374, V380, S381, Q382, S383, G384, K69, D70, P71, S148, V149, D186, T187, E211, D212, G213, R218, Q219, C223, D224, G227, H229, L253, N254, G259, P288, A290, G291, G316, R319, Y325, V346, G352, T353, G365, 1368, 1369, S372, S373, C378, F379, T385, S386, or Q387. In some embodiments, the antigen binding molecule binds within 30 angstroms of one or more of the following residues (numbering in reference to SEQ ID NO: 3): S153, S188, 1189, Q190, SI91, D192, R194, El97, G198, R199, V200, D224, R237, D238, K243, S373, D374, S376, T377, F379, 1154, T187, H193, E195, 1196, M201, V202, C223, T228, S235, G236, A239, G244, M247,1369, S372, C375, or C378.
[0525] In some embodiments, the antigen binding molecule binds within 30, 30-25, 25-20, 20-15, 15-8, 8, 8-5, 5, 5-4, 4 or less angstroms from one or more of the above residues. In some embodiments, the antigen binding molecule, when bound to PCSK9, is within at least one of the above distances, for more than one of the above noted residues. For example, in some embodiments, the antigen binding molecule is within one of the recited distances (e.g., 30, 30-25, 25-20, 20-15, 15-8, 8, 8-5, 5, 5-4, 4 or less) for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75 151 PCT/US2008/074097 WO 2009/026558 or more of the above residues. In some embodiments, the antigen binding molecule is within one of the recited distances for at least 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-95, 95-99, 99-100% of the residues identified in each group of subgroup thereof (such as only those surface residues in the group). Unless specifically stated otherwise, the distance between the antigen binding molecule and PCSK9 is the shortest distance between the covalently bonded atom on PCSK9 and the covalently bonded atom of the antigen binding molecule that are the closest atoms of PCSK9 and the antigen binding molecule. Similarly, unless specifically stated otherwise, the distance between a residue (on the antigen binding molecule or PCSK9) and another protein (either PCSK9 or the antigen binding molecule respectively), is the distance from the closest point on the identified residue to the closest covalently bonded part of the other protein. In some embodiments, the distance can be measured from the backbone of the amino acid chains. In some embodiments, the distance can be measured between an edge of the paratope and an edge (closest to one another) of the epitope. In some embodiments, the distance can be measured between the center of the surface of the paratope and the center of the surface of the epitope. As will be appreciated by one of skill in the art, the present description is applicable for each of the individual sets of residues listed herein. For example, the above ranges are contemplated generally and specifically for the 8 angstrom residues listed in Examples 28-32 and the 5 angstrom residues listed in Examples 28-32.
[0526] In some embodiments, the antigen binding molecule binds to a surface on PCSK9 that is bound by at least one of EGFa, 2IB 12, or 31H4. In some embodiments, the antigen binding molecule binds to PCSK9 at a location that overlaps with the interaction locations between PCSK9 and EFGa, Ab 31H4, and/or Ab 2IB 12 (as described in the above examples and figures). In some embodiments, the antigen binding molecule binds to PCSK9 at a position that is further away from one of the above recited residues. In some embodiments, such an antigen binding molecule can still be an effective neutralizing antigen binding molecule.
[0527] In some embodiments, the structure of the catalytic domain of PCSK9 can be described as generally being triangular (as shown in FIG. 19A). The first side of the triangle is shown as being bound by 31H4. The second side of the triangle is shown as being bound by 2IB 12, and the third side of the triangle is positioned toward the bottom of the page, immediately above the “FIG. 19A” label. In some embodiments, antigen binding molecules that bind to the first and/or second sides of the catalytic domain of PCSK9 can be useful as 152 PCT/US2008/074097 WO 2009/026558 neutralizing antibodies as they can either directly or sterically interfere with EGFa’s binding to PCSK9. As will be appreciated by one of skill in the art, when the antigen binding molecules are large enough, such as a full antibody, the antigen binding molecule need not directly bind to the EGFa binding site in order to interfere with the binding of EGFa to PCSK9.
[0528] As will be appreciated by one of skill in the art, while the EGFa domain of the LDLR has been used in many of the examples, the models and structures are still applicable to how the full length LDLR protein will interact with PCSK9. Indeed, the additional structure present on the full length LDLR protein presents additional protein space that can further be blocked by one of the antigen binding molecules. As such, if the antigen binding molecule blocks or inhibits binding of EGFa to PCSK9, it will likely be at least as, if not more, effective with the full length LDLR protein. Similarly, antigen binding molecules that are within a set distance or block various residues that are relevant for inhibiting EGFa binding, will likely be as effective, if not more effective, for the full length LDLR.
[0529] As will be appreciated by one of skill in the art, any molecule that blocks or binds to the above noted PCSK9 residues (or within the recited distances), or that inhibits one or more of the interactions noted in the above examples and figures, can be used to inhibit the interaction of EGFa (or LDLR generally) and PCSK9. As such, the molecule need not be limited to an antigen binding “protein,” as any antigen binding molecule can also serve the required purpose. Examples of antigen binding molecules include aptamers, which can be either oligonucleic acid or peptide molecules. Other examples of antigen binding molecules include avimers, peptibodies, small molecules and polymers, and modified versions of EGFa that can increase its affinity to PCSK9 and/or half-life, such as mutation of amino acids, glycosylation, pegylation, Fc fusions, and avimer fusions. As will be appreciated by one of skill in the art, in some embodiments LDLR is not an antigen binding molecule. In some embodiments, binding subsections of LDLR are not antigen binding molecules, e.g., EGFa. In some embodiments, other molecules through which PCSK9 signals in vivo are not antigen binding molecules. Such embodiments will be explicitly identified as such. EXAMPLE 33
Expression and purification of protein samples 153 PCT/US2008/074097 WO 2009/026558 [0530] The present example describes some embodiments for how the various embodiments of the PCSK9 proteins/variants were made and purified (including the LDLR EGFa domain). PCSK9 proteins/variants (e.g., PSCK9 31-692 N533A, PCSK9 449TEV and PCSK9 ProCat 31-454) were expressed in baculovirus infected Hi-5 insect cells with an N-terminal honeybee melittin signal peptide followed by a His6 tag. The PCSK9 proteins were purified by nickel affinity chromatography, ion exchange chromatography and size exclusion chromatography. The melittin-His6 tag was removed during purification by cleavage with TEV protease. The construct PCSK9 449TEV was used to generate PCSK9 ProCat (31-449) and V domain (450-692) samples. This construct had a TEV protease cleavage site inserted between PCSK9 residues 449 and 450. For the full length N555A variant for crystallography, the PCSK9 31-454 fragment, and the PCSK9 449TEV variant for crystalography, the post rTEV protein product also included an initial GAMG sequence. Thus, post rTEV cleavage, these proteins were GAMG-PCSK9. Furthermore, the PCSK9 449TEV protein included the sequence “ENLYFQ” (SEQ ID NO: 403) inserted between positions H449 and G450 of SEQ ID NO: 3. After cleavage with rTEV, the PCSK9 ProCat protein generated from this construct was GAMG-PCSK9 (31-449)-ENLYFQ and the V domain generated from this construct was PCSK9 (450-692) of SEQ ID NO: 3.
[0531] The 21B12 and 31H4 Fab fragments were expressed in E. coli. These proteins were purified by nickel affinity chromatography, size exclusion chromatography and ion exchange chromatography.
[0532] The LDLR EGFa domain (293-334) was expressed as a GST fusion protein in E. coli. The EGFa domain was purified by ion exchange chromatography, glutathione sepharose affinity chromatography and size exclusion chromatography. The GST protein was removed during the purification by cleavage with PreScission protease. EXAMPLE 34
Complex formation and crystallization [0533] The present example describes how complexes and crystals used in the above structure examination Examples were made.
[0534] The PCSK9 31 -692 N533A / 31H4 complex was made by mixing a 1.5 molar excess of the 31H4 Fab with PCSK9. The complex was purified by size exclusion 154 PCT/US2008/074097 WO 2009/026558 chromatography to remove excess 31H4 Fab. The PCSK9 31-692 N533A / 31H4 complex crystallizes in 0.1 M Tris pH 8.3, 0.2 M sodium acetate, 15% PEG 4000, 6% dextran sulfate sodium salt (Mr 5000).
[0535] The PCSK9 ProCat 31 -449 / 31H4 / 21B12 complex was made by first mixing a 1.5 molar excess of 31H4 Fab with PCSK9 31-449. The complex was separated from excess 31H4 by purification on a size exclusion chromatography column. A 1.5 molar excess of 21B12 Fab was then added to the PCSK9 31-449 / 31H4 complex. The ternary complex was separated from excess 2IB 12 by purification on a size exclusion chromatography column. The PCSK9 ProCat 31-449 / 31H4 / 21B12 complex crystallizes in 0.1 M Tris pH 8.5, 0.2 M ammonium phosphate monobasic, 50% MPD.
[0536] The PCSK9 ProCat 31-454 / EGFa complex was made by mixing a 1.2 molar excess of EGFa domain with PCSK9 31-454. The PCSK9 ProCat 31-454 / EGFa domain complex crystallizes in 0.2 M potassium formate, 20% PEG 3350. EXAMPLE 35
Data collection and structure determination [0537] The present example describes how the datasets were collected and the structures determined for the above structure examination Examples.
[0538] Initial datasets for the PCSK9 31 -692 N533A / 31H4 and PCSK9 ProCat 31 -449 / 31H4 / 2IB 12 crystals were collected on a Rigaku FR-E X-ray source. The PCSK9 ProCat 31-454 / EGFa dataset and higher resolution datasets for the PCSK9 31-692 N533A / 31H4 and PCSK9 ProCat 31-449 / 31H4 / 2IB 12 crystals were collected at the Berkeley Advanced Light Source beamline 5.0.2. All datasets were processed with denzo/scalepack or HKL2000 (Otwinowski, Z., Borek, D., Majewski, W. &amp; Minor, W. Multiparametric scaling of diffraction intensities. Acta Crystallogr A 59, 228-34 (2003)).
[0539] PCSK9 / 31H4 crystals grew in the C2 space group with unit cell dimensions a=264.9, b=137.4, c=69.9 A, β=102.8° and diffract to 2.3 A resolution. The PCSK9 / 31H4 structure was solved by molecular replacement with the program MOLREP (The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-3 (1994) using the PCSK9 structure (Piper, D.E. et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 15, 545-52 (2007)) as the starting search model. Keeping the 155 PCT/US2008/074097 WO 2009/026558 PCSK9 31-692 solution fixed, an antibody variable domain was used as a search model. Keeping the PCSK9 31-692 / antibody variable domain solution fixed, an antibody constant domain was used as a search model. The complete structure was improved with multiple rounds of model building with Quanta and refinement with cnx. (Brunger, A.T. et al. Crystallography &amp; NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54, 905-21 (1998)).
[0540] PCSK9 / 31H4 / 2 IB 12 crystals grew in the P2]2i2 space group with unit cell dimensions a=138.7, b=246.2, c=51.3 A and diffract to 2.8 A resolution. The PCSK9 / 31H4 / 2IB 12 structure was solved by molecular replacement with the program MOLREP using the PCSK9 ProCat / 31H4 variable domain as the starting search model. Keeping the PCSK9 ProCat / 31H4 variable domain fixed, a search for antibody constant domain was performed. Keeping the PCSK9 ProCat / 31H4 / 2IB 12 constant domain fixed, an antibody variable domain was used as a search model. The complete structure was improved with multiple rounds of model building with Quanta and refinement with cnx.
[0541] PCSK9 / EGFa domain crystals grew in the space group P6522 with unit cell dimensions a=b=70.6, c=321.8 A and diffract to 2.9 A resolution. The PCSK9 / EGFa domain structure was solved by molecular replacement with the program MOLREP using the PCSK9 ProCat as the starting search model. Analysis of the electron density maps showed clear electron density for the EGFa domain. The LDLR EGFa domain was fit by hand and the model was improved with multiple rounds of model building with Quanta and refinement with cnx.
[0542] Core interaction interface amino acids were determined as being all amino acid residues with at least one atom less than or equal to 5 A from the PCSK9 partner protein. 5 A was chosen as the core region cutoff distance to allow for atoms within a van der Waals radius plus a possible water-mediated hydrogen bond. Boundary interaction interface amino acids were determined as all amino acid residues with at least one atom less than or equal to 8 A from the PCSK9 partner protein but not included in the core interaction list. Less than or equal to 8 A was chosen as the boundary region cutoff distance to allow for the length of an extended arginine amino acid. Amino acids that met these distance criteria were calculated with the program PyMOL. (DeLano, W.L. The PyMOL Molecular Graphics System. (Palo Alto, 2002)). EXAMPLE 36 156 PCT/US2008/074097 WO 2009/026558
Cyrstal Structure of PCSK9 and 31A4 [0543] The crystal structure of the 31A4/PCSK9 complex was deteremined. Expression and purification of protein samples [0544] PCSK9 449TEV (a PCSK9 construct with a TEV protease cleavage site inserted between residue 449 and 450, numbering according to SEQ ID NO: 3) was expressed in baculovirus infected Hi-5 insect cells with an N-terminal honeybee melittin signal peptide followed by a His6 tag. The PCSK9 protein was purified by first by nickel affinity chromatography. TEV protease was used to remove the melittin-His6 tag and cleave the PCSK9 protein between the catalytic domain and V domain. The V domain was further purified by ion exchange chromatography and size exclusion chromatography. The 31A4 Fab fragment was expressed in E. coli. This protein was purified by nickel affinity chromatography, size exclusion chromatography and ion exchange chromatography.
Complex formation and crystallization [0545] The PCSK9 V domain / 31A4 complex was made by mixing a 1.5 molar excess of PCSK9 V domain with 31A4 Fab. The complex was separated from excess PCSK9 V domain by purification on a size exclusion chromatography column. The PCSK9 V domain / 31A4 complex crystallized in 1.1 M Succinic acid pH 7, 2% PEG MME 2000.
Data collection and structure determination [0546] The dataset for the PCSK9 V domain / 31A4 crystal was collected on a Rigaku FR-E x-ray source and processed with denzo/scalepack (Otwinowski, Z., Borek, D., Majewski, W. &amp; Minor, W. Multiparametric scaling of diffraction intensities. Acta Crystallogr A 59, 228-34 (2003)).
[0547] PCSK9 V domain / 31A4 crystals grow in the P2i2i2i space group with unit cell dimensions a=74.6, b= 131.1, c= 197.9 A with two complex molecules per asymmetric unit, and diffract to 2.2 A resolution. The PCSK9 V domain / 31A4 structure was solved by molecular replacement with the program MOLREP (CCP4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-3 (1994)) using the V domain of the PCSK9 structure (Piper, D.E. et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 15, 545-52 (2007)) as the starting search model. Keeping the PCSK9 450-692 solution fixed, an antibody variable domain was used as a search model. After initial refinement, the antibody constant domains were fit by hand. The complete structure was 157 PCT/US2008/074097 WO 2009/026558 improved with multiple rounds of model building with Quanta and refinement with cnx (Brunger, A.T. et al. Crystallography &amp; NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54, 905-21 (1998)).
[0548] Core interaction interface amino acids were determined as being all amino acid residues with at least one atom less than or equal to 5 A from the PCSK9 partner protein. 5 A was chosen as the core region cutoff distance to allow for atoms within a van der Waals radius plus a possible water-mediated hydrogen bond. Boundary interaction interface amino acids were determined as all amino acid residues with at least one atom less than or equal to 8 A from the PCSK9 partner protein but not included in the core interaction list. Less than or equal to 8 A was chosen as the boundary region cutoff distance to allow for the length of an extended arginine amino acid. Amino acids that met these distance criteria were calculated with the program PyMOL (DeLano, W.L. The PyMOL Molecular Graphics System. (Palo Alto, 2002)). Distances were calculated using the V domain "A" and 31A4 ”L1,H1" complex.
[0549] The crystal structure of the PCSK9 V domain bound to the Fab fragment of 31A4 was determined at 2.2 A resolution. The depictions of the crystal structure are provided in FIGs. 21A-21D. FIGs. 21A-21C shows that the 31A4 Fab binds to the PCSK9 V domain in the region of subdomains 1 and 2.
[0550] A model of full length PCSK9 bound the 31A4 Fab was made. The structure of full length PCSK9 was overlaid onto the PCSK9 V domain from the complex. A figure of this model is shown in FIG. 2ID. The site of the interaction between the EGFa domain of the LDLR and PCSK9 is highlighted.
[0551] Analysis of the structure shows where this antibody interacts with PCSK9 and demonstrated that antibodies that do not bind to the LDLR binding surface of PCSK9 can still inhibit the degradation of LDLR that is mediated through PCSK9 (when the results are viewed in combination with Example 40 and 41 below). In addition, analysis of the crystal structure allows for identification of specific amino acids involved in the interaction between PCSK9 and the 31A4 antibody. Furthermore, the core and boundary regions of the interface on the PCSK9 surface were also determined. Specific core PCSK9 amino acid residues of the interaction interface with 31A4 were defined as PCSK9 residues that are within 5 A of the 31A4 protein. The core residues are T468, R469, M470, A471, T472, R496, R499, E501, A502, Q503, R510, H512, F515, P540, P541, A542, E543, H565, W566, E567, V568, E569, R592, and E593. 158 PCT/US2008/074097 WO 2009/026558
Boundary PCSK9 amino acid residues of the interaction interface with 31A4 were defined as PCSK9 residues that are 5-8 A from the 31A4 protein. The boundary residues are as follows: S465, G466, P467, A473, 1474, R476, G497. E498. M500, G504, K506, L507, V508, A511. N513. A514, G516, V536, T538, A539, A544, T548, D570, L571, H591, A594, S595, and H597. Amino acid residues nearly or completely buried within the PCSK9 protein are highlighted by underline. As noted herein, the numbering references the amino acid positions of SEQ ID NO: 3 (adjusted as noted herein).
[0552] Specific core 31A4 amino acid residues of the interaction interface with PCSK9 were defined as 31A4 residues that are within 5 A of the PCSK9 protein. The core residues for the 31A4 antibody are as follows: Heavy Chain: G27, S28, F29, S30, A31, Y32, Y33, E50, N52, H53, R56, D58, K76, G98, Q99, L100, and V101; Light Chain: S31, N32, T33, Y50, S51, N52, N53, Q54, W92, and D94. Boundary 31A4 amino acid residues of the interaction interface with PCSK9 were defined as 31A4 residues that are 5-8 A from the PCSK9 protein. The boundary residues for 31A4 are as follows: Heavy Chain: V2, G26, W34, N35, W47, 151, S54, T57, Y59, A96, R97, PI02, F103, and D104; Light Chain: S26, S27, N28, G30, V34, N35, R55, P56, K67, V91, D93, S95, N97, G98, and W99.
[0553] The crystal structure also displayed the spatial requirements of this ABP in its interaction with PCSK9. As shown in this structure, surprisingly, antibodies that bind to PCSK9 without directly preventing PCSK9's interaction with the LDLR can still inhibit PCSK9's function.
[0554] In some embodiments, any antigen binding protein that binds to, covers, or prevents 31A4 from interacting with any of the above residues can be employed to bind to or neutralize PCSK9. In some embodiments, the ABP binds to or interacts with at least one of the following PCSK9 (SEQ ID NO: 3) residues: T468, R469, M470, A471, T472, R496, R499, E501, A502, Q503, R510, H512, F515, P540, P541, A542, E543, H565, W566, E567, V568, E569, R592, and E593. In some embodiments, the ABP is within 5 angstroms of one or more of the above residues. In some embodiments, the ABP binds to or interacts with at least one of the following PCSK9 (SEQ ID NO: 3) residues: S465, G466, P467, A473, 1474, R476, G497. E498. M500, G504, K506, L507, V508, A511. N513. A514, G516, V536, T538, A539, A544, T548, D570, L571, H591, A594, S595, and H597. In some embodiments, the ABP is 5 to 8 angstroms 159 PCT/US2008/074097 WO 2009/026558 from one or more of the above residues. In some embodiments, the ABP interacts, blocks, or is within 8 angstroms of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 of the above residues.
[0555] The coordinates for the crystal structures discussed in the above Examples are are presented in Table 35.1 (full length PCSK9 and 31H4), Table 35.2 (PCSK9 and EGFa), Table 35.3 (PCSK9, 31H4, and 21B12), and Table 35.4 (PCSK9 and 31A4). Antigen binding proteins and molecules that interact with the relevant areas or residues of the structure of PCSK9 (including those areas or residues within 15, 15-8, 8, 8-5, 5, or fewer angstroms from where EGFa, or the antibodies, interact with PCSK9) depicted in the figures and/or their corresponding positions on the structures from the coordinates are also contemplated.
[0556] The antibodies that are described in the coordinates were raised in E. coli and thus possess some minor amino acid differences from the fully human antibodies. The first residue in the variable region was a glutamic acid instead of a glutamine for the heavy and light chains of 2IB 12 and for the light chain for 31H4. In addition to the differences in the sequence of variable region, there were also some differences in the constant region of the antibodies described by the coordinates (again due to the fact that the antibody was raised in E. coli). FIG. 22 highlights (via underlining shading, or bold) the differences between the constant regions of the 21B12, 31H4, and 31A4 Fabs (raised in E. coli) when compared to SEQ ID NOs: 156, and 155. For 2IB 12 31H4, and 31A4, the light chain constant sequence is similar to human lambda (SEQ ID NO: 156). The underlined glycine residue is an insertion between where the 21B12 and 31H4 variable sequences stop and the lambda sequence starts.
[0557] For both 2IB 12 and 31H4, the heavy chain constant is similar to human IgG4 (SEQ ID NO: 155). The highlighted differences in FIG. 22 are shown in Table 36.1:
Table 36.1
Crystal SEQ ID NO: 155
s c K R G E G S Q K I T N D K R P S 160 PCT/US2008/074097 WO 2009/026558 [0558] In regard to 31A4, while it also has the same distinctions noted above, there are three additional differences. As shown in FIG. 22, there are two additional amino acids at the start, which comes from incomplete processing of the signal peptide in E. coli expression. In addition, there is one additional substitution in the 31A4 heavy chain constant region when compared to SEQ ID NO: 155, which is the adjustment of a L (in SEQ ID NO: 155) to a H. Finally, 31A4 does have a glutamine as the initial amino acid of the Fab, rather than the adjustment to glutamic acid noted above for 2IB 12 and 31H4.
[0559] For all three antibodies, the end of the heavy chain (boxed in dark grey) differs as well, but the amino acids are not ordered in the structure so they do not appear in the cooridnates. As will be appreciated by one of skill in the art, his-tags are not a required part of the ABP and should not be considered as part of the ABP’s sequence, unless explicitly called out by reference to a specific SEQ ID NO that includes a histidine tag and a statement that the ABP sequence “includes the Histidine tag.” EXAMPLE 37 Epitope Mapping—Binning [0560] An alternative set of binning experiments was conducted in addition to the set in Example 10. As in Example 10, ABPs that compete with each other can be thought of as binding to the same site on the target and in common parlance are said to “bin” together.
[0561] A modification of the Multiplexed Binning method described by Jia, et al (J. Immunological Methods, 288 (2004) 91-98) was used. Individual bead codes of streptavidin-coated Luminex beads was incubated in lOOul 0.5 ug/ml biotinylated monovalent mouse-antihuman IgG capture antibody (BD Pharmingen, #555785 ) for 1 hour at room temperature in the dark, then washed 3x with PBSA, phosphate buffered saline (PBS) plus 1% bovine serum albumin (BSA). Each bead code was separately incubated with 100 ul 2 ug/ml anti-PCSK9 antibody (Coating Antibody) for 1 hour then washed 3x with PBSA. The beads were pooled then dispensed to a 96-well filter plate (Millipore, #MSBVN1250). lOOul of 2 ug/ml purified PCSK9 protein was added to half the wells. Buffer was added to the other half as control. The reaction was incubated for 1 hour then washed. 100 ul of a 2 ug/ml anti-PCSK9 antibody (Detection Ab) was added to all the wells, incubated for 1 hour then washed. An irrelevant human-IgG (Jackson, #009-000-003) was run as another control. 20ul PE-conjugated 161 PCT/US2008/074097 WO 2009/026558 monovalent mouse-anti-human IgG (BD Pharmingen, #555787) was added to each well and incubated for 1 hour then washed. Beads were resuspended in lOOul PBSA and a minimum of 100 events/bead code were collected on the BioPlex instrument (BioRad).
[0562] Median Fluorescent Intensity (MFI) of the antibody pair without PCSK9 was subtracted from signal of the corresponding reaction containing PCSK9. For the antibody pair to be considered bound simultaneously, and therefore in different bins, the subtracted signal had to be greater than 3 times the signal of the antibody competing with itself and the 3 times the signal of the antibody competing with the irrelevant antibody.
[0563] The data from the above is depicted in FIGs. 23A-23D. The ABPs fell into five bins. The shaded boxes indicate ABPs that can bind simultaneously to PCSK9. The nonshaded boxes indicate those ABPs that compete with each other for binding. A summary of the results is shown in Table 37.1. 162 PCT/US2008/074097
Table 37.1. 01A12.2 27B2.1 16F12.1 11G1.5 30A4.1 03B6.1 27B2.5 22E2.1 03C4.1 13B5.1 09C9.1 12H11.1 27A6.1 13H1.1 17C2.1 28B12.1 31A4.1 21B12.2 28D6.1 31B12.1 23G1.1 31G11.1 25G4.1 31H4.1 26E10.1 08A1.2 11H4.1 08A3.1 11H8.1 11F1.1 19H9.2 26H5.1 27^7.1 27H5.1 30B9.1 02B5.1 23B5.1 27B2.6 09H6.1 WO 2009/026558 [0564] Bins 1 (competes with ΑΒΡ 21B12) and 3 (competes with 31H4) are exclusive of each other; bin 2 competes with bins 1 and 3; and Bin 4 does not compete with bins 1 and 3. Bin 5, in this example, is presented as a “catch all” bin to describe those ABPs that do not fit into the other bins. Thus, the above identified ABPs in each of the binds are representative of different types of epitope locations on PCSK9, some of which overlap with each other.
[0565] As will be appreciated by one of skill in the art, if the reference ABP prevents the binding of the probe ABP then the antibodies are said to be in the same bin. The order in which the ABPs are employed can be important. If ABP A is employed as the reference ABP and blocks the binding of ABP B the converse is not always true: ABP B used as the reference ABP will not necessarily block ABP A. There are a number of factors in play here: the binding of an ABP can cause conformational changes in the target which prevent the binding of the 163 PCT/US2008/074097 WO 2009/026558 second ABP, or epitopes which overlap but do not completely occlude each other may allow for the second ABP to still have enough high-affinity interactions with the target to allow binding. ABPs with a much higher affinity may have a greater ability to bump a blocking ABP out of the way. In general, if competition is observed in either order the ABPs are said to bin together, and if both ABPs can block each other then it is likely that the epitopes overlap more completely. EXAMPLE 38
Epitope Mapping—Western Blot [0566] The present example demonstrates whether or not the epitopes for the examined ABPs were linear or conformational. Denaturing reducing and denaturing nonreducing western blots were run to determine which antibodies have a conformational epitope. Antibodies that bind to a denaturing reducing western blot have a linear epitope and are not conformational. The results are presented in FIG. 24A and FIG. 24B. For the blot, 0.5 ug/lane of purified full-length human PCSK9 was run on a 4-12% NuPAGE Bis-Tris gel and MES SDS Running Buffer. 1 ug/ml anti-PCSK9 antibodies, except 0.5 ug/ml 31G11, were used to probe the blot. 1:5000 donkey-anti-human-IR700 secondary was used and read on a LiCOR instrument. Antibody 13H1 bound to a linear epitope on the pro-domain of PCSK9. All other antibodies displayed results that were consistent with conformational epitopes. These gels split apart the pro-domain from the rest of the protein, and the pro domain ran at about 15kDa. In addition, 3C4 and 31A4 appeared to bind to conformational epitopes which were preserved by disulfide bonds, as these antibodies bound to PCSK-9 under denaturing conditions where the disulfide bonds had been preserved (left) but reducing the samples (right) eliminated binding. EXAMPLE 39
Epitope Mapping—Arginine / Glutamic Acid Scanning [0567] Representative ABPs from each bin (from Example 37) were selected for further epitope analysis. An arginine/glutamic acid-scanning strategy was performed for mapping ABP binding to PCSK9. By way of background, this method determines if a residue is part of the structural epitope, meaning those residues in the antigen which contact or are buried by the antibody. Arginine and glutamic acid sidechains are charged and bulky and can disrupt antibody binding even if the mutated residue is not directly involved in antibody binding. 164 PCT/US2008/074097 WO 2009/026558
Residue Selection [0568] The crystal structure of PCSK9 was used to select the residues to be mutated for epitope mapping. The method used to choose residues to mutate involved both computational mechanisms and interactive structure analysis. The PCSK9 structure contained gaps of missing residues and was missing 30 amino acids in the N- (i.e., the signal sequence) and 10 amino acids in the C-termini. The internal missing residues were modeled onto the structure, but the N- and C-terminal missing residues were not. The solvent exposure ratio for each residue was calculated: the surface area of each residue in the context of the protein (SA1) was divided by the surface area of the residue in a trimer with flanking glycines (SA2) with a conserved backbone structure. Residues with solvent exposure ratio greater than 10% (R10) were selected as well as the 40 missing terminal residues. From these, prolines and glycines with positive Φ angles were excluded to reduce the possibility of misfolding. The number of residues to be mutated in the V domain was reduced by using a solvent exposure ratio of 37% along with visual inspection of the entire protein to bring the total number of mutations to 285. Various orientations of the surface of PCSK9 with these various classes identifies are shown in FIG. 25A-25F. In these figures, lightest gray denotes areas that were not selected or were deselected, darker gray denotes those residues selected).
Cloning and Expression [0569] Once the residues to be altered were identified, the various residues were altered. Human PCSK9 was cloned into the pTT5 vector with a C-terminal Flag-His tag. Mutants were made from this original construct by site-directed mutagenesis using a QuikChange II kit from Stratagene. Sense and anti-sense oligonucleotides used for mutagenesis were designed using Amgen’s MutaGenie software. All PCSK9 constructs were expressed in transiently-transfected 293-6E cells in 24-well plates and re-racked into three 96-well plates with a non-mutated PCSK9 control (wild-type, WT) in each plate. Expression levels and integrity of the recombinant proteins in conditioned media were checked by Western blot. Of the 285 mutants originally selected, 41 failed in cloning or expression. 244 mutants were used for epitope mapping. An alignment of the PCSK9 parent sequence and a representative PCSK9 sequence with the 244 mutated residues is shown in FIG. 26. Separate constructs were made containing a single mutation. For the purposes of the epitope sequences and the epitope based 165 PCT/US2008/074097 WO 2009/026558 inventions involving changes in binding, the sequences are provided in reference to SEQ ID NO: 1 and/or SEQ ID NO: 303. The sequences in FIG. 26 were the sequences used for the present binding epitope studies. One of skill in the art will appreciate that the present results apply to other PCSK9 variants disclosed herein as well (e.g., SEQ ID NO: 1 and 3, as well as the other allelic variants).
[0570] Five antibodies, a representative of each bin, were chosen for fine epitope mapping. They were 2IB 12, 31H4, 12H11, 31A4, 3C4. All conformational epitope antibodies. Three, 21B12, 31H4, and 31A4 were also crystallized with PCSK9, as described above.
Structural and functional epitopes [0571] Epitopes can be further defined as structural or functional. Functional epitopes are generally a subset of the structural epitopes and have those residues that directly contribute to the affinity of the interaction (e.g. hydrogen bonds, ionic interactions). Structural epitopes can be thought of as the patch of the target which is covered by the antibody.
[0572] The scanning mutagenesis employed was an arginine and glutamic acid scan. These two sidechains were chosen due to their large steric bulk and their charge, which allows mutations that occur in the structural epitope to have a greater effect on antibody binding. Arginine was generally employed except when the WT reside was arginine, and in these cases the residue was mutated to glutamic acid to switch the charge.
[0573] For the purpose of epitope mapping, a bead-based multiplexed assay was used to measure antibody binding to PCSK9 and PCSK9 mutants simultaneously. Antibody binding to mutants was then compared to its binding to the wild-type in the same well. The variants were split into three groups: Group 1: 81 variants + 2 wt controls + 1 negative control + 1 other PCSK9 supernatant; Group 2: 81 variants + 2 wt controls + 2 negative controls; and Group 3: 82 variants + 2 wt control + 1 negative control.
[0574] The assay was run as follows: 85 sets of color-coded strepavidin-coated LumAvidin beads (Luminex) were bound with biotinylated anti-pentaHis antibody (Qiagen, #1019225) for 1 hour at room temperature (RT) then washed three times in PBS, 1% BSA, 0.1% Tween 20. Each color-coded bead set was then allowed to bind to a PCSK9 mutant, wild-type, or negative control in 150 ul supernatant overnight at 4°C 166 PCT/US2008/074097 WO 2009/026558 [0575] The color-coded bead sets, each associated to a specific protein, were washed and pooled. At this point, there were 3 pools of 85 bead sets, one pool for each group of mutants and controls. The beads from each pool were aliquoted to 24 wells (3 columns) of a 96-well filter plate (Millipore, #MSBVN1250). 100 ul of anti-PCSK9 antibodies in 4-fold dilutions were added to nine columns for triplicate points and incubated for 1 hour at RT and washed. 1 OOul of 1:200 dilution phycoerythrin (PE)-conjugated anti-human IgG Fc (Jackson Immunoresearch, #109-116-170) was added to each well and incubated for 1 hour at RT and washed.
[0576] Beads were resuspended in 1% BSA in PBS, shaken for lOmins and read on the BioPlex instrument (Bio-Rad). The instrument identifies each bead by its color-code thereby identifying the specific protein associated with the color code. At the same time, it measures the amount of antibody bound to the beads by fluorescence intensity of the PE dye. Antibody binding to each mutant can then be compared directly its binding to the wild type in the same pool. IL-17R chimera E was used as a negative control. A summary of all of the mutants examined is shown in Table 39.1 (with reference to the sequence numbering used in FIG. 1A and 26). 167 PCT/US2008/074097
Table 39.1
1 2 3 4 5 6 7 8 9 10 11 12 A WT PCSK9 Y8R E18R P26R A38R T56R A70R H83R E102R L128R D145R B Q1R E9R E19R E27R K39R H57R Q71R V84R L105R E129R S148R C E2R E10R D20R G29R D40R L58R A73R H86R K106R R130E pcsk9 supe test D D3R L11R G21R T30R L44R Q60R R74E K95R H109R T132R IL17R chimera E E E4R V12R L22R T31R T47R E62R R75E S97R D111R D139R WT PCSK9 F D5R AMR A23R A32R K53R R63E Y77R G98R A121R E140R G G6R L15R E24R T33R E54R R66E L78R D99R S123R Y141R H D7R S17R A25R H35R E55R R67E L82R L101R W126R Q142R
1 2 3 4 5 6 7 8 9 10 11 12 WT PCSK9 M171R E181R Q189R K213R R242E G251R L294R L321R Q352R E380R L149R V172R D182R A190R G214R K243R G262R A311R E336R M368R R384E S158R T173R G183R S191R S216R S244R R265E Q312R D337R S371R IL17R chimera E Q160R D174R T184R K192R R221E Q245R A269R D313R D344R A372R IL17R chimera E S161R E176R R185E S195R Q226R L246R Q272R Q314R T347R E373R WT PCSK9 D162R N177R F186R H196R K228R V247R R276E T317R F349R E375R R164E V178R H187R R207E T230R Q248R A277R L318R V350R T377R E167R E180R R188E D208R F240R V250R R289E T320R S351R L378R
1 2 3 4 5 6 7 8 9 10 11 12 WT PCSK9 N395R V405R W423R R446E E513R Q525R Q554R Q589R S632R A641R I386R E396R N409R Q424R D450R A514R E537R N556R Q591R T633R R650E H387R A397R A413R A433R A472R S515R V538R K579R A595R T634R R652E F388R W398R S417R H434R F485R M516R E539R V580R E597R G635R IL17R chimera E A390R E401R T418R T438R G486R R519E L541R K581R E598R S636R WT PCSK9 K391R D402R H419R R439E E488R H521R H544R E582R V620R T637R D392R Q403R G420R M440R N503R H523R V548R H583R R629E S638R V393R R404E A421R T442R T508R Q524R R552E G584R V631R E639R WO 2009/026558
Bead Variability Study [0577] Before running the epitope mapping binding assay, a validation experiment was conducted to assess the “bead region” to “bead region” (B-B) variability. In the validation experiment, all beads were conjugated with the same wild type control protein. Therefore, the difference between beads regions was due to purely B-B variance and was not confounded by difference between wild type and mutant proteins. The titration of antibody was run with twelve replications in different wells.
[0578] The objective of this statistical analysis was to estimate the B-B variability of the estimated EC50 of binding curves. The estimated B-B standard deviation (SD) was then used to build the EC50 confidence intervals of wild type and mutant proteins during curve comparison experiments.
[0579] A four-parameter logistic model was fitted to the binding data for each bead region. The resulting file, containing curve quality control (QC) results and parameter estimates 168 PCT/US2008/074097 WO 2009/026558 for top (max), bottom (min), Hillslope (slope), and natural log of EC50 (xmid) of the curves, was used as the raw data for the analysis. B-B variability for each parameter was then estimated by fitting mixed effect model using SAS PROC MIXED procedure. Only curves with “good” QC status were included in the analysis. The final mixed effect model included only residual (i.e. individual bead regions) as random effect. Least squares means (LS-mean) for each parameter were estimated by the mixed effect model as well. B-B SD was calculated by taking square root of B-B variance. Fold change between LS-mean + 2SD and LS-mean - 2SD, which represent approximately upper and lower 97.5 percentile of the population, was also calculated. The results are displayed in Table 39.2
Table 39.2 Least square mean and bead-to-bead variance estimations
Assay ID parname Ls Mean B-B Variance -2SD +2SD Fold Change* PCSK9 max 15000 997719 13002.3 16997.7 1.3 PCSK9 min 162.09 1919.66 74.5 249.7 3.4 PCSK9 slope 0.8549 0.000599 0.8 0.9 1.1 PCSK9 xmid 3.1715 0.002098 3.1 3.3 1.2 * xmid is natural log of the EC50. Fold change for xmid was converted back to original scale.
Identifying Residues in the Structural Epitope [0580] A residue was considered part of the structural epitope (a “hit”) when mutating it to arginine or glutamic acid alters antibody binding. This is seen as a shift in the EC50 or a reduction of maximum signal compared to antibody binding to wild type. Statistical analyses of antibody binding curves to wild type and mutants were used to identify statistically significant EC50 shifts. The analysis takes into consideration variation in the assay and curve fitting.
Hit Identification based on EC50 Comparison [0581] The EC50 and Bmax values were generated from a Weighted 4-Parameter Logistical model fitted to the binding data using S-PLUS with VarPower software (Insightful Corporation, Seattle WA). The EC50s of the mutant binding curves and wild type binding curves were compared. Statistically significant differences were identified as hits for further consideration. The curves with “nofit” or “badfit” flags were excluded from the analysis. 169 PCT/U S2008/074097 WO 2009/026558
The Variations in EC50 Estimates [0582] Two sources of variations were considered in the comparison of EC50 estimates, variation from the curve fit and the bead-bead variation. Wild types and mutants were linked to different beads, hence their difference are confounded with the bead-bead difference (described above). The curve fit variation was estimated by the standard error of the log EC50 estimates. Bead-bead variation was experimentally determined using an experiment where wild type controls were linked to each one of the beads (described above). The bead variation in EC50 estimates of wild type binding curve from this experiment was used to estimate the bead-bead variation in the actual epitope mapping experiment.
Testing for EC50 Shift between Mutants and Wild Type [0583] The comparisons of two EC50s (in log scale) was conducted using Student’s t-test. The t-statistic was calculated as the ratio between delta (the absolute differences between EC50 estimates) and the standard deviation of delta. The variance of delta was estimated by the sum of the three components, variance estimate of EC50 for mutant and wild type curves in the nonlinear regression and two times the bead-bead variance estimated from a separate experiment. The multiple of two for the bead-bead variance was due to the assumption that both mutant and wild type beads had the same variance. The degree of freedom of the standard deviation of delta was calculated using the Satterthwaite’s (1946) approximation. Individual p-values and confidence intervals (95% and 99%) were derived based on Student’s t distribution for each comparison. In the case of multiple wild type controls, a conservative approach was taken by picking the wild type control that was most similar to the mutant, i.e., picking the ones with the largest p-values.
[0584] Multiplicity adjustments were important to control the false positive(s) while conducting a large number of tests simultaneously. Two forms of multiplicity adjustment were implemented for this analysis: family wise error (FWE) control and false discovery rate (FDR) control. The FWE approach controls the probability that one or more hits are not real; FDR approach controls the expected proportion of false positive among the selected hits. The former approach is more conservative and less powerful than the latter one. There are many methods available for both approaches, for this analysis, the Hochberg’s (1988) method for FWE analysis 170 PCT/US2008/074097 WO 2009/026558 and Benjamini-Hochberg’s (1995) FDR method for FDR analysis were selected. Adjusted p-values for both approaches were calculated.
Results EC50 Shift [0585] Mutations whose EC50 is significantly different from wild type, e.g., having a False Discovery Rate adjusted p-value for the whole assay of 0.01 or less, were considered part of the structural epitope. All the hits also had a Familywise type I error rate adjusted p-value for each antibody of less than 0.01 except residue R185E for antibody 31H4 which had an FWE adjusted p-value per antibody of 0.0109. The residues in the structural epitope of the various antibodies determined by EC50 shift are shown in Table 39.3 (point mutations are with reference to SEQ ID NO: 1 and 303)
Table 39.3
Antibody Mutation FDR.Adjusted Pval FWE Adjusted. Hy I’val Low99 Low95 FotdChange High95 High99 Rawp· 21B12 D208R 0.0000 0.0000 0.3628 0.3844 0.4602 0.5509 0.5837 0.0000 21B12 R207E 0.0000 0.0000 1.7148 1.8488 2.3191 2.9090 3.1364 0.0000 31H4 R185E 0.0024 0.0109 1.2444 1.3525 1.7421 2.2439 2.4388 0.0000 31A4 E513R 0.0001 0.0003 1.4764 1.6219 2.1560 2.8660 3.1485 0.0000 31A4 E539R 0.0000 0.0000 1.6014 1.7461 2.2726 2.9578 3.2252 0.0000 31A4 R439E 0.0000 0.0000 3.1565 3.6501 5.5738 8.5113 9.8420 0.0000 31A4 V538R 0.0004 0.0013 1.4225 1.5700 2.1142 2.8471 3.1423 0.0000 12H11 A390R 0.0000 0.0001 1.4140 1.5286 1.9389 2.4594 2.6588 0.0000 12H11 A413R 0.0009 0.0028 1.2840 1.3891 1.7653 2.2434 2.4269 0.0000 12H11 S351R 0.0009 0.0028 1.2513 1.3444 1.6761 2.0896 2.2452 0.0000 12H11 T132R 0.0000 0.0001 1.3476 1.4392 1.7631 2.1599 2.3068 0.0000 3C4 E582R 0.0016 0.0069 1.3523 1.5025 2.0642 2.8359 3.1509 0.0000
Maximum Signal Reduction [0586] The percent maximum signal was calculated using the maximum signal from the curve fitting (BmaxPerWT) and raw data point (RawMaxPerWT). Mutations that reduced the antibody binding maximum signal by > 70% as compared to to wild type signal or that reduced the signal of one antibody compared to other antibodies by >50% when all other antibodies are at least 40% of wild type were considered hits and part of the epitope. Table 171 PCT/US2008/074097 WO 2009/026558 39.4 displays the residues that are in the structural epitope {italics) as determined by reduction of maximum signal. antibody Mutants BmaxPerWT RawMaxPerWT 21B12 A311R 141.6388 139.7010 31H4 A311R 145.2189 147.8244 31A4 A311R 103.4377 96.2214 12H11 A311R 14.9600 3C4 A311R 129.0460 131.2060 21B12 D162R 7.0520 31H4 D162R 108.8308 112.4904 31A4 D162R 98.8873 95.9268 12H11 D162R 94.6280 97.4928 3C4 D162R 101.4281 100.1586 21B12 D313R 45.8356 45.0011 31H4 D313R 45.6242 44.9706 31A4 D313R 47.9728 44.7741 12H11 D313R 16.1811 18.4262 3C4 D313R 58.5269 57.6032 21B12 D337R 61.9070 62.2852 31H4 D337R 63.1604 64.1029 31A4 D337R 62.9124 59.4852 12H11 D337R 10.8443 3C4 D337R 73.0326 73.9961 21B12 E129R 139.9772 138.9671 31H4 E129R 141.6792 139.1764 31A4 E129R 77.3005 74.8946 12H11 E129R 28.6398 29.3751 3C4 E129R 85.7701 85.7802
Table 39.4 antibody Mutants BmaxPerWT RawMaxPerWT 21B12 E167R 15.1082 31H4 E167R 127.4479 128.2698 31A4 E167R 115.3403 112.6951 12H11 E167R 111.0979 109.6813 3C4 E167R 109.3223 108.7864 21B12 H521R 133.8480 133.9791 31H4 H521R 130.2068 128.4879 31A4 H521R 124.5091 129.3218 12H11 H521R 130.7979 134.4355 3C4 H521R 22.1077 21B12 Q554R 125.9594 125.2103 31H4 Q554R 122.2045 128.7304 31A4 Q554R 113.6769 121.3369 12H11 Q554R 116.1789 118.4170 3C4 Q554R 31.8416 21B12 R164E 17.3807 19.8505 31H4 R164E 97.8218 99.6673 31A4 R164E 98.2595 96.3352 12H11 R164E 88.0067 89.8807 3C4 R164E 105.0589 105.7286 21B12 R519E 139.4598 141.2949 31H4 R519E 135.5609 140.0000 31A4 R519E 134.2303 137.1110 12H11 R519E 135.4755 137.0824 3C4 R519E 44.0091 21B12 S123R 87.6431 88.1356 31H4 S123R 85.5312 84.7668 31A4 S123R 68.4371 66.6131 12H11 S123R 20.8560 20.6910 3C4 S123R 73.6475 71.5959 (Point mutations are with reference to SEQ ID NO: 1 and FIG. 26).
[0587) Table 39.5 displays a summary of all of the hits for the various antibodies. 172 PCT/US2008/074097
Table 39.5
EC50 shift hits Bmax shift hits 21B12 31H4 31A4 12H11 3C4 21B12 31 Hli 31A4 12H11 3C4 I R207E R185E R439E T132R E582R D162R S123R R519E D208R* E513R S351R R164E E129R H521R V538R A390R E167R A311R Q554R E539R A413R D313R * decreases EC50 D337R WO 2009/026558 [0588] To further examine how these residues form part of or all of the relevant epitopes, the above noted positions were mapped onto various crystal structure models, the results are shown in FIG. 27A through 27E. FIG. 27A depicts the 21B12 epitope hits, as mapped onto a crystal structure of PCSK9 with the 21B12 antibody. The structure identifies PCSK9 residues as follows: light gray indicates those residues that were not mutated (with the exception of those residues that are explicitly indicated on the structure) and darker gray indicates those residues mutated (a minority of which failed to express). Residues that are explicitly indicated were tested (regardless of the shading indicated on the figure) and resulted in a significant change in EC50 and/or Bmax The epitope hits were based on Bmax shift. In this figure, 31H4 is behind 21 B12.
[0589] FIG. 27B depicts the 31H4 epitope hits, as mapped onto a crystal structure of PCSK9 with 31H4 and 21B12 antibodies. The structure identifies PCSK9 residues as follows: light gray indicates those residues that were not mutated (with the exception of those residues that are explicitly indicated on the structure) and darker gray indicates those residues mutated (a minority of which failed to express). Residues that are explicitly indicated were tested (regardless of the shading indicated on the figure) and resulted in a significant change in EC50 and/or Bmax . The epitope hits were based on the EC50 shift.
[0590] FIG. 27C depicts the 31A4 epitope hits, as mapped onto a crystal structure of PCSK9 with 31H4 and 21B12 antibodies. The structure identifies PCSK9 residues as follows: light gray indicates those residues that were not mutated (with the exception of those residues that are explicitly indicated on the structure) and darker gray indicates those residues mutated (a minority of which failed to express). Residues that are explicitly indicated were tested 173 PCT/US2008/074097 WO 2009/026558 (regardless of the shading indicated on the figure) and resulted in a significant change in EC50 and/or Bmax. The epitope hits were based on the EC50 shift. 31A4 antibody is known to bind to the V-domain of PCSK9, which appears consistent with the results presented in FIG. 27C.
[0591] FIG. 27D depicts the 12H11 epitope hits, as mapped onto the crystal structure of PCSK9 with 31H4 and 21B12 antibodies. The structure identifies PCSK9 residues as follows: light gray indicates those residues that were not mutated (with the exception of those residues that are explicitly indicated on the structure) and darker gray indicates those residues mutated (a minority of which failed to express). Residues that are explicitly indicated were tested (regardless of the shading indicated on the figure) and resulted in a significant change in EC50 and/or Bmax. 12H11 competes with 21B12 and 31H4 in the binning assay described above.
[0592] FIG. 27E depicts the 3C4 epitope hits, as mapped onto the crystal structure of PCSK9 with 31H4 and 2IB 12 antibodies. The structure identifies PCSK9 residues as follows: light gray indicates those residues that were not mutated (with the exception of those residues that are explicitly indicated on the structure) and darker gray indicates those residues mutated (a minority of which failed to express). Residues that are explicitly indicated were tested (regardless of the shading indicated on the figure) and resulted in a significant change in EC50 and/or Bmax.
[0593] 3C4 does not compete with 21B12 and 31H4 in the binning assay. 3C4 binds to the V-domain in the domain binding assay (see results from Example 40, FIGs. 28A and 28B).
[0594] While there were approximately a dozen mutants that could have been expected to have an effect on binding (based upon the crystal structure), the present experiment demonstrated that, surprisingly, they did not. As will be appreciated by one of skill in the art, the results presented above are in good agreement with the crystal structures and PCSK-9’s binding of these antibodies. This demonstrates that the provided structural and corresponding functional data adequately identifies the key residues and areas of interaction of the neutralizing ABPs and PCSK9. Thus, variants of the ABPs that possess the ability to bind to the above noted areas are adequately provided by the present description.
[0595] As will be appreciated by one of skill in the art, while the B-max drop and EC50 shift hits can be considered manifestations of the same phenomenon, strictly speaking, a B-max drop alone does not reflect a loss of affinity per se but, rather, the destruction of some percentage of the epitope of an antibody. Although there is no overlap in the hits determined by 174 PCT/US2008/074097 WO 2009/026558 B-max and EC50, mutations with a strong affect on binding may not allow for the generation of a useful binding curve and hence, no EC50 can be determined for such variants.
[0596] As will be appreciated by one of skill in the art, ABPs in the same bin (with the exception of bin 5, which as noted above, is a general catch all bin) likely bind to overlapping sites on the target protein. As such, the above epitopes and relevant residues can generally be extended to all such ABPs in the same bin.
[0597] To further examine the above results in regard to ΑΒΡ 31H4, position E181R, which, according to the above crystal structure, was predicted to interact with R185 to form part of the surface that interacts with the ABP, was also altered (E181R). The results, while not statistically significant on their own, were, when combined with the crystal structure, demonstrative of 31H4 interacting with E181R (data not shown). Thus, position 181 also appears to form part of the epitope for the 31H4 ABP.
[0598] As noted above, the above binding data and epitope characterization references a PCSK9 sequence (SEQ ID NO: 1) that does not include the first 30 amino acids of PCSK9. Thus, the numbering system of this protein fragment, and the SEQ ID NO:s that refer to this fragment, are shifted by 30 amino acids compared to the data and experiments that used a full length PCSK9 numbering system(such as that used in the crystal study data described above). Thus, to compare these results, an extra 30 amino acids should be added to the positions in each of the above epitope mapping results. For example, position 207 of SEQ ID NO: 1 (or SEQ ID NO: 303), correlates to position 237 of SEQ ID NO: 3 (the full length sequence, and the numbering system used throughout the rest of the specification). Table 39.6 outlines how the above noted positions, which reference SEQ ID NO: 1 (and/or SEQ ID NO: 303) correlate with SEQ ID NO: 3 (which includes the signal sequence). TABLE 39.6
AMINO ACID POSITION IN SEQ ID AMINO ACID POSITION IN SEQ ID NO: 1 (EPITOPE DATA) NO: 3 (EPITOPE DATA) 207 237 208 238 185 215 181 211 439 469 513 543 538 568 175 539 569 132 162 351 381 390 420 413 443 582 612 162 192 164 194 167 197 123 153 129 159 311 341 313 343 337 367 519 549 521 551 554 584 WO 2009/026558 PCT/US2008/074097 [0599] Thus, those embodiments described herein with reference to SEQ ID NO: 1 can also be described, by their above noted corresponding position with reference to SEQ ID NO: 3. EXAMPLE 40 PCSK9 Domain Binding Assay [0600] The present example examined where on PCSK9 the various ABPs bound.
[0601] Clear, 96 well maxisorp plates (Nunc) were coated overnight with 2 ug/ml of various anti-PCSK9 antibodies diluted in PBS. Plates were washed thoroughly with PBS/.05% Tween-20 and then blocked for two hours with 3% BSA/PBS. After washing, plates were incubated for two hours with either full length PCSK9 (aa 31-692 SEQ ID NO: 3, procat PCSK9 (aa 31-449 SEQ ID NO: 3) or v-domain PCSK9 (aa 450-692 of SEQ ID NO: 3) diluted in general assay diluent (Immunochemistry Technologies, LLC). Plates were washed and a rabbit polyclonal biotinylated anti-PCSK9 antibody (D8774), which recognizes the procat and v-domain as well as full-length PCSK9, was added at 1 ug/ml (in 1%BSA/PBS). Bound full-length, procat or v-domain PCSK9 was detected by incubation with neutravidin-HRP (Thermo Scientific) at 200 ng/ml (in 1% BSA/PBS) followed by TMB substrate (KPL) and absorbance measurement at 650 nm. The results, presented in FIGS. 28A and 28B, demonstrate the ability of the various ABS to bind to various parts of PCSK9. As shown in FIG. 28B, ABP 31A4 binds to the V domain of PCSK9. 176 PCT/US2008/074097 WO 2009/026558 EXAMPLE 41
Neutralizing, non-competitive antigen binding proteins [0602] The present example demonstrates how to identify and characterize an antigen binding protein that is non-competitive with LDLR for binding with PCSK9, but is still neutralizing towards PCSK9 activity. In other words, such an antigen binding protein will not block PCSK9 from binding to LDLR, but will prevent or reduce PCSK9 mediated LDLR degradation.
[0603] Clear, 384 well plates (Costar) were coated with 2 ug/ml of goat anti-LDL receptor antibody (R&amp;D Systems) diluted in buffer A (100 mM sodium cacodylate, pH 7.4). Plates were washed thoroughly with buffer A and then blocked for 2 hours with buffer B (1% milk in buffer A). After washing, plates were incubated for 1.5 hours with 0.4 ug/ml of LDL receptor (R&amp;D Systems) diluted in buffer C (buffer B supplemented with 10 mM CaCL). Concurrent with this incubation, 20 ng/ml of biotinylated D374Y PCSK9 was incubated with 100 ng/ml of antibody diluted in buffer A or buffer A alone (control). The LDL receptor containing plates were washed and the biotinylated D374Y PCSK9/antibody mixture was transferred to them and incubated for 1 hour at room temperature. Binding of the biotinylated D374Y to the LDL receptor was detected by incubation with streptavidin-HRP (Biosource) at 500 ng/ml in buffer C followed by TMB substrate (KPL). The signal was quenched with IN HC1 and the absorbance read at 450 nm. The results are presented in FIG. 28C, which shows that while ABP 31H4 inhibits LDLR binding, ABP 31A4 does not inhibit LDLR binding to PCSK9. In combination with the results from Example 40 and shown in FIGs. 28A and 28B, it is clear that 31A4 ABP binds to the V domain of PCSK9 and does not block the interaction of PCSK9 with LDLR.
[0604] Next, the Ability of ABP 31A4 to serve as a neutralizing ABP was further confirmed via a cell LDL uptake assay (as described in the examples above). The results of this LDL uptake assay are presented in FIG. 28D. As shown in FIG. 28D, ABP 31A4 displays significant PCSK9 neutralizing ability. Thus, in light of Example 40 and the present results, it is clear that ABPs can bind to PCSK9 without blocking the PCSK9 and LDLR binding interaction, while still being useful as neutralizing PCSK9 ABPs. 177
Incorporation by Reference 2013203748 12 Dec 2014 [0605] All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety. To the extent that any of the definitions or terms provided in the references incorporated by reference differ from the terms and discussion provided herein, the present terms and definitions control.
Equivalents [0606] The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The foregoing description and examples detail certain preferred embodiments of the invention and describe the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof.
[0607] Throughout the specification and claims, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
[0608] Each document, reference, patent application or patent cited in this text is expressly incorporated herein in their entirety by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness.
[0609] Reference to cited material or information contained in the text should not be understood as a concession that the material or information was part of the common general knowledge or was known in Australia or any other country. 178 WO 2009/026558 PCT/US2008/074097 TABLE 35.1 ATOM 1 CB THR 61 -65.324 19.274 -35.379 1.00 66.96 A C ATOM 2 OG1 THR 61 -64.490 20.386 -35.733 1.00 67.86 A O ATOM 3 CG2 THR 61 -65.574 19.285 -33.870 1.00 66.57 A C ATOM 4 C THR 61 -63.283 17.835 -35.088 1.00 62.73 A c ATOM 5 O THR 61 -63.080 16.945 -34.257 1.00 63.03 A 0 ATOM 6 N THR 61 -65.516 16.775 -35.528 1.00 66.08 A N ATOM 7 CA THR 61 -64.635 17.950 -35.808 1.00 65.41 A c ATOM 8 N ALA 62 -62.364 18.740 -35.417 1.00 59.54 A N ATOM 9 CA ALA 62 -61.013 18.712 -34.866 1.00 55.44 A C ATOM 10 CB ALA 62 -60.100 19.581 -35.709 1.00 54.24 A c ATOM 11 C ALA 62 -60.988 19.182 -33.414 1.00 53.41 A c ATOM 12 O ALA 62 -61.570 20.211 -33.075 1.00 53.36 A 0 ATOM 13 N THR 63 -60.309 18.421 -32.561 1.00 50.60 A N ATOM 14 CA THR 63 -60.219 18.743 -31.141 1.00 48.08 A c ATOM 15 CB THR 63 -60.538 17.503 -30.272 1.00 48.75 A c ATOM 16 OG1 THR 63 -59.717 16.402 -30.683 1.00 48.97 A 0 ATOM 17 CG2 THR 63 -61.997 17.104 -30.426 1.00 47.89 A c ATOM 18 C THR 63 -58.831 19.261 -30.766 1.00 46.77 A c ATOM 19 O THR 63 -57.853 19.004 -31.465 1.00 46.12 A 0 ATOM 20 N PHE 64 -58.754 19.999 -29.662 1.00 45.98 A N ATOM 21 CA PHE 64 -57.476 20.471 -29.136 1.00 44.11 A c ATOM 22 CB PHE 64 -57.537 21.980 -28.894 1.00 42.47 A c ATOM 23 CG PHE 64 -56.352 22.529 -28.150 1.00 41.54 A c ATOM 24 CDl PHE 64 -55.113 22.627 -28.764 1.00 39.91 A c ATOM 25 CD2 PHE 64 -56.484 22.964 -26.839 1.00 40.63 A c ATOM 26 CEl PHE 64 -54.024 23.149 -28.085 1.00 39.85 A c ATOM 27 CE2 PHE 64 -55.399 23.489 -26.151 1.00 40.22 A c ATOM 28 CZ PHE 64 -54.166 23.582 -26.776 1.00 39.77 A c ATOM 29 C PHE 64 -57.110 19.744 -27.841 1.00 44 . 16 A c ATOM 30 O PHE 64 -57.966 19.506 -26.982 1.00 43.98 A 0 ATOM 31 N HIS 65 -55.834 19.388 -27.711 1.00 43.51 A N ATOM 32 CA HIS 65 -55.348 18.640 -26.554 1.00 42.21 A c ATOM 33 CB HIS 65 -55.015 17.204 -26.964 1.00 42.39 A c ATOM 34 CG HIS 65 -56.168 16.477 -27.581 1.00 45.11 A c ATOM 35 CD2 HIS 65 -56.648 16.477 -28.848 1.00 46.30 A c ATOM 36 ND1 HIS 65 -57.005 15.656 -26.855 1.00 45.17 A N ATOM 37 CEl HIS 65 -57.951 15.183 -27.648 1.00 4 5.62 A c ATOM 38 NE2 HIS 65 -57.757 15.666 -28.863 1.00 45.65 A N ATOM 39 C HIS 65 -54.115 19.297 -25.941 1.00 42.51 A C ATOM 40 0 HIS 65 -53.276 19.865 -26.643 1.00 41.98 A 0 ATOM 41 N ARG 66 -54.013 19.220 -24.622 1.00 42.62 A N ATOM 42 CA ARG 66 -52.863 19.765 -23.916 1.00 43.48 A C ATOM 43 CB ARG 66 -53.152 21.202 -23.471 1.00 45.30 A c ATOM 44 CG ARG 66 -54.358 21.305 -22.561 1.00 51.92 A c ATOM 45 CD ARG 66 -54.333 22.550 -21.702 1.00 57.80 A c ATOM 46 NE ARG 66 -55.193 22.390 -20.530 1.00 63.34 A N ATOM 47 CZ ARG 66 -54.755 22.114 -19.302 1.00 66.07 A c ATOM 48 NHl ARG 66 -55.620 21.983 -18.304 1.00 68.14 A N ATOM 49 NH2 ARG 66 -53.457 21.979 -19.063 1.00 66.65 A N ATOM 50 C ARG 66 -52.570 18.890 -22.698 1.00 42.14 A C ATOM 51 O ARG 66 -53.427 18.129 -22.246 1.00 41.73 A 0 ATOM 52 N CYS 67 -51.358 18.999 -22.172 1.00 40.93 A N ATOM 53 CA CYS 67 -50.965 18.224 -21.004 1.00 41.21 A C ATOM 54 CB CYS 67 -49.500 18.505 -20.678 1.00 41.47 A c ATOM 55 SG CYS 67 -48.844 17.576 -19.295 1.00 40.60 A s ATOM 56 C CYS 67 -51.843 18.605 -19.813 1.00 43.29 A c ATOM 57 O CYS 67 -52.072 19.789 -19.555 1.00 43.45 A 0 ATOM 58 N ALA 68 -52.331 17.606 -19.088 1.00 43.43 A N ATOM 59 CA ALA 68 -53.144 17.871 -17.907 1.00 4 5.62 A c ATOM 60 CB ALA 68 -53.809 16.579 -17.416 1.00 43.28 A c ATOM 61 C ALA 68 -52.315 18.501 -16.783 1.00 46.90 A c ATOM 62 O ALA 68 -52.852 19.232 -15.949 1.00 46.15 A 0 ATOM 63 N LYS 69 -51.010 18.227 -16.767 1.00 48.41 A N ATOM 64 CA LYS 69 -50.132 18.747 -15.715 1.00 50.02 A c ATOM 65 CB LYS 69 -48.974 17.773 -15.454 1.00 52.87 A c ATOM 66 CG LYS 69 -49.388 16.305 -15.385 1.00 58.02 A c ATOM 67 CD LYS 69 -49.184 15.722 -13.990 1.00 61.71 A c ATOM 68 CE LYS 69 -50.035 14.472 -13.783 1.00 63.38 A c ATOM 69 NZ LYS 69 -50.285 14.221 -12.334 1.00 64.13 A N ATOM 70 C LYS 69 -49.575 20.110 -16.119 1.00 48.59 A c ATOM 71 0 LYS 69 -48.626 20.200 -16.891 1.00 49.36 A 0 ATOM 72 N ASP 70 -50.160 21.169 -15.576 1.00 48.35 A N ATOM 73 CA ASP 70 -49.948 22.512 -16.099 1.00 47.47 A c ATOM 74 CB ASP 70 -50.744 23.526 -15.268 1.00 52.53 A c 179 WO 2009/026558 PCT/US2008/074097 ATOM 75 CG ASP 70 -51.508 ATOM 76 OD1 ASP 70 -52.644 ATOM 77 OD2 ASP 70 -50.971 ATOM 78 C ASP 70 -48.488 ATOM 79 O ASP 70 -48.098 ATOM 80 N PRO 71 -47.665 ATOM 81 CD PRO 71 -48.023 ATOM 82 CA PRO 71 -46.258 ATOM 83 CB PRO 71 -45.723 ATOM 84 CG PRO 71 -46.688 ATOM 85 C PRO 71 -45.402 ATOM 86 O PRO 71 -44.280 ATOM 87 N TRP 72 -45.925 ATOM CO CO CA TRP 72 -45.201 ATOM 89 CB TRP 72 -45.456 ATOM 90 CG TRP 72 -44.904 ATOM 91 CD2 TRP 72 -45.042 ATOM 92 CE2 TRP 72 -44.381 ATOM 93 CE3 TRP 72 -45.659 ATOM 94 CDl TRP 72 -44.183 ATOM 95 NEl TRP 72 -43.866 ATOM 96 CZ2 TRP 72 -44.322 ATOM 97 CZ3 TRP 72 -45.600 ATOM 98 CH2 TRP 72 -44.935 ATOM 99 C TRP 72 -45.622 ATOM 100 O TRP 72 -45.074 ATOM 101 N ARG 73 -46.599 ATOM 102 CA ARG 73 -47.088 ATOM 103 CB ARG 73 -48.370 ATOM 104 CG ARG 73 -49.543 ATOM 105 CD ARG 73 -50.786 ATOM 106 NE ARG 73 -50.898 ATOM 107 CZ ARG 73 -51.976 ATOM 108 NHl ARG 73 -53.045 ATOM 109 NH2 ARG 73 -51.983 ATOM 110 C ARG 73 -46.042 ATOM 111 O ARG 73 -45.294 ATOM 112 N LEU 74 -45.986 ATOM 113 CA LEU 74 -45.086 ATOM 114 CB LEU 74 -43.966 ATOM 115 CG LEU 74 -42.990 ATOM 116 CDl LEU 74 -42.183 ATOM 117 CD2 LEU 74 -42.061 ATOM 118 C LEU 74 -45.846 ATOM 119 O LEU 74 -45.677 ATOM 120 N PRO 75 -46.687 ATOM 121 CD PRO 75 -46.820 ATOM 122 CA PRO 75 -47.519 ATOM 123 CB PRO 75 -48.351 ATOM 124 CG PRO 75 -47.545 ATOM 125 C PRO 75 -46.688 ATOM 126 O PRO 75 -45.553 ATOM 127 N GLY 76 -47.249 ATOM 128 CA GLY 76 -46.513 ATOM 129 C GLY 76 -45.937 ATOM 130 0 GLY 76 -45.480 ATOM 131 N THR 77 -45.947 ATOM 132 CA THR 77 -45.584 ATOM 133 CB THR 77 -44.197 ATOM 134 OG1 THR 77 -43.199 ATOM 135 CG2 THR 77 -43.840 ATOM 136 C THR 77 -46.647 ATOM 137 O THR 77 -47.129 ATOM 138 N TYR 78 -47.024 ATOM 139 CA TYR 78 -48.156 ATOM 140 CB TYR 78 -49.396 ATOM 141 CG TYR 78 -49.730 ATOM 142 CDl TYR 78 -49.199 ATOM 143 CEl TYR 78 -49.408 ATOM 144 CD2 TYR 78 -50.494 ATOM 145 CE2 TYR 78 -50.709 ATOM 146 CZ TYR 78 -50.157 ATOM 147 OH TYR 78 -50.305 ATOM 148 C TYR 78 -47.840 ATOM 149 O TYR 78 -47.154 ATOM 150 N VAL 79 -48.343
-16.137 1.00 57.41 A C -16.562 1.00 58.27 A O -16.399 1.00 57.80 A O -16.200 1.00 44.86 A c -17.180 1.00 45.04 A 0 -15.187 1.00 41.90 A N -13.845 1.00 40.54 A c -15.281 1.00 39.08 A c -13.857 1.00 39.03 A c -13.186 1.00 41.03 A c -16.324 1.00 37.94 A c -16.608 1.00 36.99 A 0 -16.893 1.00 36.09 A N -17.933 1.00 34.40 A c -17.806 1.00 32.15 A c -16.551 1.00 29.66 A c -16.126 1.00 28.28 A c -14.884 1.00 29.32 A c -16.674 1.00 26.21 A c -15.580 1.00 28.83 A c -14.574 1.00 27.11 A N -14.181 1.00 28.10 A c -15.978 1.00 29.75 A c -14.741 1.00 30.43 A c -19.327 1.00 33.51 A c -20.330 1.00 34.06 A 0 -19.379 1.00 33.72 A N -20.643 1.00 35.14 A c -20.407 1.00 37.00 A c -19.975 1.00 41.40 A c -19.825 1.00 45.06 A c -20.902 1.00 50.54 A N -21.127 1.00 54.08 A c -20.347 1.00 55.58 A N -22.126 1.00 54.14 A N -21.304 1.00 34.68 A C -20.619 1.00 35.28 A 0 -22.633 1.00 32.04 A N -23.385 1.00 32.47 A C -24.031 1.00 31.53 A c -23.087 1.00 32.34 A c -23.863 1.00 27.72 A c -22.437 1.00 28.10 A c -24.468 1.00 33.33 A c -25.662 1.00 33.93 A 0 -24.064 1.00 34.33 A N -22.698 1.00 33.65 A c -25.039 1.00 34.35 A c -24.174 1.00 35.25 A c -22.915 1.00 35.46 A c -26.083 1.00 33.52 A c -25.817 1.00 32.98 A 0 -27.275 1.00 32.91 A N -28.328 1.00 32.08 A c -29.371 1.00 31.14 A c -30.424 1.00 31.40 A 0 -29.080 1.00 30.23 A N -30.073 1.00 30.51 A c -29.776 1.00 32.27 A c -29.816 1.00 33.45 A 0 -30.819 1.00 32.84 A c -30.107 1.00 30.00 A c -29.064 1.00 30.45 A 0 -31.317 1.00 28.44 A N -31.514 1.00 27.71 A c -31.939 1.00 27.62 A c -30.967 1.00 29.17 A c -31.128 1.00 29.25 A c -30.183 1.00 31.96 A c -29.837 1.00 28.93 A c -28.880 1.00 32.16 A c -29.057 1.00 32.47 A c -28.082 1.00 32.98 A 0 -32.570 1.00 27.76 A c -33.559 1.00 25.34 A 0 -32.341 1.00 26.43 A N 180 WO 2009/026558 PCT/US2008/074097 ATOM 151 CA VAL 79 -48.337 19.311 -33.357 1.00 27.54 A C ATOM 152 CB VAL 79 -48.010 17.921 -32.760 1.00 28.88 A C ATOM 153 CGI VAL 79 -48.012 16.871 -33.868 1.00 27.66 A c ATOM 154 CG2 VAL 79 -46.666 17.959 -32.059 1.00 28.19 A c ATOM 155 C VAL 79 -49.726 19.259 -33.961 1.00 28.85 A c ATOM 156 O VAL 79 -50.712 18.983 -33.264 1.00 28.23 A 0 ATOM 157 N VAL 80 -49.807 19.534 -35.255 1.00 28.01 A N ATOM 158 CA VAL 80 -51.073 19.430 -35.960 1.00 28.18 A c ATOM 159 CB VAL 80 -51.194 20.529 -37.028 1.00 28.78 A c ATOM 160 CGI VAL 80 -52.524 20.404 -37.761 1.00 28.21 A c ATOM 161 CG2 VAL 80 -51.061 21.904 -36.362 1.00 26.47 A c ATOM 162 C VAL 80 -51.126 18.063 -36.617 1.00 30.35 A c ATOM 163 O VAL 80 -50.352 17.769 -37.533 1.00 30.14 A 0 ATOM 164 N VAL 81 -52.024 17.215 -36.128 1.00 30.97 A N ATOM 165 CA VAL 81 -52.139 15.869 -36.657 1.00 32.26 A c ATOM 166 CB VAL 81 -52.423 14.850 -35.534 1.00 33.61 A c ATOM 167 CGI VAL 81 -52.529 13.441 -36.121 1.00 31.68 A c ATOM 168 CG2 VAL 81 -51.316 14.915 -34.487 1.00 31.98 A c ATOM 169 C VAL 81 -53.271 15.838 -37.674 1.00 34.32 A c ATOM 170 O VAL 81 -54.400 16.235 -37.373 1.00 33.98 A 0 ATOM 171 N LEU 82 -52.955 15.387 -38.883 1.00 34.05 A N ATOM 172 CA LEU 82 -53.938 15.329 -39.961 1.00 37.51 A c ATOM 173 CB LEU 82 -53.260 15.638 -41.300 1.00 34.52 A c ATOM 174 CG LEU 82 -52.581 17. Oil -41.323 1.00 34.04 A c ATOM 175 CDl LEU 82 -52.087 17.337 -42.720 1.00 33.14 A c ATOM 176 CD2 LEU 82 -53.566 18.057 -40.857 1.00 33.19 A c ATOM 177 C LEU 82 -54.595 13.950 -40.009 1.00 39.40 A c ATOM 178 O LEU 82 -54.057 12.980 -39.475 1.00 38.11 A 0 ATOM 179 N LYS 83 -55.764 13.864 -40.634 1.00 44.40 A N ATOM 180 CA LYS 83 -56.464 12.586 -40.745 1.00 49.45 A c ATOM 181 CB LYS 83 -57.752 12.756 -41.550 1.00 50.92 A c ATOM 182 CG LYS 83 -58.854 13.495 -40.800 1.00 55.63 A c ATOM 183 CD LYS 83 -59.854 14.109 -41.767 1.00 59.44 A c ATOM 184 CE LYS 83 -60.934 14.899 -41.036 1.00 62.03 A c ATOM 185 NZ LYS 83 -61.717 15.751 -41.986 1.00 64.41 A N ATOM 186 C LYS 83 -55.560 11.562 -41.418 1.00 51.74 A c ATOM 187 0 LYS 83 -54.770 11.901 -42.301 1.00 50.75 A 0 ATOM 188 N GLU 84 -55.663 10.309 -40.997 1.00 55.37 A N ATOM 189 CA GLU 84 -54.787 9.289 -41.549 1.00 60.52 A c ATOM 190 CB GLU 84 -54.910 7.985 -40.756 1.00 63.78 A c ATOM 191 CG GLU 84 -56.292 7.371 -40.753 1.00 69.97 A c ATOM 192 CD GLU 84 -56.295 5.986 -40.129 1.00 74.43 A c ATOM 193 OE1 GLU 84 -57.294 5.631 -39.462 1.00 75.98 A 0 ATOM 194 OE2 GLU 84 -55.293 5.254 -40.306 1.00 75.33 A 0 ATOM 195 C GLU 84 -55.110 9.052 -43.022 1.00 61.14 A c ATOM 196 0 GLU 84 -56.248 9.246 -43.458 1.00 60.67 A 0 ATOM 197 N GLU 85 -54.089 8.649 -43.774 1.00 61.46 A N ATOM 198 CA GLU 85 -54.163 8.519 -45.227 1.00 63.36 A c ATOM 199 CB GLU 85 -55.532 7.980 -45.662 1.00 67.22 A c ATOM 200 CG GLU 85 -55.846 6.597 -45.096 1.00 73.81 A c ATOM 201 CD GLU 85 -56.946 5.875 -45.858 1.00 78.53 A c ATOM 202 OE1 GLU 85 -57.733 6.545 -46.567 1.00 80.96 A 0 ATOM 203 OE2 GLU 85 -57.022 4.630 -45.745 1.00 80.38 A 0 ATOM 204 C GLU 85 -53.865 9.835 -45.944 1.00 61.28 A c ATOM 205 0 GLU 85 -53.744 9.869 -47.172 1.00 61.77 A 0 ATOM 206 N THR 86 -53.735 10.917 -45.181 1.00 57.81 A N ATOM 207 CA THR 86 -53.256 12.173 -45.746 1.00 54.38 A c ATOM 208 CB THR 86 -53.297 13.312 -44.701 1.00 52.95 A c ATOM 209 OG1 THR 86 -54.654 13.549 -44.307 1.00 50.34 A 0 ATOM 210 CG2 THR 86 -52.720 14.593 -45.281 1.00 50.02 A c ATOM 211 C THR 86 -51.821 11.989 -46.243 1.00 53.59 A c ATOM 212 O THR 86 -50.973 11.435 -45.539 1.00 52.24 A 0 ATOM 213 N HIS 87 -51.562 12.442 -47.466 1.00 52.07 A N ATOM 214 CA HIS 87 -50.250 12.287 -48.084 1.00 51.71 A c ATOM 215 CB HIS 87 -50.401 12.183 -49.605 1.00 55.85 A c ATOM 216 CG HIS 87 -51.185 10.986 -50.052 1.00 63.40 A c ATOM 217 CD2 HIS 87 -52.429 10.880 -50.579 1.00 64.75 A c ATOM 218 NDl HIS 87 -50.690 9.700 -49.975 1.00 65.63 A N ATOM 219 CE 1 HIS 87 -51.597 8.854 -50.434 1.00 66.35 A c ATOM 220 NE2 HIS 87 -52.660 9.544 -50.807 1.00 65.74 A N ATOM 221 C HIS 87 -49.312 13.445 -47.732 1.00 48.81 A C ATOM 222 0 HIS 87 -49.760 14.519 -47.319 1.00 47.37 A 0 ATOM 223 N LEU 88 -48.011 13.213 -47.896 1.00 46.04 A N ATOM 224 CA LEU 88 -46.992 14.193 -47.536 1.00 44.77 A C ATOM 225 CB LEU 88 -45.601 13.697 -47.944 1.00 43.47 A c ATOM 226 CG LEU 88 -44.448 14.702 -47.814 1.00 44.24 A c 181 WO 2009/026558 PCT/US2008/074097 ATOM 227 CDl LEU 88 -44.344 ATOM 228 CD2 LEU 88 -43.149 ATOM 229 C LEU 88 -47.250 ATOM 230 O LEU 88 -47.167 ATOM 231 N SER 89 -47.568 ATOM 232 CA SER 89 -47.769 ATOM 233 CB SER 89 -47.949 ATOM 234 OG SER 89 -48.935 ATOM 235 C SER 89 -48.968 ATOM 236 O SER 89 -48.992 ATOM 237 N GLN 90 -49.954 ATOM 238 CA GLN 90 -51.101 ATOM 239 CB GLN 90 -52.241 ATOM 240 CG GLN 90 -52.820 ATOM 241 CD GLN 90 -53.850 ATOM 242 OE1 GLN 90 -53.500 ATOM 243 NE2 GLN 90 -55.127 ATOM 244 C GLN 90 -50.737 ATOM 245 0 GLN 90 -51.158 ATOM 246 N SER 91 -49.960 ATOM 247 CA SER 91 -49.456 ATOM 248 CB SER 91 -48.607 ATOM 249 OG SER 91 -49.340 ATOM 250 C SER 91 -48.596 ATOM 251 O SER 91 -48.730 ATOM 252 N GLU 92 -47.711 ATOM 253 CA GLU 92 -46.823 ATOM 254 CB GLU 92 -45.942 ATOM 255 CG GLU 92 -44.600 ATOM 256 CD GLU 92 -44.680 ATOM 257 OE1 GLU 92 -43.855 ATOM 258 OE2 GLU 92 -45.566 ATOM 259 C GLU 92 -47.649 ATOM 260 0 GLU 92 -47.367 ATOM 261 N ARG 93 -48.680 ATOM 2 62 CA ARG 93 -49.527 ATOM 263 CB ARG 93 -50.435 ATOM 264 CG ARG 93 -49.726 ATOM 265 CD ARG 93 -50.717 ATOM 266 NE ARG 93 -50.750 ATOM 267 CZ ARG 93 -51.698 ATOM 268 NHl ARG 93 -51.630 ATOM 269 NH2 ARG 93 -52.715 ATOM 270 C ARG 93 -50.387 ATOM 271 O ARG 93 -50.610 ATOM 272 N THR 94 -50.869 ATOM 273 CA THR 94 -51.674 ATOM 274 CB THR 94 -52.275 ATOM 275 OG1 THR 94 -53.069 ATOM 276 CG2 THR 94 -53.159 ATOM 277 C THR 94 -50.843 ATOM 278 O THR 94 -51.341 ATOM 279 N ALA 95 -49.574 ATOM 280 CA ALA 95 -48.687 ATOM 281 CB ALA 95 -47.331 ATOM 282 C ALA 95 -48.496 ATOM 283 O ALA 95 -48.536 ATOM 284 N ARG 96 -48.297 ATOM 285 CA ARG 96 -48.094 ATOM 286 CB ARG 96 -47.563 ATOM 287 CG ARG 96 -46.128 ATOM 288 CD ARG 96 -45.424 ATOM 289 NE ARG 96 -44.078 ATOM 290 CZ ARG 96 -42.998 ATOM 291 NHl ARG 96 -41.814 ATOM 2 92 NH2 ARG 96 -43.096 ATOM 293 C ARG 96 -49.383 ATOM 294 O ARG 96 -49.357 ATOM 295 N ARG 97 -50.512 ATOM 296 CA ARG 97 -51.805 ATOM 297 CB ARG 97 -52.915 ATOM 298 CG ARG 97 -54.299 ATOM 299 CD ARG 97 -55.098 ATOM 300 NE ARG 97 -56.533 ATOM 301 CZ ARG 97 -57.321 ATOM 302 NHl ARG 97 -58.617
-46.379 1.00 40.89 A C -48.245 1.00 42.45 A C -48.176 1.00 43.96 A C -47.508 1.00 42.78 A 0 -49.467 1.00 43.13 A N -50.187 1.00 4 3.67 A c -51.691 1.00 43.34 A c -51.926 1.00 47.73 A 0 -49.634 1.00 41.76 A c -49.663 1.00 43.20 A 0 -49.116 1.00 40.72 A N -48.471 1.00 41.68 A c -48.289 1.00 45.43 A c -49.606 1.00 51.25 A c -49.394 1.00 54.98 A c -49.059 1.00 54.79 A 0 -49.589 1.00 54.36 A N -47.114 1.00 39.35 A c -46.820 1.00 38.00 A 0 -46.297 1.00 36.66 A N -45.037 1.00 36.04 A c -44.289 1.00 36.68 A c -44.034 1.00 45.07 A 0 -45.311 1.00 34.52 A c -44.648 1.00 31.21 A 0 -46.296 1.00 34.78 A N -46.664 1.00 37.08 A c -47.847 1.00 37.84 A c -47.938 1.00 42.08 A c -48.662 1.00 43.83 A c -48.358 1.00 38.38 A 0 -49.539 1.00 45.37 A 0 -47.028 1.00 37.77 A c -46.549 1.00 36.08 A 0 -47.855 1.00 37.72 A N -48.300 1.00 37.76 A c -49.457 1.00 39.31 A c -50.808 1.00 46.60 A c -51.963 1.00 52.39 A c -52.419 1.00 56.69 A N -52.098 1.00 58.62 A c -52.563 1.00 58.46 A N -51.319 1.00 59.41 A N -47.181 1.00 35.91 A C -47.121 1.00 36.85 A 0 -46.292 1.00 34.43 A N -45.173 1.00 34.17 A C -44.401 1.00 35.39 A c -45.297 1.00 35.45 A 0 -43.246 1.00 33.36 A c -44.218 1.00 34.67 A c -43.673 1.00 34.08 A 0 -44.031 1.00 33.89 A N -43.203 1.00 35.56 A c -43.037 1.00 32.25 A c -43.816 1.00 36.52 A c -43.107 1.00 35.42 A 0 -45.132 1.00 36.12 A N -45.807 1.00 38.95 A c -47.234 1.00 37.87 A c -47.253 1.00 40.62 A c -48.575 1.00 41.07 A c -48.616 1.00 41.43 A N -48.093 1.00 41.81 A c -48.180 1.00 41.20 A N -47.481 1.00 39.73 A N -45.841 1.00 39.48 A C -45.812 1.00 39.37 A 0 -45.885 1.00 39.22 A N -45.815 1.00 41.01 A C -46.028 1.00 45.31 A c -46.199 1.00 52.12 A c -47.200 1.00 60.48 A c -46.930 1.00 66.20 A N -47.226 1.00 68.21 A c -46.940 1.00 68.65 A N 182 WO 2009/026558 PCT/US2008/074097 ATOM 303 NH2 ARG 97 -56.813 ATOM 304 C ARG 97 -51.979 ATOM 305 O ARG 97 -52.377 ATOM 306 N LEU 98 -51.674 ATOM 307 CA LEU 98 -51.764 ATOM 308 CB LEU 98 -51.356 ATOM 309 CG LEU 98 -51.216 ATOM 310 CDl LEU 98 -52.558 ATOM 311 CD2 LEU 98 -50.727 ATOM 312 C LEU 98 -50.862 ATOM 313 O LEU 98 -51.275 ATOM 314 N GLN 99 -49.635 ATOM 315 CA GLN 99 -48.693 ATOM 316 CB GLN 99 -47.359 ATOM 317 CG GLN 99 -46.377 ATOM 318 CD GLN 99 -44.931 ATOM 319 OE1 GLN 99 -44.540 ATOM 320 NE2 GLN 99 -44.129 ATOM 321 C GLN 99 -49.248 ATOM 322 0 GLN 99 -49.136 ATOM 323 N ALA 100 -49.844 ATOM 324 CA ALA 100 -50.344 ATOM 325 CB ALA 100 -50.704 ATOM 326 C ALA 100 -51.558 ATOM 327 O ALA 100 -51.685 ATOM 328 N GLN 101 -52.447 ATOM 329 CA GLN 101 -53.600 ATOM 330 CB GLN 101 -54.533 ATOM 331 CG GLN 101 -55.204 ATOM 332 CD GLN 101 -56.129 ATOM 333 OE1 GLN 101 -56.874 ATOM 334 NE2 GLN 101 -56.089 ATOM 335 C GLN 101 -53.174 ATOM 336 0 GLN 101 -53.731 ATOM 337 N ALA 102 -52.190 ATOM 338 CA ALA 102 -51.734 ATOM 339 CB ALA 102 -50.782 ATOM 340 C ALA 102 -51.037 ATOM 341 O ALA 102 -51.148 ATOM 342 N ALA 103 -50.321 ATOM 343 CA ALA 103 -49.589 ATOM 344 CB ALA 103 -48.705 ATOM 345 C ALA 103 -50.549 ATOM 346 O ALA 103 -50.268 ATOM 347 N ARG 104 -51.682 ATOM 348 CA ARG 104 -52.688 ATOM 349 CB ARG 104 -53.755 ATOM 350 CG ARG 104 -53.228 ATOM 351 CD ARG 104 -54.345 ATOM 352 NE ARG 104 -55.256 ATOM 353 CZ ARG 104 -55.105 ATOM 354 NHl ARG 104 -55.984 ATOM 355 NH2 ARG 104 -54.073 ATOM 356 C ARG 104 -53.340 ATOM 357 O ARG 104 -53.924 ATOM 358 N ARG 105 -53.232 ATOM 359 CA ARG 105 -53.775 ATOM 360 CB ARG 105 -54.477 ATOM 361 CG ARG 105 -55.681 ATOM 362 CD ARG 105 -56.288 ATOM 363 NE ARG 105 -57.613 ATOM 364 CZ ARG 105 -57.854 ATOM 365 NHl ARG 105 -59.096 ATOM 366 NH2 ARG 105 -56.859 ATOM 367 C ARG 105 -52.704 ATOM 368 O ARG 105 -52.958 ATOM 369 N GLY 106 -51.506 ATOM 370 CA GLY 106 -50.439 ATOM 371 C GLY 106 -49.558 ATOM 372 0 GLY 106 -48.806 ATOM 373 N TYR 107 -49.642 ATOM 374 CA TYR 107 -48.869 ATOM 375 CB TYR 107 -49.783 ATOM 376 CG TYR 107 -50.728 ATOM 377 CDl TYR 107 -50.404 ATOM 378 CEl TYR 107 -51.274 -47.803 1.00 70.24 A N -44.460 1.00 39.37 A C -44.393 1.00 38.18 A O -43.381 1.00 37.41 A N -42.050 1.00 35.51 A C -40.977 1.00 34.36 A C -39.563 1.00 36.07 A c -39.099 1.00 35.97 A c -38.604 1.00 36.03 A c -41.961 1.00 35.38 A c -41.446 1.00 33.36 A 0 -42.469 1.00 34.49 A N -42.409 1.00 37.42 A c -43.061 1.00 38.96 A c -42.146 1.00 40.19 A c -42.564 1.00 41.88 A c -43.683 1.00 41.48 A 0 -41.661 1.00 40.56 A N -43.099 1.00 38.67 A c -42.577 1.00 38.83 A 0 -44.273 1.00 39.11 A N -45.074 1.00 40.09 A c -46.483 1.00 38.16 A c -44.416 1.00 40.78 A c -44.396 1.00 41.97 A 0 -43.870 1.00 39.41 A N -43.160 1.00 39.71 A c -42.724 1.00 38.98 A c -43.877 1.00 41.93 A c -43.405 1.00 44.37 A c -44.192 1.00 45.91 A 0 -42.109 1.00 44.36 A N -41.940 1.00 40.25 A c -41.671 1.00 42.25 A 0 -41.203 1.00 38.45 A N -39.993 1.00 37.78 A c -39.198 1.00 35.08 A c -40.346 1.00 37.94 A c -39.615 1.00 37.67 A 0 -41.467 1.00 37.12 A N -41.901 1.00 39.38 A c -43.098 1.00 38.54 A c -42.268 1.00 41.97 A c -42.012 1.00 41.53 A 0 -42.864 1.00 42.63 A N -43.245 1.00 43.83 A c -44.139 1.00 43.90 A c -45.513 1.00 45.54 A c -46.528 1.00 48.21 A c -46.168 1.00 53.08 A N -46.558 1.00 54.45 A c -46.184 1.00 53.80 A N -47.320 1.00 52.89 A N -42.018 1.00 44.46 A C -42.105 1.00 46.11 A 0 -40.874 1.00 43.03 A N -39.630 1.00 40.77 A C -38.845 1.00 43.29 A c -39.562 1.00 45.71 A c -38.794 1.00 50.02 A c -39.305 1.00 54.91 A N -40.549 1.00 59.39 A c -40.919 1.00 61.37 A N -41.427 1.00 58.64 A N -38.763 1.00 40.45 A C -37.610 1.00 41.05 A 0 -39.320 1.00 40.26 A N -38.615 1.00 42.36 A C -37.734 1.00 43.39 A c -36.896 1.00 41.65 A 0 -37.915 1.00 43.64 A N -37.088 1.00 43.17 A c -36.521 1.00 42.03 A c -35.444 1.00 42.50 A c -34.097 1.00 41.77 A c -33.105 1.00 41.27 A c 183 WO 2009/026558 PCT/US2008/074097 ATOM 379 CD2 TYR 107 -51.955 36 ATOM 380 CE2 TYR 107 -52.835 37 ATOM 381 CZ TYR 107 -52.490 36 ATOM 382 OH TYR 107 -53.364 37 ATOM 383 C TYR 107 -47.719 36 ATOM 384 O TYR 107 -47.907 35 ATOM 385 N LEU 108 -46.528 36 ATOM 386 CA LEU 108 -45.416 35 ATOM 387 CB LEU 108 -44.090 35 ATOM 388 CG LEU 108 -42.840 35 ATOM 389 CDl LEU 108 -42.631 35 ATOM 390 CD2 LEU 108 -41.625 35 ATOM 391 C LEU 108 -45.581 33 ATOM 392 O LEU 108 -45.960 33 ATOM 393 N THR 109 -45.314 32 ATOM 394 CA THR 109 -45.293 31 ATOM 395 CB THR 109 -46.585 30 ATOM 396 OG1 THR 109 -46.667 30 ATOM 397 CG2 THR 109 -47.812 31 ATOM 398 C THR 109 -44.095 30 ATOM 399 O THR 109 -43.532 31 ATOM 400 N LYS 110 -43.699 29 ATOM 401 CA LYS 110 -42.624 28 ATOM 402 CB LYS 110 -41.374 28 ATOM 403 CG LYS 110 -40.739 30 ATOM 404 CD LYS 110 -39.687 30 ATOM 405 CE LYS 110 -39.100 31 ATOM 406 NZ LYS 110 -38.261 32 ATOM 407 C LYS 110 -43.044 27 ATOM 408 0 LYS 110 -43.505 26 ATOM 409 N ILE 111 -42.891 26 ATOM 410 CA ILE 111 -43.033 25 ATOM 411 CB ILE 111 -43.366 24 ATOM 412 CG2 ILE 111 -43.548 23 ATOM 413 CGI ILE 111 -44.646 25 ATOM 414 CDl ILE 111 -45.821 25 ATOM 415 C ILE 111 -41.689 24 ATOM 416 0 ILE 111 -40.673 25 ATOM 417 N LEU 112 -41.680 23 ATOM 418 CA LEU 112 -40.429 23 ATOM 419 CB LEU 112 -40.487 23 ATOM 420 CG LEU 112 -40.736 24 ATOM 421 CDl LEU 112 -40.836 24 ATOM 422 CD2 LEU 112 -39.608 25 ATOM 423 C LEU 112 -40.136 22 ATOM 424 O LEU 112 -38.976 21 ATOM 425 N HIS 113 -41.192 21 ATOM 426 CA HIS 113 -41.075 19 ATOM 427 CB HIS 113 -40.758 19 ATOM 428 CG HIS 113 -40.325 17 ATOM 429 CD2 HIS 113 -41.039 16 ATOM 430 NDl HIS 113 -38.999 17 ATOM 431 CEl HIS 113 -38.915 16 ATOM 432 NE2 HIS 113 -40.139 15 ATOM 433 C HIS 113 -42.377 19 ATOM 434 0 HIS 113 -43.461 19 ATOM 435 N VAL 114 -42.277 18 ATOM 436 CA VAL 114 -43.460 18 ATOM 437 CB VAL 114 -43.648 18 ATOM 438 CGI VAL 114 -44.890 17 ATOM 439 CG2 VAL 114 -43.802 20 ATOM 440 C VAL 114 -43.320 16 ATOM 441 O VAL 114 -42.368 16 ATOM 442 N PHE 115 -44.267 15 ATOM 443 CA PHE 115 -44.191 14 ATOM 444 CB PHE 115 -45.024 14 ATOM 445 CG PHE 115 -44.490 14 ATOM 446 CDl PHE 115 -44.984 15 ATOM 447 CD2 PHE 115 -43.491 14 ATOM 448 CEl PHE 115 -44.490 16 ATOM 449 CE2 PHE 115 -42.992 14 ATOM 450 CZ PHE 115 -43.494 15 ATOM 451 C PHE 115 -44.679 13 ATOM 4 52 O PHE 115 -45.672 14 ATOM 453 N HIS 116 -43.967 12 ATOM 454 CA HIS 116 -44.434 11 -35.770 1.00 41.20 A C -34.782 1.00 40.76 A C -33.452 1.00 42.29 A C -32.463 1.00 42.42 A 0 -37.842 1.00 42.45 A c -38.926 1.00 42.84 A 0 -37.259 1.00 42.23 A N -37.728 1.00 43.15 A c -37.237 1.00 46.35 A c -37.603 1.00 50.90 A c -39. 111 1.00 51.51 A c -36.885 1.00 52.89 A c -37.189 1.00 41.70 A c -36.031 1.00 42.13 A 0 -38.030 1.00 37.66 A N -37.574 1.00 35.85 A c -37.972 1.00 34.84 A c -39.400 1.00 35.33 A 0 -37.451 1.00 34.18 A c -38.174 1.00 35.46 A c -39.178 1.00 34.99 A 0 -37.551 1.00 34.81 A N -38.086 1.00 34.79 A c -37.217 1.00 38.01 A c -37.252 1.00 44.73 A c -36.164 1.00 51.66 A c -36.163 1.00 57.04 A c -34.953 1.00 60.67 A N -38.169 1.00 33.48 A c -37.182 1.00 30.94 A 0 -39.355 1.00 31.38 A N -39.502 1.00 29.98 A c -40.965 1.00 30.23 A c -41.065 1.00 27.09 A c -41.423 1.00 30.09 A c -40.511 1.00 30.43 A c -39.118 1.00 28.90 A c -39.745 1.00 28.53 A 0 -38.087 1.00 28.45 A N -37.587 1.00 27.85 A c -36.061 1.00 28.31 A c -35.266 1.00 29.90 A c -33.780 1.00 27.40 A c -35.517 1.00 25.41 A c -38.209 1.00 28.75 A c -38.297 1.00 28.71 A 0 -38.645 1.00 28.46 A N -39.129 1.00 29.20 A c -37.954 1.00 29.04 A c -38.367 1.00 29.50 A c -38.639 1.00 30.05 A c -38.533 1.00 31.19 A N -38.890 1.00 29.33 A c -38.962 1.00 30.67 A N -39.796 1.00 29.37 A C -39.336 1.00 30.57 A 0 -40.874 1.00 28.34 A N -41.461 1.00 28.24 A C -42.950 1.00 29.58 A c -43.556 1.00 24.77 A c -43.027 1.00 25.34 A c -41.363 1.00 30.01 A c -41.883 1.00 30.39 A 0 -40.679 1.00 31.76 A N -40.424 1.00 35.74 A c -39.198 1.00 33.99 A c -37.909 1.00 34.95 A c -37.391 1.00 33.81 A c -37.212 1.00 33.75 A c -36.195 1.00 33.67 A c -36.019 1.00 32.89 A c -35.509 1.00 33.21 A c -41.615 1.00 40.69 A c -42.257 1.00 42.29 A 0 -41.902 1.00 45.48 A N -42.830 1.00 51.72 A c 184 WO 2009/026558 PCT/US2008/074097 ATOM 455 CB HIS 116 -44.084 12.017 -44.279 1.00 55.93 A C ATOM 456 CG HIS 116 -42.638 12.353 -44.495 1.00 62.52 A C ATOM 457 CD2 HIS 116 -41.911 13.443 -44.143 1.00 65.77 A C ATOM 458 NDl HIS 116 -41.775 11.528 -45.187 1.00 65.95 A N ATOM 459 CEl HIS 116 -40.582 12.096 -45.255 1.00 67.64 A C ATOM 460 NE2 HIS 116 -40.638 13.260 -44.630 1.00 66.85 A N ATOM 461 C HIS 116 -43.776 10.314 -42.461 1.00 53.18 A C ATOM 4 62 0 HIS 116 -42.587 10.270 -42.142 1.00 53.78 A O ATOM 463 N GLY 117 -44.552 9.237 -42.497 1.00 54.01 A N ATOM 464 CA GLY 117 -43.996 7.932 -42.198 1.00 55.08 A C ATOM 465 C GLY 117 -44.538 7.307 -40.927 1.00 55.76 A C ATOM 466 0 GLY 117 -44.749 6.093 -40.868 1.00 58.44 A 0 ATOM 467 N LEU 118 -44.763 8.122 -39.903 1.00 54.93 A N ATOM 468 CA LEU 118 -45.369 7.62 6 -38.676 1.00 54.61 A c ATOM 469 CB LEU 118 -44.501 7.993 -37.470 1.00 54.38 A c ATOM 470 CG LEU 118 -44.413 6.966 -36.338 1.00 53.70 A c ATOM 471 CDl LEU 118 -43.981 5.612 -36.888 1.00 53.81 A c ATOM 472 CD2 LEU 118 -43.423 7.449 -35.300 1.00 54.71 A c ATOM 473 C LEU 118 -46.755 8.238 -38.526 1.00 54.27 A c ATOM 474 O LEU 118 -47.759 7.530 -38.530 1.00 57.04 A 0 ATOM 475 N LEU 119 -46.802 9.559 -38.397 1.00 52.23 A N ATOM 476 CA LEU 119 -48.061 10.289 -38.399 1.00 49.64 A c ATOM 477 CB LEU 119 -48.289 10.982 -37.050 1.00 52.24 A c ATOM 478 CG LEU 119 -48.274 10.081 -35.808 1.00 57.18 A c ATOM 479 CDl LEU 119 -48.778 10.861 -34.599 1.00 55.90 A c ATOM 480 CD2 LEU 119 -49.146 8.844 -36.045 1.00 57.99 A c ATOM 481 C LEU 119 -47.994 11.336 -39.501 1.00 46.53 A c ATOM 482 O LEU 119 -46.925 11.861 -39.808 1.00 46.48 A 0 ATOM 483 N PRO 120 -49.134 11.634 -40.127 1.00 42.44 A N ATOM 484 CD PRO 120 -50.381 10.850 -40.113 1.00 43.27 A c ATOM 485 CA PRO 120 -49.213 12.766 -41.047 1.00 40.39 A c ATOM 486 CB PRO 120 -50.352 12.380 -41.986 1.00 41.28 A c ATOM 487 CG PRO 120 -51.269 11.576 -41.117 1.00 42.77 A c ATOM 488 C PRO 120 -49.510 14.053 -40.281 1.00 36.94 A c ATOM 489 O PRO 120 -50.454 14.115 -39.494 1.00 35.42 A 0 ATOM 490 N GLY 121 -48.709 15.080 -40.524 1.00 34.63 A N ATOM 491 CA GLY 121 -48.946 16.355 -39.877 1.00 33.37 A c ATOM 4 92 C GLY 121 -47.703 17.217 -39.859 1.00 32.35 A c ATOM 493 0 GLY 121 -46.770 17.017 -40.649 1.00 31.71 A 0 ATOM 494 N PHE 122 -47.678 18.189 -38.960 1.00 29.96 A N ATOM 495 CA PHE 122 -46.524 19.062 -38.876 1.00 29.31 A c ATOM 496 CB PHE 122 -46.594 20.142 -39.967 1.00 26.41 A c ATOM 497 CG PHE 122 -47.862 20.952 -39.947 1.00 27.75 A c ATOM 498 CDl PHE 122 -47.950 22.110 -39.188 1.00 26.81 A c ATOM 499 CD2 PHE 122 -48.951 20.582 -40.726 1.00 29.77 A c ATOM 500 CEl PHE 122 -49.094 22.893 -39.204 1.00 28.13 A c ATOM 501 CE2 PHE 122 -50.104 21.358 -40.750 1.00 29.99 A c ATOM 502 CZ PHE 122 -50.171 22.519 -39.984 1.00 31.24 A c ATOM 503 C PHE 122 -46.397 19.697 -37.506 1.00 29.39 A c ATOM 504 O PHE 122 -47.327 19.652 -36.694 1.00 29.97 A 0 ATOM 505 N LEU 123 -45.224 20.273 -37.260 1.00 28.83 A N ATOM 506 CA LEU 123 -44.905 20.916 -35.996 1.00 28.28 A c ATOM 507 CB LEU 123 -43.564 20.388 -35.475 1.00 27.66 A c ATOM 508 CG LEU 123 -43.059 20.877 -34.115 1.00 29.62 A c ATOM 509 CDl LEU 123 -44.026 20.443 -33.014 1.00 28.28 A c ATOM 510 CD2 LEU 123 -41.672 20.302 -33.859 1.00 27.46 A c ATOM 511 C LEU 123 -44.803 22.405 -36.288 1.00 29.10 A c ATOM 512 O LEU 123 -44.065 22.816 -37.189 1.00 29.03 A 0 ATOM 513 N VAL 124 -45.550 23.213 -35.542 1.00 27.38 A N ATOM 514 CA VAL 124 -45.576 24.643 -35.802 1.00 26.87 A c ATOM 515 CB VAL 124 -46.916 25.073 -36.456 1.00 26.05 A c ATOM 516 CGI VAL 124 -48.076 24.763 -35.536 1.00 24.54 A c ATOM 517 CG2 VAL 124 -46.889 26.561 -36.776 1.00 28.03 A c ATOM 518 C VAL 124 -45.363 25.447 -34.526 1.00 29.30 A c ATOM 519 O VAL 124 -45.985 25.179 -33.486 1.00 28.28 A 0 ATOM 520 N LYS 125 -44.469 26.425 -34.606 1.00 29.09 A N ATOM 521 CA LYS 125 -44.318 27.401 -33.538 1.00 32.58 A c ATOM 522 CB LYS 125 -42.848 27.803 -33.411 1.00 35.01 A c ATOM 523 CG LYS 125 -42.592 28.896 -32.398 1.00 39.45 A c ATOM 524 CD LYS 125 -41.413 28.552 -31.512 1.00 47.60 A c ATOM 525 CE LYS 125 -40.270 29.542 -31.691 1.00 51.01 A c ATOM 526 NZ LYS 125 -40.658 30.922 -31.270 1.00 53.91 A N ATOM 527 C LYS 125 -45.177 28.624 -33.872 1.00 33.31 A c ATOM 528 0 LYS 125 -44.953 29.288 -34.884 1.00 32.62 A 0 ATOM 529 N MET 126 -46.168 28.908 -33.034 1.00 32.61 A N ATOM 530 CA MET 126 -47.086 30.010 -33.300 1.00 34.07 A c 185 WO 2009/026558 PCT/US2008/074097 ATOM 531 CB MET 126 -48.114 ATOM 532 CG MET 126 -49.105 ATOM 533 SD MET 126 -50.324 ATOM 534 CE MET 126 -51.558 ATOM 535 C MET 126 -47.818 ATOM 536 0 MET 126 -47.805 ATOM 537 N SER 127 -48.468 ATOM 538 CA SER 127 -49.278 ATOM 539 CB SER 127 -49.715 ATOM 540 OG SER 127 -50.780 ATOM 541 C SER 127 -50.513 ATOM 542 O SER 127 -51.135 ATOM 543 N GLY 128 -50.868 ATOM 544 CA GLY 128 -52.105 ATOM 545 C GLY 128 -53.353 ATOM 546 0 GLY 128 -54.423 ATOM 547 N ASP 129 -53.228 ATOM 548 CA ASP 129 -54.350 ATOM 549 CB ASP 129 -53.927 ATOM 550 CG ASP 129 -53.629 ATOM 551 OD1 ASP 129 -54.080 ATOM 552 OD2 ASP 129 -52.943 ATOM 553 C ASP 129 -54.878 ATOM 554 O ASP 129 -56.064 ATOM 555 N LEU 130 -53.988 ATOM 556 CA LEU 130 -54.286 ATOM 557 CB LEU 130 -53.007 ATOM 558 CG LEU 130 -52.325 ATOM 559 CDl LEU 130 -50.980 ATOM 560 CD2 LEU 130 -53.211 ATOM 561 C LEU 130 -54.916 ATOM 562 O LEU 130 -55.200 ATOM 563 N LEU 131 -55.134 ATOM 564 CA LEU 131 -55.621 ATOM 565 CB LEU 131 -55.691 ATOM 566 CG LEU 131 -54.345 ATOM 567 CDl LEU 131 -54.504 ATOM 568 CD2 LEU 131 -53.809 ATOM 569 C LEU 131 -56.979 ATOM 570 O LEU 131 -57.199 ATOM 571 N GLU 132 -57.890 ATOM 572 CA GLU 132 -59.217 ATOM 573 CB GLU 132 -60.113 ATOM 574 CG GLU 132 -60.487 ATOM 575 CD GLU 132 -61.250 ATOM 576 OE1 GLU 132 -61.985 ATOM 577 OE2 GLU 132 -61.115 ATOM 578 C GLU 132 -59.084 ATOM 579 O GLU 132 -59.755 ATOM 580 N LEU 133 -58.203 ATOM 581 CA LEU 133 -57.902 ATOM 582 CB LEU 133 -56.868 ATOM 583 CG LEU 133 -56.392 ATOM 584 CDl LEU 133 -57.518 ATOM 585 CD2 LEU 133 -55.197 ATOM 586 C LEU 133 -57.364 ATOM 587 O LEU 133 -57.798 ATOM 588 N ALA 134 -56.424 ATOM 589 CA ALA 134 -55.745 ATOM 590 CB ALA 134 -54.524 ATOM 591 C ALA 134 -56.692 ATOM 592 O ALA 134 -56.595 ATOM 593 N LEU 135 -57.611 ATOM 594 CA LEU 135 -58.586 ATOM 595 CB LEU 135 -59.368 ATOM 596 CG LEU 135 -58.641 ATOM 597 CDl LEU 135 -59.491 ATOM 598 CD2 LEU 135 -58.354 ATOM 599 C LEU 135 -59.559 ATOM 600 O LEU 135 -60.250 ATOM 601 N LYS 136 -59.608 ATOM 602 CA LYS 136 -60.506 ATOM 603 CB LYS 136 -61.132 ATOM 604 CG LYS 136 -62.148 ATOM 605 CD LYS 136 -62.611 ATOM 606 CE LYS 136 -63.461 -34.350 1.00 33.99 A C -33.839 1.00 34.58 A C -35.077 1.00 40.88 A S -34.063 1.00 35.19 A c -32.031 1.00 35.02 A c -31.050 1.00 34.82 A 0 -32.065 1.00 36.79 A N -30.950 1.00 37.25 A c -31.191 1.00 38.68 A c -30.324 1.00 38.32 A 0 -30.760 1.00 38.35 A c -31.735 1.00 37.21 A 0 -29.499 1.00 37.77 A N -29.194 1.00 38.41 A c -29.684 1.00 39.05 A c -29.770 1.00 39.27 A 0 -30.013 1.00 40.07 A N -30.590 1.00 42.01 A c -30.966 1.00 42.77 A c -29.754 1.00 46.29 A c -28.640 1.00 44.66 A 0 -29.921 1.00 48.24 A 0 -31.842 1.00 42.68 A c -32.158 1.00 43.03 A 0 -32.548 1.00 40.92 A N -33.871 1.00 39.89 A c -34.712 1.00 38.83 A c -34.993 1.00 39.26 A c -35.649 1.00 37.90 A c -35.892 1.00 38.49 A c -33.840 1.00 40.44 A c -34.890 1.00 40.55 A 0 -32.646 1.00 41.71 A N -32.522 1.00 43.42 A c -31.048 1.00 44.46 A c -30.421 1.00 47.94 A c -28.916 1.00 47.71 A c -31.088 1.00 46.48 A c -33.179 1.00 44.30 A c -33.827 1.00 43.27 A 0 -33.010 1.00 46.35 A N -33.610 1.00 48.86 A c -33.171 1.00 54.02 A c -31.691 1.00 62.96 A c -31.282 1.00 68.59 A c -32.128 1.00 71.67 A 0 -30.113 1.00 71.20 A 0 -35.126 1.00 46.75 A c -35.818 1.00 46.81 A 0 -35.632 1.00 44.75 A N -37.056 1.00 45.11 A c -37.336 1.00 45.98 A c -38.783 1.00 49.58 A c -39.652 1.00 51.14 A c -38.826 1.00 49.33 A c -37.532 1.00 44.38 A c -38.556 1.00 45.21 A 0 -36.779 1.00 42.85 A N -37.203 1.00 41.92 A c -36.316 1.00 39.84 A c -37.160 1.00 41.73 A c -37.986 1.00 41.34 A 0 -36.198 1.00 42.08 A N -36.049 1.00 43.75 A c -34.746 1.00 41.32 A c -33.463 1.00 40.82 A c -32.244 1.00 38.47 A c -33.506 1.00 37.33 A c -37.226 1.00 45.90 A c -37.394 1.00 4 6.62 A 0 -38.043 1.00 48.08 A N -39.194 1.00 49.87 A c -39.356 1.00 52.29 A c -38.274 1.00 56.29 A c -38.367 1.00 60.74 A c -37.155 1.00 63.43 A c 186 WO 2009/026558 PCT/US2008/074097 ATOM 607 NZ LYS 136 -63.810 ATOM 608 C LYS 136 -59.831 ATOM 609 0 LYS 136 -60.486 ATOM 610 N LEU 137 -58.528 ATOM 611 CA LEU 137 -57.811 ATOM 612 CB LEU 137 -56.310 ATOM 613 CG LEU 137 -55.542 ATOM 614 CDl LEU 137 -54.210 ATOM 615 CD2 LEU 137 -55.333 ATOM 616 C LEU 137 -58.331 ATOM 617 O LEU 137 -58.786 ATOM 618 N PRO 138 -58.259 ATOM 619 CD PRO 138 -57.640 ATOM 620 CA PRO 138 -58.681 ATOM 621 CB PRO 138 -58.532 ATOM 622 CG PRO 138 -57.444 ATOM 623 C PRO 138 -57.781 ATOM 62 4 O PRO 138 -56.592 ATOM 625 N HIS 139 -58.357 ATOM 62 6 CA HIS 139 -57.612 ATOM 627 CB HIS 139 -56.319 ATOM 628 CG HIS 139 -56.525 ATOM 62 9 CD2 HIS 139 -55.808 ATOM 630 NDl HIS 139 -57.578 ATOM 631 CEl HIS 139 -57.500 ATOM 632 NE2 HIS 139 -56.435 ATOM 633 C HIS 139 -57.263 ATOM 634 0 HIS 139 -56.773 ATOM 635 N VAL 140 -57.501 ATOM 636 CA VAL 140 -57.052 ATOM 637 CB VAL 140 -57.126 ATOM 638 CGI VAL 140 -56.864 ATOM 639 CG2 VAL 140 -56.103 ATOM 640 C VAL 140 -57.867 ATOM 641 O VAL 140 -59.085 ATOM 642 N ASP 141 -57.180 ATOM 643 CA ASP 141 -57.803 ATOM 644 CB ASP 141 -57.006 ATOM 645 CG ASP 141 -57.716 ATOM 646 OD1 ASP 141 -58.728 ATOM 647 OD2 ASP 141 -57.257 ATOM 648 C ASP 141 -57.826 ATOM 649 O ASP 141 -58.887 ATOM 650 N TYR 142 -56.653 ATOM 651 CA TYR 142 -56.576 ATOM 652 CB TYR 142 -56.771 ATOM 653 CG TYR 142 -55.712 ATOM 654 CDl TYR 142 -54.583 ATOM 655 CEl TYR 142 -53.614 ATOM 656 CD2 TYR 142 -55.845 ATOM 657 CE2 TYR 142 -54.879 ATOM 658 CZ TYR 142 -53.767 ATOM 659 OH TYR 142 -52.808 ATOM 660 C TYR 142 -55.245 ATOM 661 O TYR 142 -54.307 ATOM 662 N ILE 143 -55.175 ATOM 663 CA ILE 143 -53.972 ATOM 664 CB ILE 143 -54.234 ATOM 665 CG2 ILE 143 -53.001 ATOM 666 CGI ILE 143 -54.622 ATOM 667 CDl ILE 143 -54.835 ATOM 668 C ILE 143 -53.538 ATOM 669 0 ILE 143 -54.354 ATOM 670 N GLU 144 -52.258 ATOM 671 CA GLU 144 -51.760 ATOM 672 CB GLU 144 -51.252 ATOM 673 CG GLU 144 -50.743 ATOM 674 CD GLU 144 -50.533 ATOM 675 OE1 GLU 144 -51.317 ATOM 676 OE2 GLU 144 -49.584 ATOM 677 C GLU 144 -50.662 ATOM 678 0 GLU 144 -49.686 ATOM 679 N GLU 145 -50.831 ATOM 680 CA GLU 145 -49.824 ATOM 681 CB GLU 145 -50.415 ATOM 682 CG GLU 145 -49.471 -37.140 1.00 65.11 A N -40.500 1.00 49.01 A C -41.534 1.00 48.28 A O -40.457 1.00 48.46 A N -41.654 1.00 48.15 A C -41.373 1.00 45.68 A C -41.071 1.00 45.92 A c -40.435 1.00 45.13 A c -42.347 1.00 45.54 A c -42.157 1.00 50.34 A c -41.381 1.00 50.05 A 0 -43.475 1.00 51.81 A N -44.464 1.00 52.57 A c -44.072 1.00 51.58 A c -45.570 1.00 53.25 A c -45.664 1.00 54.45 A c -43.595 1.00 51.03 A c -43.365 1.00 51.14 A 0 -43.445 1.00 49.72 A N -43.104 1.00 49.11 A c -43.922 1.00 53.64 A c -45.400 1.00 58.94 A c -46.354 1.00 60.61 A c -46.055 1.00 61.11 A N -47.347 1.00 61.63 A c -47.555 1.00 62.34 A N -41.622 1.00 45.66 A C -41.200 1.00 45.43 A 0 -40.830 1.00 41.49 A N -39.446 1.00 39.22 A C -38.790 1.00 38.25 A c -37.301 1.00 3 6.67 A c -39.421 1.00 36.79 A c -38.606 1.00 40.24 A c -38.518 1.00 40.95 A 0 -37.990 1.00 40.17 A N -37.048 1.00 39.16 A c -37.017 1.00 40.87 A c -36.253 1.00 42.53 A c -35.574 1.00 46.58 A 0 -36.333 1.00 40.88 A 0 -35.658 1.00 38.98 A c -35.058 1.00 39.39 A 0 -35.151 1.00 37.04 A N -33.888 1.00 34.27 A c -32.709 1.00 34.16 A c -32.610 1.00 33.65 A c -31.824 1.00 33.96 A c -31.716 1.00 35.51 A c -33.294 1.00 34.96 A c -33.194 1.00 35.75 A c -32.400 1.00 36.08 A c -32.281 1.00 36.47 A 0 -33.753 1.00 32.82 A c -34.513 1.00 33.32 A 0 -32.787 1.00 31.85 A N -32.529 1.00 31.41 A c -32.796 1.00 30.29 A c -32.452 1.00 28.35 A c -34.262 1.00 30.00 A c -34.658 1.00 2 6.92 A c -31.074 1.00 32.89 A c -30.152 1.00 33.57 A 0 -30.860 1.00 31.53 A N -29.501 1.00 32.32 A c -29.262 1.00 34.26 A c -27.841 1.00 39.57 A c -27.496 1.00 43.13 A c -27.991 1.00 45.28 A 0 -26.731 1.00 41.06 A 0 -29.147 1.00 30.86 A c -29.882 1.00 31.43 A 0 -28.005 1.00 30.15 A N -27.476 1.00 29.60 A c -26.310 1.00 29.75 A c -25.667 1.00 33.69 A c 187 WO 2009/026558 PCT/US2008/074097 ATOM 683 CD GLU 145 -50.070 23.931 -24.404 1.00 36.75 A C ATOM 684 OE1 GLU 145 -49.915 23.325 -23.319 1.00 34.36 A O ATOM 685 OE2 GLU 145 -50.705 25.004 -24.499 1.00 39.41 A 0 ATOM 686 C GLU 145 -48.618 20.749 -26.997 1.00 28.98 A c ATOM 687 O GLU 145 -48.777 19.735 -26.312 1.00 25.84 A 0 ATOM 688 N ASP 146 -47.417 21.197 -27.350 1.00 27.03 A N ATOM 689 CA ASP 146 -46.210 20.501 -26.925 1.00 28.33 A c ATOM 690 CB ASP 146 -44.974 21.179 -27.513 1.00 30.15 A c ATOM 691 CG ASP 146 -43.820 20.205 -27.738 1.00 34.26 A c ATOM 692 OD1 ASP 146 -43.952 19.010 -27.376 1.00 33.09 A 0 ATOM 693 OD2 ASP 146 -42.781 20.640 -28.285 1.00 34.49 A 0 ATOM 694 C ASP 146 -46.119 20.489 -25.395 1.00 28.56 A c ATOM 695 O ASP 146 -46.792 21.263 -24.712 1.00 27.12 A 0 ATOM 696 N SER 147 -45.298 19.596 -24.858 1.00 28.76 A N ATOM 697 CA SER 147 -45.097 19.524 -23.415 1.00 29.70 A c ATOM 698 CB SER 147 -46.315 18.887 -22.732 1.00 31.44 A c ATOM 699 OG SER 147 -46.524 17.558 -23.186 1.00 37.75 A 0 ATOM 700 C SER 147 -43.843 18.713 -23.115 1.00 28.55 A c ATOM 701 O SER 147 -43.271 18.091 -24.015 1.00 27.48 A 0 ATOM 702 N SER 148 -43.421 18.727 -21.854 1.00 25.24 A N ATOM 703 CA SER 148 -42.114 18.204 -21.478 1.00 26.40 A c ATOM 704 CB SER 148 -41.591 18.950 -20.244 1.00 27.71 A c ATOM 705 OG SER 148 -41.445 20.339 -20.503 1.00 28.90 A 0 ATOM 706 C SER 148 -42.137 16.710 -21.178 1.00 27.07 A c ATOM 707 O SER 148 -43.147 16.173 -20.707 1.00 27.21 A 0 ATOM 708 N VAL 149 -41.016 16.046 -21.441 1.00 25.66 A N ATOM 709 CA VAL 149 -40.784 14.704 -20.915 1.00 24.89 A c ATOM 710 CB VAL 149 -40.688 13.659 -22.044 1.00 25.33 A c ATOM 711 CGI VAL 149 -41.989 13.632 -22.833 1.00 24.08 A c ATOM 712 CG2 VAL 149 -39.513 13.983 -22.962 1.00 21.20 A c ATOM 713 C VAL 149 -39.485 14.704 -20. 111 1.00 26.06 A c ATOM 714 O VAL 149 -38.609 15.546 -20.335 1.00 25.28 A 0 ATOM 715 N PHE 150 -39.370 13.768 -19.172 1.00 24.42 A N ATOM 716 CA PHE 150 -38.287 13.797 -18.188 1.00 25.00 A c ATOM 717 CB PHE 150 -38.824 14.250 -16.820 1.00 20.88 A c ATOM 718 CG PHE 150 -39.485 15.601 -16.838 1.00 24.00 A c ATOM 719 CDl PHE 150 -40.842 15.721 -17.094 1.00 23.42 A c ATOM 720 CD2 PHE 150 -38.752 16.752 -16.574 1.00 22.91 A c ATOM 721 CEl PHE 150 -41.457 16.958 -17.086 1.00 22.83 A c ATOM 722 CE2 PHE 150 -39.360 17.998 -16.565 1.00 21.63 A c ATOM 723 CZ PHE 150 -40.712 18.103 -16.820 1.00 23.76 A c ATOM 724 C PHE 150 -37.642 12.421 -18.033 1.00 23.77 A c ATOM 725 O PHE 150 -38.326 11.399 -18.040 1.00 23.53 A 0 ATOM 726 N ALA 151 -36.326 12.404 -17.874 1.00 24.56 A N ATOM 727 CA ALA 151 -35.626 11.185 -17.508 1.00 25.41 A c ATOM 728 CB ALA 151 -34.193 11.513 -17.136 1.00 24.13 A c ATOM 729 C ALA 151 -36.332 10.537 -16.324 1.00 28.65 A c ATOM 730 O ALA 151 -36.760 11.228 -15.395 1.00 28.24 A 0 ATOM 731 N GLN 152 -36.467 9.213 -16.349 1.00 30.75 A N ATOM 732 CA GLN 152 -36.936 8.504 -15.160 1.00 32.33 A c ATOM 733 CB GLN 152 -38.119 7.599 -15.515 1.00 30.09 A c ATOM 734 CG GLN 152 -39.322 8.338 -16.062 1.00 2 6.52 A c ATOM 735 CD GLN 152 -39.871 9.357 -15.078 1.00 29.34 A c ATOM 736 OE1 GLN 152 -40.420 8.999 -14.037 1.00 26.44 A 0 ATOM 737 NE2 GLN 152 -39.722 10.637 -15.405 1.00 27.86 A N ATOM 738 C GLN 152 -35.802 7.678 -14.544 1.00 34.54 A c ATOM 739 0 GLN 152 -36.084 6.635 -13.913 1.00 35.69 A 0 ATOM 740 OXT GLN 152 -34.632 8.101 -14.686 1.00 36.82 A 0 TER 741 GLN 152 A ATOM 742 CB SER 153 -18.830 -12.304 -7.860 1.00 80.02 B c ATOM 743 OG SER 153 -19.427 -13.535 -8.246 1.00 82.63 B 0 ATOM 744 C SER 153 -20.846 -11.007 -8.585 1.00 76.11 B c ATOM 745 O SER 153 -20.475 -10.397 -9.589 1.00 76.49 B 0 ATOM 746 N SER 153 -20.624 -11.755 -6.227 1.00 78.23 B N ATOM 747 CA SER 153 -19.883 -11.272 -7.430 1.00 78.01 B c ATOM 748 N ILE 154 -22.081 -11.479 -8.439 1.00 72.80 B N ATOM 749 CA ILE 154 -23.127 -11.189 -9.412 1.00 68.74 B C ATOM 750 CB ILE 154 -23.892 -12.470 -9.810 1.00 69.24 B c ATOM 751 CG2 ILE 154 -25.019 -12.132 -10.773 1.00 67.60 B c ATOM 752 CGI ILE 154 -22.925 -13.469 -10.450 1.00 70.75 B c ATOM 753 CDl ILE 154 -22.160 -12.910 -11.639 1.00 70.73 B c ATOM 754 C ILE 154 -24.115 -10.187 -8.825 1.00 65.36 B c ATOM 755 0 ILE 154 -24.664 -10.406 -7.742 1.00 65.44 B 0 ATOM 756 N PRO 155 -24.353 -9.072 -9.536 1.00 61.02 B N ATOM 757 CD PRO 155 -23.763 -8.705 -10.836 1.00 60.32 B c ATOM 758 CA PRO 155 -25.287 -8.050 -9.051 1.00 56.72 B c 188 WO 2009/026558 PCT/US2008/074097 ATOM 759 CB PRO 155 -25.337 -7 ATOM 760 CG PRO 155 -24.044 -7 ATOM 761 C PRO 155 -26.648 -8 ATOM 7 62 O PRO 155 -27.121 -9 ATOM 763 N TRP 156 -27.273 -8 ATOM 764 CA TRP 156 -28.513 -8 ATOM 765 CB TRP 156 -29.045 -8 ATOM 766 CG TRP 156 -29.708 -6 ATOM 767 CD2 TRP 156 -31.083 -6 ATOM 768 CE2 TRP 156 -31.263 -5 ATOM 769 CE3 TRP 156 -32.178 -7 ATOM 770 CDl TRP 156 -29.125 -5 ATOM 771 NEl TRP 156 -30.054 -4 ATOM 772 CZ2 TRP 156 -32.494 -4 ATOM 773 CZ3 TRP 156 -33.402 -6 ATOM 774 CH2 TRP 156 -33.550 -5 ATOM 775 C TRP 156 -29.572 -8 ATOM 776 O TRP 156 -30.349 -9 ATOM 111 N ASN 157 -29.592 -7 ATOM 778 CA ASN 157 -30.608 -7 ATOM 779 CB ASN 157 -30.586 -6 ATOM 780 CG ASN 157 -29.204 -5 ATOM 781 OD1 ASN 157 -28.302 -5 ATOM 782 ND2 ASN 157 -29.024 -5 ATOM 783 C ASN 157 -30.433 -8 ATOM 784 0 ASN 157 -31.416 -8 ATOM 785 N LEU 158 -29.187 -8 ATOM 786 CA LEU 158 -28.925 -9 ATOM 787 CB LEU 158 -27.458 -9 ATOM 788 CG LEU 158 -27.030 -8 ATOM 789 CDl LEU 158 -25.669 -8 ATOM 790 CD2 LEU 158 -28.074 -8 ATOM 791 C LEU 158 -29.282 -11 ATOM 792 O LEU 158 -29.812 -11 ATOM 793 N GLU 159 -28.989 -11 ATOM 794 CA GLU 159 -29.383 -12 ATOM 795 CB GLU 159 -28.799 -12 ATOM 796 CG GLU 159 -29.709 -13 ATOM 797 CD GLU 159 -29.956 -12 ATOM 798 OE1 GLU 159 -31.037 -12 ATOM 799 OE2 GLU 159 -29.068 -12 ATOM 800 C GLU 159 -30.906 -12 ATOM 801 0 GLU 159 -31.453 -13 ATOM 802 N ARG 160 -31.583 -11 ATOM 803 CA ARG 160 -33.016 -11 ATOM 804 CB ARG 160 -33.447 -10 ATOM 805 CG ARG 160 -34.890 -10 ATOM 806 CD ARG 160 -35.116 -11 ATOM 807 NE ARG 160 -34.131 -11 ATOM 808 CZ ARG 160 -34.313 -10 ATOM 809 NHl ARG 160 -33.360 -10 ATOM 810 NH2 ARG 160 -35.450 -9 ATOM 811 C ARG 160 -33.874 -12 ATOM 812 O ARG 160 -34.907 -12 ATOM 813 N ILE 161 -33.449 -11 ATOM 814 CA ILE 161 -34.165 -11 ATOM 815 CB ILE 161 -33.882 -10 ATOM 816 CG2 ILE 161 -34.367 -9 ATOM 817 CGI ILE 161 -32.387 -10 ATOM 818 CDl ILE 161 -32.035 -9 ATOM 819 C ILE 161 -33.786 -13 ATOM 820 0 ILE 161 -34.429 -13 ATOM 821 N THR 162 -32.738 -13 ATOM 822 CA THR 162 -32.312 -15 ATOM 823 CB THR 162 -30.803 -15 ATOM 824 OG1 THR 162 -30.059 -14 ATOM 825 CG2 THR 162 -30.395 -16 ATOM 826 C THR 162 -33.082 -16 ATOM 827 O THR 162 -33.004 -16 ATOM 828 N PRO 163 -33.840 -17 ATOM 829 CD PRO 163 -33.917 -17 ATOM 830 CA PRO 163 -34.684 -18 ATOM 831 CB PRO 163 -35.566 -18 ATOM 832 CG PRO 163 -34.720 -18 ATOM 833 C PRO 163 -33.869 -19 ATOM 834 O PRO 163 -32.664 -19 -10.194 1.00 57.80 B C -10.926 1.00 58.94 B C -8.768 1.00 53.19 B c -9.529 1.00 52.31 B 0 -7.671 1.00 49.27 B N -7.221 1.00 47.58 B c -5.978 1.00 45.42 B c -6.286 1.00 46.00 B c -6.635 1.00 44.51 B c -6.836 1.00 44.08 B c -6.798 1.00 44 . 17 B c -6.290 1.00 45.31 B c -6.620 1.00 45.73 B N -7.189 1.00 44.63 B c -7.150 1.00 46.04 B c -7.342 1.00 44 . 87 B c -8.319 1.00 46.81 B c -8.470 1.00 46.89 B 0 -9.084 1.00 45.77 B N -10.110 1.00 44.93 B c -10.592 1.00 43.13 B c -10.993 1.00 42.32 B c -10.159 1.00 43.42 B 0 -12.276 1.00 38.97 B N -11.302 1.00 44.94 B c -11.907 1.00 43.18 B 0 -11.646 1.00 47.58 B N -12.742 1.00 50.92 B c -13.166 1.00 49.39 B c -13.884 1.00 50.63 B c -14.531 1.00 48.36 B c -14.933 1.00 48.22 B c -12.338 1.00 52.96 B c -13.139 1.00 54.48 B 0 -11.091 1.00 55.23 B N -10.541 1.00 58.07 B c -9.132 1.00 61.02 B c -8.161 1.00 66.59 B c -6.876 1.00 71.01 B c -6.747 1.00 71.63 B 0 -5.992 1.00 72.55 B 0 -10.490 1.00 58.29 B c -10.695 1.00 56.29 B 0 -10.230 1.00 59.46 B N -9.944 1.00 60.58 B c -9.347 1.00 59.26 B c -8.869 1.00 59.38 B c -7.746 1.00 60.25 B c -6.678 1.00 60.39 B N -5.601 1.00 61.06 B c -4.681 1.00 59.91 B N -5.442 1.00 61.11 B N -11.172 1.00 61.99 B C -11.064 1.00 61.34 B 0 -12.335 1.00 63.71 B N -13.575 1.00 66.31 B C -14.652 1.00 64.21 B c -14.172 1.00 63.31 B c -14.970 1.00 63.10 B c -16.159 1.00 62.54 B c -14.144 1.00 68.85 B c -15.068 1.00 68.03 B 0 -13.590 1.00 72.56 B N -14.016 1.00 77.56 B c -13.772 1.00 77.41 B c -14.582 1.00 76.98 B 0 -14.120 1.00 76.95 B c -13.277 1.00 81.06 B c -12.054 1.00 80.79 B 0 -14.024 1.00 85.12 B N -15.493 1.00 86.11 B c -13.499 1.00 88.61 B c -14.689 1.00 87.63 B c -15.875 1.00 86.84 B c -12.999 1.00 92.41 B c -13.242 1.00 91.73 B 0 189 WO 2009/026558 PCT/US2008/074097 ATOM 835 N PRO 164 -34.527 -20.342 -12.296 1.00 96.24 B N ATOM 836 CD PRO 164 -35.931 -20.261 -11.855 1.00 97.02 B C ATOM 837 CA PRO 164 -33.868 -21.552 -11.788 1.00 99.15 B C ATOM 838 CB PRO 164 -35.004 -22.323 -11.117 1.00 98.26 B c ATOM 839 CG PRO 164 -35.994 -21.271 -10.743 1.00 97.35 B c ATOM 840 C PRO 164 -33.181 -22.377 -12.878 1.00102.09 B c ATOM 841 O PRO 164 -31.965 -22.576 -12.843 1.00101.97 B 0 ATOM 842 N ARG 165 -33.962 -22.851 -13.844 1.00105.51 B N ATOM 843 CA ARG 165 -33.429 -23.677 -14.924 1.00109.14 B c ATOM 844 CB ARG 165 -34.487 -24.687 -15.379 1.00111.03 B c ATOM 845 CG ARG 165 -33.981 -26.117 -15.510 1.00114.19 B c ATOM 846 CD ARG 165 -32.793 -26.214 -16.458 1.00116.65 B c ATOM 847 NE ARG 165 -32.370 -27.598 -16.661 1.00118.62 B N ATOM 848 CZ ARG 165 -32.623 -28.306 -17.759 1.00119.70 B c ATOM 849 NHl ARG 165 -32.201 -29.560 -17.854 1.00120.20 B N ATOM 850 NH2 ARG 165 -33.293 -27.758 -18.764 1.00119.97 B N ATOM 851 C ARG 165 -33.005 -22.809 -16.108 1.00110.22 B C ATOM 852 O ARG 165 -33.766 -22.624 -17.056 1.00110.60 B 0 ATOM 853 N TYR 166 -31.787 -22.282 -16.052 1.00111.28 B N ATOM 854 CA TYR 166 -31.320 -21.344 -17.066 1.00112.25 B C ATOM 855 CB TYR 166 -30.758 -20.088 -16.391 1.00113.37 B c ATOM 856 CG TYR 166 -30.241 -19.042 -17.354 1.00114.53 B c ATOM 857 CDl TYR 166 -28.954 -18.532 -17.228 1.00114.68 B c ATOM 858 CEl TYR 166 -28.471 -17.583 -18.110 1.00115.01 B c ATOM 859 CD2 TYR 166 -31.035 -18.570 -18.393 1.00114.92 B c ATOM 8 60 CE2 TYR 166 -30.561 -17.619 -19.281 1.00114.93 B c ATOM 861 CZ TYR 166 -29.278 -17.130 -19.135 1.00115.16 B c ATOM 8 62 OH TYR 166 -28.797 -16.189 -20.017 1.00115.03 B 0 ATOM 8 63 C TYR 166 -30.265 -21.965 -17.981 1.00112.12 B c ATOM 864 O TYR 166 -29.207 -22.397 -17.525 1.00111.99 B 0 ATOM 865 N TYR 171 -28.363 -19.940 -25.299 1.00 96.76 B N ATOM 866 CA TYR 171 -29.633 -19.258 -25.518 1.00 96.87 B c ATOM 867 CB TYR 171 -29.623 -17.883 -24.836 1.00 96.75 B c ATOM 868 CG TYR 171 -30.934 -17.536 -24.160 1.00 96.85 B c ATOM 869 CDl TYR 171 -31.135 -17.811 -22.812 1.00 96.51 B c ATOM 870 CEl TYR 171 -32.345 -17.539 -22.198 1.00 96.16 B c ATOM 871 CD2 TYR 171 -31.984 -16.972 -24.877 1.00 96.54 B c ATOM 872 CE2 TYR 171 -33.199 -16.697 -24.270 1.00 95.77 B c ATOM 873 CZ TYR 171 -33.373 -16.984 -22.932 1.00 96.10 B c ATOM 874 OH TYR 171 -34.584 -16.727 -22.327 1.00 97.20 B 0 ATOM 875 C TYR 171 -29.890 -19.090 -27.013 1.00 97.20 B c ATOM 876 O TYR 171 -28.992 -19.292 -27.833 1.00 97.67 B 0 ATOM 877 N LEU 179 -27.947 -9.679 -34.479 1.00 67.11 B N ATOM 878 CA LEU 179 -29.202 -9.880 -35.196 1.00 67.55 B c ATOM 879 CB LEU 179 -29.749 -11.274 -34.885 1.00 68.43 B c ATOM 880 CG LEU 179 -30.345 -12.050 -36.062 1.00 70.66 B c ATOM 881 CDl LEU 179 -30.862 -13.395 -35.557 1.00 70.04 B c ATOM 882 CD2 LEU 179 -31.457 -11.237 -36.722 1.00 68.78 B c ATOM 883 C LEU 179 -30.251 -8.816 -34.831 1.00 66.57 B c ATOM 884 O LEU 179 -30.917 -8.255 -35.704 1.00 67.25 B 0 ATOM 885 N VAL 180 -30.392 -8.542 -33.537 1.00 63.99 B N ATOM 886 CA VAL 180 -31.393 -7.595 -33.052 1.00 61.13 B c ATOM 887 CB VAL 180 -32.163 -8.180 -31.836 1.00 61.02 B c ATOM 888 CGI VAL 180 -31.183 -8.638 -30.773 1.00 60.46 B c ATOM 889 CG2 VAL 180 -33.110 -7.133 -31.260 1.00 60.55 B c ATOM 890 C VAL 180 -30.765 -6.260 -32.651 1.00 58.49 B c ATOM 891 O VAL 180 -29.693 -6.223 -32.049 1.00 58.27 B 0 ATOM 8 92 N GLU 181 -31.434 -5.162 -32.988 1.00 56.10 B N ATOM 893 CA GLU 181 -30.940 -3.838 -32.618 1.00 54.53 B c ATOM 894 CB GLU 181 -30.896 -2.931 -33.852 1.00 56.53 B c ATOM 895 CG GLU 181 -29.749 -1.928 -33.833 1.00 62.79 B c ATOM 896 CD GLU 181 -28.759 -2.146 -34.968 1.00 66.51 B c ATOM 897 OE1 GLU 181 -27.537 -2.078 -34.714 1.00 69.34 B 0 ATOM 898 OE2 GLU 181 -29.201 -2.383 -36.116 1.00 68.31 B 0 ATOM 899 C GLU 181 -31.810 -3.196 -31.532 1.00 51.03 B c ATOM 900 0 GLU 181 -33.041 -3.231 -31.609 1.00 50.12 B 0 ATOM 901 N VAL 182 -31.166 -2.615 -30.522 1.00 46.36 B N ATOM 902 CA VAL 182 -31.879 -1.871 -29.485 1.00 44.68 B c ATOM 903 CB VAL 182 -31.417 -2.288 -28.073 1.00 44.84 B c ATOM 904 CGI VAL 182 -32.258 -1.584 -27.023 1.00 43.44 B c ATOM 905 CG2 VAL 182 -31.521 -3.796 -27.911 1.00 47.01 B c ATOM 906 C VAL 182 -31.643 -0.365 -29.633 1.00 43.25 B c ATOM 907 O VAL 182 -30.504 0.099 -29.566 1.00 42.77 B 0 ATOM 908 N TYR 183 -32.715 0.397 -29.837 1.00 39.38 B N ATOM 909 CA TYR 183 -32.602 1.851 -29.872 1.00 38.75 B c ATOM 910 CB TYR 183 -33.594 2.448 -30.872 1.00 39.87 B c 190 WO 2009/026558 PCT/US2008/074097 ATOM 911 CG TYR 183 -33.217 2 ATOM 912 CDl TYR 183 -33.512 1 ATOM 913 CEl TYR 183 -33.177 0 ATOM 914 CD2 TYR 183 -32.575 3 ATOM 915 CE2 TYR 183 -32.235 3 ATOM 916 CZ TYR 183 -32.539 1 ATOM 917 OH TYR 183 -32.209 1 ATOM 918 C TYR 183 -32.859 2 ATOM 919 O TYR 183 -33.803 2 ATOM 920 N LEU 184 -32.005 3 ATOM 921 CA LEU 184 -32.155 4 ATOM 922 CB LEU 184 -30.872 3 ATOM 923 CG LEU 184 -30.740 4 ATOM 92 4 CDl LEU 184 -31.760 4 ATOM 92 5 CD2 LEU 184 -29.326 4 ATOM 92 6 C LEU 184 -32.438 5 ATOM 927 O LEU 184 -31.631 6 ATOM 928 N LEU 185 -33.587 6 ATOM 92 9 CA LEU 185 -33.857 7 ATOM 930 CB LEU 185 -35.280 7 ATOM 931 CG LEU 185 -35.549 7 ATOM 932 CDl LEU 185 -35.598 6 ATOM 933 CD2 LEU 185 -36.866 8 ATOM 934 C LEU 185 -33.685 8 ATOM 935 O LEU 185 -34.515 7 ATOM 936 N ASP 186 -32.610 8 ATOM 937 CA ASP 186 -32.280 9 ATOM 938 CB ASP 186 -31.663 8 ATOM 939 CG ASP 186 -31.865 8 ATOM 940 OD1 ASP 186 -32.984 8 ATOM 941 OD2 ASP 186 -30.909 8 ATOM 942 C ASP 186 -31.307 10 ATOM 943 O ASP 186 -31.315 11 ATOM 944 N THR 187 -30.474 10 ATOM 945 CA THR 187 -29.470 11 ATOM 946 CB THR 187 -28.870 11 ATOM 947 OG1 THR 187 -28.137 10 ATOM 948 CG2 THR 187 -29.968 12 ATOM 949 C THR 187 -28.341 11 ATOM 950 O THR 187 -28.362 10 ATOM 951 N SER 188 -27.360 12 ATOM 952 CA SER 188 -26.153 11 ATOM 953 CB SER 188 -25.196 12 ATOM 954 OG SER 188 -24.937 13 ATOM 955 C SER 188 -25.525 10 ATOM 956 O SER 188 -25.828 10 ATOM 957 N ILE 189 -24.680 9 ATOM 958 CA ILE 189 -24.001 8 ATOM 959 CB ILE 189 -24.496 7 ATOM 960 CG2 ILE 189 -26.000 7 ATOM 961 CGI ILE 189 -24.132 7 ATOM 962 CDl ILE 189 -24.517 5 ATOM 963 C ILE 189 -22.494 8 ATOM 964 0 ILE 189 -22.009 9 ATOM 965 N GLN 190 -21.763 8 ATOM 966 CA GLN 190 -20.313 8 ATOM 967 CB GLN 190 -19.717 8 ATOM 968 CG GLN 190 -18.210 7 ATOM 969 CD GLN 190 -17.488 8 ATOM 970 OE1 GLN 190 -17.364 10 ATOM 971 NE2 GLN 190 -17.008 8 ATOM 972 C GLN 190 -19.971 6 ATOM 973 0 GLN 190 -19.828 5 ATOM 974 N SER 191 -19.854 6 ATOM 975 CA SER 191 -19.731 5 ATOM 976 CB SER 191 -20.052 5 ATOM 977 OG SER 191 -19.186 6 ATOM 978 C SER 191 -18.351 4 ATOM 979 O SER 191 -18.156 3 ATOM 980 N ASP 192 -17.404 5 ATOM 981 CA ASP 192 -16.056 5 ATOM 982 CB ASP 192 -15.052 6 ATOM 983 CG ASP 192 -14.726 6 ATOM 984 OD1 ASP 192 -15.012 6 ATOM 985 OD2 ASP 192 -14.181 8 ATOM 986 C ASP 192 -15.944 4 -32.319 1.00 42.94 B C -32.959 1.00 43.91 B C -34.290 1.00 46.07 B c -33.049 1.00 43.64 B c -34.379 1.00 44.65 B c -34.994 1.00 45.86 B c -36.319 1.00 48.85 B 0 -28.492 1.00 37.29 B c -27.804 1.00 34.89 B 0 -28.097 1.00 35.24 B N -26.835 1.00 34.10 B c -26.008 1.00 32.18 B c -24.750 1.00 35.23 B c -23.708 1.00 32.47 B c -24.190 1.00 32.96 B c -27.122 1.00 33.43 B c -27.755 1.00 32.77 B 0 -26.669 1.00 33.29 B N -26.690 1.00 35.12 B c -27.183 1.00 34.68 B c -28.664 1.00 37.37 B c -28.923 1.00 38.05 B c -29.057 1.00 39.00 B c -25.290 1.00 35.69 B c -24.413 1.00 36.10 B 0 -25.086 1.00 35.47 B N -23.759 1.00 38.43 B c -22.920 1.00 44.90 B c -21.424 1.00 53.04 B c -20.929 1.00 56.81 B 0 -20.743 1.00 55.06 B 0 -23.842 1.00 37.51 B c -24.816 1.00 36.47 B 0 -22.818 1.00 34.82 B N -22.830 1.00 35.00 B c -21.426 1.00 33.57 B c -21.004 1.00 33.38 B 0 -20.416 1.00 30.31 B c -23.756 1.00 36.71 B c -24.304 1.00 36.59 B 0 -23.937 1.00 36.36 B N -24.641 1.00 39.03 B c -24.728 1.00 39.14 B c -23.443 1.00 42.99 B 0 -23.851 1.00 39.61 B c -22.666 1.00 38.53 B 0 -24.509 1.00 39.46 B N -23.833 1.00 40.86 B c -24.326 1.00 41.34 B c -24.131 1.00 38.20 B c -25.797 1.00 42.75 B c -26.342 1.00 41.61 B c -24.041 1.00 41.60 B c -24.946 1.00 40.48 B 0 -23.177 1.00 43.69 B N -23.273 1.00 44.38 B c -21.861 1.00 46.59 B c -21.793 1.00 52.20 B c -22.678 1.00 57.06 B c -22.337 1.00 59.79 B 0 -23.828 1.00 56.64 B N -23.996 1.00 44.38 B c -23.367 1.00 43.59 B 0 -25.318 1.00 44.25 B N -26.131 1.00 46.81 B c -27.597 1.00 45.03 B c -28.106 1.00 45.93 B 0 -26.035 1.00 47.69 B c -26.520 1.00 48.01 B 0 -25.410 1.00 49.21 B N -25.198 1.00 52.01 B c -25.056 1.00 54.81 B c -26.379 1.00 60.16 B c -27.436 1.00 62.13 B 0 -26.361 1.00 61.90 B 0 -23.959 1.00 51.65 B c 191 WO 2009/026558 PCT/US2008/074097 ATOM 987 0 ASP 192 -14.901 3.577 -23.721 1.00 52.13 B O ATOM 988 N HIS 193 -17.001 4 . 124 -23.159 1.00 50.05 B N ATOM 989 CA HIS 193 -16.932 3.376 -21.914 1.00 48.15 B C ATOM 990 CB HIS 193 -18.204 3.569 -21.091 1.00 44.37 B C ATOM 991 CG HIS 193 -18.091 3.048 -19.693 1.00 43.27 B c ATOM 992 CD2 HIS 193 -17.873 3.686 -18.518 1.00 40.34 B c ATOM 993 ND1 HIS 193 -18.178 1.705 -19.389 1.00 42.52 B N ATOM 994 CEl HIS 193 -18.020 1.538 -18.088 1.00 40.12 B c ATOM 995 NE2 HIS 193 -17.833 2.725 -17.536 1.00 40.42 B N ATOM 996 C HIS 193 -16.725 1.891 -22.188 1.00 48.80 B C ATOM 997 0 HIS 193 -17.291 1.333 -23.131 1.00 48.40 B 0 ATOM 998 N ARG 194 -15.918 1.256 -21.347 1.00 49.72 B N ATOM 999 CA ARG 194 -15.475 -0.106 -21.594 1.00 51.21 B C ATOM 1000 CB ARG 194 -14.469 -0.527 -20.520 1.00 55.14 B c ATOM 1001 CG ARG 194 -13.596 -1.708 -20.912 1.00 62.40 B c ATOM 1002 CD ARG 194 -14.042 -2.993 -20.227 1.00 68.22 B c ATOM 1003 NE ARG 194 -13.251 -4 . 143 -20.660 1.00 73.86 B N ATOM 1004 CZ ARG 194 -13.497 -5.402 -20.306 1.00 76.07 B c ATOM 1005 NHl ARG 194 -12.721 -6.383 -20.754 1.00 77.25 B N ATOM 1006 NH2 ARG 194 -14.516 -5.685 -19.504 1.00 76.69 B N ATOM 1007 C ARG 194 -16.650 -1.077 -21.620 1.00 49.97 B C ATOM 1008 O ARG 194 -16.568 -2.141 -22.227 1.00 49.91 B 0 ATOM 1009 N GLU 195 -17.748 -0.710 -20.969 1.00 48.05 B N ATOM 1010 CA GLU 195 -18.907 -1.591 -20.911 1.00 46.66 B C ATOM 1011 CB GLU 195 -19.884 -1.116 -19.833 1.00 47.09 B c ATOM 1012 CG GLU 195 -19.582 -1.665 -18.442 1.00 48.87 B c ATOM 1013 CD GLU 195 -19.912 -3.146 -18.320 1.00 51.11 B c ATOM 1014 OE1 GLU 195 -18.981 -3.979 -18.447 1.00 52.26 B 0 ATOM 1015 OE2 GLU 195 -21.100 -3.478 -18.101 1.00 48.64 B 0 ATOM 1016 C GLU 195 -19.634 -1.698 -22.247 1.00 46.38 B c ATOM 1017 0 GLU 195 -20.254 -2.718 -22.542 1.00 44.77 B 0 ATOM 1018 N ILE 196 -19.557 -0.648 -23.057 1.00 46.54 B N ATOM 1019 CA ILE 196 -20.347 -0.599 -24.280 1.00 48.16 B c ATOM 1020 CB ILE 196 -21.486 0.446 -24.164 1.00 46.92 B c ATOM 1021 CG2 ILE 196 -22.476 0.015 -23.102 1.00 45.09 B c ATOM 1022 CGI ILE 196 -20.904 1.822 -23.830 1.00 47.02 B c ATOM 1023 CD1 ILE 196 -21.951 2.902 -23.616 1.00 47.07 B c ATOM 1024 C ILE 196 -19.533 -0.296 -25.537 1.00 50.05 B c ATOM 1025 0 ILE 196 -20.061 -0.348 -26.647 1.00 50.50 B 0 ATOM 1026 N GLU 197 -18.253 0.015 -25.371 1.00 52.60 B N ATOM 1027 CA GLU 197 -17.453 0.482 -26.497 1.00 55.84 B c ATOM 1028 CB GLU 197 -16.007 0.709 -26.068 1.00 59.17 B c ATOM 1029 CG GLU 197 -15.164 1.378 -27.140 1.00 66.13 B c ATOM 1030 CD GLU 197 -13.691 1.374 -26.800 1.00 71.16 B c ATOM 1031 OE1 GLU 197 -13.222 0.370 -26.214 1.00 74.15 B 0 ATOM 1032 OE2 GLU 197 -13.003 2.371 -27.116 1.00 72.99 B 0 ATOM 1033 C GLU 197 -17.478 -0.479 -27.685 1.00 55.61 B c ATOM 1034 0 GLU 197 -17.271 -1.684 -27.536 1.00 55.13 B 0 ATOM 1035 N GLY 198 -17.740 0.071 -28.866 1.00 56.15 B N ATOM 1036 CA GLY 198 -17.715 -0.727 -30.077 1.00 56.83 B c ATOM 1037 C GLY 198 -18.987 -1.514 -30.321 1.00 57.44 B c ATOM 1038 0 GLY 198 -19.150 -2.122 -31.377 1.00 58.60 B 0 ATOM 1039 N ARG 199 -19.892 -1.513 -29.349 1.00 57.74 B N ATOM 1040 CA ARG 199 -21.160 -2.213 -29.500 1.00 57.82 B c ATOM 1041 CB ARG 199 -21.349 -3.211 -28.355 1.00 58.86 B c ATOM 1042 CG ARG 199 -20.312 -4.333 -28.336 1.00 63.05 B c ATOM 1043 CD ARG 199 -20.287 -5.097 -29.659 1.00 67.78 B c ATOM 1044 NE ARG 199 -21.503 -5.885 -29.868 1.00 71.51 B N ATOM 1045 CZ ARG 199 -21.995 -6.214 -31.060 1.00 72.46 B c ATOM 1046 NHl ARG 199 -23.109 -6.933 -31.145 1.00 72.69 B N ATOM 1047 NH2 ARG 199 -21.376 -5.821 -32.168 1.00 73.16 B N ATOM 1048 C ARG 199 -22.353 -1.256 -29.568 1.00 57.64 B C ATOM 1049 O ARG 199 -23.429 -1.633 -30.030 1.00 58.42 B 0 ATOM 1050 N VAL 200 -22.169 -0.023 -29.105 1.00 56.67 B N ATOM 1051 CA VAL 200 -23.198 1.001 -29.266 1.00 56.34 B C ATOM 1052 CB VAL 200 -23.575 1.661 -27.921 1.00 56.89 B c ATOM 1053 CGI VAL 200 -24.037 0.602 -26.933 1.00 59.60 B c ATOM 1054 CG2 VAL 200 -22.390 2.424 -27.369 1.00 58.38 B c ATOM 1055 C VAL 200 -22.735 2.095 -30.219 1.00 55.25 B c ATOM 1056 O VAL 200 -21.632 2.629 -30.089 1.00 55.38 B 0 ATOM 1057 N MET 201 -23.588 2.421 -31.182 1.00 53.57 B N ATOM 1058 CA MET 201 -23.303 3.491 -32.122 1.00 53.33 B c ATOM 1059 CB MET 201 -23.629 3.037 -33.542 1.00 57.41 B c ATOM 1060 CG MET 201 -23.473 4 . 127 -34.587 1.00 65.55 B c ATOM 1061 SD MET 201 -24.977 4.367 -35.566 1.00 76.08 B s ATOM 1062 CE MET 201 -24.388 5.567 -36.805 1.00 73.70 B c 192 WO 2009/026558 PCT/US2008/074097 ATOM 1063 c MET 201 -24.129 4 ATOM 1064 0 MET 201 -25.322 4 ATOM 1065 N VAL 202 -23.486 5 ATOM 1066 CA VAL 202 -24.199 7 ATOM 10 67 CB VAL 202 -23.269 8 ATOM 1068 CGI VAL 202 -24.025 9 ATOM 1069 CG2 VAL 202 -22.721 7 ATOM 1070 C VAL 202 -24.724 7 ATOM 1071 O VAL 202 -23.941 7 ATOM 1072 N THR 203 -26.042 7 ATOM 1073 CA THR 203 -26.621 8 ATOM 1074 CB THR 203 -28.127 7 ATOM 1075 OG1 THR 203 -28.818 8 ATOM 1076 CG2 THR 203 -28.411 6 ATOM 1077 C THR 203 -26.413 9 ATOM 1078 O THR 203 -26.080 10 ATOM 1079 N ASP 204 -26.595 10 ATOM 1080 CA ASP 204 -26.440 11 ATOM 1081 CB ASP 204 -25.818 12 ATOM 1082 CG ASP 204 -26.486 11 ATOM 1083 OD1 ASP 204 -27.729 11 ATOM 1084 OD2 ASP 204 -25.761 11 ATOM 1085 C ASP 204 -27.752 12 ATOM 1086 0 ASP 204 -27.864 13 ATOM 1087 N PHE 205 -28.737 11 ATOM 1088 CA PHE 205 -29.985 12 ATOM 1089 CB PHE 205 -31.130 11 ATOM 1090 CG PHE 205 -32.449 11 ATOM 1091 CDl PHE 205 -32.800 12 ATOM 1092 CD2 PHE 205 -33.292 12 ATOM 1093 CE1 PHE 205 -33.958 12 ATOM 1094 CE2 PHE 205 -34.455 13 ATOM 1095 CZ PHE 205 -34.786 13 ATOM 1096 C PHE 205 -29.882 13 ATOM 1097 O PHE 205 -29.454 12 ATOM 1098 N GLU 206 -30.287 14 ATOM 1099 CA GLU 206 -30.548 14 ATOM 1100 CB GLU 206 -29.245 15 ATOM 1101 CG GLU 206 -28.695 16 ATOM 1102 CD GLU 206 -27.488 17 ATOM 1103 OE1 GLU 206 -26.372 17 ATOM 1104 OE2 GLU 206 -27.655 17 ATOM 1105 C GLU 206 -31.520 16 ATOM 1106 O GLU 206 -31.401 16 ATOM 1107 N ASN 207 -32.491 16 ATOM 1108 CA ASN 207 -33.505 17 ATOM 1109 CB ASN 207 -34.736 16 ATOM 1110 CG ASN 207 -35.636 17 ATOM 1111 OD1 ASN 207 -35.748 18 ATOM 1112 ND2 ASN 207 -36.291 18 ATOM 1113 C ASN 207 -33.864 17 ATOM 1114 0 ASN 207 -34.658 16 ATOM 1115 ' N VAL 208 -33.257 18 ATOM 1116 CA VAL 208 -33.467 18 ATOM 1117 CB VAL 208 -32.274 18 ATOM 1118 CGI VAL 208 -32.051 16 ATOM 1119 CG2 VAL 208 -31.016 18 ATOM 1120 C VAL 208 -33.628 20 ATOM 1121 O VAL 208 -33.063 20 ATOM 1122 N PRO 209 -34.408 20 ATOM 1123 CD PRO 209 -35.207 19 ATOM 1124 CA PRO 209 -34.536 21 ATOM 1125 CB PRO 209 -35.713 21 ATOM 1126 CG PRO 209 -35.683 20 ATOM 1127 C PRO 209 -33.256 22 ATOM 1128 O PRO 209 -32.478 21 ATOM 1129 N GLU 210 -33.045 23 ATOM 1130 CA GLU 210 -32.010 24 ATOM 1131 CB GLU 210 -32.237 25 ATOM 1132 CG GLU 210 -31.186 26 ATOM 1133 CD GLU 210 -31.540 28 ATOM 1134 OE1 GLU 210 -32.743 28 ATOM 1135 OE2 GLU 210 -30.622 29 ATOM 1136 C GLU 210 -32.079 24 ATOM 1137 O GLU 210 -33.165 23 ATOM 1138 N GLU 211 -30.927 23
-31.773 1.00 50.12 B C -31.491 1.00 49.66 B O -31.786 1.00 46.03 B N -31.616 1.00 43.65 B C -31.051 1.00 42.67 B C -30.928 1.00 39.96 B c -29.699 1.00 42.01 B c -32.970 1.00 42.11 B c -33.847 1.00 41.82 B 0 -33.146 1.00 39.83 B N -34.367 1.00 39.51 B c -34.458 1.00 37.45 B c -33.499 1.00 38.09 B 0 -34.179 1.00 33.14 B c -34.327 1.00 41.01 B c -33.284 1.00 41.22 B 0 -35.446 1.00 41.79 B N -35.378 1.00 44.36 B c -36.671 1.00 49.04 B c -37.913 1.00 55.58 B c -37.895 1.00 58.79 B 0 -38.907 1.00 57.72 B 0 -35.059 1.00 41.84 B c -35.232 1.00 42.04 B 0 -34.571 1.00 38.16 B N -34.147 1.00 36.96 B c -34.078 1.00 35.73 B c -33.744 1.00 36.34 B c -32.428 1.00 34.81 B c -34.750 1.00 36.67 B c -32.122 1.00 34.86 B c -34.450 1.00 36.51 B c -33.136 1.00 36.57 B c -32.787 1.00 37.17 B c -31.799 1.00 35.61 B 0 -32.741 1.00 36.47 B N -31.469 1.00 39.25 B c -30.821 1.00 43.55 B c -31.344 1.00 51.60 B c -30.544 1.00 57.35 B c -31.118 1.00 58.84 B 0 -29.344 1.00 56.01 B 0 -31.617 1.00 37.64 B c -32.526 1.00 36.38 B 0 -30.711 1.00 34.24 B N -30.673 1.00 32.56 B c -31.466 1.00 30.25 B c -31.868 1.00 31.68 B c -33.054 1.00 32.01 B 0 -30.888 1.00 28.37 B N -29.196 1.00 32.44 B c -28.624 1.00 30.19 B 0 -28.579 1.00 30.82 B N -27.163 1.00 30.29 B c -26.309 1.00 28.56 B c -26.560 1.00 27.68 B c -26.641 1.00 25.16 B c -26.924 1.00 31.06 B c -27.651 1.00 30.60 B 0 -25.897 1.00 30.47 B N -25.072 1.00 30.10 B c -25.447 1.00 31.51 B c -24.474 1.00 31.36 B c -23.932 1.00 29.45 B c -24.774 1.00 31.01 B c -24.234 1.00 28.87 B 0 -24.838 1.00 33.74 B N -24.068 1.00 36.85 B c -24.171 1.00 41.10 B c -24.925 1.00 52.07 B c -25.021 1.00 56.74 B c -25.188 1.00 57.58 B 0 -24.924 1.00 61.67 B 0 -22.586 1.00 33.62 B c -22.037 1.00 31.67 B 0 -21.940 1.00 34.04 B N 193 WO 2009/026558 PCT/US2008/074097 ATOM 1139 CA GLU 211 -30.877 23.780 -20.478 1.00 35.09 B C ATOM 1140 CB GLU 211 -29.440 23.595 -19.993 1.00 37.07 B C ATOM 1141 CG GLU 211 -28.520 22.943 -21.003 1.00 45.78 B c ATOM 1142 CD GLU 211 -28.779 21.466 -21.132 1.00 49.35 B c ATOM 1143 OE1 GLU 211 -29.395 20.908 -20.197 1.00 53.87 B 0 ATOM 1144 OE2 GLU 211 -28.372 20.867 -22.156 1.00 49.08 B 0 ATOM 1145 C GLU 211 -31.414 25.075 -19.887 1.00 34.57 B c ATOM 1146 0 GLU 211 -31.403 26.112 -20.552 1.00 33.61 B 0 ATOM 1147 N ASP 212 -31.876 25.020 -18.640 1.00 34.88 B N ATOM 1148 CA ASP 212 -32.155 26.237 -17.880 1.00 33.98 B c ATOM 1149 CB ASP 212 -33.019 25.913 -16.654 1.00 36.73 B c ATOM 1150 CG ASP 212 -33.263 27.131 -15.764 1.00 39.80 B c ATOM 1151 OD1 ASP 212 -32.845 28.252 -16.132 1.00 43.49 B 0 ATOM 1152 OD2 ASP 212 -33.873 26.965 -14.692 1.00 43.52 B 0 ATOM 1153 C ASP 212 -30.828 26.858 -17.438 1.00 34.59 B c ATOM 1154 O ASP 212 -30.185 26.385 -16.492 1.00 34.03 B 0 ATOM 1155 N GLY 213 -30.425 27.920 -18.127 1.00 34.74 B N ATOM 1156 CA GLY 213 -29.103 28.488 -17.926 1.00 35.64 B c ATOM 1157 C GLY 213 -28.796 29.033 -16.535 1.00 37.75 B c ATOM 1158 0 GLY 213 -27.629 29.101 -16.151 1.00 38.98 B 0 ATOM 1159 N THR 214 -29.818 29.422 -15.776 1.00 38.08 B N ATOM 1160 CA THR 214 -29.594 29.989 -14.444 1.00 39.22 B c ATOM 1161 CB THR 214 -30.863 30.667 -13.889 1.00 39.16 B c ATOM 1162 OG1 THR 214 -31.853 29.671 -13.609 1.00 42.43 B 0 ATOM 1163 CG2 THR 214 -31.427 31.653 -14.900 1.00 40.99 B c ATOM 1164 C THR 214 -29.145 28.934 -13.429 1.00 38.48 B c ATOM 1165 O THR 214 -28.695 29.273 -12.334 1.00 41.23 B 0 ATOM 1166 N ARG 215 -29.278 27.661 -13.790 1.00 36.13 B N ATOM 1167 CA ARG 215 -28.842 26.571 -12.926 1.00 33.09 B c ATOM 1168 CB ARG 215 -30.044 25.753 -12.458 1.00 35.26 B c ATOM 1169 CG ARG 215 -30.978 26.507 -11.525 1.00 39.25 B c ATOM 1170 CD ARG 215 -31.976 25.562 -10.860 1.00 38.84 B c ATOM 1171 NE ARG 215 -33.095 25.240 -11.741 1.00 41.79 B N ATOM 1172 CZ ARG 215 -34.023 24.325 -11.469 1.00 42.83 B c ATOM 1173 NHl ARG 215 -35.005 24.102 -12.330 1.00 42.89 B N ATOM 1174 NH2 ARG 215 -33.965 23.631 -10.341 1.00 40.76 B N ATOM 1175 C ARG 215 -27.850 25.649 -13.621 1.00 31.31 B C ATOM 1176 O ARG 215 -27.465 24.620 -13.072 1.00 30.45 B 0 ATOM 1177 N PHE 216 -27.440 26.007 -14.831 1.00 29.98 B N ATOM 1178 CA PHE 216 -26.577 25.126 -15.606 1.00 31.33 B C ATOM 1179 CB PHE 216 -27.099 25.006 -17.041 1.00 30.11 B c ATOM 1180 CG PHE 216 -26.373 23.979 -17.865 1.00 30.31 B c ATOM 1181 CDl PHE 216 -25.816 24.317 -19.090 1.00 30.81 B c ATOM 1182 CD2 PHE 216 -26.258 22.671 -17.419 1.00 29.75 B c ATOM 1183 CEl PHE 216 -25.156 23.363 -19.861 1.00 32.24 B c ATOM 1184 CE2 PHE 216 -25.602 21.712 -18.178 1.00 30.04 B c ATOM 1185 CZ PHE 216 -25.049 22.056 -19.402 1.00 31.01 B c ATOM 1186 C PHE 216 -25.122 25.604 -15.618 1.00 33.88 B c ATOM 1187 O PHE 216 -24.824 26.718 -16.051 1.00 33.72 B 0 ATOM 1188 N HIS 217 -24.226 24.750 -15.128 1.00 34.66 B N ATOM 1189 CA HIS 217 -22.795 25.014 -15.165 1.00 36.02 B c ATOM 1190 CB HIS 217 -22.209 25.037 -13.748 1.00 39.37 B c ATOM 1191 CG HIS 217 -22.800 26.089 -12.860 1.00 44.56 B c ATOM 1192 CD2 HIS 217 -24.077 26.516 -12.707 1.00 46.84 B c ATOM 1193 NDl HIS 217 -22.040 26.842 -11.990 1.00 47.01 B N ATOM 1194 CEl HIS 217 -22.822 27.688 -11.341 1.00 46.30 B c ATOM 1195 NE2 HIS 217 -24.062 27.510 -11.757 1.00 48.13 B N ATOM 1196 C HIS 217 -22.147 23.897 -15.962 1.00 36.30 B C ATOM 1197 0 HIS 217 -21.915 22.804 -15.445 1.00 35.57 B 0 ATOM 1198 N ARG 218 -21.855 24.183 -17.223 1.00 37.33 B N ATOM 1199 CA ARG 218 -21.393 23.173 -18.161 1.00 40.43 B C ATOM 1200 CB ARG 218 -21.112 23.836 -19.514 1.00 43.99 B c ATOM 1201 CG ARG 218 -20.457 22.930 -20.535 1.00 52.67 B c ATOM 1202 CD ARG 218 -21.475 22.263 -21.444 1.00 60.20 B c ATOM 1203 NE ARG 218 -21.024 20.935 -21.860 1.00 66.00 B N ATOM 1204 CZ ARG 218 -21.834 19.961 -22.267 1.00 67.40 B c ATOM 1205 NHl ARG 218 -21.333 18.783 -22.622 1.00 67.52 B N ATOM 1206 NH2 ARG 218 -23.145 20.168 -22.323 1.00 68.80 B N ATOM 1207 C ARG 218 -20.150 22.423 -17.666 1.00 39.21 B C ATOM 1208 O ARG 218 -20.039 21.212 -17.841 1.00 38.82 B 0 ATOM 1209 N GLN 219 -19.220 23.136 -17.042 1.00 39.79 B N ATOM 1210 CA GLN 219 -17.972 22.517 -16.608 1.00 41.38 B C ATOM 1211 CB GLN 219 -16.984 23.584 -16.120 1.00 44 . 07 B c ATOM 1212 CG GLN 219 -16.482 24.518 -17.227 1.00 53.87 B c ATOM 1213 CD GLN 219 -14.958 24.512 -17.374 1.00 59.95 B c ATOM 1214 OE1 GLN 219 -14.421 24.216 -18.452 1.00 62.01 B 0 194 WO 2009/026558 PCT/US2008/074097 ATOM 1215 NE2 GLN 219 -14.256 24 ATOM 1216 C GLN 219 -18.180 21 ATOM 1217 O GLN 219 -17.400 20 ATOM 1218 N ALA 220 -19.234 21 ATOM 1219 CA ALA 220 -19.503 20 ATOM 1220 CB ALA 220 -20.027 21 ATOM 1221 C ALA 220 -20.489 19 ATOM 1222 0 ALA 220 -20.497 18 ATOM 1223 N SER 221 -21.312 19 ATOM 1224 CA SER 221 -22.373 18 ATOM 1225 CB SER 221 -23.316 19 ATOM 1226 OG SER 221 -24.304 18 ATOM 1227 C SER 221 -21.854 17 ATOM 1228 O SER 221 -20.932 17 ATOM 1229 N LYS 222 -22.449 16 ATOM 1230 CA LYS 222 -22.186 15 ATOM 1231 CB LYS 222 -22.026 14 ATOM 1232 CG LYS 222 -20.878 14 ATOM 1233 CD LYS 222 -21.183 13 ATOM 1234 CE LYS 222 -19.918 13 ATOM 1235 NZ LYS 222 -20.212 12 ATOM 1236 C LYS 222 -23.353 14 ATOM 1237 0 LYS 222 -24.327 14 ATOM 1238 N CYS 223 -23.260 15 ATOM 1239 CA CYS 223 -24.398 15 ATOM 1240 C CYS 223 -24.721 13 ATOM 1241 0 CYS 223 -25.844 13 ATOM 1242 CB CYS 223 -24.148 16 ATOM 1243 SG CYS 223 -24.066 17 ATOM 1244 N ASP 224 -23.736 12 ATOM 1245 CA ASP 224 -23.820 11 ATOM 1246 CB ASP 224 -22.448 11 ATOM 1247 CG ASP 224 -21.896 11 ATOM 1248 OD1 ASP 224 -22.698 12 ATOM 1249 OD2 ASP 224 -20.653 11 ATOM 1250 C ASP 224 -24.318 10 ATOM 1251 O ASP 224 -24.500 9 ATOM 1252 N SER 225 -24.514 11 ATOM 1253 CA SER 225 -24.670 10 ATOM 1254 CB SER 225 -24.814 10 ATOM 1255 OG SER 225 -25.257 10 ATOM 1256 C SER 225 -25.838 9 ATOM 1257 O SER 225 -25.671 7 ATOM 1258 N HIS 226 -27.018 9 ATOM 1259 CA HIS 226 -28.235 8 ATOM 1260 CB HIS 226 -29.458 9 ATOM 1261 CG HIS 226 -30.774 9 ATOM 1262 CD2 HIS 226 -31.387 8 ATOM 1263 ND1 HIS 226 -31.659 8 ATOM 1264 CEl HIS 226 -32.760 8 ATOM 1265 NE2 HIS 226 -32.621 8 ATOM 1266 C HIS 226 -28.206 7 ATOM 1267 0 HIS 226 -28.456 6 ATOM 1268 N GLY 227 -27.887 8 ATOM 1269 CA GLY 227 -27.905 7 ATOM 1270 C GLY 227 -26.827 6 ATOM 1271 0 GLY 227 -27.082 5 ATOM 1272 N THR 228 -25.623 6 ATOM 1273 CA THR 228 -24.514 5 ATOM 1274 CB THR 228 -23.218 6 ATOM 1275 OG1 THR 228 -22.857 7 ATOM 1276 CG2 THR 228 -22.085 5 ATOM 1277 C THR 228 -24.866 4 ATOM 1278 O THR 228 -24.596 3 ATOM 1279 N HIS 229 -25.473 4 ATOM 1280 CA HIS 229 -25.755 3 ATOM 1281 CB HIS 229 -26.279 4 ATOM 1282 CG HIS 229 -26.547 3 ATOM 1283 CD2 HIS 229 -25.754 3 ATOM 1284 ND1 HIS 229 -27.758 2 ATOM 1285 CEl HIS 229 -27.700 2 ATOM 1286 NE2 HIS 229 -26.494 2 ATOM 1287 C HIS 229 -26.787 2 ATOM 1288 0 HIS 229 -26.699 1 ATOM 1289 N LEU 230 -27.764 3 ATOM 1290 CA LEU 230 -28.840 2 ,
-16.289 1.00 62.25 B N -15.519 1.00 37.67 B C -15.406 1.00 37.10 B O -14.725 1.00 35.89 B N -13.638 1.00 35.91 B C -12.427 1.00 33.00 B C -14.037 1.00 35.70 B c -13.453 1.00 36.94 B 0 -15.039 1.00 37.81 B N -15.444 1.00 39.11 B c -16.411 1.00 40.05 B c -16.916 1.00 44 .84 B 0 -16.087 1.00 38.84 B c -16.900 1.00 38.31 B 0 -15.715 1.00 39.04 B N -16.396 1.00 41.16 B c -15.377 1.00 42.57 B c -14.402 1.00 46.43 B c -13.100 1.00 53.68 B c -12.377 1.00 57.05 B c -11.418 1.00 57.68 B N -17.321 1.00 41.01 B c -16.904 1.00 42.43 B 0 -18.576 1.00 41.97 B N -19.484 1.00 44.73 B c -19.876 1.00 42.78 B c -20.280 1.00 42.75 B 0 -20.745 1.00 48.24 B c -20.440 1.00 61.09 B s -19.735 1.00 42.89 B N -20.215 1.00 41.94 B c -20.677 1.00 45.97 B c -21.828 1.00 51.61 B c -22.585 1.00 55.30 B 0 -21.978 1.00 55.41 B 0 -19.163 1.00 40.44 B c -19.446 1.00 40.53 B 0 -17.943 1.00 39.18 B N -16.817 1.00 38.21 B c -15.527 1.00 38.32 B c -14.488 1.00 45.34 B 0 -16.939 1.00 35.49 B c -16.727 1.00 35.90 B 0 -17.275 1.00 34.83 B N -17.285 1.00 34.19 B c -17.415 1.00 33.13 B c -17.207 1.00 34.07 B c -16.078 1.00 33.89 B c -18.238 1.00 33.86 B N -17.753 1.00 34.25 B c -16.445 1.00 35.48 B N -18.440 1.00 34.61 B C -18.248 1.00 34.03 B 0 -19.639 1.00 33.03 B N -20.795 1.00 33.67 B C -20.768 1.00 33.99 B c -21.140 1.00 32.66 B 0 -20.332 1.00 33.72 B N -20.305 1.00 35.16 B c -19.759 1.00 36.04 B c -20.564 1.00 36.59 B 0 -19.778 1.00 35.96 B c -19.399 1.00 35.86 B c -19.716 1.00 34.91 B 0 -18.262 1.00 36.05 B N -17.264 1.00 35.40 B c -15.990 1.00 35.21 B c -14.879 1.00 34.42 B c -13.879 1.00 35.18 B c -14.726 1.00 36.17 B N -13.681 1.00 38.58 B c -13.150 1.00 37.21 B N -17.817 1.00 36.81 B C -17.603 1.00 37.62 B 0 -18.540 1.00 37.41 B N -19.092 1.00 36.89 B C 195 WO 2009/026558 PCT/US2008/074097 ATOM 1291 CB LEU 230 -29.971 3.580 -19.591 1.00 35.14 B C ATOM 1292 CG LEU 230 -30.761 4.295 -18.489 1.00 36.53 B C ATOM 1293 CDl LEU 230 -31.805 5.216 -19.118 1.00 34.66 B c ATOM 1294 CD2 LEU 230 -31.430 3.263 -17.585 1.00 31.80 B c ATOM 1295 C LEU 230 -28.345 1.773 -20.224 1.00 37.42 B c ATOM 1296 O LEU 230 -28.719 0.602 -20.300 1.00 37.18 B 0 ATOM 1297 N ALA 231 -27.505 2.317 -21.099 1.00 36.72 B N ATOM 1298 CA ALA 231 -26.895 1.514 -22.154 1.00 37.67 B c ATOM 1299 CB ALA 231 -25.934 2.365 -22.967 1.00 38.58 B c ATOM 1300 C ALA 231 -26.145 0.353 -21.506 1.00 38.18 B c ATOM 1301 0 ALA 231 -26.195 -0.781 -21.985 1.00 38.02 B 0 ATOM 1302 N GLY 232 -25.466 0.650 -20.403 1.00 37.63 B N ATOM 1303 CA GLY 232 -24.740 -0.371 -19.674 1.00 37.42 B c ATOM 1304 C GLY 232 -25.634 -1.433 -19.062 1.00 39.21 B c ATOM 1305 0 GLY 232 -25.294 -2.620 -19.096 1.00 39.54 B 0 ATOM 1306 N VAL 233 -26.774 -1.025 -18.504 1.00 37.80 B N ATOM 1307 CA VAL 233 -27.706 -1.991 -17.932 1.00 36.04 B c ATOM 1308 CB VAL 233 -28.907 -1.305 -17.247 1.00 34.34 B c ATOM 1309 CGI VAL 233 -29.925 -2.348 -16.842 1.00 32.45 B c ATOM 1310 CG2 VAL 233 -28.446 -0.528 -16.024 1.00 32.92 B c ATOM 1311 C VAL 233 -28.246 -2.917 -19.014 1.00 37.82 B c ATOM 1312 O VAL 233 -28.417 -4.113 -18.788 1.00 38.19 B 0 ATOM 1313 N VAL 234 -28.514 -2.363 -20.191 1.00 38.91 B N ATOM 1314 CA VAL 234 -29.036 -3.164 -21.291 1.00 39.62 B c ATOM 1315 CB VAL 234 -29.552 -2.271 -22.453 1.00 39.19 B c ATOM 1316 CGI VAL 234 -29.920 -3.138 -23.640 1.00 37.07 B c ATOM 1317 CG2 VAL 234 -30.775 -1.470 -22.005 1.00 38.06 B c ATOM 1318 C VAL 234 -27.980 -4.127 -21.849 1.00 41.00 B c ATOM 1319 O VAL 234 -28.241 -5.323 -22.000 1.00 38.81 B 0 ATOM 1320 N SER 235 -26.788 -3.609 -22.141 1.00 41.61 B N ATOM 1321 CA SER 235 -25.837 -4.343 -22.969 1.00 43.40 B c ATOM 1322 CB SER 235 -25.888 -3.804 -24.395 1.00 43.13 B c ATOM 1323 OG SER 235 -25.378 -2.486 -24.430 1.00 43.09 B 0 ATOM 1324 C SER 235 -24.384 -4.320 -22.493 1.00 44.31 B c ATOM 1325 O SER 235 -23.488 -4.670 -23.256 1.00 44.63 B 0 ATOM 1326 N GLY 236 -24.141 -3.903 -21.255 1.00 44.68 B N ATOM 1327 CA GLY 236 -22.771 -3.852 -20.768 1.00 47.17 B c ATOM 1328 C GLY 236 -22.139 -5.234 -20.731 1.00 48.76 B c ATOM 1329 0 GLY 236 -22.823 -6.220 -20.447 1.00 47.27 B 0 ATOM 1330 N ARG 237 -20.840 -5.327 -21.011 1.00 50.91 B N ATOM 1331 CA ARG 237 -20.216 -6.644 -21.113 1.00 54.98 B c ATOM 1332 CB ARG 237 -18.866 -6.565 -21.839 1.00 57.32 B c ATOM 1333 CG ARG 237 -17.921 -5.481 -21.369 1.00 62.69 B c ATOM 1334 CD ARG 237 -16.673 -5.455 -22.254 1.00 67.42 B c ATOM 1335 NE ARG 237 -16.997 -5.685 -23.664 1.00 72.57 B N ATOM 1336 CZ ARG 237 -16.678 -4.861 -24.663 1.00 74.70 B c ATOM 1337 NHl ARG 237 -17.021 -5.164 -25.911 1.00 74.47 B N ATOM 1338 NH2 ARG 237 -16.013 -3.737 -24.420 1.00 75.30 B N ATOM 1339 C ARG 237 -20.047 -7.351 -19.772 1.00 54.54 B C ATOM 1340 O ARG 237 -20.056 -8.578 -19.716 1.00 56.23 B 0 ATOM 1341 N ASP 238 -19.911 -6.584 -18.694 1.00 54.25 B N ATOM 1342 CA ASP 238 -19.780 -7.167 -17.362 1.00 54.09 B C ATOM 1343 CB ASP 238 -18.663 -6.463 -16.580 1.00 56.58 B c ATOM 1344 CG ASP 238 -17.288 -6.673 -17.199 1.00 59.27 B c ATOM 1345 OD1 ASP 238 -17.167 -7.481 -18.144 1.00 60.55 B 0 ATOM 1346 OD2 ASP 238 -16.323 -6.026 -16.738 1.00 61.66 B 0 ATOM 1347 C ASP 238 -21.077 -7.101 -16.556 1.00 53.15 B c ATOM 1348 O ASP 238 -21.436 -8.060 -15.875 1.00 52.85 B 0 ATOM 1349 N ALA 239 -21.775 -5.970 -16.627 1.00 52.70 B N ATOM 1350 CA ALA 239 -22.913 -5.727 -15.742 1.00 50.29 B c ATOM 1351 CB ALA 239 -22.663 -4.476 -14.915 1.00 49.27 B c ATOM 1352 C ALA 239 -24.243 -5.607 -16.483 1.00 49.76 B c ATOM 1353 0 ALA 239 -25.267 -5.280 -15.881 1.00 48.97 B 0 ATOM 1354 N GLY 240 -24.229 -5.881 -17.783 1.00 48.12 B N ATOM 1355 CA GLY 240 -25.448 -5.783 -18.566 1.00 47.47 B c ATOM 1356 C GLY 240 -26.327 -7.023 -18.552 1.00 47.44 B c ATOM 1357 0 GLY 240 -25.912 -8.098 -18.113 1.00 48.79 B 0 ATOM 1358 N VAL 241 -27.553 -6.872 -19.042 1.00 46.01 B N ATOM 1359 CA VAL 241 -28.499 -7.977 -19.115 1.00 45.03 B c ATOM 1360 CB VAL 241 -29.949 -7.465 -19.065 1.00 43.05 B c ATOM 1361 CGI VAL 241 -30.907 -8.578 -19.431 1.00 39.38 B c ATOM 1362 CG2 VAL 241 -30.261 -6.939 -17.668 1.00 42.38 B c ATOM 1363 C VAL 241 -28.307 -8.797 -20.388 1.00 47.14 B c ATOM 1364 O VAL 241 -28.223 -10.025 -20.334 1.00 47.85 B 0 ATOM 1365 N ALA 242 -28.243 -8.114 -21.528 1.00 46.60 B N ATOM 1366 CA ALA 242 -27.917 -8.759 -22.797 1.00 48.43 B c 196 WO 2009/026558 PCT/US2008/074097 ATOM 1367 CB ALA 242 -28.913 -8.342 -23.873 1.00 45.85 B C ATOM 1368 C ALA 242 -26.504 -8.350 -23.202 1.00 50.23 B C ATOM 1369 0 ALA 242 -26.312 -7.414 -23.983 1.00 50.74 B 0 ATOM 1370 N LYS 243 -25.517 -9.058 -22.663 1.00 51.90 B N ATOM 1371 CA LYS 243 -24.134 -8.615 -22.748 1.00 53.47 B c ATOM 1372 CB LYS 243 -23.239 -9.546 -21.923 1.00 54.37 B c ATOM 1373 CG LYS 243 -23.605 -9.581 -20.437 1.00 56.48 B c ATOM 1374 CD LYS 243 -22.714 -10.528 -19.649 1.00 57.08 B c ATOM 1375 CE LYS 243 -23.346 -10.907 -18.314 1.00 58.87 B c ATOM 1376 NZ LYS 243 -23.227 -9.834 -17.291 1.00 59.43 B N ATOM 1377 C LYS 243 -23.658 -8.552 -24.196 1.00 53.57 B c ATOM 1378 0 LYS 243 -23.857 -9.491 -24.972 1.00 53.48 B 0 ATOM 1379 N GLY 244 -23.047 -7.425 -24.555 1.00 53.12 B N ATOM 1380 CA GLY 244 -22.519 -7.255 -25.896 1.00 51.90 B c ATOM 1381 C GLY 244 -23.555 -6.909 -26.952 1.00 52.11 B c ATOM 1382 0 GLY 244 -23.209 -6.729 -28.121 1.00 51.13 B 0 ATOM 1383 N ALA 245 -24.823 -6.810 -26.557 1.00 51.54 B N ATOM 1384 CA ALA 245 -25.892 -6.538 -27.517 1.00 49.79 B c ATOM 1385 CB ALA 245 -27.240 -6.513 -26.814 1.00 49.57 B c ATOM 1386 C ALA 245 -25.663 -5.221 -28.248 1.00 48.94 B c ATOM 1387 0 ALA 245 -25.013 -4.308 -27.732 1.00 50.04 B 0 ATOM 1388 N SER 246 -2 6.206 -5.135 -29.455 1.00 47.10 B N ATOM 1389 CA SER 246 -25.985 -3.992 -30.326 1.00 46.40 B c ATOM 1390 CB SER 246 -26.152 -4.432 -31.785 1.00 46.20 B c ATOM 1391 OG SER 246 -26.115 -3.332 -32.676 1.00 49.27 B 0 ATOM 1392 C SER 246 -26.971 -2.866 -29.992 1.00 46.30 B c ATOM 1393 O SER 246 -28.166 -3.109 -29.813 1.00 4 6.52 B 0 ATOM 1394 N MET 247 -26.475 -1.635 -29.909 1.00 44.47 B N ATOM 1395 CA MET 247 -27.341 -0.506 -29.591 1.00 43.77 B c ATOM 1396 CB MET 247 -27.184 -0.116 -28.120 1.00 44 . 42 B c ATOM 1397 CG MET 247 -27.610 -1.193 -27.145 1.00 47.82 B c ATOM 1398 SD MET 247 -27.687 -0.576 -25.455 1.00 51.27 B s ATOM 1399 CE MET 247 -29.166 0.438 -25.535 1.00 48.79 B c ATOM 1400 C MET 247 -27.092 0.718 -30.464 1.00 42.00 B c ATOM 1401 0 MET 247 -25.972 0.962 -30.916 1.00 39.97 B 0 ATOM 1402 N ARG 248 -28.155 1.480 -30.694 1.00 39.53 B N ATOM 1403 CA ARG 248 -28.057 2.770 -31.359 1.00 39.90 B c ATOM 1404 CB ARG 248 -28.716 2.699 -32.739 1.00 42.19 B c ATOM 1405 CG ARG 248 -28.111 1.636 -33.646 1.00 47.22 B c ATOM 1406 CD ARG 248 -28.800 1.575 -35.001 1.00 52.45 B c ATOM 1407 NE ARG 248 -28.003 2.220 -36.040 1.00 59.77 B N ATOM 1408 CZ ARG 248 -28.404 3.269 -36.754 1.00 64.16 B c ATOM 1409 NH1 ARG 248 -27.599 3.789 -37.674 1.00 65.74 B N ATOM 1410 NH2 ARG 248 -29.609 3.798 -36.560 1.00 65.15 B N ATOM 1411 C ARG 248 -28.751 3.816 -30.492 1.00 39.62 B C ATOM 1412 O ARG 248 -29.907 3.641 -30.096 1.00 39.17 B 0 ATOM 1413 N SER 249 -28.047 4.901 -30.185 1.00 37.99 B N ATOM 1414 CA SER 249 -28.588 5.898 -29.280 1.00 37.24 B C ATOM 1415 CB SER 249 -27.549 6.265 -28.214 1.00 36.64 B c ATOM 1416 OG SER 249 -26.336 6.689 -28.805 1.00 42.82 B 0 ATOM 1417 C SER 249 -29.048 7.147 -30.020 1.00 36.18 B c ATOM 1418 O SER 249 -28.395 7.608 -30.960 1.00 36.34 B 0 ATOM 1419 N LEU 250 -30.192 7.674 -29.595 1.00 33.93 B N ATOM 1420 CA LEU 250 -30.690 8.965 -30.062 1.00 33.58 B c ATOM 1421 CB LEU 250 -32.085 8.810 -30.683 1.00 31.97 B c ATOM 1422 CG LEU 250 -32.225 8.090 -32.028 1.00 35.15 B c ATOM 1423 CD1 LEU 250 -31.875 6.607 -31.885 1.00 32.63 B c ATOM 1424 CD2 LEU 250 -33.649 8.2 62 -32.537 1.00 29.57 B c ATOM 1425 C LEU 250 -30.784 9.893 -28.853 1.00 32.36 B c ATOM 1426 O LEU 250 -31.214 9.472 -27.778 1.00 32.19 B 0 ATOM 1427 N ARG 251 -30.403 11.153 -29.024 1.00 31.24 B N ATOM 1428 CA ARG 251 -30.497 12.105 -27.924 1.00 31.28 B c ATOM 1429 CB ARG 251 -29.299 13.049 -27.937 1.00 32.49 B c ATOM 1430 CG ARG 251 -29.320 14.019 -26.778 1.00 34.71 B c ATOM 1431 CD ARG 251 -28.075 14.868 -26.739 1.00 35.70 B c ATOM 1432 NE ARG 251 -27.962 15.534 -25.447 1.00 39.37 B N ATOM 1433 CZ ARG 251 -27.585 16.796 -25.294 1.00 38.08 B c ATOM 1434 NH1 ARG 251 -27.282 17.528 -26.356 1.00 38.81 B N ATOM 1435 NH2 ARG 251 -27.518 17.322 -24.082 1.00 38.72 B N ATOM 1436 C ARG 251 -31.785 12.929 -27.951 1.00 30.86 B C ATOM 1437 O ARG 251 -31.947 13.813 -28.800 1.00 31.68 B 0 ATOM 1438 N VAL 252 -32.697 12.643 -27.021 1.00 28.82 B N ATOM 1439 CA VAL 2 52 -33.927 13.423 -26.892 1.00 28.33 B C ATOM 1440 CB VAL 2 52 -35.187 12.564 -27.173 1.00 28.02 B c ATOM 1441 CGI VAL 2 52 -35.122 12.000 -28.589 1.00 27.63 B c ATOM 1442 CG2 VAL 2 52 -35.295 11.437 -26.162 1.00 25.95 B c 197 WO 2009/026558 PCT/US2008/074097 ATOM 1443 c VAL 252 -34.084 14 ATOM 1444 0 VAL 252 -35.091 14 ATOM 1445 N LEU 253 -33.092 13 ATOM 1446 CA LEU 253 -33.075 14 ATOM 1447 CB LEU 253 -33.128 13 ATOM 1448 CG LEU 253 -34.374 12 ATOM 1449 CDl LEU 253 -34.152 11 ATOM 1450 CD2 LEU 253 -35.602 13 ATOM 1451 C LEU 253 -31.798 15 ATOM 1452 O LEU 253 -30.723 14 ATOM 1453 N ASN 254 -31.908 16 ATOM 1454 CA ASN 254 -30.723 17 ATOM 1455 CB ASN 254 -31. 111 18 ATOM 1456 CG ASN 254 -31.999 19 ATOM 1457 ODl ASN 254 -32.052 18 ATOM 1458 ND2 ASN 254 -32.704 20 ATOM 1459 C ASN 254 -29.940 17 ATOM 1460 0 ASN 254 -30.229 16 ATOM 1461 N CYS 255 -28.941 17 ATOM 14 62 CA CYS 255 -28.069 17 ATOM 1463 C CYS 255 -28.845 17 ATOM 1464 0 CYS 255 -28.449 16 ATOM 1465 CB CYS 255 -26.944 18 ATOM 1466 SG CYS 255 -25.816 18 ATOM 1467 N GLN 256 -29.948 18 ATOM 1468 CA GLN 256 -30.795 18 ATOM 1469 CB GLN 256 -31.304 19 ATOM 1470 CG GLN 256 -30.203 20 ATOM 1471 CD GLN 256 -30.618 22 ATOM 1472 OEl GLN 256 -31.569 22 ATOM 1473 NE2 GLN 256 -29.889 23 ATOM 1474 C GLN 256 -31.955 17 ATOM 1475 0 GLN 256 -32.960 17 ATOM 1476 N GLY 257 -31.806 16 ATOM 1477 CA GLY 257 -32.761 15 ATOM 1478 C GLY 257 -34.124 15 ATOM 1479 0 GLY 257 -35.115 14 ATOM 1480 N LYS 258 -34.183 16 ATOM 1481 CA LYS 258 -35.462 17 ATOM 1482 CB LYS 258 -35.657 18 ATOM 1483 CG LYS 258 -37.070 19 ATOM 1484 CD LYS 258 -37.359 20 ATOM 1485 CE LYS 258 -37.363 21 ATOM 1486 NZ LYS 258 -38.425 22 ATOM 1487 C LYS 258 -35.557 17 ATOM 1488 0 LYS 258 -34.595 17 ATOM 1489 N GLY 259 -36.715 16 ATOM 1490 CA GLY 259 -36.963 16 ATOM 1491 C GLY 259 -38.363 17 ATOM 1492 0 GLY 259 -39.028 17 ATOM 1493 N THR 260 -38.822 17 ATOM 1494 CA THR 260 -40.191 17 ATOM 1495 CB THR 260 -40.210 18 ATOM 1496 OGl THR 260 -39.565 18 ATOM 1497 CG2 THR 260 -39.479 19 ATOM 1498 C THR 260 -40.920 16 ATOM 1499 O THR 260 -40.289 15 ATOM 1500 N VAL 261 -42.248 16 ATOM 1501 CA VAL 261 -43.038 15 ATOM 1502 CB VAL 261 -44.558 15 ATOM 1503 CGI VAL 261 -45.328 14 ATOM 1504 CG2 VAL 261 -45.019 15 ATOM 1505 C VAL 261 -42.682 15 ATOM 1506 O VAL 261 -42.517 14 ATOM 1507 N SER 2 62 -42.542 16 ATOM 1508 CA SER 2 62 -42.305 16 ATOM 1509 CB SER 262 -42.371 18 ATOM 1510 OG SER 262 -41.371 19 ATOM 1511 C SER 2 62 -40.955 16 ATOM 1512 O SER 2 62 -40.839 15 ATOM 1513 N GLY 263 -39.943 16 ATOM 1514 CA GLY 263 -38.631 16 ATOM 1515 C GLY 263 -38.647 14 ATOM 1516 0 GLY 263 -37.978 13 ATOM 1517 N THR 264 -39.429 13 ATOM 1518 CA THR 264 -39.541 12 -25.521 1.00 27.82 B C -25.259 1.00 28.30 B O -24.652 1.00 26.78 B N -23.349 1.00 27.02 B C -22.222 1.00 23.74 B C -22.136 1.00 24.22 B c -21.061 1.00 23.90 B c -21.807 1.00 21.35 B c -23.223 1.00 25.77 B c -23.570 1.00 26.91 B 0 -22.732 1.00 26.13 B N -22.575 1.00 26.64 B c -22.552 1.00 24.80 B c -21.380 1.00 25.34 B c -20.374 1.00 22.46 B 0 -21.505 1.00 22.21 B N -21.314 1.00 27.37 B c -20.670 1.00 25.26 B 0 -20.974 1.00 28.60 B N -19.837 1.00 31.55 B c -18.526 1.00 29.84 B c -17.561 1.00 29.79 B 0 -19.756 1.00 39.06 B c -21.190 1.00 50.83 B s -18.499 1.00 25.96 B N -17.319 1.00 25.56 B c -17.118 1.00 26.50 B c -16.621 1.00 27.07 B c -16.546 1.00 29.99 B c -17.202 1.00 29.18 B 0 -15.740 1.00 28.68 B N -17.400 1.00 25.12 B c -16.714 1.00 25.75 B 0 -18.231 1.00 25.10 B N -18.221 1.00 24.84 B c -18.805 1.00 26.13 B c -18.570 1.00 24.93 B 0 -19.571 1.00 24.07 B N -20.040 1.00 28.15 B c -19.522 1.00 32.37 B c -19.644 1.00 39.14 B c -18.588 1.00 41.81 B c -19.204 1.00 45.11 B c -18.618 1.00 47.02 B N -21.568 1.00 27.03 B c -22.274 1.00 25.30 B 0 -22.072 1.00 26.32 B N -23.507 1.00 25.87 B c -23.804 1.00 26.15 B c -22.920 1.00 25.50 B 0 -25.041 1.00 25.47 B N -25.394 1.00 25.25 B c -26.335 1.00 25.76 B c -27.572 1.00 24.26 B 0 -25.689 1.00 22.58 B c -26.082 1.00 24.53 B c -26.647 1.00 25.79 B 0 -26.027 1.00 25.73 B N -26.789 1.00 25.75 B c -26.619 1.00 25.68 B c -27.717 1.00 23.94 B c -25.262 1.00 24.05 B c -28.271 1.00 27.72 B c -28.953 1.00 28.50 B 0 -28.766 1.00 26.86 B N -30.193 1.00 28.93 B c -30.557 1.00 28.78 B c -29.887 1.00 30.58 B 0 -30.599 1.00 29.25 B c -31.655 1.00 30.56 B 0 -29.756 1.00 27.34 B N -30.051 1.00 25.52 B c -30.038 1.00 27.31 B c -30.836 1.00 27.93 B 0 -29.130 1.00 27.25 B N -29.020 1.00 27.72 B c 198 WO 2009/026558 PCT/US2008/074097 ATOM 1519 CB THR 264 -40.297 12 ATOM 1520 OG1 THR 264 -39.571 12 ATOM 1521 CG2 THR 264 -40.431 10 ATOM 1522 C THR 264 -40.250 11 ATOM 1523 O THR 264 -39.831 10 ATOM 1524 N LEU 265 -41.305 12 ATOM 1525 CA LEU 265 -41.970 12 ATOM 1526 CB LEU 265 -43.076 13 ATOM 1527 CG LEU 265 -44.282 13 ATOM 1528 CDl LEU 265 -45.239 14 ATOM 1529 CD2 LEU 265 -44.970 11 ATOM 1530 C LEU 265 -40.984 12 ATOM 1531 O LEU 265 -40.900 11 ATOM 1532 N ILE 266 -40.238 13 ATOM 1533 CA ILE 266 -39.268 13 ATOM 1534 CB ILE 266 -38.591 14 ATOM 1535 CG2 ILE 266 -37.539 14 ATOM 1536 CGI ILE 266 -39.657 15 ATOM 1537 CDl ILE 266 -39.111 17 ATOM 1538 C ILE 266 -38.219 12 ATOM 1539 0 ILE 266 -37.689 11 ATOM 1540 N GLY 267 -37.928 11 ATOM 1541 CA GLY 267 -36.995 10 ATOM 1542 C GLY 267 -37.617 9 ATOM 1543 0 GLY 267 -36.952 8 ATOM 1544 N LEU 268 -38.897 9 ATOM 1545 CA LEU 268 -39.597 7 ATOM 1546 CB LEU 268 -40.980 7 ATOM 1547 CG LEU 268 -40.963 7 ATOM 1548 CDl LEU 268 -42.378 7 ATOM 1549 CD2 LEU 268 -40.279 6 ATOM 1550 C LEU 268 -39.732 7 ATOM 1551 O LEU 268 -39.605 6 ATOM 1552 N GLU 269 -39.970 8 ATOM 1553 CA GLU 269 -40.034 8 ATOM 1554 CB GLU 269 -40.449 10 ATOM 1555 CG GLU 269 -40.399 10 ATOM 1556 CD GLU 269 -40.936 11 ATOM 1557 OE1 GLU 269 -40.121 12 ATOM 1558 OE2 GLU 269 -42.171 11 ATOM 1559 C GLU 269 -38.687 8 ATOM 1560 O GLU 269 -38.640 7 ATOM 1561 N PHE 270 -37.599 9 ATOM 1562 CA PHE 270 -36.251 8 ATOM 1563 CB PHE 270 -35.221 9 ATOM 1564 CG PHE 270 -33.793 8 ATOM 1565 CDl PHE 270 -33.013 9 ATOM 1566 CD2 PHE 270 -33.219 7 ATOM 1567 CEl PHE 270 -31.679 9 ATOM 1568 CE2 PHE 270 -31.890 7 ATOM 1569 CZ PHE 270 -31.119 8 ATOM 1570 C PHE 270 -36.050 7 ATOM 1571 O PHE 270 -35.440 6 ATOM 1572 N ILE 271 -36.556 6 ATOM 1573 CA ILE 271 -36.427 5 ATOM 1574 CB ILE 271 -36.898 4 ATOM 1575 CG2 ILE 271 -37.081 3 ATOM 1576 CGI ILE 271 -35.873 5 ATOM 1577 CDl ILE 271 -36.342 4 ATOM 1578 C ILE 271 -37.243 4 ATOM 1579 0 ILE 271 -36.798 3 ATOM 1580 N ARG 272 -38.439 4 ATOM 1581 CA ARG 272 -39.271 4 ATOM 1582 CB ARG 272 -40.590 5 ATOM 1583 CG ARG 272 -41.536 4 ATOM 1584 CD ARG 272 -41.632 3 ATOM 1585 NE ARG 272 -42.740 2 ATOM 1586 CZ ARG 272 -42.873 1 ATOM 1587 NHl ARG 272 -43.923 1 ATOM 1588 NH2 ARG 272 -41.961 0 ATOM 1589 C ARG 272 -38.532 4 ATOM 1590 O ARG 272 -38.598 3 ATOM 1591 N LYS 273 -37.811 5 ATOM 1592 CA LYS 273 -37.071 5 ATOM 1593 CB LYS 273 -36.497 7 ATOM 1594 CG LYS 273 -36.154 7 -27.718 1.00 30.16 B C -26.588 1.00 30.13 B O -27.581 1.00 29.89 B c -30.253 1.00 28.07 B c -30.775 1.00 28.06 B 0 -30.724 1.00 26.93 B N -31.962 1.00 29.22 B c -32.324 1.00 32.15 B c -31.394 1.00 36.81 B c -31.906 1.00 37.93 B c -31.331 1.00 35.61 B c -33.126 1.00 28.75 B c -33.824 1.00 30.75 B 0 -33.325 1.00 28.71 B N -34.400 1.00 28.41 B c -34.408 1.00 27.07 B c -35.506 1.00 24.79 B c -34.618 1.00 28.34 B c -34.626 1.00 27.25 B c -34.261 1.00 30.28 B c -35.252 1.00 31.29 B 0 -33.030 1.00 31.04 B N -32.829 1.00 30.24 B c -33.185 1.00 31.88 B c -33.746 1.00 30.74 B 0 -32.865 1.00 31.46 B N -33.224 1.00 33.36 B c -32.566 1.00 29.79 B c -31.034 1.00 30.96 B c -30.496 1.00 28.19 B c -30.593 1.00 30.02 B c -34.744 1.00 34.79 B c -35.316 1.00 36.35 B 0 -35.399 1.00 35.31 B N -36.857 1.00 37.68 B c -37.356 1.00 38.65 B c -38.862 1.00 45.31 B c -39.363 1.00 49.12 B c -39.599 1.00 50.11 B 0 -39.523 1.00 51.18 B 0 -37.479 1.00 36.64 B c -38.473 1.00 35.50 B 0 -36.882 1.00 35.93 B N -37.310 1.00 35.58 B c -36.399 1.00 35.25 B c -36.712 1.00 33.73 B c -37.505 1.00 35.52 B c -36.190 1.00 34.10 B c -37.770 1.00 35.84 B c -36.451 1.00 36.68 B c -37.243 1.00 34.03 B c -37.272 1.00 35.72 B c -38.167 1.00 34.84 B 0 -36.222 1.00 37.31 B N -36.064 1.00 37.51 B c -34.662 1.00 36.29 B c -34.616 1.00 35.12 B c -33.615 1.00 37.36 B c -32.182 1.00 35.75 B c -37.126 1.00 39.47 B c -37.689 1.00 39.37 B 0 -37.395 1.00 41.04 B N -38.448 1.00 44.21 B c -38.516 1.00 44.70 B c -39.595 1.00 47.39 B c -39.624 1.00 49.12 B c -40.470 1.00 54.01 B N -40.970 1.00 53.68 B c -41.727 1.00 53.00 B N -40.723 1.00 51.99 B N -39.781 1.00 46.71 B C -40.607 1.00 45.87 B 0 -39.969 1.00 49.33 B N -41.200 1.00 52.95 B C -41.189 1.00 55.26 B c -42.556 1.00 58.76 B c 199 WO 2009/026558 PCT/US2008/074097 ATOM 1595 CD LYS 273 -37.012 8.960 -42.878 1.00 63.12 B C ATOM 1596 CE LYS 273 -36.916 10.023 -41.780 1.00 66.31 B C ATOM 1597 NZ LYS 273 -37.681 11.264 -42.104 1.00 67.27 B N ATOM 1598 C LYS 273 -35.937 4.740 -41.351 1.00 54.29 B C ATOM 1599 0 LYS 273 -35.729 4 .192 -42.428 1.00 54.42 B O ATOM 1600 N SER 274 -35.212 4 . 492 -40.265 1.00 56.43 B N ATOM 1601 CA SER 274 -34.101 3.547 -40.283 1.00 59.57 B C ATOM 1602 CB SER 274 -33.378 3.548 -38.936 1.00 59.27 B C ATOM 1603 OG SER 274 -32.785 4.806 -38.679 1.00 63.53 B 0 ATOM 1604 C SER 274 -34.588 2.137 -40.578 1.00 61.72 B c ATOM 1605 O SER 274 -33.957 1.398 -41.327 1.00 62.46 B 0 ATOM 1606 N GLN 275 -35.717 1.774 -39.980 1.00 63.45 B N ATOM 1607 CA GLN 275 -36.247 0.423 -40.080 1.00 65.81 B c ATOM 1608 CB GLN 275 -37.531 0.308 -39.258 1.00 63.90 B c ATOM 1609 CG GLN 275 -38.092 -1.096 -39.169 1.00 62.86 B c ATOM 1610 CD GLN 275 -39.504 -1.118 -38.619 1.00 61.93 B c ATOM 1611 OE1 GLN 275 -40.202 -0.105 -38.636 1.00 62.80 B 0 ATOM 1612 NE2 GLN 275 -39.932 -2.275 -38.129 1.00 60.07 B N ATOM 1613 C GLN 275 -36.530 0.032 -41.528 1.00 68.65 B c ATOM 1614 0 GLN 275 -36.466 -1.146 -41.886 1.00 69.70 B 0 ATOM 1615 N LEU 276 -36.838 1.021 -42.359 1.00 71.49 B N ATOM 1616 CA LEU 276 -37.200 0.763 -43.748 1.00 75.33 B c ATOM 1617 CB LEU 276 -37.977 1.950 -44.316 1.00 73.74 B c ATOM 1618 CG LEU 276 -39.275 2.267 -43.577 1.00 73.60 B c ATOM 1619 CDl LEU 276 -39.941 3.488 -44.189 1.00 72.59 B c ATOM 1620 CD2 LEU 276 -40.191 1.060 -43.637 1.00 72.21 B c ATOM 1621 C LEU 276 -35.981 0.489 -44.621 1.00 78.31 B c ATOM 1622 O LEU 276 -35.921 -0.525 -45.315 1.00 80.06 B 0 ATOM 1623 N VAL 277 -35.008 1.392 -44.581 1.00 81.41 B N ATOM 1624 CA VAL 277 -33.861 1.310 -45.475 1.00 84.34 B c ATOM 1625 CB VAL 277 -33.217 2.702 -45.684 1.00 84.33 B c ATOM 162 6 CGI VAL 277 -32.431 3.098 -44.444 1.00 83.58 B c ATOM 1627 CG2 VAL 277 -32.328 2.690 -46.925 1.00 84.75 B c ATOM 1628 C VAL 277 -32.803 0.357 -44.921 1.00 86.12 B c ATOM 1629 O VAL 277 -31.731 0.196 -45.505 1.00 87.28 B 0 ATOM 1630 N GLN 278 -33.103 -0.271 -43.790 1.00 87.17 B N ATOM 1631 CA GLN 278 -32.162 -1.200 -43.173 1.00 88.06 B c ATOM 1632 CB GLN 278 -31.904 -0.802 -41.716 1.00 89.74 B c ATOM 1633 CG GLN 278 -31.033 0.439 -41.567 1.00 92.15 B c ATOM 1634 CD GLN 278 -30.362 0.529 -40.207 1.00 93.65 B c ATOM 1635 OE1 GLN 278 -29.199 0.927 -40.102 1.00 93.33 B 0 ATOM 1636 NE2 GLN 278 -31.092 0.161 -39.158 1.00 93.86 B N ATOM 1637 C GLN 278 -32.653 -2.642 -43.247 1.00 87.50 B c ATOM 1638 0 GLN 278 -33.829 -2.897 -43.517 1.00 86.93 B 0 ATOM 1639 N PRO 279 -31.747 -3.606 -43.013 1.00 87.19 B N ATOM 1640 CD PRO 279 -30.371 -3.404 -42.522 1.00 87.00 B c ATOM 1641 CA PRO 279 -32.081 -5.029 -43.144 1.00 86.05 B c ATOM 1642 CB PRO 279 -30.748 -5.735 -42.902 1.00 86.93 B c ATOM 1643 CG PRO 279 -29.961 -4.772 -42.064 1.00 86.83 B c ATOM 1644 C PRO 279 -33.141 -5.447 -42.134 1.00 84.78 B c ATOM 1645 O PRO 279 -32.885 -5.457 -40.927 1.00 84.29 B 0 ATOM 1646 N VAL 280 -34.328 -5.791 -42.629 1.00 82.85 B N ATOM 1647 CA VAL 280 -35.447 -6.087 -41.744 1.00 81.21 B c ATOM 1648 CB VAL 280 -36.705 -6.529 -42.531 1.00 81.67 B c ATOM 1649 CGI VAL 280 -37.219 -5.370 -43.376 1.00 82.27 B c ATOM 1650 CG2 VAL 280 -36.384 -7.730 -43.407 1.00 82.13 B c ATOM 1651 C VAL 280 -35.077 -7.170 -40.739 1.00 78.95 B c ATOM 1652 O VAL 280 -34.685 -8.280 -41.109 1.00 79.20 B 0 ATOM 1653 N GLY 281 -35.190 -6.817 -39.463 1.00 75.44 B N ATOM 1654 CA GLY 281 -34.881 -7.733 -38.382 1.00 70.08 B c ATOM 1655 C GLY 281 -35.525 -7.216 -37.112 1.00 65.88 B c ATOM 1656 0 GLY 281 -36.125 -6.140 -37.118 1.00 65.69 B 0 ATOM 1657 N PRO 282 -35.426 -7.955 -36.000 1.00 61.85 B N ATOM 1658 CD PRO 282 -34.668 -9.198 -35.779 1.00 60.16 B c ATOM 1659 CA PRO 282 -36.086 -7.478 -34.782 1.00 58.35 B c ATOM 1660 CB PRO 282 -35.892 -8.629 -33.797 1.00 58.52 B c ATOM 1661 CG PRO 282 -34.665 -9.334 -34.282 1.00 59.82 B c ATOM 1662 C PRO 282 -35.450 -6.182 -34.288 1.00 54.89 B c ATOM 1663 O PRO 282 -34.226 -6.045 -34.290 1.00 53.58 B 0 ATOM 1664 N LEU 283 -36.271 -5.223 -33.875 1.00 51.11 B N ATOM 1665 CA LEU 283 -35.724 -4.084 -33.152 1.00 49.71 B c ATOM 1666 CB LEU 283 -35.573 -2.863 -34.070 1.00 51.30 B c ATOM 1667 CG LEU 283 -36.798 -2.124 -34.592 1.00 53.34 B c ATOM 1668 CDl LEU 283 -36.331 -1.003 -35.513 1.00 55.23 B c ATOM 1669 CD2 LEU 283 -37.712 -3.082 -35.342 1.00 55.78 B c ATOM 1670 C LEU 283 -36.509 -3.712 -31.904 1.00 46.72 B c 200 WO 2009/026558 PCT/US2008/074097 ATOM 1671 0 LEU 283 -37.742 -3 ATOM 1672 N VAL 284 -35.756 -3 ATOM 1673 CA VAL 284 -36.301 -2 ATOM 1674 CB VAL 284 -35.610 -3 ATOM 1675 CGI VAL 284 -36.194 -3 ATOM 1676 CG2 VAL 284 -35.765 -5 ATOM 1677 C VAL 284 -36.040 -1 ATOM 1678 O VAL 284 -34.955 -0 ATOM 1679 N VAL 285 -37.041 -0 ATOM 1680 CA VAL 285 -36.884 0 ATOM 1681 CB VAL 285 -37.877 1 ATOM 1682 CGI VAL 285 -37.805 2 ATOM 1683 CG2 VAL 285 -37.555 1 ATOM 1684 C VAL 285 -37.113 0 ATOM 1685 O VAL 285 -38.186 0 ATOM 1686 N LEU 286 -36.093 1 ATOM 1687 CA LEU 286 -36.168 1 ATOM 1688 CB LEU 286 -34.864 1 ATOM 1689 CG LEU 286 -34.687 1 ATOM 1690 CDl LEU 286 -35.823 1 ATOM 1691 CD2 LEU 286 -33.365 1 ATOM 1692 C LEU 286 -36.430 3 ATOM 1693 O LEU 286 -35.642 4 ATOM 1694 N LEU 287 -37.546 3 ATOM 1695 CA LEU 287 -37.976 4 ATOM 1696 CB LEU 287 -39.387 5 ATOM 1697 CG LEU 287 -39.574 5 ATOM 1698 CDl LEU 287 -41.043 5 ATOM 1699 CD2 LEU 287 -39.074 6 ATOM 1700 C LEU 287 -37.980 5 ATOM 1701 O LEU 287 -39.026 5 ATOM 1702 N PRO 288 -36.811 5 ATOM 1703 CD PRO 288 -35.532 5 ATOM 1704 CA PRO 288 -36.699 5 ATOM 1705 CB PRO 288 -35.239 5 ATOM 1706 CG PRO 288 -34.536 5 ATOM 1707 C PRO 288 -37.060 6 ATOM 1708 O PRO 288 -36.271 7 ATOM 1709 N LEU 289 -38.247 7 ATOM 1710 CA LEU 289 -38.643 8 ATOM 1711 CB LEU 289 -38.173 9 ATOM 1712 CG LEU 289 -38.586 9 ATOM 1713 CDl LEU 289 -40.055 9 ATOM 1714 CD2 LEU 289 -37.695 10 ATOM 1715 C LEU 289 -40.151 8 ATOM 1716 O LEU 289 -40.824 7 ATOM 1717 N ALA 290 -40.685 9 ATOM 1718 CA ALA 290 -42.134 10 ATOM 1719 CB ALA 290 -42.656 9 ATOM 1720 C ALA 290 -42.546 11 ATOM 1721 0 ALA 290 -41.813 12 ATOM 1722 N GLY 291 -43.725 11 ATOM 1723 CA GLY 291 -44.355 13 ATOM 1724 C GLY 291 -45.814 12 ATOM 1725 0 GLY 291 -46.195 11 ATOM 1726 N GLY 292 -46.632 13 ATOM 1727 CA GLY 292 -48.053 13 ATOM 1728 C GLY 292 -48.682 12 ATOM 1729 0 GLY 292 -48.090 12 ATOM 1730 N TYR 293 -49.877 12 ATOM 1731 CA TYR 293 -50.562 11 ATOM 1732 CB TYR 293 -51.984 11 ATOM 1733 CG TYR 293 -52.862 10 ATOM 1734 CDl TYR 293 -52.816 9 ATOM 1735 CEl TYR 293 -53.555 9 ATOM 1736 CD2 TYR 293 -53.679 11 ATOM 1737 CE2 TYR 293 -54.418 11 ATOM 1738 CZ TYR 293 -54.351 10 ATOM 1739 OH TYR 293 -55.069 9 ATOM 1740 C TYR 293 -50.616 12 ATOM 1741 O TYR 293 -51.099 13 ATOM 1742 N SER 294 -50.117 11 ATOM 1743 CA SER 294 -50.139 12 ATOM 1744 CB SER 294 -48.714 13 ATOM 1745 OG SER 294 -48.628 13 ATOM 1746 C SER 294 -50.766 11 -31.872 1.00 44.82 B O -30.870 1.00 43.49 B N -29.589 1.00 39.58 B C -28.433 1.00 40.26 B C -27.093 1.00 37.10 B c -28.634 1.00 36.99 B c -29.427 1.00 38.56 B c -29.752 1.00 36.89 B 0 -28.935 1.00 35.58 B N -28.646 1.00 32.71 B c -29.464 1.00 32.36 B c -29.019 1.00 32.21 B c -30.951 1.00 32.10 B c -27.161 1.00 31.36 B c -26.629 1.00 29.48 B 0 -26.497 1.00 31.80 B N -25.074 1.00 30.07 B c -24.395 1.00 29.18 B c -22.920 1.00 30.76 B c -22.088 1.00 28.26 B c -22.422 1.00 30.08 B c -24.842 1.00 31.06 B c -25.265 1.00 30.24 B 0 -24.174 1.00 32.05 B N -23.859 1.00 33.54 B c -24.398 1.00 35.72 B c -25.911 1.00 39.35 B c -26.265 1.00 39.79 B c -26.409 1.00 40.77 B c -22.345 1.00 33.23 B c -21.697 1.00 34.79 B 0 -21.766 1.00 32.54 B N -22.440 1.00 31.44 B c -20.310 1.00 32.08 B c -20.048 1.00 31.66 B c -21.298 1.00 32.64 B c -19.835 1.00 31.22 B c -19.162 1.00 31.60 B 0 -20.203 1.00 30.48 B N -19.929 1.00 29.51 B c -21.062 1.00 28.77 B c -22.485 1.00 30.49 B c -22.733 1.00 28.81 B c -23.505 1.00 27.89 B c -19.808 1.00 28.98 B c -20.185 1.00 30.19 B 0 -19.274 1.00 27.61 B N -19.168 1.00 26.79 B c -17.925 1.00 25.41 B c -19.118 1.00 26.19 B c -18.613 1.00 25.46 B 0 -19.665 1.00 25.85 B N -19.521 1.00 24.71 B c -19.196 1.00 25.09 B c -18.858 1.00 25.42 B 0 -19.293 1.00 25.44 B N -19.062 1.00 25.43 B c -20.201 1.00 29.85 B c -21.281 1.00 28.22 B 0 -19.967 1.00 30.01 B N -20.999 1.00 30.44 B c -20.549 1.00 34.81 B c -21.689 1.00 36.25 B c -22.131 1.00 39.72 B c -23.230 1.00 42.49 B c -22.372 1.00 37.69 B c -23.467 1.00 40.77 B c -23.895 1.00 42.73 B c -25.001 1.00 46.40 B 0 -22.277 1.00 30.43 B c -22.268 1.00 28.65 B 0 -23.373 1.00 29.63 B N -24.663 1.00 30.31 B c -25.067 1.00 30.52 B c -26.461 1.00 32.50 B 0 -25.753 1.00 31.59 B c 201 WO 2009/026558 PCT/US2008/074097 ATOM 1747 0 SER 294 -50.261 10.657 -26.070 1.00 33.33 B O ATOM 1748 N ARG 295 -51.863 12.213 -26.328 1.00 32.46 B N ATOM 1749 CA ARG 295 -52.540 11.471 -27.382 1.00 34.59 B C ATOM 1750 CB ARG 295 -53.791 12.231 -27.839 1.00 36.79 B C ATOM 1751 CG ARG 295 -54.144 11.990 -29.293 1.00 42.69 B c ATOM 1752 CD ARG 295 -55.529 11.403 -29.477 1.00 43.11 B c ATOM 1753 NE ARG 295 -56.529 12.421 -29.789 1.00 44 . 13 B N ATOM 1754 CZ ARG 295 -57.453 12.301 -30.741 1.00 43.05 B c ATOM 1755 NH1 ARG 295 -57.506 11.207 -31.488 1.00 40.61 B N ATOM 1756 NH2 ARG 295 -58.340 13.269 -30.932 1.00 41.43 B N ATOM 1757 C ARG 295 -51.620 11.207 -28.580 1.00 33.96 B C ATOM 1758 O ARG 295 -51.573 10.084 -29.097 1.00 34.38 B 0 ATOM 1759 N VAL 296 -50.878 12.225 -29.012 1.00 31.60 B N ATOM 1760 CA VAL 296 -50.047 12.080 -30.200 1.00 30.10 B C ATOM 1761 CB VAL 296 -49.564 13.476 -30.748 1.00 29.55 B c ATOM 1762 CGI VAL 296 -48.665 14.165 -29.744 1.00 26.60 B c ATOM 1763 CG2 VAL 296 -48.836 13.296 -32.081 1.00 27.87 B c ATOM 1764 C VAL 296 -48.845 11.173 -29.929 1.00 31.23 B c ATOM 1765 O VAL 296 -48.451 10.380 -30.788 1.00 32.00 B 0 ATOM 1766 N LEU 297 -48.268 11.259 -28.734 1.00 29.72 B N ATOM 1767 CA LEU 297 -47.151 10.381 -28.405 1.00 29.56 B c ATOM 1768 CB LEU 297 -46.496 10.813 -27.092 1.00 30.51 B c ATOM 1769 CG LEU 297 -45.183 10.098 -26.782 1.00 30.69 B c ATOM 1770 CDl LEU 297 -44.244 10.249 -27.966 1.00 30.90 B c ATOM 1771 CD2 LEU 297 -44.554 10.680 -2 5.52 6 1.00 30.10 B c ATOM 1772 C LEU 297 -47.602 8.919 -28.301 1.00 30.80 B c ATOM 1773 O LEU 297 -46.916 8.015 -28.786 1.00 30.98 B 0 ATOM 1774 N ASN 298 -48.751 8.682 -27.673 1.00 28.12 B N ATOM 1775 CA ASN 298 -49.312 7.333 -27.628 1.00 28.96 B c ATOM 1776 CB ASN 298 -50.579 7.291 -26.758 1.00 25.34 B c ATOM 1777 CG ASN 298 -50.267 7.390 -25.270 1.00 30.20 B c ATOM 1778 OD1 ASN 298 -49.120 7.635 -24.877 1.00 29.99 B 0 ATOM 1779 ND2 ASN 298 -51.286 7.203 -24.435 1.00 28.93 B N ATOM 1780 C ASN 298 -49.631 6.815 -29.032 1.00 30.19 B c ATOM 1781 0 ASN 298 -49.391 5.644 -29.323 1.00 30.64 B 0 ATOM 1782 N ALA 299 -50.155 7.684 -29.899 1.00 29.73 B N ATOM 1783 CA ALA 299 -50.489 7.284 -31.271 1.00 31.32 B c ATOM 1784 CB ALA 299 -51.300 8.386 -31.974 1.00 26.66 B c ATOM 1785 C ALA 299 -49.244 6.957 -32.094 1.00 32.43 B c ATOM 1786 0 ALA 299 -49.247 6.012 -32.883 1.00 34.42 B 0 ATOM 1787 N ALA 300 -48.177 7.728 -31.913 1.00 32.41 B N ATOM 1788 CA ALA 300 -46.930 7.441 -32.615 1.00 34.19 B c ATOM 1789 CB ALA 300 -45.915 8.553 -32.362 1.00 32.82 B c ATOM 1790 C ALA 300 -46.362 6.091 -32.161 1.00 35.95 B c ATOM 1791 0 ALA 300 -45.826 5.32 6 -32.968 1.00 35.23 B 0 ATOM 1792 N CYS 301 -46.483 5.798 -30.870 1.00 35.94 B N ATOM 1793 CA CYS 301 -45.982 4.537 -30.341 1.00 38.41 B c ATOM 1794 CB CYS 301 -46.000 4.550 -28.809 1.00 35.59 B c ATOM 1795 SG CYS 301 -44.722 5.609 -28.072 1.00 39.73 B s ATOM 1796 C CYS 301 -46.810 3.364 -30.857 1.00 39.27 B c ATOM 1797 O CYS 301 -46.260 2.319 -31.207 1.00 38.08 B 0 ATOM 1798 N GLN 302 -48.128 3.535 -30.913 1.00 40.20 B N ATOM 1799 CA GLN 302 -48.982 2.474 -31.431 1.00 43.44 B c ATOM 1800 CB GLN 302 -50.454 2.857 -31.318 1.00 44.90 B c ATOM 1801 CG GLN 302 -51.371 1.816 -31.935 1.00 49.59 B c ATOM 1802 CD GLN 302 -52.832 2.201 -31.856 1.00 53.42 B c ATOM 1803 OE1 GLN 302 -53.351 2.884 -32.741 1.00 56.88 B 0 ATOM 1804 NE2 GLN 302 -53.509 1.760 -30.798 1.00 52.21 B N ATOM 1805 C GLN 302 -48.649 2.178 -32.892 1.00 43.80 B c ATOM 1806 0 GLN 302 -48.551 1.021 -33.298 1.00 44.02 B 0 ATOM 1807 N ARG 303 -48.467 3.230 -33.677 1.00 43.42 B N ATOM 1808 CA ARG 303 -48.146 3.068 -35.083 1.00 45.57 B c ATOM 1809 CB ARG 303 -48.065 4.440 -35.747 1.00 49.32 B c ATOM 1810 CG ARG 303 -48.758 4.523 -37.097 1.00 58.51 B c ATOM 1811 CD ARG 303 -47.880 3.939 -38.194 1.00 66.09 B c ATOM 1812 NE ARG 303 -48.459 4.098 -39.527 1.00 72.79 B N ATOM 1813 CZ ARG 303 -47.840 3.755 -40.655 1.00 75.84 B c ATOM 1814 NH1 ARG 303 -48.439 3.933 -41.828 1.00 78.15 B N ATOM 1815 NH2 ARG 303 -46.617 3.236 -40.611 1.00 75.76 B N ATOM 1816 C ARG 303 -46.828 2.304 -35.266 1.00 45.17 B C ATOM 1817 O ARG 303 -46.701 1.481 -36.169 1.00 45.58 B 0 ATOM 1818 N LEU 304 -45.850 2.564 -34.405 1.00 44.81 B N ATOM 1819 CA LEU 304 -44.571 1.860 -34.489 1.00 44.87 B C ATOM 1820 CB LEU 304 -43.534 2.512 -33.572 1.00 44.25 B c ATOM 1821 CG LEU 304 -42.401 3.336 -34.182 1.00 45.66 B c ATOM 1822 CDl LEU 304 -41.558 3.899 -33.052 1.00 46.67 B c 202 WO 2009/026558 PCT/US2008/074097 ATOM 1823 CD2 LEU 304 -41.537 2 ATOM 1824 C LEU 304 -44.741 0 ATOM 1825 0 LEU 304 -44.161 -0 ATOM 1826 N ALA 305 -45.536 0 ATOM 1827 CA ALA 305 -45.766 -1 ATOM 1828 CB ALA 305 -46.657 -1 ATOM 1829 C ALA 305 -46.406 -2 ATOM 1830 0 ALA 305 -46.089 -3 ATOM 1831 N ARG 306 -47.300 -1 ATOM 1832 CA ARG 306 -47.972 -2 ATOM 1833 CB ARG 306 -49.248 -1 ATOM 1834 CG ARG 306 -50.258 -1 ATOM 1835 CD ARG 306 -51.626 -0 ATOM 1836 NE ARG 306 -52.625 -1 ATOM 1837 CZ ARG 306 -53.925 -0 ATOM 1838 NH1 ARG 306 -54.765 -0 ATOM 1839 NH2 ARG 306 -54.385 -0 ATOM 1840 C ARG 306 -47.070 -2 ATOM 1841 O ARG 306 -47.418 -3 ATOM 1842 N ALA 307 -45.910 -1 ATOM 1843 CA ALA 307 -44.895 -2 ATOM 1844 CB ALA 307 -44.162 -0 ATOM 1845 C ALA 307 -43.897 -3 ATOM 1846 0 ALA 307 -42.846 -3 ATOM 1847 N GLY 308 -44 .218 -3 ATOM 1848 CA GLY 308 -43.385 -4 ATOM 1849 C GLY 308 -42.267 -4 ATOM 1850 0 GLY 308 -41.354 -5 ATOM 1851 N VAL 309 -42.324 -3 ATOM 1852 CA VAL 309 -41.312 -2 ATOM 1853 CB VAL 309 -41.060 -1 ATOM 1854 CGI VAL 309 -40.007 -0 ATOM 1855 CG2 VAL 309 -40.616 -0 ATOM 1856 C VAL 309 -41.739 -3 ATOM 1857 O VAL 309 -42.892 -2 ATOM 1858 N VAL 310 -40.804 -3 ATOM 1859 CA VAL 310 -41.023 -3 ATOM 1860 CB VAL 310 -40.163 -4 ATOM 1861 CGI VAL 310 -40.404 -5 ATOM 1862 CG2 VAL 310 -40.483 -6 ATOM 1863 C VAL 310 -40.625 -2 ATOM 1864 O VAL 310 -39.440 -2 ATOM 1865 N LEU 311 -41.608 -1 ATOM 1866 CA LEU 311 -41.322 -0 ATOM 1867 CB LEU 311 -42.283 0 ATOM 1868 CG LEU 311 -42.024 1 ATOM 1869 CDl LEU 311 -42.701 0 ATOM 1870 CD2 LEU 311 -42.552 2 ATOM 1871 C LEU 311 -41.410 -0 ATOM 1872 O LEU 311 -42.376 -1 ATOM 1873 N VAL 312 -40.394 -0 ATOM 1874 CA VAL 312 -40.347 -0 ATOM 1875 CB VAL 312 -39.169 -1 ATOM 1876 CGI VAL 312 -39.200 -1 ATOM 1877 CG2 VAL 312 -39.225 -2 ATOM 1878 C VAL 312 -40.165 0 ATOM 1879 O VAL 312 -39.319 1 ATOM 1880 N THR 313 -40.950 1 ATOM 1881 CA THR 313 -40.906 2 ATOM 1882 CB THR 313 -42.075 3 ATOM 1883 OG1 THR 313 -41.854 4 ATOM 1884 CG2 THR 313 -43.405 2 ATOM 1885 C THR 313 -40.971 2 ATOM 1886 O THR 313 -41.479 1 ATOM 1887 N ALA 314 -40.456 3 ATOM 1888 CA ALA 314 -40.574 3 ATOM 1889 CB ALA 314 -39.636 4 ATOM 1890 C ALA 314 -42.017 3 ATOM 1891 0 ALA 314 -42.696 4 ATOM 1892 N ALA 315 -42.480 3 ATOM 1893 CA ALA 315 -43.813 3 ATOM 1894 CB ALA 315 -44.191 2 ATOM 1895 C ALA 315 -43.904 4 ATOM 1896 0 ALA 315 -44.992 5 ATOM 1897 N GLY 316 -42.766 5 ATOM 1898 CA GLY 316 -42.761 6 -35 . 105 1. .00 44 , .90 B C -34 . 086 1 .00 44 . .94 B C -34 .698 1. . 00 45. .02 B 0 -33 . 047 1 .00 45. . 15 B N -32 . 548 1 .00 46, . 08 B c -31 .310 1 .00 42 , . 15 B c -33 .62 9 1. .00 47 . .90 B c -33 .754 1 .00 48 , . 31 B 0 -34 .414 1. .00 49, . 18 B N -35 .482 1. .00 51, .26 B c -35 .895 1 .00 53, . 10 B c -34 .759 1, . 00 59, . 04 B c -35 .228 1 .00 63, . 57 B c -34 .168 1, . 00 68, .39 B N -34 .332 1 .00 71, .24 B c -33 .313 1. .00 71, . 47 B N -35 .518 1. .00 72 , .89 B N -36 .691 1, . 00 50 , .78 B C -37 .590 1 .00 51, . 65 B 0 -36 .706 1. .00 48 , . 97 B N -37 .719 1, . 00 47 , .77 B C -38 . 088 1. .00 47 , .29 B c -37 .221 1 .00 48 , .22 B c -37 .833 1, . 00 48 , .90 B 0 -36 . 100 1, . 00 47 , .59 B N -35 . 604 1, . 00 47 . .86 B c -34 . 648 1, . 00 47 , .93 B c -34 .408 1, . 00 50 , .24 B 0 -34 .099 1, . 00 45, .49 B N -33 . 145 1, . 00 41, .95 B c -33, .264 1, . 00 42 , .45 B c -32 , .256 1, . 00 41 , .14 B c -34 , . 674 1, . 00 42 , .26 B c -31 .714 1, . 00 40 , . 15 B c -31, .343 1, . 00 40 , .60 B 0 -30 , . 917 1, . 00 38 . .32 B N -29, .488 1, . 00 35. , 74 B c -28 , .942 1, . 00 36, .40 B c -27 , .449 1, . 00 35. . 15 B c -29, . 689 1, . 00 35. , 82 B c -28 , .743 1, . 00 35 , .88 B c -28 , . 665 1, . 00 35. , 37 B 0 -28 , . 199 1, . 00 34 . , 34 B N -27 , .407 1, . 00 34 . , 02 B c -27 , .768 1, . 00 35. .30 B c -29, . 138 1, . 00 41. , 31 B c -30 , .213 1 , . 00 42 . ,98 B c -29, . 168 1, . 00 41. , 58 B c -25, .915 1, . 00 33. , 33 B c -25, . 439 1 , .00 32 . .23 B 0 -2 5, . 184 1. .00 31. .89 B N -23 , .739 1. .00 31. ,45 B c -23 , .335 1 , .00 30 . ,23 B c -21, .836 1. , 00 29. , 35 B c -24 , . 109 1 , .00 29. ,71 B c -23 , . 079 1. , 00 32 . ,28 B c -23 , .507 1. .00 30 . ,28 B 0 -22 , . 041 1. .00 31. .04 B N -21 , .411 1. .00 32 . .69 B c -21 , .908 1. .00 34 . .74 B c -21 , .471 1. , 00 40 . ,86 B 0 -21 , .339 1. , 00 34 . ,22 B c -19, .890 1. .00 32 . ,73 B c -19, .341 1. , 00 31. .28 B 0 -19. ,216 1. , 00 31. 17 B N -17 , .7 67 1. , 00 29. ,71 B c -17 . .235 1. , 00 27 . ,09 B c -17 , .383 1. , 00 30. 01 B c -18 . , 071 1. , 00 31. .46 B 0 -16. ,278 1. , 00 29. .03 B N -15. .7 67 1. .00 28 . . 17 B c -14 . , 663 1. , 00 28 . 01 B c -15. ,227 1 . , 00 27 . 59 B c -15. . 194 1. .00 26. 65 B 0 -14 . ,795 1 . .00 26. 83 B N -14 . , 123 1 . , 00 27 . 76 B c 203 WO 2009/026558 PCT/US2008/074097 ATOM 1899 c GLY 316 -42.447 6.543 -12.635 1.00 29.58 B C ATOM 1900 0 GLY 316 -42.688 5.505 -12.019 1.00 29.69 B O ATOM 1901 N ASN 317 -41.924 7.621 -12.053 1.00 28.12 B N ATOM 1902 CA ASN 317 -41.375 7.586 -10.702 1.00 26.22 B C ATOM 1903 CB ASN 317 -39.962 8.172 -10.705 1.00 25.39 B C ATOM 1904 CG ASN 317 -38.976 7.290 -11.441 1.00 27.85 B c ATOM 1905 OD1 ASN 317 -39.265 6.123 -11.712 1.00 27.83 B 0 ATOM 1906 ND2 ASN 317 -37.807 7.839 -11.772 1.00 24.72 B N ATOM 1907 C ASN 317 -42.214 8.332 -9.675 1.00 27.33 B c ATOM 1908 0 ASN 317 -41.697 8.759 -8.637 1.00 26.61 B 0 ATOM 1909 N PHE 318 -43.504 8.494 -9.948 1.00 26.04 B N ATOM 1910 CA PHE 318 -44.293 9.446 -9.180 1.00 27.75 B c ATOM 1911 CB PHE 318 -45.017 10.392 -10.146 1.00 28.25 B c ATOM 1912 CG PHE 318 -44.086 11.087 -11.107 1.00 29.82 B c ATOM 1913 CDl PHE 318 -43.300 12.146 -10.684 1.00 29.15 B c ATOM 1914 CD2 PHE 318 -43.966 10.653 -12.419 1.00 26.83 B c ATOM 1915 CEl PHE 318 -42.405 12.760 -11.553 1.00 29.49 B c ATOM 1916 CE2 PHE 318 -43.076 11.261 -13.288 1.00 29.07 B c ATOM 1917 CZ PHE 318 -42.293 12.316 -12.855 1.00 28.36 B c ATOM 1918 C PHE 318 -45.284 8.806 -8.208 1.00 28.02 B c ATOM 1919 O PHE 318 -46.189 9.477 -7.708 1.00 25.42 B 0 ATOM 1920 N ARG 319 -45.102 7.514 -7.945 1.00 28.99 B N ATOM 1921 CA ARG 319 -46.019 6.760 -7.097 1.00 31.68 B c ATOM 1922 CB ARG 319 -45.726 7.047 -5.624 1.00 35.03 B c ATOM 1923 CG ARG 319 -46.361 6.058 -4.674 1.00 40.29 B c ATOM 1924 CD ARG 319 -45.680 6.070 -3.317 1.00 43.31 B c ATOM 1925 NE ARG 319 -46.115 4.937 -2.505 1.00 50.86 B N ATOM 1926 CZ ARG 319 -45.568 4.592 -1.340 1.00 55.39 B c ATOM 1927 NHl ARG 319 -44.555 5.299 -0.845 1.00 56.32 B N ATOM 1928 NH2 ARG 319 -46.034 3.537 -0.673 1.00 54.10 B N ATOM 1929 C ARG 319 -47.462 7.131 -7.428 1.00 30.53 B C ATOM 1930 O ARG 319 -48.235 7.551 -6.566 1.00 30.48 B 0 ATOM 1931 N ASP 32 0 -47.809 6.969 -8.696 1.00 30.77 B N ATOM 1932 CA ASP 320 -49.078 7.444 -9.226 1.00 31.58 B C ATOM 1933 CB ASP 320 -48.857 8.803 -9.906 1.00 33.04 B c ATOM 1934 CG ASP 32 0 -50.140 9.599 -10.080 1.00 35.04 B c ATOM 1935 OD1 ASP 320 -51.190 9.185 -9.540 1.00 37.48 B 0 ATOM 1936 OD2 ASP 320 -50.095 10.649 -10.766 1.00 36.23 B 0 ATOM 1937 C ASP 320 -49.594 6.412 -10.240 1.00 31.73 B c ATOM 1938 O ASP 320 -48.915 5.423 -10.546 1.00 29.24 B 0 ATOM 1939 N ASP 321 -50.795 6.649 -10.751 1.00 31.26 B N ATOM 1940 CA ASP 321 -51.382 5.803 -11.782 1.00 32.35 B c ATOM 1941 CB ASP 321 -52.880 6.109 -11.894 1.00 35.85 B c ATOM 1942 CG ASP 321 -53.610 5.160 -12.831 1.00 40.53 B c ATOM 1943 OD1 ASP 321 -52.947 4.460 -13.623 1.00 41.07 B 0 ATOM 1944 OD2 ASP 321 -54.859 5.116 -12.772 1.00 46.57 B 0 ATOM 1945 C ASP 321 -50.691 6.067 -13.123 1.00 31.57 B c ATOM 1946 O ASP 321 -50.791 7.163 -13.671 1.00 30.24 B 0 ATOM 1947 N ALA 322 -50.007 5.052 -13.648 1.00 30.47 B N ATOM 1948 CA ALA 322 -49.207 5.181 -14.862 1.00 30.58 B c ATOM 1949 CB ALA 322 -48.459 3.876 -15.132 1.00 2 9.62 B c ATOM 1950 C ALA 322 -50.035 5.562 -16.085 1.00 32.45 B c ATOM 1951 0 ALA 322 -49.496 5.993 -17.108 1.00 32.37 B 0 ATOM 1952 N CYS 323 -51.347 5.410 -15.989 1.00 33.17 B N ATOM 1953 CA CYS 323 -52.199 5.763 -17.114 1.00 36.70 B c ATOM 1954 C CYS 323 -52.321 7.285 -17.294 1.00 34.79 B c ATOM 1955 0 CYS 32 3 -52.950 7.757 -18.244 1.00 35.34 B 0 ATOM 1956 CB CYS 32 3 -53.595 5.156 -16.942 1.00 41.21 B c ATOM 1957 SG CYS 32 3 -53.747 3.326 -16.881 1.00 51.68 B s ATOM 1958 N LEU 32 4 -51.723 8.053 -16.388 1.00 32.69 B N ATOM 1959 CA LEU 324 -51.751 9.516 -16.496 1.00 31.24 B c ATOM 1960 CB LEU 324 -51.868 10.146 -15.108 1.00 31.16 B c ATOM 1961 CG LEU 324 -53.119 9.756 -14.313 1.00 36.04 B c ATOM 1962 CDl LEU 324 -53.026 10.321 -12.893 1.00 34.08 B c ATOM 1963 CD2 LEU 324 -54.363 10.281 -15.024 1.00 33.82 B c ATOM 1964 C LEU 324 -50.497 10.047 -17.192 1.00 29.73 B c ATOM 1965 O LEU 324 -50.338 11.258 -17.366 1.00 28.10 B 0 ATOM 1966 N TYR 325 -49.619 9.126 -17.586 1.00 28.37 B N ATOM 1967 CA TYR 325 -48.319 9.457 -18.161 1.00 27.58 B c ATOM 1968 CB TYR 325 -47.211 8.953 -17.225 1.00 24.47 B c ATOM 1969 CG TYR 32 5 -47.331 9.551 -15.838 1.00 26.90 B c ATOM 1970 CDl TYR 32 5 -46.692 10.742 -15.519 1.00 25.31 B c ATOM 1971 CEl TYR 32 5 -46.917 11.372 -14.301 1.00 27.10 B c ATOM 1972 CD2 TYR 32 5 -48.187 8.992 -14.890 1.00 24.93 B c ATOM 1973 CE2 TYR 325 -48.413 9.614 -13.672 1.00 25.78 B c ATOM 1974 CZ TYR 325 -47.779 10.807 -13.389 1.00 26.84 B c 204 WO 2009/026558 PCT/US2008/074097 ATOM 1975 OH TYR 325 -48.035 11 ATOM 1976 C TYR 325 -48.167 8 ATOM 1977 O TYR 325 -48.836 7 ATOM 1978 N SER 326 -47.293 9 ATOM 1979 CA SER 326 -46.932 8 ATOM 1980 CB SER 326 -47.539 9 ATOM 1981 OG SER 326 -48.955 9 ATOM 1982 C SER 326 -45.417 8 ATOM 1983 O SER 326 -44.732 9 ATOM 1984 N PRO 327 -44.872 7 ATOM 1985 CD PRO 327 -43.446 7 ATOM 1986 CA PRO 327 -45.635 6 ATOM 1987 CB PRO 327 -44.677 6 ATOM 1988 CG PRO 327 -43.319 6 ATOM 1989 C PRO 327 -46.133 5 ATOM 1990 O PRO 327 -46.680 4 ATOM 1991 N ALA 328 -45.954 5 ATOM 1992 CA ALA 328 -46.395 4 ATOM 1993 CB ALA 328 -46.348 5 ATOM 1994 C ALA 328 -47.805 4 ATOM 1995 0 ALA 328 -48.063 2 ATOM 1996 N SER 329 -48.712 5 ATOM 1997 CA SER 329 -50.122 4 ATOM 1998 CB SER 329 -51.012 5 ATOM 1999 OG SER 329 -50.757 7 ATOM 2000 C SER 329 -50.467 4 ATOM 2001 O SER 329 -51.615 3 ATOM 2002 N ALA 330 -49.494 4 ATOM 2003 CA ALA 330 -49.737 3 ATOM 2004 CB ALA 330 -48.570 3 ATOM 2005 C ALA 330 -49.923 2 ATOM 2006 0 ALA 330 -49.071 1 ATOM 2007 N PRO 331 -51.054 1 ATOM 2008 CD PRO 331 -52.211 2 ATOM 2009 CA PRO 331 -51.352 0 ATOM 2010 CB PRO 331 -52.786 -0 ATOM 2011 CG PRO 331 -53.367 1 ATOM 2012 C PRO 331 -50.373 -0 ATOM 2013 O PRO 331 -50.012 -1 ATOM 2014 N GLU 332 -49.933 -0 ATOM 2015 CA GLU 332 -49.056 -1 ATOM 2016 CB GLU 332 -49.176 -1 ATOM 2017 CG GLU 332 -49.292 0 ATOM 2018 CD GLU 332 -50.640 0 ATOM 2019 OE1 GLU 332 -51.647 0 ATOM 2 02 0 OE2 GLU 332 -50.688 1 ATOM 2 021 C GLU 332 -47.597 -1 ATOM 2022 0 GLU 332 -46.767 -2 ATOM 2023 N VAL 333 -47.286 -0 ATOM 2024 CA VAL 333 -45.942 -0 ATOM 2025 CB VAL 333 -45.622 1 ATOM 2026 CGI VAL 333 -44.275 1 ATOM 2027 CG2 VAL 333 -45.625 1 ATOM 2028 C VAL 333 -45.821 -1 ATOM 2029 O VAL 333 -46.752 -1 ATOM 2030 N ILE 334 -44.679 -1 ATOM 2031 CA ILE 334 -44.452 -2 ATOM 2032 CB ILE 334 -43.411 -3 ATOM 2033 CG2 ILE 334 -43.133 -4 ATOM 2034 CGI ILE 334 -43.944 -4 ATOM 2035 CDl ILE 334 -42.924 -5 ATOM 2036 C ILE 334 -43.974 -1 ATOM 2037 0 ILE 334 -42.896 -1 ATOM 2038 N THR 335 -44.802 -1 ATOM 2039 CA THR 335 -44.595 -0 ATOM 2040 CB THR 335 -45.916 0 ATOM 2041 OG1 THR 335 -46.402 0 ATOM 2042 CG2 THR 335 -45.717 1 ATOM 2043 C THR 335 -44.086 -1 ATOM 2044 O THR 335 -44.718 -2 ATOM 2045 N VAL 336 -42.945 -0 ATOM 2046 CA VAL 336 -42.243 -1 ATOM 2047 CB VAL 336 -40.832 -1 ATOM 2048 CGI VAL 336 -40.221 -2 ATOM 2049 CG2 VAL 336 -40.893 -2 ATOM 2050 C VAL 336 -42.101 -0 -12.203 1.00 29.69 B O -19.550 1.00 28.62 B C -19.872 1.00 28.99 B O -20.372 1.00 28.16 B N -21.649 1.00 27.92 B C -22.813 1.00 27.53 B C -22.795 1.00 29.55 B 0 -21.786 1.00 29.65 B c -21.264 1.00 28.75 B 0 -22.514 1.00 30.05 B N -22.891 1.00 29.85 B c -23.212 1.00 30.77 B c -24.297 1.00 30.62 B c -23.736 1.00 32.87 B c -22.333 1.00 32.88 B c -22.844 1.00 34.26 B 0 -21.020 1.00 30.65 B N -20.099 1.00 31.33 B c -18.650 1.00 29.11 B c -20.427 1.00 31.48 B c -20.381 1.00 30.12 B 0 -20.760 1.00 32.07 B N -20.930 1.00 32.34 B c -20.652 1.00 31.27 B c -21.575 1.00 29.75 B 0 -22.313 1.00 34.16 B c -22.560 1.00 35.28 B 0 -23.218 1.00 35.08 B N -24.531 1.00 38.27 B C -25.467 1.00 34.75 B C -24.365 1.00 40.98 B C -23.797 1.00 39.23 B O -24.846 1.00 45.25 B N -25.439 1.00 46.82 B C -24.530 1.00 48.31 B C -25.039 1.00 48.39 B c -25.047 1.00 49.16 B c -25.156 1.00 49.41 B c -24.532 1.00 51.91 B 0 -26.377 1.00 46.64 B N -27.097 1.00 46.33 B c -28.605 1.00 49.01 B c -29.001 1.00 57.16 B c -28.631 1.00 60.17 B c -29.323 1.00 59.75 B 0 -27.646 1.00 61.46 B 0 -2 6.665 1.00 44 . 15 B c -27.091 1.00 45.37 B 0 -25.816 1.00 41.02 B N -25.261 1.00 37.77 B c -24.918 1.00 38.27 B c -24.232 1.00 37.40 B c -26.188 1.00 35.51 B c -23.986 1.00 36.92 B c -23.182 1.00 39.57 B 0 -23.800 1.00 33.69 B N -22.582 1.00 32.34 B c -22.825 1.00 33.09 B c -21.531 1.00 29.80 B c -23.889 1.00 34.39 B c -24.336 1.00 36.56 B c -21.487 1.00 31.39 B c -21.581 1.00 31.20 B 0 -20.459 1.00 29.87 B N -19.428 1.00 27.70 B c -19.129 1.00 28.65 B c -20.335 1.00 28.99 B 0 -18.064 1.00 28.22 B c -18.162 1.00 28.59 B c -17.658 1.00 26.97 B 0 -17.652 1.00 27.73 B N -16.599 1.00 27.54 B c -17.063 1.00 28.07 B c -16.070 1.00 26.47 B c -18.460 1.00 27.88 B c -15.310 1.00 28.83 B c 205 WO 2009/026558 PCT/US2008/074097 ATOM 2051 0 VAL 336 -41.441 0 ATOM 2052 N GLY 337 -42.716 -1 ATOM 2053 CA GLY 337 -42.482 -0 ATOM 2054 C GLY 337 -41.205 -1 ATOM 2055 0 GLY 337 -40.568 -1 ATOM 2056 N ALA 338 -40.825 -0 ATOM 2057 CA ALA 338 -39.560 -0 ATOM 2058 CB ALA 338 -38.677 0 ATOM 2059 C ALA 338 -39.764 -1 ATOM 2060 0 ALA 338 -40.581 -1 ATOM 2061 N THR 339 -39.010 -2 ATOM 2062 CA THR 339 -39.001 -3 ATOM 2063 CB THR 339 -39.556 -4 ATOM 2064 OG1 THR 339 -38.991 -5 ATOM 2 0 65 CG2 THR 339 -41.079 -4 ATOM 2066 C THR 339 -37.577 -3 ATOM 2067 O THR 339 -36.603 -3 ATOM 2068 N ASN 340 -37.456 -3 ATOM 2069 CA ASN 340 -36.147 -3 ATOM 2070 CB ASN 340 -36.175 -2 ATOM 2071 CG ASN 340 -37.163 -3 ATOM 2072 OD1 ASN 340 -37.492 -4 ATOM 2073 ND2 ASN 340 -37.639 -2 ATOM 2074 C ASN 340 -35.680 -5 ATOM 2075 0 ASN 340 -36.291 -5 ATOM 2076 N ALA 341 -34.593 -5 ATOM 2077 CA ALA 341 -33.991 -6 ATOM 2078 CB ALA 341 -32.656 -6 ATOM 2079 C ALA 341 -34.914 -7 ATOM 2080 0 ALA 341 -34.759 -8 ATOM 2081 N GLN 342 -35.875 -6 ATOM 2082 CA GLN 342 -36.859 -7 ATOM 2083 CB GLN 342 -37.226 -6 ATOM 2084 CG GLN 342 -36.050 -6 ATOM 2085 CD GLN 342 -35.164 -5 ATOM 2086 OE1 GLN 342 -35.658 -4 ATOM 2087 NE2 GLN 342 -33.848 -5 ATOM 2088 C GLN 342 -38.118 -7 ATOM 2089 0 GLN 342 -39.140 -8 ATOM 2090 N ASP 343 -38.037 -7 ATOM 2091 CA ASP 343 -39.170 -7 ATOM 2092 CB ASP 343 -39.621 -9 ATOM 2093 CG ASP 343 -38.718 -9 ATOM 2094 OD1 ASP 343 -38.041 -9 ATOM 2095 OD2 ASP 343 -38.691 -11 ATOM 2096 C ASP 343 -40.371 -6 ATOM 2097 O ASP 343 -41.501 -7 ATOM 2098 N GLN 344 -40.132 -5 ATOM 2099 CA GLN 344 -41.194 -4 ATOM 2100 CB GLN 344 -41.142 -4 ATOM 2101 CG GLN 344 -41.297 -5 ATOM 2102 CD GLN 344 -42.386 -6 ATOM 2103 OE1 GLN 344 -43.575 -6 ATOM 2104 NE2 GLN 344 -41.979 -7 ATOM 2105 C GLN 344 -41.068 -3 ATOM 2106 0 GLN 344 -39.986 -3 ATOM 2107 N PRO 345 -42.176 -2 ATOM 2108 CD PRO 345 -43.521 -2 ATOM 2109 CA PRO 345 -42.139 -1 ATOM 2110 CB PRO 345 -43.569 -0 ATOM 2111 CG PRO 345 -44.400 -2 ATOM 2112 C PRO 345 -41.123 -0 ATOM 2113 O PRO 345 -41.083 -0 ATOM 2114 N VAL 346 -40.304 0 ATOM 2115 CA VAL 346 -39.250 0 ATOM 2116 CB VAL 346 -38.282 1 ATOM 2117 CGI VAL 346 -37.162 2 ATOM 2118 CG2 VAL 346 -37.701 -0 ATOM 2119 C VAL 346 -39.826 2 ATOM 2120 O VAL 346 -40.746 2 ATOM 2121 N THR 347 -39.292 2 ATOM 2122 CA THR 347 -39.591 4 ATOM 2123 CB THR 347 -39.701 4 ATOM 2124 OG1 THR 347 -38.467 4 ATOM 2125 CG2 THR 347 -40.832 3 ATOM 2126 C THR 347 -38.464 5 -15.294 1.00 28.91 B O -14.233 1.00 28.31 B N -12.915 1.00 27.90 B C -12.289 1.00 2 9.62 B C -12.846 1.00 29.27 B 0 -11.135 1.00 29.78 B N -10.490 1.00 32.25 B c -10.348 1.00 29.13 B c -9.118 1.00 32.86 B c -8.317 1.00 32.98 B 0 -8.861 1.00 33.23 B N -7.561 1.00 33.80 B c -7.667 1.00 34.64 B c -8.819 1.00 35.54 B 0 -7.774 1.00 32.31 B c -7.006 1.00 34.89 B c -7.749 1.00 34.08 B 0 -5.702 1.00 34.66 B N -5.069 1.00 37.60 B c -3.765 1.00 38.22 B c -2.753 1.00 40.64 B c -2.771 1.00 37.96 B 0 -1.859 1.00 40.07 B N -4.799 1.00 38.46 B c -5.262 1.00 38.14 B 0 -4.046 1.00 39.59 B N -3.783 1.00 42.44 B c -3.059 1.00 41.05 B c -2.971 1.00 43.87 B c -2.988 1.00 43.82 B 0 -2.263 1.00 45.12 B N -1.546 1.00 47.53 B c -0.222 1.00 49.70 B c 0.734 1.00 55.38 B c 0.378 1.00 61.16 B c 0.073 1.00 63.32 B 0 0.415 1.00 61.47 B N -2.386 1.00 4 7.92 B c -1.876 1.00 48.27 B 0 -3.673 1.00 47.35 B N -4.589 1.00 47.37 B c -4.669 1.00 49.86 B c -5.560 1.00 52.80 B c -6.457 1.00 52.60 B 0 -5.366 1.00 56.09 B 0 -4.227 1.00 45.38 B c -4.607 1.00 46.25 B 0 -3.498 1.00 42.74 B N -3.199 1.00 42.66 B c -1.720 1.00 44.37 B c -0.745 1.00 46.69 B c -1.167 1.00 49.58 B c -1.194 1.00 50.25 B 0 -1.498 1.00 47.71 B N -4.081 1.00 40.29 B c -4.570 1.00 39.64 B 0 -4.289 1.00 38.37 B N -3.745 1.00 38.04 B c -5.136 1.00 37.61 B c -5.068 1.00 36.21 B c -4.664 1.00 37.92 B c -4.604 1.00 36.80 B c -3.406 1.00 36.00 B 0 -5.493 1.00 34.88 B N -5.082 1.00 35.68 B c -6.251 1.00 37.41 B c -5.790 1.00 41.37 B c -6.769 1.00 39.72 B c -4.593 1.00 35.58 B c -5.199 1.00 36.23 B 0 -3.494 1.00 35.01 B N -3.118 1.00 35.51 B c -1.582 1.00 37.60 B c -0.967 1.00 39.20 B 0 -1.021 1.00 34.55 B c -3.635 1.00 33.43 B c 206 WO 2009/026558 PCT/US2008/074097 ATOM 2127 0 THR 347 -37.300 4 ATOM 2128 N LEU 348 -38.820 6 ATOM 2129 CA LEU 348 -37.833 7 ATOM 2130 CB LEU 348 -37.946 7 ATOM 2131 CG LEU 348 -37.908 5 ATOM 2132 CDl LEU 348 -38.457 6 ATOM 2133 CD2 LEU 348 -36.477 5 ATOM 2134 C LEU 348 -38.141 8 ATOM 2135 O LEU 348 -39.136 9 ATOM 2136 N GLY 349 -37.304 8 ATOM 2137 CA GLY 349 -37.703 10 ATOM 2138 C GLY 349 -38.999 9 ATOM 2139 0 GLY 349 -39.113 8 ATOM 2140 N THR 350 -39.988 10 ATOM 2141 CA THR 350 -41.280 10 ATOM 2142 CB THR 350 -41.941 11 ATOM 2143 OG1 THR 350 -42.291 12 ATOM 2144 CG2 THR 350 -40.985 12 ATOM 2145 C THR 350 -42.253 9 ATOM 2146 O THR 350 -43.407 9 ATOM 2147 N LEU 351 -41.790 9 ATOM 2148 CA LEU 351 -42.617 8 ATOM 2149 CB LEU 351 -42.669 9 ATOM 2150 CG LEU 351 -43.186 11 ATOM 2151 CDl LEU 351 -43.285 12 ATOM 2152 CD2 LEU 351 -44.552 11 ATOM 2153 C LEU 351 -42.038 7 ATOM 2154 O LEU 351 -41.513 6 ATOM 2155 N GLY 352 -42.129 7 ATOM 2156 CA GLY 352 -41.659 5 ATOM 2157 C GLY 352 -42.283 5 ATOM 2158 0 GLY 352 -42.842 6 ATOM 2159 N THR 353 -42.188 4 ATOM 2160 CA THR 353 -42.672 3 ATOM 2161 CB THR 353 -42.424 1 ATOM 2162 OG1 THR 353 -42.923 1 ATOM 2163 CG2 THR 353 -43.124 1 ATOM 2164 C THR 353 -44.164 3 ATOM 2165 O THR 353 -44.906 3 ATOM 2166 N ASN 354 -44.588 4 ATOM 2167 CA ASN 354 -46.005 4 ATOM 2168 CB ASN 354 -46.194 4 ATOM 2169 CG ASN 354 -46.090 6 ATOM 2170 OD1 ASN 354 -46.028 6 ATOM 2171 ND2 ASN 354 -46.079 6 ATOM 2172 C ASN 354 -46.625 2 ATOM 2173 0 ASN 354 -45.915 1 ATOM 2174 N PHE 355 -47.948 2 ATOM 2175 CA PHE 355 -48.665 1 ATOM 2176 CB PHE 355 -49.041 1 ATOM 2177 CG PHE 355 -49.523 2 ATOM 2178 CDl PHE 355 -48.712 2 ATOM 2179 CD2 PHE 355 -50.759 2 ATOM 2180 CEl PHE 355 -49.128 4 ATOM 2181 CE2 PHE 355 -51.185 4 ATOM 2182 CZ PHE 355 -50.370 4 ATOM 2183 C PHE 355 -49.920 1 ATOM 2184 O PHE 355 -50.086 2 ATOM 2185 N GLY 356 -50.792 0 ATOM 2186 CA GLY 356 -52.069 0 ATOM 2187 C GLY 356 -52.135 -0 ATOM 2188 0 GLY 356 -51.204 -1 ATOM 2189 N ARG 357 -53.242 -0 ATOM 2190 CA ARG 357 -53.536 -1 ATOM 2191 CB ARG 357 -55. Oil -1 ATOM 2192 CG ARG 357 -55.381 0 ATOM 2193 CD ARG 357 -56.832 0 ATOM 2194 NE ARG 357 -57.105 1 ATOM 2195 CZ ARG 357 -56.884 2 ATOM 2196 NHl ARG 357 -57.153 3 ATOM 2197 NH2 ARG 357 -56.406 1 ATOM 2198 C ARG 357 -52.683 -1 ATOM 2199 O ARG 357 -52.661 -1 ATOM 2200 N CYS 358 -51.997 0 ATOM 2201 CA CYS 358 -51.170 0 ATOM 2202 C CYS 358 -49.745 -0 -3 . 611 1. , 00 31. ,83 B O -4 . 122 1. , 00 32 . ,22 B N -4 . 627 1. , 00 30 . ,40 B C -6. 158 1. , 00 29. , 53 B C -6. 886 1. , 00 30 . 64 B c -8 . 307 1. , 00 27 . ,70 B c -6. 912 1. , 00 26, .20 B c -3 . 974 1. , 00 28 . 73 B c -4 . 303 1. , 00 27 . ,79 B 0 -3 . 035 1. , 00 28 . ,70 B N -2 . 193 1. , 00 27 . ,69 B c -1. 508 1. , 00 28 . , 80 B c -0 . 998 1. , 00 28 . , 55 B 0 -1. 509 1. , 00 28 . ,59 B N -0 . 900 1. , 00 28 . ,89 B c -0 . 331 1. , 00 30 . , 10 B c -1. 411 1, . 00 26, .35 B 0 0 . 634 1, . 00 27 . ,56 B c -1. 906 1, . 00 30 . , 35 B c -1. 576 1, . 00 29. ,28 B 0 -3. 137 1, . 00 29, .53 B N -4 . , 178 1, . 00 30 . , 47 B c -5. .409 1, . 00 28 , .80 B c -5 . , 126 1, . 00 30 . , 54 B c -6. , 426 1, . 00 30 . , 77 B c -4 . ,448 1, . 00 25 , .93 B c -4 . ,539 1, . 00 30 . , 64 B c -3 . , 677 1, . 00 31. . 17 B 0 -5 . , 804 1, . 00 30 . , 87 B N -6. , 181 1, . 00 30 , . 18 B c -7 . ,466 1, . 00 30 , .83 B c -8 . 233 1, . 00 30 , .98 B 0 -7 . ,715 1, . 00 29, .91 B N -8 . 974 1, . 00 29, . 17 B c -9. , 074 1, . 00 32 , . 00 B c -10 . 333 1, . 00 28 , .63 B 0 -7 . , 924 1, . 00 28 , . 13 B c -9. , 122 1, . 00 28 , .69 B c -8 . , 140 1, . 00 26, .24 B 0 -10 . , 352 1, . 00 27 , .36 B N -10 . , 680 1, . 00 28 , . 00 B c -12 . , 055 1, . 00 30 , . 00 B c -12 . ,010 1, . 00 31, .69 B c -10 . , 938 1, . 00 29, .46 B 0 -13 . , 184 1, . 00 30 , .77 B N -10 . , 692 1, . 00 29, . 07 B c -10 . , 658 1. , 00 28 , .69 B 0 -10 . ,741 1, . 00 28 , . 04 B N -10 . , 658 1, . 00 29, . 51 B c -9. ,201 1, . 00 29 . 13 B c -8 . ,465 1, . 00 29, .69 B c -7 . , 522 1, .00 30 , . 05 B c -8 . ,752 1, . 00 27 , . 67 B c -6. , 887 1, .00 28 , . 38 B c -8 . , 121 1, . 00 27 , . 82 B c -7 . , 189 1, . 00 28 , .92 B c -11. , 527 1, . 00 30 .09 B c -12 , .309 1, . 00 30 , .27 B 0 -11. , 398 1, . 00 28 , .41 B N -12 . , 091 1, . 00 28 , . 33 B c -13 . , 314 1, . 00 30 , . 65 B c -13 . , 603 1, .00 29, .89 B 0 -14 . , 041 1, . 00 32 .66 B N -15. ,109 1, . 00 34 .90 B c -15. ,493 1, . 00 34 .24 B c -15. ,994 1 . 00 34 .62 B c -16, .383 1, . 00 36 .26 B c -16, .856 1, . 00 40 .35 B N -18 . ,102 1, . 00 43 . 01 B c -18 . ,448 1 . 00 42 , .62 B N -19, . 005 1 . 00 41, . 68 B N -16, .358 1 . 00 36 .92 B C -17 . ,242 1 . 00 38 . 02 B 0 -16, .441 1 . 00 36 .61 B N -17 , .612 1 . 00 35 .72 B C -17 . ,458 1 . 00 35, .12 B c 207 WO 2009/026558 PCT/US2008/074097 ATOM 2203 0 CYS 358 -48.966 -0 ATOM 2204 CB CYS 358 -51.153 1 ATOM 2205 SG CYS 358 -52.749 2 ATOM 2206 N VAL 359 -49.413 -0 ATOM 2207 CA VAL 359 -48.133 -1 ATOM 2208 CB VAL 359 -47.739 -1 ATOM 2209 CGI VAL 359 -46.472 -1 ATOM 2210 CG2 VAL 359 -47.546 0 ATOM 2211 C VAL 359 -48.233 -2 ATOM 2212 O VAL 359 -49.117 -3 ATOM 2213 N ASP 360 -47.325 -3 ATOM 2214 CA ASP 360 -47.394 -4 ATOM 2215 CB ASP 360 -46.818 -4 ATOM 2216 CG ASP 360 -47.665 -3 ATOM 2217 OD1 ASP 360 -48.754 -4 ATOM 2218 OD2 ASP 360 -47.253 -2 ATOM 2219 C ASP 360 -46.669 -5 ATOM 2220 O ASP 360 -47.138 -6 ATOM 2221 N LEU 361 -45.529 -5 ATOM 2222 CA LEU 361 -44.819 -5 ATOM 2223 CB LEU 361 -44.105 -7 ATOM 2224 CG LEU 361 -42.822 -6 ATOM 2225 CDl LEU 361 -42.187 -8 ATOM 2226 CD2 LEU 361 -43.123 -6 ATOM 2227 C LEU 361 -43.809 -4 ATOM 2228 O LEU 361 -43.605 -3 ATOM 2229 N PHE 3 62 -43.188 -5 ATOM 2230 CA PHE 362 -42.132 -4 ATOM 2231 CB PHE 362 -42.420 -4 ATOM 2232 CG PHE 3 62 -43.654 -3 ATOM 2233 CDl PHE 362 -43.569 -2 ATOM 2234 CD2 PHE 362 -44.906 -4 ATOM 2235 CEl PHE 362 -44.715 -1 ATOM 2236 CE2 PHE 362 -46.055 -3 ATOM 2237 CZ PHE 362 -45.960 -2 ATOM 2238 C PHE 362 -40.791 -5 ATOM 2239 O PHE 362 -40.741 -6 ATOM 2240 N ALA 363 -39.710 -4 ATOM 2241 CA ALA 363 -38.369 -5 ATOM 2242 CB ALA 363 -37.893 -5 ATOM 2243 C ALA 363 -37.427 -4 ATOM 2244 0 ALA 363 -37.762 -3 ATOM 2245 N PRO 364 -36.241 -5 ATOM 2246 CD PRO 364 -35.706 -6 ATOM 2247 CA PRO 364 -35.321 -4 ATOM 2248 CB PRO 364 -34.068 -5 ATOM 2249 CG PRO 364 -34.587 -6 ATOM 2250 C PRO 364 -35.032 -2 ATOM 2251 O PRO 364 -34.633 -2 ATOM 2252 N GLY 365 -35.234 -2 ATOM 2253 CA GLY 365 -35.031 -0 ATOM 2254 C GLY 365 -34.405 0 ATOM 2255 0 GLY 365 -34.394 1 ATOM 2256 N GLU 366 -33.889 -0 ATOM 2257 CA GLU 366 -33.183 0 ATOM 2258 CB GLU 366 -33.917 -0 ATOM 2259 CG GLU 366 -33.248 0 ATOM 2260 CD GLU 366 -34.106 0 ATOM 2261 OE1 GLU 366 -34.917 1 ATOM 2262 OE2 GLU 366 -33.970 -0 ATOM 2263 C GLU 366 -31.758 -0 ATOM 2264 0 GLU 366 -31.525 -1 ATOM 2265 N ASP 367 -30.805 0 ATOM 2266 CA ASP 367 -29.431 0 ATOM 2267 CB ASP 367 -29.395 -0 ATOM 2268 CG ASP 367 -28.009 -1 ATOM 2269 OD1 ASP 367 -27. Oil -0 ATOM 2270 OD2 ASP 367 -27.924 -2 ATOM 2271 C ASP 367 -28.901 -0 ATOM 2272 O ASP 367 -28.403 -1 ATOM 2273 N ILE 368 -29.028 -0 ATOM 2274 CA ILE 368 -28.660 -1 ATOM 2275 CB ILE 368 -29.666 -0 ATOM 2276 CG2 ILE 368 -29.280 -1 ATOM 2277 CGI ILE 368 -31.077 -1 ATOM 2278 CDl ILE 368 -31.243 -2 -18.410 1.00 34.79 B O -17.870 1.00 36.69 B C -18.519 1.00 43.14 B S -16.255 1.00 33.77 B N -16.000 1.00 34.99 B C -14.506 1.00 34.05 B C -14.236 1.00 33.57 B c -14.127 1.00 35.28 B c -16.357 1.00 36.56 B c -15.874 1.00 36.77 B 0 -17.193 1.00 37.85 B N -17.641 1.00 39.04 B c -19.054 1.00 40.07 B c -20.093 1.00 45.74 B c -20.443 1.00 46.61 B 0 -20.553 1.00 46.26 B 0 -16.688 1.00 38.35 B c -16.416 1.00 38.52 B 0 -16.173 1.00 37.53 B N -15.160 1.00 3 6.62 B c -15.797 1.00 36.73 B c -16.601 1.00 38.67 B c -16.944 1.00 39.40 B c -17.870 1.00 36.31 B c -14.461 1.00 35.32 B c -14.870 1.00 36.05 B 0 -13.405 1.00 33.99 B N -12.694 1.00 33.08 B c -11.190 1.00 30.37 B c -10.831 1.00 30.89 B c -10.348 1.00 30.96 B c -11.021 1.00 29.23 B c -10.065 1.00 30.60 B c -10.741 1.00 31.39 B c -10.264 1.00 31.01 B c -12.943 1.00 33.60 B c -13.376 1.00 34.30 B 0 -12.676 1.00 31.44 B N -12.817 1.00 33.53 B c -14.276 1.00 28.46 B c -11.869 1.00 34.75 B c -11.364 1.00 36.92 B 0 -11.606 1.00 35.95 B N -12.149 1.00 36.33 B c -10.645 1.00 36.66 B c -10.733 1.00 36.17 B c -11.198 1.00 36.16 B c -11.003 1.00 38.49 B c -12.129 1.00 38.54 B 0 -10.043 1.00 38.32 B N -10.315 1.00 39.76 B c -9.179 1.00 40.07 B c -9.212 1.00 41.59 B 0 -8.172 1.00 40.60 B N -7.080 1.00 40.85 B c -5.752 1.00 42.58 B c -4.559 1.00 48.40 B c -3.304 1.00 54.29 B c -3. 111 1.00 57.21 B 0 -2.509 1.00 57.42 B 0 -6.965 1.00 40.03 B c -7.067 1.00 40.58 B 0 -6.750 1.00 39.89 B N -6.463 1.00 41.10 B c -5.141 1.00 42.64 B c -4.795 1.00 45.84 B c -5.074 1.00 44.71 B 0 -4.241 1.00 48.26 B 0 -7.609 1.00 40.40 B c -7.396 1.00 40.34 B 0 -8.827 1.00 39.65 B N -10.041 1.00 37.49 B c -11.182 1.00 36.39 B c -12.429 1.00 34.37 B c -10.751 1.00 36.39 B c -10.488 1.00 34.86 B c 208 WO 2009/026558 PCT/US2008/074097 ATOM 2279 c ILE 368 -27.273 -0 ATOM 2280 0 ILE 368 -27.066 0 ATOM 2281 N ILE 369 -26.321 -1 ATOM 2282 CA ILE 369 -24.942 -1 ATOM 2283 CB ILE 369 -23.963 -2 ATOM 2284 CG2 ILE 369 -24.175 -3 ATOM 2285 CGI ILE 369 -22.513 -1 ATOM 2286 CDl ILE 369 -22.120 -0 ATOM 2287 C ILE 369 -24.832 -1 ATOM 2288 0 ILE 369 -25.458 -1 ATOM 2289 N GLY 370 -24.059 -0 ATOM 2290 CA GLY 370 -23.903 0 ATOM 2291 C GLY 370 -22.820 1 ATOM 2292 0 GLY 370 -22.236 1 ATOM 2293 N ALA 371 -22.554 1 ATOM 2294 CA ALA 371 -21.494 2 ATOM 2295 CB ALA 371 -21.434 2 ATOM 2296 C ALA 371 -21.666 3 ATOM 2297 0 ALA 371 -22.748 4 ATOM 2298 N SER 372 -20.587 4 ATOM 2299 CA SER 372 -20.548 5 ATOM 2300 CB SER 372 -19.956 5 ATOM 2301 OG SER 372 -19.422 7 ATOM 2302 C SER 372 -19.698 6 ATOM 2303 O SER 372 -18.614 5 ATOM 2304 N SER 373 -20.184 7 ATOM 2305 CA SER 373 -19.452 8 ATOM 2306 CB SER 373 -20.398 9 ATOM 2307 OG SER 373 -21.089 10 ATOM 2308 C SER 373 -18.294 8 ATOM 2309 O SER 373 -17.564 9 ATOM 2310 N ASP 374 -18.133 8 ATOM 2311 CA ASP 374 -16.982 9 ATOM 2312 CB ASP 374 -16.901 8 ATOM 2313 CG ASP 374 -17.947 9 ATOM 2314 OD1 ASP 374 -18.587 10 ATOM 2315 OD2 ASP 374 -18.124 9 ATOM 2316 C ASP 374 -15.689 9 ATOM 2317 O ASP 374 -14.824 9 ATOM 2318 N CYS 375 -15.563 7 ATOM 2319 CA CYS 375 -14.369 7 ATOM 2320 C CYS 375 -14.696 5 ATOM 2321 0 CYS 375 -15.668 5 ATOM 2322 CB CYS 375 -13.242 7 ATOM 2323 SG CYS 375 -13.124 5 ATOM 2324 N SER 376 -13.883 5 ATOM 2325 CA SER 376 -14.237 4 ATOM 2326 CB SER 376 -13.244 4 ATOM 2327 OG SER 376 -11.912 4 ATOM 2328 C SER 376 -14.334 3 ATOM 2329 O SER 376 -14.848 2 ATOM 2330 N THR 377 -13.847 2 ATOM 2331 CA THR 377 -13.944 1 ATOM 2332 CB THR 377 -12.543 1 ATOM 2333 OG1 THR 377 -11.827 2 ATOM 2334 CG2 THR 377 -11.754 0 ATOM 2335 C THR 377 -14.745 1 ATOM 2336 O THR 377 -14.872 0 ATOM 2337 N CYS 378 -15.289 3 ATOM 2338 CA CYS 378 -15.970 3 ATOM 2339 C CYS 378 -17.405 2 ATOM 2340 0 CYS 378 -18.055 2 ATOM 2341 CB CYS 378 -15.942 4 ATOM 2342 SG CYS 378 -14.291 5 ATOM 2343 N PHE 379 -17.883 2 ATOM 2344 CA PHE 379 -19.251 1 ATOM 2345 CB PHE 379 -19.256 0 ATOM 2346 CG PHE 379 -18.985 -0 ATOM 2347 CDl PHE 379 -17.686 -0 ATOM 2348 CD2 PHE 379 -20.030 -1 ATOM 2349 CEl PHE 379 -17.435 -1 ATOM 2350 CE2 PHE 379 -19.784 -1 ATOM 2351 CZ PHE 379 -18.485 -2 ATOM 2352 C PHE 379 -19.993 2 ATOM 2353 O PHE 379 -19.377 3 ATOM 2354 N VAL 380 -21.317 2
-10.488 1.00 38.13 B C -10.850 1.00 39.56 B O -10.464 1.00 38.77 B N -10.793 1.00 38.05 B C -10.257 1.00 40.93 B C -10.994 1.00 40.09 B c -10.431 1.00 41.68 B c -9.512 1.00 43.24 B c -12.310 1.00 36.91 B c -13.032 1.00 36.69 B 0 -12.793 1.00 35.97 B N -14.227 1.00 33.72 B c -14.582 1.00 35.47 B c -13.704 1.00 35.95 B 0 -15.876 1.00 35.98 B N -16.342 1.00 36.57 B c -17.872 1.00 35.87 B c -15.846 1.00 37.33 B c -15.947 1.00 37.39 B 0 -15.314 1.00 37.76 B N -14.962 1.00 39.26 B c -13.568 1.00 38.89 B c -13.430 1.00 38.76 B 0 -15.970 1.00 41.19 B c -16.325 1.00 41.88 B 0 -16.429 1.00 41.46 B N -17.417 1.00 44.85 B c -18.148 1.00 44.46 B c -17.241 1.00 45.05 B 0 -16.792 1.00 46.64 B c -17.499 1.00 45.89 B 0 -15.474 1.00 48.09 B N -14.777 1.00 51.70 B c -13.334 1.00 53.53 B c -12.428 1.00 57.35 B c -12.841 1.00 56.93 B 0 -11.296 1.00 59.88 B 0 -15.489 1.00 52.87 B c -15.718 1.00 52.95 B 0 -15.826 1.00 53.58 B N -16.484 1.00 54.62 B c -17.154 1.00 53.54 B c -16.787 1.00 52.45 B 0 -15.460 1.00 58.13 B c -14.667 1.00 62.82 B s -18.130 1.00 52.69 B N -19.023 1.00 52.99 B c -20.186 1.00 55.67 B c -19.715 1.00 60.26 B 0 -18.358 1.00 51.31 B c -18.956 1.00 51.62 B 0 -17.129 1.00 50.35 B N -16.406 1.00 50.61 B c -16.063 1.00 50.74 B c -15.275 1.00 50.85 B 0 -17.343 1.00 49.43 B c -15.115 1.00 51.23 B c -14.336 1.00 51.68 B 0 -14.898 1.00 50.52 B N -13.654 1.00 50.70 B c -13.638 1.00 48.67 B c -14.676 1.00 47.78 B 0 -13.456 1.00 55.40 B c -12.988 1.00 65.66 B s -12.456 1.00 47.08 B N -12.291 1.00 45.71 B c -11.908 1.00 45.48 B c -13.056 1.00 47.99 B c -13.490 1.00 47.70 B c -13.703 1.00 48.07 B c -14.549 1.00 48.26 B c -14.765 1.00 48.64 B c -15.187 1.00 47.52 B c -11.211 1.00 44 . 80 B c -10.296 1.00 43.54 B 0 -11.316 1.00 42.05 B N 209 WO 2009/026558 PCT/US2008/074097 ATOM 2355 CA VAL 380 -22.127 3 ATOM 2356 CB VAL 380 -22.259 5 ATOM 2357 CGI VAL 380 -23.084 5 ATOM 2358 CG2 VAL 380 -22.875 5 ATOM 2359 C VAL 380 -23.510 2 ATOM 2360 O VAL 380 -23.989 2 ATOM 2361 N SER 381 -24.143 3 ATOM 2362 CA SER 381 -25.440 2 ATOM 2363 CB SER 381 -25.420 1 ATOM 2364 OG SER 381 -26.290 0 ATOM 2365 C SER 381 -26.535 3 ATOM 2366 O SER 381 -26.363 4 ATOM 2367 N GLN 382 -27.652 3 ATOM 2368 CA GLN 382 -28.749 4 ATOM 2369 CB GLN 382 -28.698 4 ATOM 2370 CG GLN 382 -27.519 5 ATOM 2371 CD GLN 382 -27.521 6 ATOM 2372 OE1 GLN 382 -26.583 7 ATOM 2373 NE2 GLN 382 -28.573 6 ATOM 2374 C GLN 382 -30.110 3 ATOM 2375 0 GLN 382 -30.231 2 ATOM 2376 N SER 383 -31.129 4 ATOM 2377 CA SER 383 -32.485 3 ATOM 2378 CB SER 383 -32.823 3 ATOM 2379 OG SER 383 -31.868 3 ATOM 2380 C SER 383 -33.545 4 ATOM 2381 O SER 383 -33.435 5 ATOM 2382 N GLY 384 -34.574 3 ATOM 2383 CA GLY 384 -35.681 4 ATOM 2384 C GLY 384 -36.335 3 ATOM 2385 0 GLY 384 -35.765 2 ATOM 2386 N THR 385 -37.523 3 ATOM 2387 CA THR 385 -38.168 2 ATOM 2388 CB THR 385 -39.672 3 ATOM 2389 OG1 THR 385 -39.818 4 ATOM 2390 CG2 THR 385 -40.441 3 ATOM 2391 C THR 385 -37.457 2 ATOM 2392 O THR 385 -37.699 2 ATOM 2393 N SER 386 -36.571 3 ATOM 2394 CA SER 386 -35.708 3 ATOM 2395 CB SER 386 -34.783 5 ATOM 2396 OG SER 386 -35.443 6 ATOM 2397 C SER 386 -34.850 2 ATOM 2398 O SER 386 -34.772 1 ATOM 2399 N GLN 387 -34.208 2 ATOM 2400 CA GLN 387 -33.372 1 ATOM 2401 CB GLN 387 -32.711 1 ATOM 2402 CG GLN 387 -31.445 1 ATOM 2403 CD GLN 387 -31.704 3 ATOM 2404 OE1 GLN 387 -30.868 4 ATOM 2405 NE2 GLN 387 -32.869 3 ATOM 2406 C GLN 387 -34.190 -0 ATOM 2407 0 GLN 387 -33.733 -1 ATOM 2408 N ALA 388 -35.401 -0 ATOM 2409 CA ALA 388 -36.252 -1 ATOM 2410 CB ALA 388 -37.524 -1 ATOM 2411 C ALA 388 -36.607 -1 ATOM 2412 0 ALA 388 -36.515 -2 ATOM 2413 N ALA 389 -37.004 -0 ATOM 2414 CA ALA 389 -37.349 -0 ATOM 2415 CB ALA 389 -37.793 0 ATOM 2416 C ALA 389 -36.150 -1 ATOM 2417 0 ALA 389 -36.309 -1 ATOM 2418 N ALA 390 -34.954 -0 ATOM 2419 CA ALA 390 -33.736 -1 ATOM 2420 CB ALA 390 -32.518 -0 ATOM 2421 C ALA 390 -33.546 -2 ATOM 2422 0 ALA 390 -33.020 -3 ATOM 2423 N HIS 391 -33.975 -3 ATOM 2424 CA HIS 391 -33.864 -4 ATOM 2425 CB HIS 391 -34.258 -5 ATOM 2426 CG HIS 391 -33.151 -4 ATOM 2427 CD2 HIS 391 -32.270 -5 ATOM 2428 NDl HIS 391 -32.831 -3 ATOM 2429 CEl HIS 391 -31.798 -3 ATOM 2430 NE2 HIS 391 -31.439 -5
-10.332 1.00 40.25 B C -10.681 1.00 40.74 B C -11.954 1.00 41.04 B c -9.522 1.00 40.29 B c -10.228 1.00 40.11 B c -11.164 1.00 41.19 B 0 -9.078 1.00 40.08 B N -8.795 1.00 40.60 B c -7.377 1.00 42.23 B c -7.255 1.00 50.37 B 0 -8.916 1.00 38.85 B c -8.436 1.00 37.49 B 0 -9.556 1.00 38.13 B N -9.728 1.00 38.91 B c -11.135 1.00 40.19 B c -11.344 1.00 43.50 B c -12.706 1.00 46.54 B c -13.047 1.00 48.47 B 0 -13.491 1.00 46.84 B N -9.492 1.00 37.66 B c -9.541 1.00 36.85 B 0 -9.232 1.00 36.81 B N -8.985 1.00 35.64 B c -7.496 1.00 33.25 B c -6.722 1.00 36.82 B 0 -9.776 1.00 34.96 B c -9.952 1.00 36.04 B 0 -10.227 1.00 32.10 B N -10.940 1.00 31.63 B c -11.913 1.00 31.40 B c -12.214 1.00 30.25 B 0 -12.414 1.00 28.45 B N -13.363 1.00 30.65 B c -13.567 1.00 29.80 B c -13.991 1.00 29.28 B 0 -12.277 1.00 28.97 B c -14.726 1.00 31.82 B c -15.537 1.00 32.77 B 0 -14.974 1.00 31.74 B N -16.157 1.00 33.93 B c -16.234 1.00 33.38 B c -16.832 1.00 36.51 B 0 -16.139 1.00 34.63 B c -17.141 1.00 34.01 B 0 -14.999 1.00 33.67 B N -14.838 1.00 33.04 B c -13.457 1.00 34.28 B c -13.356 1.00 37.41 B c -13.583 1.00 40.32 B c -14.147 1.00 40.63 B 0 -13.148 1.00 39.93 B N -15.022 1.00 33.03 B c -15.660 1.00 34.05 B 0 -14.477 1.00 31.18 B N -14.606 1.00 31.67 B c -13.771 1.00 28.74 B c -16.073 1.00 32.05 B c -16.565 1.00 31.61 B 0 -16.775 1.00 31.17 B N -18.190 1.00 32.08 B c -18.771 1.00 30.72 B c -18.974 1.00 32.23 B c -19.880 1.00 31.54 B 0 -18.611 1.00 32.68 B N -19.274 1.00 34.67 B c -18.713 1.00 31.96 B c -19.113 1.00 35.82 B c -20.009 1.00 37.57 B 0 -17.980 1.00 35.70 B N -17.754 1.00 36.87 B c -16.317 1.00 37.29 B c -15.331 1.00 40.99 B c -14.813 1.00 42.03 B c -14.781 1.00 42.60 B N -13.968 1.00 43.92 B c -13.970 1.00 43.61 B N 210 WO 2009/026558 PCT/US2008/074097 ATOM 2431 c HIS 391 -34.754 -5.411 -18.717 1.00 35.90 B C ATOM 2 4 32 0 HIS 391 -34.342 -6.416 -19.292 1.00 36.51 B O ATOM 2433 N VAL 392 -35.981 -4.935 -18.886 1.00 34.43 B N ATOM 2434 CA VAL 392 -36.923 -5.612 -19.755 1.00 33.29 B C ATOM 2435 CB VAL 392 -38.351 -5.076 -19.546 1.00 32.77 B C ATOM 2436 CGI VAL 392 -39.298 -5.720 -20.546 1.00 27.80 B c ATOM 2437 CG2 VAL 392 -38.811 -5.369 -18.108 1.00 29.54 B c ATOM 2438 C VAL 392 -36.527 -5.460 -21.221 1.00 35.56 B c ATOM 2439 O VAL 392 -36.869 -6.308 -22.043 1.00 35.03 B 0 ATOM 2440 N ALA 393 -35.799 -4.392 -21.549 1.00 34.87 B N ATOM 2441 CA ALA 393 -35.324 -4.205 -22.918 1.00 36.30 B c ATOM 2442 CB ALA 393 -34.815 -2.771 -23.126 1.00 33.77 B c ATOM 2443 C ALA 393 -34.207 -5.200 -23.204 1.00 36.76 B c ATOM 2444 0 ALA 393 -34.095 -5.712 -24.316 1.00 36.97 B 0 ATOM 2445 N GLY 394 -33.387 -5.467 -22.191 1.00 37.87 B N ATOM 2446 CA GLY 394 -32.357 -6.481 -22.312 1.00 39.01 B c ATOM 2447 C GLY 394 -32.949 -7.871 -22.474 1.00 40.10 B c ATOM 2448 0 GLY 394 -32.509 -8.648 -23.324 1.00 39.59 B 0 ATOM 2449 N ILE 395 -33.956 -8.181 -21.664 1.00 39.13 B N ATOM 2450 CA ILE 395 -34.650 -9.455 -21.757 1.00 39.13 B c ATOM 2451 CB ILE 395 -35.748 -9.560 -20.674 1.00 38.01 B c ATOM 2 4 52 CG2 ILE 395 -36.645 -10.753 -20.945 1.00 36.45 B c ATOM 2453 CGI ILE 395 -35.098 -9.659 -19.294 1.00 36.97 B c ATOM 2454 CDl ILE 395 -36.095 -9.694 -18.144 1.00 37.21 B c ATOM 2455 C ILE 395 -35.273 -9.623 -23.138 1.00 40.54 B c ATOM 2456 0 ILE 395 -35.123 -10.667 -23.769 1.00 41.76 B 0 ATOM 2457 N ALA 396 -35.961 -8.591 -23.615 1.00 40.97 B N ATOM 2458 CA ALA 396 -36.552 -8.636 -24.946 1.00 41.51 B c ATOM 2459 CB ALA 396 -37.257 -7.324 -25.256 1.00 40.19 B c ATOM 2460 C ALA 396 -35.480 -8.907 -25.994 1.00 43.15 B c ATOM 2461 0 ALA 396 -35.696 -9.683 -26.925 1.00 42.21 B 0 ATOM 2462 N ALA 397 -34.323 -8.265 -25.838 1.00 43.28 B N ATOM 2463 CA ALA 397 -33.256 -8.384 -26.824 1.00 44.93 B c ATOM 2464 CB ALA 397 -32.144 -7.388 -26.517 1.00 41.15 B c ATOM 2465 C ALA 397 -32.691 -9.805 -26.871 1.00 46.63 B c ATOM 2466 0 ALA 397 -32.350 -10.308 -27.941 1.00 46.80 B 0 ATOM 2467 N MET 398 -32.594 -10.450 -25.714 1.00 48.13 B N ATOM 2468 CA MET 398 -32.121 -11.827 -25.656 1.00 50.03 B c ATOM 2469 CB MET 398 -31.804 -12.228 -24.218 1.00 52.81 B c ATOM 2470 CG MET 398 -30.565 -11.560 -23.665 1.00 57.71 B c ATOM 2471 SD MET 398 -29.966 -12.387 -22.193 1.00 67.28 B s ATOM 2472 CE MET 398 -28.585 -13.313 -22.886 1.00 65.86 B c ATOM 2473 C MET 398 -33.148 -12.788 -26.231 1.00 49.80 B c ATOM 2474 0 MET 398 -32.789 -13.787 -26.851 1.00 50.58 B 0 ATOM 2475 N MET 399 -34.425 -12.485 -26.028 1.00 47.98 B N ATOM 2476 CA MET 399 -35.484 -13.327 -26.562 1.00 47.27 B c ATOM 2477 CB MET 399 -36.840 -12.911 -25.990 1.00 45.22 B c ATOM 2478 CG MET 399 -37.017 -13.255 -24.527 1.00 45.38 B c ATOM 2479 SD MET 399 -38.534 -12.577 -23.818 1.00 48.51 B s ATOM 2480 CE MET 399 -39.806 -13.462 -24.743 1.00 46.63 B c ATOM 2481 C MET 399 -35.530 -13.262 -28.081 1.00 47.45 B c ATOM 2482 0 MET 399 -35.728 -14.277 -28.746 1.00 49.42 B 0 ATOM 2483 N LEU 400 -35.351 -12.069 -28.632 1.00 47.24 B N ATOM 2484 CA LEU 400 -35.459 -11.880 -30.073 1.00 47.13 B c ATOM 2485 CB LEU 400 -35.760 -10.413 -30.387 1.00 44 . 02 B c ATOM 2486 CG LEU 400 -37.187 -10. Oil -30. Oil 1.00 44.58 B c ATOM 2487 CDl LEU 400 -37.354 -8.501 -30.076 1.00 43.41 B c ATOM 2488 CD2 LEU 400 -38.164 -10.711 -30.952 1.00 42.10 B c ATOM 2489 C LEU 400 -34.183 -12.319 -30.775 1.00 48.10 B c ATOM 2490 O LEU 400 -34.180 -12.610 -31.971 1.00 47.33 B 0 ATOM 2491 N SER 401 -33.094 -12.366 -30.023 1.00 50.32 B N ATOM 2492 CA SER 401 -31.834 -12.838 -30.567 1.00 53.70 B c ATOM 2493 CB SER 401 -30.697 -12.527 -29.594 1.00 54.32 B c ATOM 2494 OG SER 401 -29.444 -12.848 -30.170 1.00 57.99 B 0 ATOM 2495 C SER 401 -31.918 -14.344 -30.813 1.00 54.86 B c ATOM 2496 O SER 401 -31.319 -14.864 -31.754 1.00 54.93 B 0 ATOM 2497 N ALA 402 -32.675 -15.036 -29.968 1.00 55.61 B N ATOM 2498 CA ALA 402 -32.846 -16.477 -30.100 1.00 57.04 B c ATOM 2499 CB ALA 402 -33.043 -17.113 -28.726 1.00 55.75 B c ATOM 2500 C ALA 402 -34.024 -16.815 -31.006 1.00 58.15 B c ATOM 2501 0 ALA 402 -34.006 -17.836 -31.688 1.00 60.14 B 0 ATOM 2502 N GLU 403 -35.045 -15.964 -31.011 1.00 58.70 B N ATOM 2503 CA GLU 403 -36.194 -16.160 -31.889 1.00 59.99 B c ATOM 2504 CB GLU 403 -37.413 -16.601 -31.081 1.00 62.05 B c ATOM 2505 CG GLU 403 -37.226 -17.901 -30.323 1.00 66.30 B c ATOM 2506 CD GLU 403 -38.523 -18.402 -29.719 1.00 69.10 B c 211 WO 2009/026558 PCT/US2008/074097 ATOM 2507 OE1 GLU 403 -38.640 -18 ATOM 2508 OE2 GLU 403 -39.429 -18 ATOM 2509 C GLU 403 -36.539 -14 ATOM 2510 0 GLU 403 -37.484 -14 ATOM 2511 N PRO 404 -35.783 -14 ATOM 2512 CD PRO 404 -34.707 -15 ATOM 2513 CA PRO 404 -35.905 -13 ATOM 2514 CB PRO 404 -34.887 -13 ATOM 2515 CG PRO 404 -33.905 -14 ATOM 2516 C PRO 404 -37.311 -13 ATOM 2517 O PRO 404 -37.687 -12 ATOM 2518 N GLU 405 -38.085 -14 ATOM 2519 CA GLU 405 -39.386 -14 ATOM 2 52 0 CB GLU 405 -39.648 -15 ATOM 2 521 CG GLU 405 -40.630 -15 ATOM 2522 CD GLU 405 -40.025 -14 ATOM 2523 OE1 GLU 405 -39.331 -13 ATOM 2524 OE2 GLU 405 -40.244 -15 ATOM 2 52 5 C GLU 405 -40.511 -13 ATOM 2 52 6 0 GLU 405 -41.654 -13 ATOM 2527 N LEU 406 -40.184 -13 ATOM 2528 CA LEU 406 -41.152 -13 ATOM 2529 CB LEU 406 -40.458 -13 ATOM 2530 CG LEU 406 -40.619 -14 ATOM 2531 CDl LEU 406 -39.995 -14 ATOM 2532 CD2 LEU 406 -42.085 -14 ATOM 2533 C LEU 406 -41.835 -12 ATOM 2534 O LEU 406 -41.177 -11 ATOM 2535 N THR 407 -43.152 -12 ATOM 2536 CA THR 407 -43.900 -10 ATOM 2537 CB THR 407 -45.320 -11 ATOM 2538 OG1 THR 407 -46.078 -11 ATOM 2539 CG2 THR 407 -45.264 -12 ATOM 2540 C THR 407 -44.029 -10 ATOM 2541 O THR 407 -43.786 -10 ATOM 2542 N LEU 408 -44.424 -9 ATOM 2543 CA LEU 408 -44.622 -8 ATOM 2544 CB LEU 408 -45.075 -6 ATOM 2545 CG LEU 408 -45.567 -5 ATOM 2546 CDl LEU 408 -44.511 -5 ATOM 2547 CD2 LEU 408 -45.904 -4 ATOM 2548 C LEU 408 -45.651 -8 ATOM 2549 O LEU 408 -45.408 -9 ATOM 2550 N ALA 409 -46.791 -9 ATOM 2551 CA ALA 409 -47.849 -9 ATOM 2552 CB ALA 409 -49.023 -10 ATOM 2553 C ALA 409 -47.339 -11 ATOM 2554 0 ALA 409 -47.599 -11 ATOM 2555 N GLU 410 -46.602 -12 ATOM 2556 CA GLU 410 -46.036 -13 ATOM 2557 CB GLU 410 -45.371 -14 ATOM 2558 CG GLU 410 -46.344 -14 ATOM 2559 CD GLU 410 -45.650 -15 ATOM 2560 OE1 GLU 410 -46.351 -15 ATOM 2561 OE2 GLU 410 -44.413 -15 ATOM 2562 C GLU 410 -45.015 -12 ATOM 2563 0 GLU 410 -44.977 -13 ATOM 2564 N LEU 411 -44 .186 -11 ATOM 2565 CA LEU 411 -43.159 -11 ATOM 2 566 CB LEU 411 -42.219 -10 ATOM 2567 CG LEU 411 -41.034 -10 ATOM 2568 CDl LEU 411 -39.814 -9 ATOM 2569 CD2 LEU 411 -41.398 -8 ATOM 2570 C LEU 411 -43.780 -11 ATOM 2571 O LEU 411 -43.311 -11 ATOM 2572 N ARG 412 -44.839 -10 ATOM 2573 CA ARG 412 -45.516 -9 ATOM 2574 CB ARG 412 -46.621 -8 ATOM 2575 CG ARG 412 -47.375 -8 ATOM 2576 CD ARG 412 -48.584 -7 ATOM 2577 NE ARG 412 -48.208 -6 ATOM 2578 CZ ARG 412 -48.520 -6 ATOM 2579 NHl ARG 412 -48.126 -5 ATOM 2580 NH2 ARG 412 -49.230 -7 ATOM 2581 C ARG 412 -46.120 -10 ATOM 2582 O ARG 412 -45.977 -10 -28.474 1.00 70.24 B O -30.494 1.00 71.43 B O -32.654 1.00 60.03 B C -32.304 1.00 59.11 B O -33.723 1.00 60.25 B N -34.235 1.00 60.12 B C -34.502 1.00 60.18 B C -35.629 1.00 59.91 B c -35.090 1.00 60.66 B c -35.044 1.00 60.30 B c -35.397 1.00 60.57 B 0 -35.106 1.00 60.27 B N -35.752 1.00 61.10 B c -36.500 1.00 65.84 B c -37.662 1.00 73.21 B c -38.874 1.00 77.69 B c -38.689 1.00 79.87 B 0 -40.012 1.00 79.14 B 0 -34.754 1.00 58.30 B c -35.149 1.00 57.76 B 0 -33.463 1.00 55.23 B N -32.414 1.00 52.90 B c -31.057 1.00 53.28 B c -30.053 1.00 53.34 B c -28.738 1.00 53.19 B c -29.858 1.00 52.98 B c -32.696 1.00 51.51 B c -33.058 1.00 52.21 B 0 -32.521 1.00 49.89 B N -32.661 1.00 48.26 B c -33.201 1.00 48.96 B c -32.234 1.00 49.44 B 0 -34.499 1.00 49.09 B c -31.306 1.00 47.33 B c -30.263 1.00 47.26 B 0 -31.328 1.00 45.56 B N -30.100 1.00 43.80 B c -30.426 1.00 42.62 B c -29.245 1.00 41.47 B c -28.163 1.00 40.64 B c -29.731 1.00 42.36 B c -29.197 1.00 43.17 B c -28.007 1.00 42.28 B 0 -29.771 1.00 43.40 B N -29.007 1.00 44.35 B c -29.922 1.00 44 .12 B c -28.322 1.00 44.96 B c -27.137 1.00 43.20 B 0 -29.066 1.00 44.33 B N -28.506 1.00 46.70 B c -29.608 1.00 50.37 B c -30.661 1.00 57.24 B c -31.909 1.00 61.50 B c -32.769 1.00 65.56 B 0 -32.035 1.00 61.64 B 0 -27.419 1.00 44.90 B c -26.374 1.00 44.41 B 0 -27.662 1.00 43.46 B N -26.700 1.00 41.39 B c -27.303 1.00 41.35 B c -26.428 1.00 41.21 B c -27.296 1.00 42.34 B c -25.626 1.00 43.75 B c -25.408 1.00 40.36 B c -24.313 1.00 39.22 B 0 -25.531 1.00 38.70 B N -24.353 1.00 39.79 B c -24.763 1.00 39.43 B c -23.573 1.00 40.81 B c -24.013 1.00 42.83 B c -24.891 1.00 46.65 B N -26.181 1.00 4 9.92 B c -26.891 1.00 51.57 B N -26.766 1.00 50.17 B N -23.501 1.00 40.47 B C -22.271 1.00 39.56 B 0 212 WO 2009/026558 PCT/US2008/074097 ATOM 2583 N GLN 413 -46.791 -11 ATOM 2584 CA GLN 413 -47.414 -12 ATOM 2585 CB GLN 413 -48.226 -13 ATOM 2586 CG GLN 413 -49.486 -13 ATOM 2587 CD GLN 413 -50.730 -13 ATOM 2588 OE1 GLN 413 -50.652 -14 ATOM 2589 NE2 GLN 413 -51.888 -13 ATOM 2590 C GLN 413 -46.362 -13 ATOM 2591 0 GLN 413 -46.598 -14 ATOM 2592 N ARG 414 -45.197 -13 ATOM 2593 CA ARG 414 -44.119 -14 ATOM 2594 CB ARG 414 -43.034 -15 ATOM 2595 CG ARG 414 -43.365 -16 ATOM 2596 CD ARG 414 -42.260 -16 ATOM 2597 NE ARG 414 -42.618 -17 ATOM 2598 CZ ARG 414 -43.771 -17 ATOM 2599 NHl ARG 414 -44.692 -16 ATOM 2600 NH2 ARG 414 -44.005 -18 ATOM 2601 C ARG 414 -43.502 -14 ATOM 2602 O ARG 414 -43.229 -14 ATOM 2603 N LEU 415 -43.283 -12 ATOM 2604 CA LEU 415 -42.792 -11 ATOM 2605 CB LEU 415 -42.684 -10 ATOM 2606 CG LEU 415 -41.424 -10 ATOM 2607 CDl LEU 415 -41.516 -8 ATOM 2608 CD2 LEU 415 -40.210 -10 ATOM 2609 C LEU 415 -43.726 -12 ATOM 2610 O LEU 415 -43.279 -12 ATOM 2611 N ILE 416 -45.026 -11 ATOM 2612 CA ILE 416 -46.013 -12 ATOM 2613 CB ILE 416 -47.445 -11 ATOM 2614 CG2 ILE 416 -48.453 -12 ATOM 2615 CGI ILE 416 -47.576 -10 ATOM 2616 CDl ILE 416 -48.959 -9 ATOM 2617 C ILE 416 -45.985 -13 ATOM 2618 0 ILE 416 -46.015 -13 ATOM 2619 N HIS 417 -45.920 -14 ATOM 2 62 0 CA HIS 417 -46.011 -15 ATOM 2 621 CB HIS 417 -46.122 -16 ATOM 2622 CG HIS 417 -46.218 -18 ATOM 2623 CD2 HIS 417 -45.281 -19 ATOM 2624 ND1 HIS 417 -47.385 -18 ATOM 2625 CE1 HIS 417 -47.162 -20 ATOM 2 62 6 NE2 HIS 417 -45.894 -20 ATOM 2627 C HIS 417 -44.836 -16 ATOM 2628 0 HIS 417 -45.018 -17 ATOM 2629 N PHE 418 -43.638 -15 ATOM 2630 CA PHE 418 -42.432 -16 ATOM 2631 CB PHE 418 -41.310 -16 ATOM 2632 CG PHE 418 -41.549 -17 ATOM 2633 CDl PHE 418 -42.039 -17 ATOM 2634 CD2 PHE 418 -41.291 -19 ATOM 2635 CEl PHE 418 -42.269 -18 ATOM 2636 CE2 PHE 418 -41.519 -20 ATOM 2637 CZ PHE 418 -42.009 -19 ATOM 2638 C PHE 418 -41.931 -15 ATOM 2639 O PHE 418 -40.865 -15 ATOM 2640 N SER 419 -42.694 -14 ATOM 2641 CA SER 419 -42.356 -13 ATOM 2642 CB SER 419 -43.176 -12 ATOM 2643 OG SER 419 -42.857 -11 ATOM 2644 C SER 419 -42.638 -14 ATOM 2645 O SER 419 -43.483 -15 ATOM 2646 N ALA 420 -41.941 -13 ATOM 2647 CA ALA 420 -42.274 -14 ATOM 2648 CB ALA 420 -41.183 -13 ATOM 2649 C ALA 420 -43.615 -13 ATOM 2650 0 ALA 420 -43.809 -12 ATOM 2651 N LYS 421 -44.536 -14 ATOM 2652 CA LYS 421 -45.865 -14 ATOM 2653 CB LYS 421 -46.913 -15 ATOM 2654 CG LYS 421 -47.365 -15 ATOM 2655 CD LYS 421 -46.221 -15 ATOM 2656 CE LYS 421 -46.722 -16 ATOM 2657 NZ LYS 421 -47.727 -15 ATOM 2658 C LYS 421 -45.935 -13 -24.156 1.00 o o B N -23.456 1.00 38.98 B C -24.432 1.00 37.49 B C -24.982 1.00 35.37 B c -24.154 1.00 38.44 B c -23.079 1.00 37.99 B 0 -24.655 1.00 38.63 B N -22.765 1.00 38.99 B c -21.676 1.00 39.28 B 0 -23.387 1.00 40.24 B N -22.787 1.00 43.34 B c -23.825 1.00 46.55 B c -24.712 1.00 52.72 B c -25.713 1.00 58.62 B c -26.599 1.00 65.06 B N -27.262 1.00 68.06 B c -27.146 1.00 68.20 B N -28.049 1.00 69.29 B N -21.583 1.00 44.39 B C -20.564 1.00 44.57 B 0 -21.693 1.00 44.56 B N -20.555 1.00 45.03 B C -20.906 1.00 46.00 B c -21.661 1.00 46.93 B c -22.037 1.00 46.93 B c -20.789 1.00 44.97 B c -19.368 1.00 44 . 14 B c -18.247 1.00 43.74 B 0 -19.620 1.00 43.81 B N -18.556 1.00 44.62 B c -19.063 1.00 43.70 B c -17.978 1.00 41.87 B c -19.475 1.00 43.04 B c -19.974 1.00 40.89 B c -17.982 1.00 46.84 B c -16.765 1.00 47.38 B 0 -18.865 1.00 48.11 B N -18.452 1.00 48.47 B c -19.675 1.00 50.72 B c -19.327 1.00 52.76 B c -19.319 1.00 52.85 B c -18.879 1.00 54.15 B N -18.607 1.00 54.24 B c -18.865 1.00 53.33 B N -17.593 1.00 48.85 B C -16.654 1.00 49.47 B 0 -17.906 1.00 48.81 B N -17.229 1.00 50.61 B C -18.247 1.00 53.20 B c -19.181 1.00 56.54 B c -20.460 1.00 56.42 B c -18.775 1.00 58.19 B c -21.320 1.00 57.36 B c -19.632 1.00 58.59 B c -20.906 1.00 57.63 B c -16.089 1.00 50.45 B c -15.523 1.00 50.20 B 0 -15.751 1.00 49.81 B N -14.615 1.00 49.94 B c -14.664 1.00 50.42 B c -15.811 1.00 53.88 B 0 -13.299 1.00 48.56 B c -13.238 1.00 49.17 B 0 -12.242 1.00 47.18 B N -10.909 1.00 47.78 B c -9.926 1.00 45.27 B c -10.475 1.00 48.76 B c -10.530 1.00 50.00 B 0 -10.054 1.00 48.99 B N -9.635 1.00 50.27 B c -10.019 1.00 52.20 B c -11.477 1.00 53.70 B c -12.432 1.00 58.05 B c -13.797 1.00 59.76 B c -14.413 1.00 60.22 B N -8.125 1.00 51.72 B c 213 WO 2009/026558 PCT/US2008/074097 ATOM 2659 0 LYS 421 -45.293 -14 ATOM 2660 N ASP 422 -46.711 -12 ATOM 2661 CA ASP 422 -47.116 -12 ATOM 2662 CB ASP 422 -47.980 -13 ATOM 2663 CG ASP 422 -49.341 -13 ATOM 2664 OD1 ASP 422 -50.008 -12 ATOM 2665 OD2 ASP 422 -49.744 -15 ATOM 2666 C ASP 422 -45.987 -12 ATOM 2667 O ASP 422 -46.155 -12 ATOM 2668 N VAL 423 -44.843 -12 ATOM 2669 CA VAL 423 -43.753 -11 ATOM 2670 CB VAL 423 -42.385 -11 ATOM 2 671 CGI VAL 423 -42.114 -13 ATOM 2 672 CG2 VAL 423 -42.361 -11 ATOM 2673 C VAL 423 -43.878 -10 ATOM 2674 O VAL 423 -43.196 -10 ATOM 2675 N ILE 424 -44.756 -9 ATOM 2 67 6 CA ILE 424 -44.927 -8 ATOM 2677 CB ILE 424 -45.264 -7 ATOM 2678 CG2 ILE 424 -45.468 -5 ATOM 2679 CGI ILE 424 -44.148 -7 ATOM 2680 CDl ILE 424 -44.528 -6 ATOM 2681 C ILE 424 -46.059 -8 ATOM 2682 0 ILE 424 -47.160 -8 ATOM 2683 N ASN 425 -45.802 -7 ATOM 2684 CA ASN 425 -46.873 -7 ATOM 2685 CB ASN 425 -46.306 -6 ATOM 2686 CG ASN 425 -47.398 -6 ATOM 2687 OD1 ASN 425 -48.587 -6 ATOM 2688 ND2 ASN 425 -46.997 -6 ATOM 2689 C ASN 425 -47.668 -5 ATOM 2690 0 ASN 425 -47.196 -4 ATOM 2691 N GLU 426 -48.883 -6 ATOM 2692 CA GLU 426 -49.667 -5 ATOM 2693 CB GLU 426 -50.764 -5 ATOM 2694 CG GLU 426 -51.692 -6 ATOM 2695 CD GLU 426 -52.426 -7 ATOM 2696 OE1 GLU 426 -52.050 -7 ATOM 2697 OE2 GLU 426 -53.377 -8 ATOM 2698 C GLU 426 -50.286 -4 ATOM 2699 0 GLU 426 -51.016 -3 ATOM 2700 N ALA 427 -49.997 -4 ATOM 2701 CA ALA 427 -50.452 -3 ATOM 2702 CB ALA 427 -50.142 -3 ATOM 2703 C ALA 427 -49.772 -1 ATOM 2704 0 ALA 427 -50.293 -0 ATOM 2705 N TRP 428 -48.610 -1 ATOM 2706 CA TRP 428 -47.888 -0 ATOM 2707 CB TRP 428 -46.564 -1 ATOM 2708 CG TRP 428 -45.580 0 ATOM 2709 CD2 TRP 428 -45.451 0 ATOM 2710 CE2 TRP 428 -44.347 1 ATOM 2711 CE3 TRP 428 -46.157 1 ATOM 2712 CDl TRP 428 -44.580 0 ATOM 2713 NEl TRP 428 -43.835 1 ATOM 2714 CZ2 TRP 428 -43.932 2 ATOM 2715 CZ3 TRP 428 -45.742 2 ATOM 2716 CH2 TRP 428 -44.640 2 ATOM 2717 C TRP 428 -48.724 0 ATOM 2718 O TRP 428 -48.662 1 ATOM 2719 N PHE 429 -49.511 -0 ATOM 2720 CA PHE 429 -50.352 0 ATOM 2721 CB PHE 429 -50.741 -0 ATOM 2722 CG PHE 429 -49.569 -1 ATOM 2723 CDl PHE 429 -49.537 -2 ATOM 2724 CD2 PHE 429 -48.493 -0 ATOM 2725 CEl PHE 429 -48.448 -3 ATOM 2726 CE2 PHE 429 -47.403 -1 ATOM 2727 CZ PHE 429 -47.380 -2 ATOM 2728 C PHE 429 -51.616 0 ATOM 2729 O PHE 429 -52.095 0 ATOM 2730 N PRO 430 -52.180 1 ATOM 2731 CD PRO 430 -51.705 2 ATOM 2732 CA PRO 430 -53.488 2 ATOM 2733 CB PRO 430 -53.822 3 ATOM 2734 CG PRO 430 -52.943 3 -7.340 1.00 51.06 B O -7.731 1.00 51.17 B N -6.343 1.00 52.74 B C -5.899 1.00 55.89 B C -6.571 1.00 60.38 B c -6.588 1.00 62.29 B 0 -7.085 1.00 63.14 B 0 -5.339 1.00 51.77 B c -4.157 1.00 51.33 B 0 -5.791 1.00 51.65 B N -4.867 1.00 50.55 B c -5.564 1.00 52.04 B c -5.942 1.00 51.21 B c -6.803 1.00 51.94 B c -4.238 1.00 50.83 B c -3.260 1.00 50.92 B 0 -4.797 1.00 49.90 B N -4.335 1.00 48.89 B c -5.511 1.00 47.42 B c -5.006 1.00 46.42 B c -6.551 1.00 46.55 B c -7.846 1.00 44.25 B c -3.316 1.00 49.43 B c -3.544 1.00 49.10 B 0 -2.205 1.00 51.29 B N -1.256 1.00 53.93 B c 0.143 1.00 53.60 B c 1 . 179 1.00 55.99 B c 0.856 1.00 56.43 B 0 2.433 1.00 57.69 B N -1.728 1.00 54.29 B c -1.654 1.00 55.32 B 0 -2.200 1.00 54.68 B N -2.863 1.00 56.26 B c -3.708 1.00 59.36 B c -2.922 1.00 65.60 B c -3.807 1.00 70.48 B c -4.999 1.00 71.64 B 0 -3.303 1.00 71.69 B 0 -1.901 1.00 55.20 B c -2.327 1.00 54.27 B 0 -0.611 1.00 53.77 B N 0.375 1.00 52.69 B c 1.788 1.00 51.14 B c 0.125 1.00 51.48 B c 0.505 1.00 50.75 B 0 -0.524 1.00 49.80 B N -0.896 1.00 49.29 B c -1.566 1.00 51.42 B c -1.742 1.00 55.20 B c -2.883 1.00 55.07 B c -2.642 1.00 55.79 B c -4.085 1.00 54.96 B c -0.879 1.00 55.62 B c -1.414 1.00 55.96 B N -3.561 1.00 54.75 B c -5.000 1.00 53.56 B c -4.730 1.00 52.93 B c -1.838 1.00 48.43 B c -1.767 1.00 47.88 B 0 -2.709 1.00 44.61 B N -3.645 1.00 43.45 B c -4.832 1.00 41.72 B c -5.525 1.00 43.10 B c -5.745 1.00 42.99 B c -5.943 1.00 41.43 B c -6.368 1.00 43.54 B c -6.567 1.00 42.19 B c -6.780 1.00 42.81 B c -2.951 1.00 43.79 B c -2.008 1.00 44.37 B 0 -3.414 1.00 43.28 B N -4.448 1.00 43.12 B c -2.877 1.00 44.00 B c -3.600 1.00 41.64 B c -4.791 1.00 42.89 B c 214 WO 2009/026558 PCT/US2008/074097 ATOM 2735 c PRO 430 -54.508 1 ATOM 2736 0 PRO 430 -54.406 0 ATOM 2737 N GLU 431 -55.488 1 ATOM 2738 CA GLU 431 -56.412 -0 ATOM 2739 CB GLU 431 -57.493 0 ATOM 2740 CG GLU 431 -58.513 -1 ATOM 2741 CD GLU 431 -59.551 -0 ATOM 2742 OE1 GLU 431 -59.472 0 ATOM 2743 OE2 GLU 431 -60.446 -1 ATOM 2744 C GLU 431 -57.073 -0 ATOM 2745 0 GLU 431 -57.153 -1 ATOM 2746 N ASP 432 -57.543 0 ATOM 2747 CA ASP 432 -58.306 0 ATOM 2748 CB ASP 432 -59.094 2 ATOM 2749 CG ASP 432 -58.192 3 ATOM 2750 OD1 ASP 432 -56.988 3 ATOM 2751 OD2 ASP 432 -58.699 4 ATOM 2752 C ASP 432 -57.440 0 ATOM 2753 O ASP 432 -57.948 0 ATOM 2754 N GLN 433 -56.141 0 ATOM 2755 CA GLN 433 -55.230 -0 ATOM 2756 CB GLN 433 -54.055 0 ATOM 2757 CG GLN 433 -54.442 2 ATOM 2758 CD GLN 433 -54.838 2 ATOM 2759 OE1 GLN 433 -54.530 1 ATOM 2760 NE2 GLN 433 -55.523 3 ATOM 2761 C GLN 433 -54.685 -1 ATOM 2762 0 GLN 433 -54.026 -2 ATOM 2763 N ARG 434 -54.950 -2 ATOM 2764 CA ARG 434 -54.354 -3 ATOM 2765 CB ARG 434 -54.660 -3 ATOM 2766 CG ARG 434 -53.833 -3 ATOM 2767 CD ARG 434 -54.429 -3 ATOM 2768 NE ARG 434 -53.674 -2 ATOM 2769 CZ ARG 434 -54.127 -1 ATOM 2770 NH1 ARG 434 -53.360 -1 ATOM 2771 NH2 ARG 434 -55.343 -2 ATOM 2772 C ARG 434 -54.827 -4 ATOM 2773 O ARG 434 -54.049 -5 ATOM 2774 N VAL 435 -56.093 -4 ATOM 2775 CA VAL 435 -56.615 -5 ATOM 2776 CB VAL 435 -58.163 -5 ATOM 2777 CGI VAL 435 -58.772 -4 ATOM 2778 CG2 VAL 435 -58.660 -6 ATOM 2779 C VAL 435 -56.167 -5 ATOM 2780 O VAL 435 -56.031 -6 ATOM 2781 N LEU 436 -55.917 -3 ATOM 2782 CA LEU 436 -55.553 -3 ATOM 2783 CB LEU 436 -55.896 -1 ATOM 2784 CG LEU 436 -57.362 -1 ATOM 2785 CD1 LEU 436 -57.563 -0 ATOM 2786 CD2 LEU 436 -58.195 -2 ATOM 2787 C LEU 436 -54.079 -3 ATOM 2788 O LEU 436 -53.700 -3 ATOM 2789 N THR 437 -53.246 -3 ATOM 2790 CA THR 437 -51.802 -3 ATOM 2791 CB THR 437 -51.070 -3 ATOM 2792 OG1 THR 437 -51.579 -1 ATOM 2793 CG2 THR 437 -49.576 -2 ATOM 2794 C THR 437 -51.238 -5 ATOM 2795 O THR 437 -51.376 -5 ATOM 2796 N PRO 438 -50.580 -5 ATOM 2797 CD PRO 438 -50.366 -4 ATOM 2798 CA PRO 438 -50.051 -6 ATOM 2799 CB PRO 438 -49.477 -7 ATOM 2800 CG PRO 438 -50.153 -5 ATOM 2801 C PRO 438 -48.983 -7 ATOM 2802 O PRO 438 -48.046 -6 ATOM 2803 N ASN 439 -49.124 -8 ATOM 2804 CA ASN 439 -48.128 -8 ATOM 2805 CB ASN 439 -48.802 -9 ATOM 2806 CG ASN 439 -47.993 -9 ATOM 2807 OD1 ASN 439 -46.780 -9 ATOM 2808 ND2 ASN 439 -48.659 -9 ATOM 2809 C ASN 439 -47.074 -9 ATOM 2810 O ASN 439 -47.017 -10 -3.147 1.00 46.37 B C -4.141 1.00 45.21 B O -2.257 1.00 48.35 B N -2.274 1.00 51.07 B C -1.209 1.00 55.08 B C -1.154 1.00 61.74 B c -0.057 1.00 67.18 B c 0.670 1.00 67.29 B 0 0.078 1.00 69.23 B 0 -3.633 1.00 50.09 B c -4.127 1.00 49.89 B 0 -4.232 1.00 48.97 B N -5.470 1.00 49.55 B c -5.696 1.00 53.81 B c -5.900 1.00 58.64 B c -5.558 1.00 61.37 B 0 -6.407 1.00 61.51 B 0 -6.697 1.00 48.17 B c -7.815 1.00 48.22 B 0 -6.488 1.00 4 5.67 B N -7.588 1.00 44.78 B c -7.605 1.00 43.98 B c -7.909 1.00 44.11 B c -9.360 1.00 45.54 B c -10.222 1.00 45.75 B 0 -9.636 1.00 4 6.92 B N -7.468 1.00 44 . 14 B c -8.376 1.00 42.38 B 0 -6.339 1.00 44.08 B N -6.068 1.00 45.47 B c -4.635 1.00 45.94 B c -3.623 1.00 48.40 B c -2.233 1.00 48.11 B c -1.314 1.00 49.63 B N -0.141 1.00 50.56 B c 0.62 4 1.00 50.03 B N 0.267 1.00 49.58 B N -7.045 1.00 45.92 B C -7.460 1.00 46.72 B 0 -7.428 1.00 44.65 B N -8.353 1.00 46.78 B C -8.286 1.00 47.93 B c -8.817 1.00 46.92 B c -9.061 1.00 48.93 B c -9.780 1.00 46.07 B c -10.614 1.00 47.62 B 0 -10.051 1.00 44.26 B N -11.394 1.00 41.98 B c -11.568 1.00 42.62 B c -11.362 1.00 43.63 B c -11.533 1.00 44.20 B c -12.366 1.00 44.78 B c -11.725 1.00 40.11 B c -12.891 1.00 40.58 B 0 -10.708 1.00 38.98 B N -10.918 1.00 38.27 B c -9.797 1.00 36.73 B c -9.721 1.00 38.09 B 0 -10.077 1.00 35.50 B c -10.959 1.00 38.94 B c -10.003 1.00 39.17 B 0 -12.068 1.00 39.47 B N -13.299 1.00 39.57 B c -12.182 1.00 38.85 B c -13.601 1.00 39.01 B c -14.333 1.00 41.00 B c -11.129 1.00 39.53 B c -10.967 1.00 39.03 B 0 -10.418 1.00 39.63 B N -9.437 1.00 4 0.67 B c -8.293 1.00 38.48 B c -7. Oil 1.00 39.26 B c -7.017 1.00 37.92 B 0 -5.902 1.00 38.27 B N -10.119 1.00 40.97 B c -9.904 1.00 42.65 B 0 215 WO 2009/026558 PCT/US2008/074097 ATOM 2811 N LEU 440 -46.245 -8 ATOM 2812 CA LEU 440 -45.272 -9 ATOM 2813 CB LEU 440 -45.709 -9 ATOM 2814 CG LEU 440 -47.068 -10 ATOM 2815 CDl LEU 440 -47.350 -9 ATOM 2816 CD2 LEU 440 -47.070 -11 ATOM 2817 C LEU 440 -43.903 -9 ATOM 2818 O LEU 440 -43.789 -7 ATOM 2819 N VAL 441 -42.868 -9 ATOM 2820 CA VAL 441 -41.505 -9 ATOM 2821 CB VAL 441 -40.738 -9 ATOM 2822 CGI VAL 441 -39.296 -9 ATOM 2823 CG2 VAL 441 -41.427 -8 ATOM 2824 C VAL 441 -40.778 -10 ATOM 2825 O VAL 441 -40.721 -11 ATOM 2826 N ALA 442 -40.224 -9 ATOM 2827 CA ALA 442 -39.686 -9 ATOM 2828 CB ALA 442 -39.105 -8 ATOM 2829 C ALA 442 -38.621 -10 ATOM 2830 O ALA 442 -37.872 -10 ATOM 2831 N ALA 443 -38.565 -11 ATOM 2832 CA ALA 443 -37.482 -12 ATOM 2833 CB ALA 443 -37.823 -14 ATOM 2834 C ALA 443 -37.282 -13 ATOM 2835 0 ALA 443 -38.227 -13 ATOM 2836 N LEU 444 -36.049 -13 ATOM 2837 CA LEU 444 -35.764 -14 ATOM 2838 CB LEU 444 -34.263 -14 ATOM 2839 CG LEU 444 -33.435 -13 ATOM 2840 CDl LEU 444 -32.002 -13 ATOM 2841 CD2 LEU 444 -33.493 -13 ATOM 2842 C LEU 444 -36.495 -15 ATOM 2843 O LEU 444 -36.498 -16 ATOM 2844 N PRO 445 -37.133 -16 ATOM 2845 CD PRO 445 -37.575 -15 ATOM 2846 CA PRO 445 -37.611 -17 ATOM 2847 CB PRO 445 -38.227 -17 ATOM 2848 CG PRO 445 -38.647 -15 ATOM 2849 C PRO 445 -36.445 -18 ATOM 2850 O PRO 445 -35.362 -18 ATOM 2851 N PRO 446 -36.651 -19 ATOM 2852 CD PRO 446 -37.943 -19 ATOM 2853 CA PRO 446 -35.597 -20 ATOM 2854 CB PRO 446 -36.232 -21 ATOM 2855 CG PRO 446 -37.698 -21 ATOM 2856 C PRO 446 -35.212 -21 ATOM 2857 O PRO 446 -34.532 -22 ATOM 2858 N SER 447 -35.651 -2 0 ATOM 2859 CA SER 447 -35.758 -21 ATOM 2860 CB SER 447 -37.050 -22 ATOM 2861 OG SER 447 -38.112 -21 ATOM 2862 C SER 447 -35.741 -2 0 ATOM 2863 O SER 447 -36.541 -19 ATOM 2864 N THR 448 -34.832 -20 ATOM 2865 CA THR 448 -34.918 -20 ATOM 2866 CB THR 448 -33.801 -2 0 ATOM 2867 OG1 THR 448 -32.534 -20 ATOM 2868 CG2 THR 448 -33.977 -20 ATOM 2869 C THR 448 -36.260 -20 ATOM 2870 O THR 448 -36.811 -19 ATOM 2871 N HIS 449 -36.766 -21 ATOM 2872 CA HIS 449 -38.137 -22 ATOM 2873 CB HIS 449 -38.453 -22 ATOM 2874 CG HIS 449 -39.916 -22 ATOM 2875 CD2 HIS 449 -41.006 -22 ATOM 2876 NDl HIS 449 -40.394 -22 ATOM 2877 CEl HIS 449 -41.715 -22 ATOM 2878 NE2 HIS 449 -42.112 -22 ATOM 2879 C HIS 449 -38.379 -23 ATOM 2880 0 HIS 449 -38.521 -23 ATOM 2881 N TRP 453 -45.204 -26 ATOM 2882 CA TRP 453 -46.152 -25 ATOM 2883 CB TRP 453 -46.794 -25 ATOM 2884 CG TRP 453 -47.498 -2 4 ATOM 2885 CD2 TRP 453 -48.830 -2 4 ATOM 2886 CE2 TRP 453 -49.061 -22 -10.949 1.00 42.11 B N -11.774 1.00 41.16 B C -13.239 1.00 40.54 B C -13.613 1.00 42.30 B c -15.085 1.00 40.42 B c -13.350 1.00 43.28 B c -11.689 1.00 41.93 B c -11.825 1.00 41.74 B 0 -11.477 1.00 40.59 B N -11.592 1.00 41.54 B c -10.271 1.00 41.16 B c -10.442 1.00 38.34 B c -9.173 1.00 38.68 B c -12.710 1.00 43.69 B c -12.724 1.00 44.56 B 0 -13.644 1.00 43.06 B N -14.878 1.00 43.65 B c -15.740 1.00 41.79 B c -14.617 1.00 44.49 B c -13.645 1.00 44.26 B 0 -15.498 1.00 46.18 B N -15.495 1.00 50.11 B c -14.570 1.00 48.90 B c -16.921 1.00 52.32 B c -17.709 1.00 51.83 B 0 -17.253 1.00 56.33 B N -18.520 1.00 61.28 B c -18.656 1.00 61.00 B c -19.170 1.00 63.12 B c -18.669 1.00 63.64 B c -20.692 1.00 64.35 B c -18.584 1.00 64.69 B c -17.619 1.00 64.31 B 0 -19.723 1.00 69.05 B N -20.811 1.00 69.76 B c -19.905 1.00 73.71 B c -21.302 1.00 72.46 B c -21.487 1.00 71.36 B c -19.793 1.00 78.03 B c -20.325 1.00 78.13 B 0 -19.080 1.00 82.32 B N -18.510 1.00 83.90 B c -18.854 1.00 85.07 B c -17.861 1.00 84.72 B c -18.128 1.00 84.66 B c -20.162 1.00 87.03 B c -20.165 1.00 87.51 B 0 -21.271 1.00 89.12 B N -22.525 1.00 90.87 B c -22.518 1.00 91.88 B c -21.998 1.00 92.23 B 0 -23.756 1.00 90.74 B c -23.874 1.00 90.17 B 0 -24.679 1.00 91.65 B N -26.032 1.00 94.19 B c -26.906 1.00 93.55 B c -26.417 1.00 93.33 B 0 -28.356 1.00 94.55 B c -26.617 1.00 93.02 B c -27.471 1.00 92.63 B 0 -26.150 1.00 95.06 B N -26.413 1.00 97.82 B c -27.911 1.00 99.76 B c -28.218 1.00102.61 B c -27.445 1.00103.41 B c -29.452 1.00103.87 B N -29.427 1.00104.64 B c -28.221 1.00104.60 B N -25.893 1.00 97.73 B C -24.688 1.00 98.20 B 0 -27.136 1.00 95.56 B N -27.487 1.00 95.17 B C -28.844 1.00 99.16 B c -29.442 1.00103.55 B c -29.151 1.00105.47 B c -29.923 1.00106.65 B c 216 WO 2009/026558 PCT/US2008/074097 ATOM 2887 CE3 TRP 453 -49.848 -2 4 ATOM 2888 CDl TRP 453 -46.992 -23 ATOM 2889 NEl TRP 453 -47.924 -22 ATOM 2890 CZ2 TRP 453 -50.268 -22 ATOM 2891 CZ3 TRP 453 -51.046 -23 ATOM 2892 CH2 TRP 453 -51.246 -22 ATOM 2893 C TRP 453 -47.238 -25 ATOM 2894 O TRP 453 -47.614 -26 ATOM 2895 N GLN 454 -47.738 -24 ATOM 2896 CA GLN 454 -48.759 -23 ATOM 2897 CB GLN 454 -48.099 -23 ATOM 2898 CG GLN 454 -46.758 -22 ATOM 2899 CD GLN 454 -46.034 -23 ATOM 2900 OE1 GLN 454 -44.803 -2 3 ATOM 2901 NE2 GLN 454 -46.796 -23 ATOM 2902 C GLN 454 -49.641 -22 ATOM 2903 0 GLN 454 -49.328 -21 ATOM 2904 N LEU 455 -50.752 -22 ATOM 2905 CA LEU 455 -51.741 -21 ATOM 2906 CB LEU 455 -53.148 -22 ATOM 2907 CG LEU 455 -54.309 -21 ATOM 2908 CDl LEU 455 -54.324 -20 ATOM 2909 CD2 LEU 455 -55.611 -21 ATOM 2910 C LEU 455 -51.576 -20 ATOM 2911 0 LEU 455 -51.792 -20 ATOM 2912 N PHE 456 -51.200 -19 ATOM 2913 CA PHE 456 -50.964 -18 ATOM 2914 CB PHE 456 -49.730 -17 ATOM 2915 CG PHE 456 -48.446 -18 ATOM 2916 CDl PHE 456 -48.030 -18 ATOM 2917 CD2 PHE 456 -47.649 -18 ATOM 2918 CEl PHE 456 -46.839 -19 ATOM 2919 CE2 PHE 456 -46.457 -18 ATOM 2920 CZ PHE 456 -46.052 -19 ATOM 2 921 C PHE 456 -52.156 -17 ATOM 2922 0 PHE 456 -52.654 -16 ATOM 2923 N CYS 457 -52.611 -16 ATOM 2 92 4 CA CYS 457 -53.642 -15 ATOM 2 92 5 C CYS 457 -53.203 -14 ATOM 2 92 6 0 CYS 457 -52.406 -15 ATOM 2927 CB CYS 457 -54.951 -16 ATOM 2 92 8 SG CYS 457 -55.799 -17 ATOM 2 92 9 N ARG 458 -53.741 -13 ATOM 2930 CA ARG 458 -53.467 -12 ATOM 2931 CB ARG 458 -52.447 -11 ATOM 2932 CG ARG 458 -52.907 -10 ATOM 2933 CD ARG 458 -51.781 -10 ATOM 2934 NE ARG 458 -51.841 -8 ATOM 2935 CZ ARG 458 -52.288 -7 ATOM 2936 NHl ARG 458 -52.301 -6 ATOM 2937 NH2 ARG 458 -52.706 -8 ATOM 2938 C ARG 458 -54.770 -11 ATOM 2939 0 ARG 458 -55.714 -11 ATOM 2940 N THR 459 -54.822 -11 ATOM 2941 CA THR 459 -55.998 -10 ATOM 2942 CB THR 459 -56.336 -10 ATOM 2943 OG1 THR 459 -56.615 -11 ATOM 2944 CG2 THR 459 -57.555 -9 ATOM 2945 C THR 459 -55.787 -8 ATOM 2946 0 THR 459 -54.721 -8 ATOM 2947 N VAL 460 -56.806 -8 ATOM 2948 CA VAL 460 -56.747 -6 ATOM 2949 CB VAL 460 -56.849 -6 ATOM 2950 CGI VAL 460 -56.918 -4 ATOM 2951 CG2 VAL 460 -55.657 -7 ATOM 2952 C VAL 4 60 -57.896 -5 ATOM 2953 0 VAL 4 60 -59.059 -6 ATOM 2954 N TRP 461 -57.577 -5 ATOM 2955 CA TRP 461 -58.606 -4 ATOM 2956 CB TRP 461 -58.210 -3 ATOM 2957 CG TRP 461 -58.327 -4 ATOM 2958 CD2 TRP 461 -59.316 -5 ATOM 2959 CE2 TRP 461 -59.013 -6 ATOM 2960 CE3 TRP 461 -60.426 -4 ATOM 2961 CDl TRP 461 -57.490 -6 ATOM 2962 NEl TRP 461 -57.894 -6
-28.313 1.00106.05 B C -30.355 1.00105.12 B C -30.649 1.00106.63 B N -29.881 1.00107.38 B C -28.273 1.00107.05 B C -29.052 1.00107.25 B c -26.416 1.00 92.26 B c -25.779 1.00 92.72 B 0 -26.218 1.00 87.21 B N -25.203 1.00 81.58 B c -23.827 1.00 83.76 B c -23.846 1.00 86.32 B c -22.515 1.00 88.32 B c -22.458 1.00 88.83 B 0 -21.434 1.00 88.87 B N -25.486 1.00 76.01 B c -26.343 1.00 74.63 B 0 -24.759 1.00 69.41 B N -24.956 1.00 63.14 B c -24.850 1.00 60.88 B c -24.893 1.00 60.03 B c -26.226 1.00 60.46 B c -24.681 1.00 59.51 B c -23.928 1.00 59.87 B c -22.735 1.00 58.28 B 0 -24.399 1.00 56.42 B N -23.517 1.00 53.64 B c -23.971 1.00 55.54 B c -23.830 1.00 57.27 B c -22.594 1.00 58.30 B c -24.934 1.00 59.52 B c -22.456 1.00 60.51 B c -24.805 1.00 61.44 B c -23.561 1.00 60.76 B c -23.496 1.00 50.46 B c -24.547 1.00 50.85 B 0 -22.298 1.00 47.18 B N -22.136 1.00 45.36 B c -21.102 1.00 44.05 B c -20.219 1.00 43.28 B 0 -21.660 1.00 45.94 B c -22.771 1.00 45.03 B s -21.209 1.00 42.97 B N -20.249 1.00 42.03 B c -20.827 1.00 40.47 B c -22.127 1.00 42.86 B c -22.866 1.00 44.13 B c -22.622 1.00 49.28 B N -23.485 1.00 47.66 B c -23.135 1.00 50.19 B N -24.690 1.00 47.08 B N -19.950 1.00 41.18 B C -20.746 1.00 39.62 B 0 -18.805 1.00 39.42 B N -18.453 1.00 39.74 B C -16.964 1.00 38.66 B c -16.683 1.00 41.49 B 0 -16.603 1.00 38.15 B c -18.764 1.00 40.32 B c -18.491 1.00 41.35 B 0 -19.336 1.00 39.71 B N -19.670 1.00 40.13 B c -21.193 1.00 40.81 B c -21.512 1.00 39.94 B c -21.885 1.00 40.01 B c -19.007 1.00 41.10 B c -19.350 1.00 41.34 B 0 -18.058 1.00 40.15 B N -17.438 1.00 41.32 B c -16.013 1.00 40.29 B c -15.025 1.00 39.72 B c -13.997 1.00 38.69 B c -13.272 1.00 40.64 B c -13.618 1.00 37.91 B c -14.891 1.00 39.19 B c -13.836 1.00 40.77 B N 217 WO 2009/026558 PCT/US2008/074097 ATOM 2963 CZ2 TRP 461 -59.783 -6 ATOM 2964 CZ3 TRP 461 -61.189 -4 ATOM 2965 CH2 TRP 461 -60.863 -5 ATOM 2966 C TRP 461 -58.835 -2 ATOM 2967 O TRP 461 -57.895 -2 ATOM 2968 N SER 4 62 -60.091 -2 ATOM 2969 CA SER 4 62 -60.421 -1 ATOM 2970 CB SER 4 62 -61.849 -1 ATOM 2971 OG SER 4 62 -62.779 -1 ATOM 2972 C SER 4 62 -60.310 -0 ATOM 2973 O SER 4 62 -60.104 -0 ATOM 2974 N ALA 463 -60.460 1 ATOM 2975 CA ALA 463 -60.634 2 ATOM 2976 CB ALA 463 -60.531 3 ATOM 2977 C ALA 463 -61.998 2 ATOM 2978 0 ALA 463 -62.918 1 ATOM 2979 N HIS 464 -62.118 2 ATOM 2980 CA HIS 464 -63.404 2 ATOM 2981 CB HIS 464 -63.204 3 ATOM 2982 CG HIS 464 -64.295 3 ATOM 2983 CD2 HIS 464 -65.503 4 ATOM 2984 ND1 HIS 464 -64.191 2 ATOM 2985 CEl HIS 464 -65.287 2 ATOM 2986 NE2 HIS 464 -66.100 3 ATOM 2987 C HIS 464 -64.389 3 ATOM 2988 0 HIS 464 -63.996 4 ATOM 2989 N SER 465 -65.667 3 ATOM 2990 CA SER 465 -66.655 3 ATOM 2991 CB SER 465 -67.866 2 ATOM 2992 OG SER 465 -68.608 2 ATOM 2993 C SER 465 -67.141 5 ATOM 2994 O SER 465 -67.431 5 ATOM 2995 N GLY 466 -67.240 5 ATOM 2996 CA GLY 466 -67.851 6 ATOM 2997 C GLY 466 -69.263 6 ATOM 2998 0 GLY 466 -69.931 5 ATOM 2999 N PRO 467 -69.744 7 ATOM 3000 CD PRO 467 -68.954 8 ATOM 3001 CA PRO 467 -71.005 7 ATOM 3002 CB PRO 4 67 -70.953 8 ATOM 3003 CG PRO 4 67 -69.503 8 ATOM 3004 C PRO 4 67 -72.283 7 ATOM 3005 O PRO 467 -73.355 6 ATOM 3006 N THR 468 -72.171 7 ATOM 3007 CA THR 468 -73.337 7 ATOM 3008 CB THR , 468 -72.914 8 ATOM 3009 OG1 THR 468 -72.106 9 ATOM 3010 CG2 THR 468 -74.140 8 ATOM 3011 C THR 468 -74.178 6 ATOM 3012 O THR 468 -73.651 5 ATOM 3013 N ARG 469 -75.488 6 ATOM 3014 CA ARG 469 -76.407 5 ATOM 3015 CB ARG 469 -77.854 6 ATOM 3016 CG ARG 469 -78.326 6 ATOM 3017 CD ARG 469 -79.787 7 ATOM 3018 NE ARG 469 -80.366 7 ATOM 3019 CZ ARG 469 -81.164 6 ATOM 3020 NHl ARG 469 -81.644 7 ATOM 3021 NH2 ARG 469 -81.486 5 ATOM 3022 C ARG 469 -76.243 4 ATOM 3023 O ARG 469 -76.478 3 ATOM 3024 N MET 470 -75.841 5 ATOM 3025 CA MET 470 -75.657 4 ATOM 3026 CB MET 470 -76.405 5 ATOM 3027 CG MET 470 -77.923 5 ATOM 3028 SD MET 470 -78.555 3 ATOM 3029 CE MET 470 -78.069 3 ATOM 3030 C MET 470 -74.179 4 ATOM 3031 0 MET 470 -73.837 4 ATOM 3032 N ALA 471 -73.308 4 ATOM 3033 CA ALA 471 -71.867 4 ATOM 3034 CB ALA 471 -71.123 5 ATOM 3035 C ALA 471 -71.406 3 ATOM 3036 0 ALA 471 -71.870 2 ATOM 3037 N THR 472 -70.491 3 ATOM 3038 CA THR 472 -69.941 1 -12.191 1.00 39.89 B C -12.543 1.00 39.15 B C -11.841 1.00 39.06 B c -18.246 1.00 42.82 B c -18.774 1.00 42.86 B 0 -18.339 1.00 44.55 B N -18.981 1.00 46.47 B c -19.521 1.00 45.66 B c -18.452 1.00 43.37 B 0 -17.956 1.00 48.34 B c -16.764 1.00 46.67 B 0 -18.429 1.00 50.60 B N -17.537 1.00 54.46 B c -18.325 1.00 52.98 B c -16.860 1.00 56.97 B c -17.396 1.00 57.30 B 0 -15.683 1.00 61.61 B N -15.000 1.00 65.67 B c -13.725 1.00 68.34 B c -12.715 1.00 71.76 B c -12.599 1.00 73.40 B c -11.644 1.00 73.71 B N -10.910 1.00 74.59 B c -11.468 1.00 75.04 B N -15.926 1.00 67.55 B C -16.697 1.00 67.46 B 0 -15.847 1.00 70.08 B N -16.806 1.00 72.95 B C -16.852 1.00 71.92 B c -15.648 1.00 70.23 B 0 -16.487 1.00 75.78 B c -17.393 1.00 75.65 B 0 -15.200 1.00 78.79 B N -14.794 1.00 83.44 B c -14.272 1.00 86.66 B c -14.649 1.00 87.19 B 0 -13.400 1.00 89.00 B N -12.924 1.00 89.56 B c -12.655 1.00 90.53 B c -11.649 1.00 90.49 B c -11.549 1.00 90.14 B c -13.496 1.00 91.90 B c -13.016 1.00 92.02 B 0 -14.741 1.00 93.44 B N -15.612 1.00 95.40 B c -17.059 1.00 95.23 B c -17.060 1.00 95.12 B 0 -17.934 1.00 94.69 B c -15.635 1.00 97.16 B c -15.509 1.00 97.49 B 0 -15.798 1.00 98.73 B N -15.781 1.00 99.90 B c -15.688 1.00102.98 B c -16.911 1.00106.29 B c -16.781 1.00108.83 B c -18.069 1.00111.09 B N -18.789 1.00112.01 B c -19.951 1.00112.06 B N -18.345 1.00112.44 B N -17.032 1.00 98.96 B C -17.002 1.00 98.89 B 0 -18.128 1.00 97.91 B N -19.401 1.00 96.48 B C -20.515 1.00 98.76 B c -20.432 1.00101.49 B c -21.034 1.00104.46 B s -22.774 1.00102.90 B c -19.770 1.00 94.05 B c -20.938 1.00 93.54 B 0 -18.771 1.00 90.93 B N -18.998 1.00 87.61 B c -17.800 1.00 87.53 B c -19.251 1.00 85.13 B c -18.598 1.00 85.32 B 0 -20.203 1.00 81.39 B N -20.528 1.00 77.96 B c 218 WO 2009/026558 PCT/US2008/074097 ATOM 3039 CB THR 472 -70.443 1 ATOM 3040 OG1 THR 472 -70.026 2 ATOM 3041 CG2 THR 472 -71.962 1 ATOM 3042 C THR 472 -68.412 1 ATOM 3043 O THR 472 -67.789 2 ATOM 3044 N ALA 473 -67.813 0 ATOM 3045 CA ALA 473 -66.366 0 ATOM 3046 CB ALA 473 -65.827 0 ATOM 3047 C ALA 473 -66.020 -0 ATOM 3048 0 ALA 473 -66.775 -1 ATOM 3049 N ILE 474 -64.879 -0 ATOM 3050 CA ILE 474 -64.443 -1 ATOM 3051 CB ILE 474 -64.477 -0 ATOM 3052 CG2 ILE 474 -64.014 -1 ATOM 3053 CGI ILE 474 -65.896 0 ATOM 3054 CDl ILE 474 -65.983 0 ATOM 3055 C ILE 474 -63.026 -1 ATOM 3056 0 ILE 474 -62.100 -0 ATOM 3057 N ALA 475 -62.864 -3 ATOM 3058 CA ALA 475 -61.548 -3 ATOM 3059 CB ALA 475 -61.525 -4 ATOM 3060 C ALA 475 -61.222 -4 ATOM 3061 0 ALA 475 -62.025 -5 ATOM 3062 N ARG 476 -60.046 -3 ATOM 3063 CA ARG 476 -59.651 -4 ATOM 3064 CB ARG 476 -59.378 -3 ATOM 3065 CG ARG 476 -60.608 -2 ATOM 3066 CD ARG 476 -60.279 -1 ATOM 3067 NE ARG 476 -61.444 -0 ATOM 3068 CZ ARG 476 -61.840 0 ATOM 3069 NH1 ARG 476 -61.160 0 ATOM 3070 NH2 ARG 476 -62.925 1 ATOM 3071 C ARG 476 -58.411 -5 ATOM 3072 O ARG 476 -57.620 -5 ATOM 3073 N CYS 477 -58.247 -6 ATOM 3074 CA CYS 477 -57.048 -7 ATOM 3075 C CYS 477 -56.135 -6 ATOM 3076 0 CYS 477 -56.556 -5 ATOM 3077 CB CYS 477 -57.416 -8 ATOM 3078 SG CYS 477 -58.397 -9 ATOM 3079 N ALA 478 -54.883 -6 ATOM 3080 CA ALA 478 -53.979 -6 ATOM 3081 CB ALA 478 -52.579 -7 ATOM 3082 C ALA 478 -54.502 -7 ATOM 3083 0 ALA 478 -55.233 -8 ATOM 3084 N PRO 479 -54.131 -6 ATOM 3085 CD PRO 479 -53.268 -5 ATOM 3086 CA PRO 479 -54.627 -7 ATOM 3087 CB PRO 479 -53.914 -6 ATOM 3088 CG PRO 479 -53.584 -4 ATOM 3089 C PRO 479 -54.370 -8 ATOM 3090 O PRO 479 -55.207 -9 ATOM 3091 N ASP 480 -53.217 -9 ATOM 3092 CA ASP 480 -52.884 -10 ATOM 3093 CB ASP 480 -51.368 -10 ATOM 3094 CG ASP 480 -50.655 -10 ATOM 3095 OD1 ASP 480 -51.324 -9 ATOM 3096 OD2 ASP 480 -49.430 -10 ATOM 3097 C ASP 480 -53.566 -11 ATOM 3098 O ASP 480 -53.440 -12 ATOM 3099 N GLU 481 -54.281 -10 ATOM 3100 CA GLU 481 -54.880 -11 ATOM 3101 CB GLU 481 -54.680 -11 ATOM 3102 CG GLU 481 -53.231 -11 ATOM 3103 CD GLU 481 -53.058 -10 ATOM 3104 OE1 GLU 481 -52.173 -10 ATOM 3105 OE2 GLU 481 -53.811 -9 ATOM 3106 C GLU 481 -56.370 -12 ATOM 3107 0 GLU 481 -57.041 -11 ATOM 3108 N GLU 482 -56.879 -13 ATOM 3109 CA GLU 482 -58.315 -13 ATOM 3110 CB GLU 482 -58.594 -14 ATOM 3111 CG GLU 482 -57.890 -15 ATOM 3112 CD GLU 482 -58.568 -14 ATOM 3113 OE1 GLU 482 -59.695 -14 ATOM 3114 OE2 GLU 482 -57.975 -15 -21.911 1.00 78.06 B C -22.933 1.00 77.52 B O -21.921 1.00 77.75 B c -20.539 1.00 75.20 B c -20.922 1.00 74.74 B 0 -20.113 1.00 71.92 B N -20.194 1.00 68.57 B c -18.858 1.00 67.75 B c -21.297 1.00 66.77 B c -21.554 1.00 66.07 B 0 -21.947 1.00 64.89 B N -23.025 1.00 63.32 B c -24.369 1.00 64.64 B c -25.482 1.00 63.94 B c -24.652 1.00 67.76 B c -25.843 1.00 71.25 B c -22.801 1.00 61.20 B c -22.575 1.00 62.29 B 0 -22.866 1.00 57.61 B N -22.783 1.00 54.56 B c -21.662 1.00 53.14 B c -24.113 1.00 53.19 B c -24.643 1.00 52.48 B 0 -24.655 1.00 52.78 B N -25.960 1.00 52.83 B c -26.936 1.00 55.93 B c -27.326 1.00 61.00 B c -28.382 1.00 64.35 B c -28.700 1.00 67.87 B N -27.978 1.00 70.61 B c -26.894 1.00 70.19 B N -28.331 1.00 71.97 B N -25.873 1.00 51.34 B C -24.938 1.00 51.28 B 0 -26.863 1.00 50.36 B N -26.983 1.00 50.00 B C -28.053 1.00 49.37 B c -28.852 1.00 48.36 B 0 -27.358 1.00 51.30 B c -26.112 1.00 54.92 B s -28.065 1.00 49.69 B N -29.163 1.00 52.29 B c -28.852 1.00 50.02 B c -30.443 1.00 54.47 B c -30.394 1.00 54.91 B 0 -31.608 1.00 56.47 B N -31.723 1.00 56.66 B c -32.919 1.00 56.71 B c -33.905 1.00 57.17 B c -33.097 1.00 57.72 B c -33.235 1.00 56.70 B c -33.849 1.00 56.36 B 0 -32.822 1.00 56.51 B N -33.077 1.00 56.90 B c -33.009 1.00 60.77 B c -34.244 1.00 65.51 B c -35.090 1.00 67.40 B 0 -34.372 1.00 67.85 B 0 -32.113 1.00 55.43 B c -32.262 1.00 55.84 B 0 -31.125 1.00 52.35 B N -30.074 1.00 50.24 B c -28.704 1.00 47.61 B c -28.221 1.00 46.45 B c -26.934 1.00 44.57 B c -26.123 1.00 42.50 B 0 -26.737 1.00 43.51 B 0 -30.306 1.00 49.74 B c -30.967 1.00 49.49 B 0 -29.759 1.00 48.52 B N -29.740 1.00 46.82 B c -30.040 1.00 46.77 B c -31.271 1.00 49.47 B c -32.554 1.00 51.58 B c -32.472 1.00 50.06 B 0 -33.638 1.00 54.21 B 0 219 WO 2009/026558 PCT/US2008/074097 ATOM 3115 c GLU 482 -58.851 -13 ATOM 3116 0 GLU 482 -58.211 -13 ATOM 3117 N LEU 483 -60.024 -12 ATOM 3118 CA LEU 483 -60.709 -12 ATOM 3119 CB LEU 483 -61.583 -11 ATOM 3120 CG LEU 483 -62.243 -10 ATOM 3121 CD1 LEU 483 -62.160 -9 ATOM 3122 CD2 LEU 483 -63.684 -11 ATOM 3123 C LEU 483 -61.570 -13 ATOM 3124 O LEU 483 -62.583 -13 ATOM 3125 N LEU 484 -61.165 -14 ATOM 3126 CA LEU 484 -61.836 -15 ATOM 3127 CB LEU 484 -60.820 -16 ATOM 3128 CG LEU 484 -59.820 -17 ATOM 3129 CD1 LEU 484 -59.149 -18 ATOM 3130 CD2 LEU 484 -60.544 -17 ATOM 3131 C LEU 484 -62.908 -15 ATOM 3132 O LEU 484 -63.754 -16 ATOM 3133 N SER 485 -62.873 -14 ATOM 3134 CA SER 485 -63.958 -14 ATOM 3135 CB SER 485 -63.866 -15 ATOM 3136 OG SER 485 -62.827 -14 ATOM 3137 C SER 485 -63.972 -12 ATOM 3138 O SER 485 -63.101 -11 ATOM 3139 N CYS 486 -64.968 -12 ATOM 3140 CA CYS 486 -65.299 -10 ATOM 3141 C CYS 486 -66.118 -10 ATOM 3142 0 CYS 486 -67.213 -11 ATOM 3143 CB CYS 486 -66.103 -10 ATOM 3144 SG CYS 486 -66.813 -8 ATOM 3145 N SER 487 -65.581 -10 ATOM 3146 CA SER 487 -66.331 -10 ATOM 3147 CB SER 487 -65.750 -11 ATOM 3148 OG SER 487 -64.402 -10 ATOM 3149 C SER 487 -66.328 -8 ATOM 3150 O SER 487 -65.852 -7 ATOM 3151 N SER 488 -66.872 -8 ATOM 3152 CA SER 488 -66.998 -7 ATOM 3153 CB SER 488 -68.295 -6 ATOM 3154 OG SER 488 -69.420 -7 ATOM 3155 C SER 488 -66.963 -7 ATOM 3156 O SER 488 -67.233 -8 ATOM 3157 N PHE 489 -66.614 -5 ATOM 3158 CA PHE 489 -66.478 -5 ATOM 3159 CB PHE 489 -65.049 -6 ATOM 3160 CG PHE 489 -64.765 -5 ATOM 3161 CD1 PHE 489 -65.412 -6 ATOM 3162 CD2 PHE 489 -63.842 -4 ATOM 3163 CEl PHE 489 -65.145 -6 ATOM 3164 CE2 PHE 489 -63.570 -4 ATOM 3165 CZ PHE 489 -64.223 -5 ATOM 3166 C PHE 489 -66.829 -4 ATOM 3167 O PHE 489 -66.417 -3 ATOM 3168 N SER 490 -67.604 -4 ATOM 3169 CA SER 490 -67.931 -2 ATOM 3170 CB SER 490 -69.370 -2 ATOM 3171 OG SER 490 -69.721 -1 ATOM 3172 C SER 490 -67.779 -3 ATOM 3173 O SER 490 -68.275 -4 ATOM 3174 N ARG 491 -67.085 -2 ATOM 3175 CA ARG 491 -66.842 -2 ATOM 3176 CB ARG 491 -65.779 -1 ATOM 3177 CG ARG 491 -64.422 -1 ATOM 3178 CD ARG 491 -63.325 -0 ATOM 3179 NE ARG 491 -62.027 -0 ATOM 3180 CZ ARG 491 -61.603 -0 ATOM 3181 NHl ARG 491 -60.408 -0 ATOM 3182 NH2 ARG 491 -62.373 0 ATOM 3183 C ARG 491 -68.133 -2 ATOM 3184 O ARG 491 -68.302 -2 ATOM 3185 N SER 4 92 -69.047 -1 ATOM 3186 CA SER 4 92 -70.354 -1 ATOM 3187 CB SER 492 -71.028 0 ATOM 3188 OG SER 492 -71.317 -0 ATOM 3189 C SER 4 92 -71.240 -2 ATOM 3190 O SER 492 -72.065 -2 -28.356 1.00 45.01 B C -27.352 1.00 44 . 86 B O -28.301 1.00 44 . 07 B N -27.030 1.00 45.33 B C -27.075 1.00 46.54 B C -25.742 1.00 49.38 B c -25.513 1.00 52.67 B c -25.745 1.00 51.11 B c -26.731 1.00 44 . 81 B c -27.390 1.00 44 . 85 B 0 -25.741 1.00 44.25 B N -25.459 1.00 43.90 B c -25.064 1.00 41.25 B c -26.151 1.00 40.18 B c -25.797 1.00 38.70 B c -27.465 1.00 40.84 B c -24.380 1.00 44.90 B c -24.262 1.00 46.30 B 0 -23.587 1.00 46.22 B N -22.647 1.00 46.47 B c -21.450 1.00 46.34 B c -20.580 1.00 45.49 B 0 -22.152 1.00 46.84 B c -22.486 1.00 47.34 B 0 -21.333 1.00 48.22 B N -21.000 1.00 49.92 B c -19.719 1.00 49.99 B c -19.675 1.00 50.31 B 0 -22.151 1.00 52.24 B c -21.890 1.00 59.49 B s -18.672 1.00 49.69 B N -17.431 1.00 49.46 B c -16.328 1.00 48.38 B c -16.063 1.00 49.39 B 0 -16.989 1.00 49.59 B c -17.713 1.00 49.27 B 0 -15.807 1.00 49.56 B N -15.333 1.00 51.42 B c -15.853 1.00 50.06 B c -15.358 1.00 50.85 B 0 -13.814 1.00 53.00 B c -13.135 1.00 54.35 B 0 -13.284 1.00 55.50 B N -11.842 1.00 58.01 B c -11.405 1.00 56.05 B c -9.959 1.00 56.36 B c -8.949 1.00 56.87 B c -9.611 1.00 55.96 B c -7.615 1.00 56.29 B c -8.281 1.00 55.63 B c -7.281 1.00 55.87 B c -11.405 1.00 60.88 B c -12.028 1.00 60.67 B 0 -10.330 1.00 64.50 B N -9.704 1.00 68.24 B c -10.038 1.00 68.91 B c -9.418 1.00 72.44 B 0 -8.200 1.00 70.33 B c -7.636 1.00 70.86 B 0 -7.549 1.00 72.98 B N -6.118 1.00 75.53 B c -5.666 1.00 77.17 B c -6.308 1.00 80.24 B c -5.687 1.00 82.34 B c -6.299 1.00 83.86 B N -7.434 1.00 84.91 B c -7.917 1.00 84 . 85 B N -8.086 1.00 84.91 B N -5.334 1.00 76.00 B C -4.248 1.00 75.57 B 0 -5.901 1.00 77.48 B N -5.290 1.00 79.37 B C -5.911 1.00 79.14 B c -7.282 1.00 79.09 B 0 -5.494 1.00 80.75 B c -4.642 1.00 81.44 B 0 220 WO 2009/026558 PCT/US2008/074097 ATOM 3191 N GLY 493 -71.062 -2 ATOM 3192 CA GLY 493 -71.864 -4 ATOM 3193 C GLY 493 -73.023 -3 ATOM 3194 0 GLY 493 -73.689 -4 ATOM 3195 N LYS 494 -73.263 -2 ATOM 3196 CA LYS 494 -74.352 -2 ATOM 3197 CB LYS 494 -74.821 -0 ATOM 3198 CG LYS 494 -75.389 -0 ATOM 3199 CD LYS 494 -75.838 0 ATOM 3200 CE LYS 494 -76.744 0 ATOM 3201 NZ LYS 494 -76.058 0 ATOM 3202 C LYS 494 -73.900 -2 ATOM 3203 0 LYS 494 -73.266 -1 ATOM 3204 N ARG 495 -74.232 -3 ATOM 3205 CA ARG 495 -73.848 -3 ATOM 3206 CB ARG 495 -72.525 -3 ATOM 3207 CG ARG 495 -72.587 -5 ATOM 3208 CD ARG 495 -71.211 -5 ATOM 3209 NE ARG 495 -71.292 -7 ATOM 3210 CZ ARG 495 -71.266 -8 ATOM 3211 NHl ARG 495 -71.350 -9 ATOM 3212 NH2 ARG 495 -71.150 -8 ATOM 3213 C ARG 495 -74.930 -3 ATOM 3214 0 ARG 495 -75.787 -4 ATOM 3215 N ARG 496 -74.890 -3 ATOM 3216 CA ARG 496 -75.827 -4 ATOM 3217 CB ARG 496 -76.653 -3 ATOM 3218 CG ARG 496 -77.599 -2 ATOM 3219 CD ARG 496 -78.601 -1 ATOM 3220 NE ARG 496 -77.937 -1 ATOM 3221 CZ ARG 496 -78.553 -0 ATOM 3222 NHl ARG 496 -79.855 -0 ATOM 3223 NH2 ARG 496 -77.864 0 ATOM 3224 C ARG 496 -75.124 -5 ATOM 3225 0 ARG 496 -75.604 -5 ATOM 3226 N GLY 497 -73.985 -6 ATOM 3227 CA GLY 497 -73.320 -7 ATOM 3228 C GLY 497 -72.398 -6 ATOM 3229 0 GLY 497 -71.964 -5 ATOM 3230 N GLU 498 -72.098 -7 ATOM 3231 CA GLU 498 -71.173 -7 ATOM 3232 CB GLU 498 -69.744 -7 ATOM 3233 CG GLU 498 -69.474 -9 ATOM 3234 CD GLU 498 -70.106 -9 ATOM 3235 OE1 GLU 498 -69.782 -9 ATOM 3236 OE2 GLU 498 -70.927 -10 ATOM 3237 C GLU 498 -71.550 -8 ATOM 3238 0 GLU 498 -72.284 -9 ATOM 3239 N ARG 499 -71.046 -7 ATOM 3240 CA ARG 499 -71.295 -8 ATOM 3241 CB ARG 499 -72.483 -7 ATOM 3242 CG ARG 499 -72.297 -6 ATOM 3243 CD ARG 499 -73.461 -5 ATOM 3244 NE ARG 499 -73.573 -6 ATOM 3245 CZ ARG 499 -74.571 -6 ATOM 3246 NHl ARG 499 -74.582 -6 ATOM 3247 NH2 ARG 499 -75.558 -5 ATOM 32 4 8 C ARG 499 -70.065 -8 ATOM 3249 0 ARG 499 -69.243 -7 ATOM 3250 N MET 500 -69.939 -9 ATOM 3251 CA MET 500 -68.895 -9 ATOM 3252 CB MET 500 -68.290 -10 ATOM 3253 CG MET 500 -67.541 -11 ATOM 3254 SD MET 500 -67.019 -12 ATOM 3255 CE MET 500 -68.472 -13 ATOM 3256 C MET 500 -69.471 -8 ATOM 3257 0 MET 500 -70.349 -9 ATOM 3258 N GLU 501 -68.971 -7 ATOM 3259 CA GLU 501 -69.475 -6 ATOM 3260 CB GLU 501 -69.823 -5 ATOM 3261 CG GLU 501 -70.879 -5 ATOM 32 62 CD GLU 501 -71.193 -3 ATOM 3263 OE1 GLU 501 -70.530 -2 ATOM 3264 OE2 GLU 501 -72.102 -3 ATOM 3265 C GLU 501 -68.432 -6 ATOM 3266 0 GLU 501 -67.253 -7 -6.631 1.00 81.13 B N -6.939 1.00 80.72 B C -7.858 1.00 80.78 B C -8.378 1.00 80.89 B 0 -8.060 1.00 80.45 B N -8.917 1.00 79.64 B c -8.484 1.00 81.16 B c -7.071 1.00 83.07 B c -6.712 1.00 84.54 B c -5.483 1.00 85.65 B c -4.255 1.00 85.21 B N -10.369 1.00 78.44 B c -10.805 1.00 78.70 B 0 -11.115 1.00 77.53 B N -12.519 1.00 76.32 B c -12.655 1.00 76.14 B c -12.128 1.00 75.82 B c -12.011 1.00 76.68 B c -11.477 1.00 77.74 B N -12.223 1.00 78.22 B c -11.649 1.00 78.62 B N -13.541 1.00 78.31 B N -13.297 1.00 75.33 B C -12.708 1.00 75.07 B 0 -14.619 1.00 74.53 B N -15.464 1.00 74.26 B C -16.299 1.00 75.26 B c -15.472 1.00 77.17 B c -16.354 1.00 78.98 B c -17.358 1.00 82.03 B N -18.398 1.00 83.71 B c -18.580 1.00 84.51 B N -19.260 1.00 84.84 B N -16.374 1.00 73.26 B C -17.467 1.00 72.51 B 0 -15.917 1.00 71.89 B N -16.632 1.00 70.45 B C -17.747 1.00 69.59 B c -17.776 1.00 69.36 B 0 -18.670 1.00 68.77 B N -19.760 1.00 68.48 B c -19.350 1.00 67.95 B c -19.254 1.00 67.56 B c -18.030 1.00 68.08 B c -16.895 1.00 67.57 B 0 -18.202 1.00 69.43 B 0 -21.024 1.00 68.67 B c -20.968 1.00 67.70 B 0 -22.162 1.00 69.43 B N -23.434 1.00 72.09 B c -24.149 1.00 74.63 B c -24.460 1.00 79.98 B c -25.277 1.00 83.74 B c -26.557 1.00 88.28 B N -27.420 1.00 90.00 B c -28.559 1.00 90.05 B N -27.142 1.00 90.84 B N -24.329 1.00 72.18 B C -24.200 1.00 71.77 B 0 -25.232 1.00 73.12 B N -26.245 1.00 74.86 B C -26.439 1.00 75.04 B c -25.231 1.00 75.98 B c -25.437 1.00 77.64 B s -24.783 1.00 75.19 B c -27.565 1.00 75.89 B c -28.147 1.00 75.73 B 0 -28.029 1.00 77.75 B N -29.242 1.00 79.49 B c -28.975 1.00 80.04 B c -27.908 1.00 82.37 B c -27.702 1.00 83.60 B c -28.343 1.00 83.92 B 0 -26.901 1.00 84.18 B 0 -30.343 1.00 80.62 B c -30.080 1.00 81.37 B 0 221 WO 2009/026558 PCT/US2008/074097 ATOM 3267 N ALA 502 -68.871 -6 ATOM 3268 CA ALA 502 -67.950 -6 ATOM 3269 CB ALA 502 -68.497 -7 ATOM 3270 C ALA 502 -67.739 -4 ATOM 3271 0 ALA 502 -68.689 -4 ATOM 3272 N GLN 503 -66.485 -4 ATOM 3273 CA GLN 503 -66.143 -3 ATOM 3274 CB GLN 503 -65.807 -2 ATOM 3275 CG GLN 503 -66.989 -2 ATOM 3276 CD GLN 503 -66.707 -1 ATOM 3277 OE1 GLN 503 -65.587 -0 ATOM 3278 NE2 GLN 503 -67.723 -0 ATOM 3279 C GLN 503 -64.941 -3 ATOM 3280 0 GLN 503 -63.865 -3 ATOM 3281 N GLY 504 -65.127 -2 ATOM 3282 CA GLY 504 -64.066 -2 ATOM 3283 C GLY 504 -63.668 -4 ATOM 3284 0 GLY 504 -62.487 -4 ATOM 3285 N GLY 505 -64.652 -5 ATOM 3286 CA GLY 505 -64.376 -6 ATOM 3287 C GLY 505 -63.505 -7 ATOM 3288 0 GLY 505 -62.900 -8 ATOM 3289 N LYS 506 -63.434 -6 ATOM 3290 CA LYS 506 -62.694 -7 ATOM 3291 CB LYS 506 -61.499 -6 ATOM 3292 CG LYS 506 -60.246 -7 ATOM 3293 CD LYS 506 -59.493 -7 ATOM 3294 CE LYS 506 -58.221 -8 ATOM 3295 NZ LYS 506 -57.438 -8 ATOM 3296 C LYS 506 -63.631 -7 ATOM 3297 0 LYS 506 -64.476 -6 ATOM 3298 N LEU 507 -63.487 -8 ATOM 3299 CA LEU 507 -64.313 -8 ATOM 3300 CB LEU 507 -64.419 -10 ATOM 3301 CG LEU 507 -65.504 -10 ATOM 3302 CDl LEU 507 -65.466 -12 ATOM 3303 CD2 LEU 507 -66.861 -10 ATOM 3304 C LEU 507 -63.774 -7 ATOM 3305 O LEU 507 -62.596 -7 ATOM 3306 N VAL 508 -64.647 -6 ATOM 3307 CA VAL 508 -64.284 -6 ATOM 3308 CB VAL 508 -64.402 -4 ATOM 3309 CGI VAL 508 -63.534 -4 ATOM 3310 CG2 VAL 508 -65.850 -4 ATOM 3311 C VAL 508 -65.181 -6 ATOM 3312 O VAL 508 -66.215 -7 ATOM 3313 N CYS 509 -64.773 -6 ATOM 3314 CA CYS 509 -65.501 -6 ATOM 3315 C CYS 509 -66.128 -5 ATOM 3316 0 CYS 509 -65.421 -4 ATOM 3317 CB CYS 509 -64.533 -7 ATOM 3318 SG CYS 509 -65.198 -7 ATOM 3319 N ARG 510 -67.455 -5 ATOM 3320 CA ARG 510 -68.173 -3 ATOM 3321 CB ARG 510 -69.146 -3 ATOM 3322 CG ARG 510 -69.977 -2 ATOM 3323 CD ARG 510 -69.457 -1 ATOM 3324 NE ARG 510 -70.306 -0 ATOM 3325 CZ ARG 510 -69.871 0 ATOM 3326 NHl ARG 510 -70.715 0 ATOM 3327 NH2 ARG 510 -68.590 0 ATOM 3328 C ARG 510 -68.940 -4 ATOM 3329 O ARG 510 -69.755 -5 ATOM 3330 N ALA 511 -68.674 -3 ATOM 3331 CA ALA 511 -69.380 -3 ATOM 3332 CB ALA 511 -68.390 -3 ATOM 3333 C ALA 511 -70.366 -2 ATOM 3334 0 ALA 511 -70.060 -1 ATOM 3335 N HIS 512 -71.552 -2 ATOM 3336 CA HIS 512 -72.610 -1 ATOM 3337 CB HIS 512 -73.915 -2 ATOM 3338 CG HIS 512 -73.832 -2 ATOM 3339 CD2 HIS 512 -73.653 -3 ATOM 3340 NDl HIS 512 -73.926 -1 ATOM 3341 CEl HIS 512 -73.807 -2 ATOM 3342 NE2 HIS 512 -73.640 -3
-31.577 1.00 81.89 B N -32.684 1.00 83.20 B C -33.942 1.00 83.17 B C -32.918 1.00 84.38 B c -32.889 1.00 84.50 B 0 -33.133 1.00 85.34 B N -33.521 1.00 85.73 B c -32.291 1.00 85.79 B c -31.379 1.00 87.34 B c -30.381 1.00 88.20 B c -30.304 1.00 88.07 B 0 -29.610 1.00 88.12 B N -34.456 1.00 86.14 B c -34.081 1.00 86.49 B 0 -35.675 1.00 85.95 B N -36.659 1.00 84.92 B c -36.918 1.00 84.27 B c -37.096 1.00 84.30 B 0 -36.929 1.00 83.46 B N -37.221 1.00 82.44 B c -36.172 1.00 81.46 B c -36.426 1.00 81.89 B 0 -34.992 1.00 79.89 B N -33.870 1.00 77.91 B c -33.519 1.00 79.66 B c -33.110 1.00 81.29 B c -34.332 1.00 83.87 B c -33.940 1.00 85.75 B c -35.136 1.00 86.14 B N -32.669 1.00 75.15 B c -32.465 1.00 74.81 B 0 -31.877 1.00 71.57 B N -30.684 1.00 68.58 B c -30.294 1.00 70.01 B c -31.017 1.00 71.09 B c -30.572 1.00 72.08 B c -30.716 1.00 70.93 B c -29.505 1.00 65.55 B c -29.162 1.00 65.40 B 0 -28.891 1.00 62.61 B N -27.706 1.00 60.31 B c -27.958 1.00 59.66 B c -29.141 1.00 58.42 B c -28.199 1.00 58.70 B c -26.534 1.00 59.23 B c -26.713 1.00 58.09 B 0 -25.335 1.00 59.26 B N -24.119 1.00 60.27 B c -23.534 1.00 61.97 B c -23.065 1.00 62.31 B 0 -23.113 1.00 59.87 B c -21.476 1.00 60.83 B s -23.565 1.00 63.76 B N -23.107 1.00 65.70 B c -24.191 1.00 67.66 B c -23.801 1.00 71.78 B c -24.473 1.00 76.06 B c -25.585 1.00 79.19 B N -26.643 1.00 81.45 B c -27.605 1.00 82.26 B N -26.746 1.00 81.82 B N -21.817 1.00 66.34 B C -21.751 1.00 66.22 B 0 -20.794 1.00 67.79 B N -19.525 1.00 69.49 B C -18.375 1.00 69.05 B c -19.359 1.00 72.13 B c -19.685 1.00 71.53 B 0 -18.852 1.00 75.10 B N -18.709 1.00 77.76 B c -19.305 1.00 79.16 B c -20.773 1.00 80.99 B c -21.442 1.00 81.47 B c -21.735 1.00 81.65 B N -22.933 1.00 81.85 B c -22.783 1.00 81.72 B N 222 WO 2009/026558 PCT/US2008/074097 ATOM 3343 c HIS 512 -72.814 -1 ATOM 3344 0 HIS 512 -72.797 -2 ATOM 3345 N ASN 513 -73.006 -0 ATOM 3346 CA ASN 513 -73.163 0 ATOM 3347 CB ASN 513 -72.626 1 ATOM 3348 CG ASN 513 -72.534 2 ATOM 3349 OD1 ASN 513 -72.666 1 ATOM 3350 ND2 ASN 513 -72.304 3 ATOM 3351 C ASN 513 -74.626 0 ATOM 3352 0 ASN 513 -75.534 0 ATOM 3353 N ALA 514 -74.847 0 ATOM 3354 CA ALA 514 -76.188 0 ATOM 3355 CB ALA 514 -76.222 -0 ATOM 3356 C ALA 514 -76.608 1 ATOM 3357 0 ALA 514 -75.762 2 ATOM 3358 N PHE 515 -77.916 1 ATOM 3359 CA PHE 515 -78.440 3 ATOM 3360 CB PHE 515 -79.951 3 ATOM 3361 CG PHE 515 -80.327 2 ATOM 3362 CDl PHE 515 -81.351 1 ATOM 3363 CD2 PHE 515 -79.658 3 ATOM 3364 CEl PHE 515 -81.701 1 ATOM 3365 CE2 PHE 515 -80.003 2 ATOM 3366 CZ PHE 515 -81.026 1 ATOM 3367 C PHE 515 -78.147 3 ATOM 3368 O PHE 515 -78.217 5 ATOM 3369 N GLY 516 -77.816 3 ATOM 3370 CA GLY 516 -77.447 3 ATOM 3371 C GLY 516 -75.972 3 ATOM 3372 0 GLY 516 -75.559 3 ATOM 3373 N GLY 517 -75.175 3 ATOM 3374 CA GLY 517 -73.790 2 ATOM 3375 C GLY 517 -72.776 3 ATOM 3376 0 GLY 517 -73.064 4 ATOM 3377 N GLU 518 -71.577 3 ATOM 3378 CA GLU 518 -70.512 4 ATOM 3379 CB GLU 518 -69.724 4 ATOM 3380 CG GLU 518 -69.853 3 ATOM 3381 CD GLU 518 -69.338 2 ATOM 3382 OE1 GLU 518 -68.149 1 ATOM 3383 OE2 GLU 518 -70.124 1 ATOM 3384 C GLU 518 -69.557 4 ATOM 3385 0 GLU 518 -68.691 5 ATOM 3386 N GLY 519 -69.717 3 ATOM 3387 CA GLY 519 -68.872 2 ATOM 3388 C GLY 519 -68.469 1 ATOM 3389 0 GLY 519 -68.432 0 ATOM 3390 N VAL 520 -68.164 0 ATOM 3391 CA VAL 520 -67.812 -0 ATOM 3392 CB VAL 520 -68.924 -1 ATOM 3393 CGI VAL 520 -70.216 -1 ATOM 3394 CG2 VAL 520 -69.128 -0 ATOM 3395 C VAL 520 -66.525 -0 ATOM 3396 0 VAL 520 -66.190 0 ATOM 3397 N TYR 521 -65.806 -1 ATOM 3398 CA TYR 521 -64.711 -2 ATOM 3399 CB TYR 521 -63.522 -2 ATOM 3400 CG TYR 521 -62.891 -1 ATOM 3401 CDl TYR 521 -63.254 -1 ATOM 3402 CEl TYR 521 -62.667 -0 ATOM 3403 CD2 TYR 521 -61.919 -0 ATOM 3404 CE2 TYR 521 -61.326 0 ATOM 3405 CZ TYR 521 -61.704 0 ATOM 3406 OH TYR 521 -61.120 1 ATOM 3407 C TYR 521 -65.161 -3 ATOM 3408 0 TYR 521 -65.941 -4 ATOM 3409 N ALA 522 -64.671 -3 ATOM 3410 CA ALA 522 -64.726 -4 ATOM 3411 CB ALA 522 -64.927 -3 ATOM 3412 C ALA 522 -63.401 -5 ATOM 3413 0 ALA 522 -62.348 -4 ATOM 3414 N ILE 523 -63.456 -6 ATOM 3415 CA ILE 523 -62.257 -7 ATOM 3416 CB ILE 523 -62.240 -7 ATOM 3417 CG2 ILE 523 -60.937 -8 ATOM 3418 CGI ILE 523 -62.406 -6 -17.244 1.00 78.56 B C -16.371 1.00 77.69 B 0 -16.981 1.00 80.56 B N -15.613 1.00 83.31 B C -15.495 1.00 82.08 B C -14.054 1.00 81.68 B c -13.120 1.00 81.74 B 0 -13.867 1.00 80.52 B N -15.172 1.00 85.41 B c -15.987 1.00 85.81 B 0 -13.880 1.00 87.99 B N -13.311 1.00 91.44 B c -11.962 1.00 90.86 B c -13.149 1.00 94.10 B c -13.074 1.00 94.52 B 0 -13.094 1.00 96.76 B N -13.033 1.00 98.60 B c -13.296 1.00101.08 B c -14.671 1.00103.86 B c -14.840 1.00104.87 B c -15.795 1.00104.65 B c -16.103 1.00105.30 B c -17.061 1.00105.48 B c -17.215 1.00105.53 B c -11.692 1.00 98.36 B c -11.576 1.00 98.94 B 0 -10.684 1.00 97.52 B N -9.394 1.00 96.59 B c -9.061 1.00 96.24 B c -7.925 1.00 96.40 B 0 -10.049 1.00 95.19 B N -9.787 1.00 92.79 B c -10.079 1.00 91.22 B c -10.794 1.00 91.57 B 0 -9.525 1.00 89.22 B N -9.645 1.00 86.83 B c -8.334 1.00 89.07 B c -7.443 1.00 92.53 B c -8.105 1.00 94.95 B c -7.912 1.00 96.07 B 0 -8.813 1.00 96.67 B 0 -10.798 1.00 83.45 B c -11.122 1.00 83.02 B 0 -11.413 1.00 79.54 B N -12.536 1.00 73.49 B c -12.522 1.00 69.03 B c -11.468 1.00 68.16 B 0 -13.701 1.00 64.49 B N -13.838 1.00 60.24 B c -14.570 1.00 59.70 B c -13.780 1.00 60.31 B c -15.968 1.00 58.45 B c -14.632 1.00 57.65 B c -15.462 1.00 55.74 B 0 -14.376 1.00 55.08 B N -15.252 1.00 53.22 B c -14.438 1.00 52.94 B c -13.537 1.00 53.88 B c -12.200 1.00 54.58 B c -11.362 1.00 55.31 B c -14.016 1.00 53.24 B c -13.185 1.00 54.89 B c -11.859 1.00 55.53 B c -11.021 1.00 57.45 B 0 -16.215 1.00 51.73 B c -15.853 1.00 51.92 B 0 -17.446 1.00 49.79 B N -18.350 1.00 48.15 B c -19.782 1.00 47.08 B c -18.220 1.00 48.00 B c -18.090 1.00 48.65 B 0 -18.240 1.00 45.80 B N -18.080 1.00 43.99 B c -16.715 1.00 43.33 B c -16.529 1.00 42.17 B c -15.618 1.00 43.33 B c 223 WO 2009/026558 PCT/US2008/074097 ATOM 3419 CDl ILE 523 -62.845 -7 ATOM 3420 c ILE 523 -62.187 -8 ATOM 3421 0 ILE 523 -63.005 -9 ATOM 3422 N ALA 524 -61.207 -8 ATOM 3423 CA ALA 524 -61.078 -9 ATOM 3424 CB ALA 524 -60.713 -8 ATOM 3425 C ALA 524 -60.024 -10 ATOM 3426 0 ALA 524 -59.078 -9 ATOM 3427 N ARG 525 -60.200 -11 ATOM 3428 CA ARG 525 -59.173 -12 ATOM 3429 CB ARG 525 -59.781 -13 ATOM 3430 CG ARG 525 -58.773 -14 ATOM 3431 CD ARG 525 -58.041 -14 ATOM 3432 NE ARG 525 -57.191 -15 ATOM 3433 CZ ARG 525 -56.069 -15 ATOM 3434 NH1 ARG 525 -55.376 -16 ATOM 3435 NH2 ARG 525 -55.643 -14 ATOM 3436 C ARG 525 -58.628 -12 ATOM 3437 O ARG 525 -59.364 -12 ATOM 3438 N CYS 526 -57.342 -12 ATOM 3439 CA CYS 526 -56.764 -12 ATOM 3440 C CYS 526 -55.720 -13 ATOM 3441 0 CYS 526 -54.816 -13 ATOM 3442 CB CYS 526 -56.121 -10 ATOM 3443 SG CYS 526 -57.256 -9 ATOM 3444 N CYS 527 -55.837 -13 ATOM 3445 CA CYS 527 -55.014 -15 ATOM 3446 C CYS 527 -54.445 -15 ATOM 3447 0 CYS 527 -55.045 -14 ATOM 3448 CB CYS 527 -55.830 -16 ATOM 3449 SG CYS 527 -56.857 -16 ATOM 3450 N LEU 528 -53.287 -15 ATOM 3451 CA LEU 528 -52.702 -16 ATOM 3452 CB LEU 528 -51.176 -16 ATOM 3453 CG LEU 528 -50.603 -14 ATOM 3454 CDl LEU 528 -49.103 -14 ATOM 3455 CD2 LEU 528 -50.934 -13 ATOM 3456 C LEU 528 -53.145 -17 ATOM 3457 O LEU 528 -52.695 -18 ATOM 3458 N LEU 529 -54.042 -17 ATOM 3459 CA LEU 529 -54.606 -18 ATOM 3460 CB LEU 529 -56.102 -18 ATOM 3461 CG LEU 529 -56.625 -20 ATOM 3462 CDl LEU 529 -58.118 -20 ATOM 3463 CD2 LEU 529 -55.929 -21 ATOM 3464 C LEU 529 -54.418 -18 ATOM 3465 O LEU 529 -55.236 -18 ATOM 3466 N PRO 530 -53.332 -19 ATOM 3467 CD PRO 530 -52.292 -20 ATOM 3468 CA PRO 530 -53.078 -19 ATOM 3469 CB PRO 530 -51.726 -20 ATOM 3470 CG PRO 530 -51.557 -20 ATOM 3471 C PRO 530 -54.184 -20 ATOM 3472 O PRO 530 -54.712 -21 ATOM 3473 N GLN 531 -54.538 -19 ATOM 3474 CA GLN 531 -55.518 -20 ATOM 3475 CB GLN 531 -54.988 -21 ATOM 3476 CG GLN 531 -53.804 -21 ATOM 3477 CD GLN 531 -52.752 -22 ATOM 3478 OE1 GLN 531 -53.063 -23 ATOM 3479 NE2 GLN 531 -51.496 -22 ATOM 3480 C GLN 531 -56.863 -20 ATOM 3481 0 GLN 531 -57.506 -21 ATOM 3482 N ALA 532 -57.288 -19 ATOM 3483 CA ALA 532 -58.562 -19 ATOM 3484 CB ALA 532 -58.439 -19 ATOM 3485 C ALA 532 -59.632 -18 ATOM 3486 0 ALA 532 -59.369 -17 ATOM 3487 N ALA 533 -60.840 -19 ATOM 3488 CA ALA 533 -61.998 -18 ATOM 3489 CB ALA 533 -62.599 -19 ATOM 3490 C ALA 533 -63.017 -18 ATOM 3491 0 ALA 533 -63.818 -19 ATOM 3492 N CYS 534 -62.975 -17 ATOM 3493 CA CYS 534 -63.886 -17 ATOM 3494 C CYS 534 -65.066 -16 -14.295 1.00 41.92 B C -19.165 1.00 44.59 B C -19.209 1.00 46.06 B 0 -20.048 1.00 42.53 B N -21.179 1.00 41.89 B c -22.431 1.00 41.27 B c -20.898 1.00 41.28 B c -20.150 1.00 41.18 B 0 -21.497 1.00 41.36 B N -21.451 1.00 41.15 B c -20.924 1.00 40.18 B c -20.566 1.00 39.48 B c -19.268 1.00 37.58 B c -18.924 1.00 37.63 B N -18.221 1.00 38.00 B c -17.975 1.00 35.82 B N -17.761 1.00 37.77 B N -22.869 1.00 40.98 B C -23.787 1.00 41.72 B 0 -23.050 1.00 41.85 B N -24.387 1.00 42.79 B C -24.581 1.00 42.97 B c -23.761 1.00 44 . 19 B 0 -24.615 1.00 45.96 B c -24.431 1.00 49.70 B s -25.674 1.00 43.71 B N -25.851 1.00 43.31 B c -27.257 1.00 43.72 B c -28.226 1.00 41.42 B 0 -25.559 1.00 42.73 B c -24.051 1.00 43.67 B s -27.355 1.00 46.11 B N -28.644 1.00 49.34 B c -28.565 1.00 49.97 B c -28.532 1.00 51.33 B c -28.316 1.00 51.51 B c -29.840 1.00 50.91 B c -29.064 1.00 51.31 B c -28.511 1.00 51.03 B 0 -30.043 1.00 52.37 B N -30.548 1.00 53.39 B c -30.230 1.00 53.20 B c -29.423 1.00 52.77 B c -29.646 1.00 52.41 B c -29.849 1.00 53.54 B c -32.057 1.00 54.80 B c -32.799 1.00 53.85 B 0 -32.532 1.00 56.84 B N -31.760 1.00 57.17 B c -33.976 1.00 58.95 B c -34.096 1.00 58.96 B c -32.809 1.00 58.65 B c -34.772 1.00 60.63 B c -34.353 1.00 59.30 B 0 -35.909 1.00 62.90 B N -36.832 1.00 65.75 B c -37.431 1.00 67.57 B c -38.356 1.00 72.19 B c -38.173 1.00 75.19 B c -37.801 1.00 76.85 B 0 -38.429 1.00 76.74 B N -36.175 1.00 65.84 B c -36.427 1.00 66.30 B 0 -35.330 1.00 66.37 B N -34.652 1.00 66.44 B c -33.211 1.00 66.93 B c -35.373 1.00 66.62 B c -35.891 1.00 67.32 B 0 -35.407 1.00 66.62 B N -35.893 1.00 66.37 B c -37.101 1.00 65.70 B c -34.763 1.00 66.18 B c -34.563 1.00 66.80 B 0 -34.020 1.00 65.19 B N -32.903 1.00 64.70 B c -33.307 1.00 64.08 B c 224 WO 2009/026558 PCT/US2008/074097 ATOM 3495 0 CYS 534 -65.030 -15 ATOM 3496 CB CYS 534 -63.164 -16 ATOM 3497 SG CYS 534 -61.664 -17 ATOM 3498 N SER 535 -66.107 -16 ATOM 3499 CA SER 535 -67.332 -15 ATOM 3500 CB SER 535 -68.104 -16 ATOM 3501 OG SER 535 -68.461 -17 ATOM 3502 C SER 535 -68.192 -15 ATOM 3503 O SER 535 -67.978 -16 ATOM 3504 N VAL 536 -69.162 -14 ATOM 3505 CA VAL 536 -70.068 -14 ATOM 3506 CB VAL 536 -70.133 -13 ATOM 3507 CGI VAL 536 -71.068 -13 ATOM 3508 CG2 VAL 536 -68.743 -12 ATOM 3509 C VAL 536 -71.471 -15 ATOM 3510 O VAL 536 -71.923 -14 ATOM 3511 N HIS 537 -72.153 -15 ATOM 3512 CA HIS 537 -73.527 -16 ATOM 3513 CB HIS 537 -73.586 -17 ATOM 3514 CG HIS 537 -72.754 -18 ATOM 3515 CD2 HIS 537 -71.437 -18 ATOM 3516 ND1 HIS 537 -73.269 -18 ATOM 3517 CEl HIS 537 -72.306 -18 ATOM 3518 NE2 HIS 537 -71.184 -18 ATOM 3519 C HIS 537 -74.395 -15 ATOM 3520 0 HIS 537 -74.074 -16 ATOM 3521 N THR 538 -75.493 -15 ATOM 3522 CA THR 538 -76.318 -14 ATOM 3523 CB THR 538 -76.397 -13 ATOM 3524 OG1 THR 538 -75.077 -12 ATOM 3525 CG2 THR 538 -77.238 -12 ATOM 3526 C THR 538 -77.740 -15 ATOM 3527 O THR 538 -78.284 -15 ATOM 3528 N ALA 539 -78.335 -15 ATOM 3529 CA ALA 539 -79.752 -15 ATOM 3530 CB ALA 539 -79.933 -16 ATOM 3531 C ALA 539 -80.416 -14 ATOM 3532 0 ALA 539 -79.932 -14 ATOM 3533 N PRO 540 -81.537 -13 ATOM 3534 CD PRO 540 -82.164 -14 ATOM 3535 CA PRO 540 -82.293 -12 ATOM 3536 CB PRO 540 -83.360 -12 ATOM 3537 CG PRO 540 -83.517 -13 ATOM 3538 C PRO 540 -82.898 -13 ATOM 3539 O PRO 540 -82.934 -14 ATOM 3540 N PRO 541 -83.380 -12 ATOM 3541 CD PRO 541 -83.368 -11 ATOM 3542 CA PRO 541 -83.932 -13 ATOM 3543 CB PRO 541 -84.361 -11 ATOM 3544 CG PRO 541 -83.528 -10 ATOM 3545 C PRO 541 -85.103 -14 ATOM 3546 O PRO 541 -85.968 -13 ATOM 3547 N ALA 542 -85.120 -15 ATOM 3548 CA ALA 542 -86.190 -16 ATOM 3549 CB ALA 542 -85.685 -17 ATOM 3550 C ALA 542 -87.377 -15 ATOM 3551 0 ALA 542 -88.513 -15 ATOM 3552 N GLU 543 -87.100 -15 ATOM 3553 CA GLU 543 -88.102 -15 ATOM 3554 CB GLU 543 -88.709 -13 ATOM 3555 CG GLU 543 -89.515 -12 ATOM 3556 CD GLU 543 -89.438 -11 ATOM 3557 OE1 GLU 543 -90.443 -10 ATOM 3558 OE2 GLU 543 -88.369 -10 ATOM 3559 C GLU 543 -89.202 -16 ATOM 3560 0 GLU 543 -89.605 -16 ATOM 3561 N ALA 544 -89.682 -16 ATOM 3562 CA ALA 544 -90.647 -17 ATOM 3563 CB ALA 544 -91.991 -16 ATOM 3564 C ALA 544 -90.118 -18 ATOM 3565 0 ALA 544 -90.876 -19 ATOM 3566 N SER 545 -88.810 -18 ATOM 3567 CA SER 545 -88.169 -19 ATOM 3568 CB SER 545 -87.431 -19 ATOM 3569 OG SER 545 -86.831 -20 ATOM 3570 C SER 545 -87.189 -20 -34.333 1.00 63.92 B O -31.733 1.00 64.32 B C -31.140 1.00 66.91 B S -32.482 1.00 64.06 B N -32.756 1.00 64.37 B C -33.894 1.00 65.10 B C -33.551 1.00 67.16 B 0 -31.500 1.00 64.34 B c -30.578 1.00 64.67 B 0 -31.467 1.00 64.90 B N -30.331 1.00 65.96 B c -29.791 1.00 65.53 B c -28.594 1.00 64.39 B c -29.405 1.00 65.88 B c -30.738 1.00 67.18 B c -31.843 1.00 65.81 B 0 -29.840 1.00 69.33 B N -30.076 1.00 72.07 B c -30.277 1.00 73.31 B c -31.423 1.00 75.71 B c -31.502 1.00 76.61 B c -32.686 1.00 76.54 B N -33.494 1.00 77.41 B c -32.800 1.00 78.04 B N -28.894 1.00 73.31 B C -27.745 1.00 73.15 B 0 -29.182 1.00 75.42 B N -28.141 1.00 77.29 B C -28.311 1.00 77.11 B c -28.274 1.00 76.83 B 0 -27.203 1.00 76.60 B c -28.151 1.00 79.06 B c -29.207 1.00 78.65 B 0 -26.968 1.00 80.99 B N -26.845 1.00 83.77 B c -26.265 1.00 83.09 B c -25.944 1.00 86.16 B c -24.850 1.00 86.73 B 0 -26.396 1.00 88.31 B N -27.707 1.00 88.43 B c -25.592 1.00 90.15 B c -26.556 1.00 89.67 B c -27.559 1.00 89.11 B c -24.344 1.00 92.40 B c -24.219 1.00 91.96 B 0 -23.400 1.00 94.77 B N -23.433 1.00 94.86 B c -22.141 1.00 97.44 B c -21.393 1.00 96.46 B c -21.986 1.00 95.58 B c -22.362 1.00100.50 B c -23.201 1.00100.57 B 0 -21.604 1.00104.26 B N -21.700 1.00107.63 B c -21.250 1.00107.30 B c -20.843 1.00110.11 B c -21.316 1.00110.36 B 0 -19.578 1.00113.18 B N -18.666 1.00116.02 B c -19.254 1.00116.65 B c -18.263 1.00118.13 B c -18.547 1.00118.89 B c -18.316 1.00119.23 B 0 -19.002 1.00118.98 B 0 -18.376 1.00117.48 B c -19.258 1.00117.72 B 0 -17.134 1.00118.85 B N -16.688 1.00120.01 B c -17.382 1.00119.80 B c -16.987 1.00120.71 B c -17.014 1.00121.08 B 0 -17.212 1.00120.84 B N -17.617 1.00120.61 B c -18.942 1.00120.62 B c -19.392 1.00121.09 B 0 -16.548 1.00120.42 B c 225 WO 2009/026558 PCT/US2008/074097 ATOM 3571 0 SER 545 -87. Oil -19 ATOM 3572 N MET 546 -86.559 -21 ATOM 3573 CA MET 546 -85.549 -21 ATOM 3574 CB MET 546 -85.530 -23 ATOM 3575 CG MET 546 -84.814 -24 ATOM 3576 SD MET 546 -85.634 -23 ATOM 3577 CE MET 546 -84.540 -24 ATOM 3578 C MET 546 -84.161 -21 ATOM 3579 0 MET 546 -83.141 -21 ATOM 3580 N GLY 547 -84.131 -20 ATOM 3581 CA GLY 547 -82.868 -19 ATOM 3582 C GLY 547 -82.687 -19 ATOM 3583 0 GLY 547 -83.268 -2 0 ATOM 3584 N THR 548 -81.879 -18 ATOM 3585 CA THR 548 -81.561 -18 ATOM 3586 CB THR 548 -81.332 -16 ATOM 3587 OG1 THR 548 -82.486 -15 ATOM 3588 CG2 THR 548 -81.089 -16 ATOM 3589 C THR 548 -80.296 -18 ATOM 3590 O THR 548 -79.298 -18 ATOM 3591 N ARG 549 -80.342 -19 ATOM 3592 CA ARG 549 -79.255 -20 ATOM 3593 CB ARG 549 -79.680 -22 ATOM 3594 CG ARG 549 -80.069 -22 ATOM 3595 CD ARG 549 -80.915 -23 ATOM 3596 NE ARG 549 -81.482 -23 ATOM 3597 CZ ARG 549 -80.888 -24 ATOM 3598 NHl ARG 549 -81.478 -24 ATOM 3599 NH2 ARG 549 -79.707 -25 ATOM 3600 C ARG 549 -78.808 -20 ATOM 3601 O ARG 549 -79.616 -20 ATOM 3602 N VAL 550 -77.509 -20 ATOM 3603 CA VAL 550 -76.959 -20 ATOM 3604 CB VAL 550 -76.520 -19 ATOM 3605 CGI VAL 550 -75.387 -18 ATOM 3606 CG2 VAL 550 -76.093 -19 ATOM 3607 C VAL 550 -75.751 -21 ATOM 3608 O VAL 550 -75.046 -21 ATOM 3609 N HIS 551 -75.522 -22 ATOM 3610 CA HIS 551 -74.368 -23 ATOM 3611 CB HIS 551 -74.732 -24 ATOM 3612 CG HIS 551 -75.882 -25 ATOM 3613 CD2 HIS 551 -75.968 -25 ATOM 3614 NDl HIS 551 -77.129 -25 ATOM 3615 CEl HIS 551 -77.933 -25 ATOM 3616 NE2 HIS 551 -77.253 -2 5 ATOM 3617 C HIS 551 -73.800 -22 ATOM 3618 0 HIS 551 -74.450 -22 ATOM 3619 N CYS 552 -72.575 -23 ATOM 3620 CA CYS 552 -71.885 -23 ATOM 3621 C CYS 552 -72.362 -24 ATOM 3622 0 CYS 552 -71.934 -25 ATOM 3623 CB CYS 552 -70.375 -23 ATOM 3624 SG CYS 552 -69.677 -22 ATOM 3625 N HIS 553 -73.247 -24 ATOM 3626 CA HIS 553 -73.889 -25 ATOM 3627 CB HIS 553 -75.055 -24 ATOM 3628 CG HIS 553 -76.263 -24 ATOM 3629 CD2 HIS 553 -76.626 -23 ATOM 3630 NDl HIS 553 -77.290 -25 ATOM 3631 CEl HIS 553 -78.234 -24 ATOM 3632 NE2 HIS 553 -77.857 -23 ATOM 3633 C HIS 553 -72.910 -26 ATOM 3634 0 HIS 553 -72.901 -27 ATOM 3635 N GLN 554 -72.091 -25 ATOM 3636 CA GLN 554 -71.197 -25 ATOM 3637 CB GLN 554 -70.435 -24 ATOM 3638 CG GLN 554 -71.323 -23 ATOM 3639 CD GLN 554 -70.578 -22 ATOM 3640 OE1 GLN 554 -70.183 -21 ATOM 3641 NE2 GLN 554 -70.376 -21 ATOM 3642 C GLN 554 -70.204 -26 ATOM 3643 0 GLN 554 -69.724 -26 ATOM 3644 N GLN 555 -69.900 -27 ATOM 3645 CA GLN 555 -68.960 -28 ATOM 3646 CB GLN 555 -69.080 -30 -15.522 1.00120.46 B O -16.789 1.00120.05 B N -15.875 1.00119.53 B C -15.921 1.00120.98 B C -17.132 1.00122.54 B c -18.707 1.00124.63 B s -19.851 1.00124.00 B c -16.225 1.00118.19 B c -15.803 1.00118.60 B 0 -17.001 1.00115.77 B N -17.351 1.00112.18 B c -18.842 1.00109.64 B c -19.654 1.00109.67 B 0 -19.205 1.00106.80 B N -20.604 1.00103.45 B c -20.848 1.00102.95 B c -20.422 1.00102.38 B 0 -22.322 1.00102.67 B c -20.989 1.00101.35 B c -20.270 1.00101.40 B 0 -22.120 1.00 98.30 B N -22.504 1.00 95.33 B c -22.300 1.00 97.27 B c -20.871 1.00 99.72 B c -20.793 1.00101.92 B c -19.459 1.00104.40 B N -18.475 1.00105.40 B c -17.289 1.00105.68 B N -18.677 1.00105.41 B N -23.946 1.00 92.19 B C -24.828 1.00 91.75 B 0 -24.174 1.00 88.72 B N -25.520 1.00 85.99 B C -25.963 1.00 85.94 B c -25.080 1.00 85.93 B c -27.420 1.00 85.60 B c -25.532 1.00 84.16 B c -24.532 1.00 83.76 B 0 -26.657 1.00 82.33 B N -26.788 1.00 81.02 B c -26.390 1.00 83.78 B c -27.158 1.00 86.60 B c -28.431 1.00 87.05 B c -26.600 1.00 87.85 B N -27.496 1.00 88.26 B c -28.615 1.00 88.32 B N -28.198 1.00 78.87 B C -29.135 1.00 78.95 B 0 -28.334 1.00 76.26 B N -29.612 1.00 74.68 B C -30.456 1.00 76.00 B c -30.253 1.00 75.80 B 0 -29.387 1.00 71.57 B c -28.252 1.00 67.04 B s -31.406 1.00 77.76 B N -32.212 1.00 79.66 B c -33.013 1.00 84.15 B c -32.188 1.00 88.61 B c -31.553 1.00 90.41 B c -31.981 1.00 90.68 B N -31.256 1.00 91.59 B c -30.983 1.00 91.84 B N -33.177 1.00 78.29 B C -33.317 1.00 78.79 B 0 -33.841 1.00 75.87 B N -34.878 1.00 73.89 B C -35.516 1.00 76.44 B c -36.140 1.00 80.50 B c -36.395 1.00 83.46 B c -37.527 1.00 83.91 B 0 -35.337 1.00 84.48 B N -34.340 1.00 71.10 B c -33.212 1.00 70.66 B 0 -35.161 1.00 67.93 B N -34.792 1.00 65.48 B c -35.762 1.00 66.77 B c 226 WO 2009/026558 PCT/US2008/074097 ATOM 3647 CG GLN 555 -70.449 -30 ATOM 3648 CD GLN 555 -70.635 -31 ATOM 3649 OE1 GLN 555 -70.909 -31 ATOM 3650 NE2 GLN 555 -70.483 -32 ATOM 3651 C GLN 555 -67.535 -2 8 ATOM 3652 0 GLN 555 -67.166 -27 ATOM 3653 N GLY 556 -66.737 -28 ATOM 3654 CA GLY 556 -65.364 -28 ATOM 3655 C GLY 556 -65.237 -26 ATOM 3656 0 GLY 556 -64.138 -2 6 ATOM 3657 N HIS 557 -66.363 -2 6 ATOM 3658 CA HIS 557 -66.359 -24 ATOM 3659 CB HIS 557 -67.488 -24 ATOM 3660 CG HIS 557 -67.257 -23 ATOM 3661 CD2 HIS 557 -67.399 -22 ATOM 3662 NDl HIS 557 -66.794 -2 4 ATOM 3663 CEl HIS 557 -66.658 -23 ATOM 3664 NE2 HIS 557 -67.018 -22 ATOM 3665 C HIS 557 -66.517 -25 ATOM 3666 0 HIS 557 -67.488 -25 ATOM 3667 N VAL 558 -65.551 -24 ATOM 3668 CA VAL 558 -65.494 -24 ATOM 3669 CB VAL 558 -64.078 -25 ATOM 3670 CGI VAL 558 -64.079 -25 ATOM 3671 CG2 VAL 558 -63.581 -26 ATOM 3672 C VAL 558 -65.884 -23 ATOM 3673 O VAL 558 -65.607 -22 ATOM 3674 N LEU 559 -66.536 -23 ATOM 3675 CA LEU 559 -66.947 -22 ATOM 3676 CB LEU 559 -68.119 -23 ATOM 3677 CG LEU 559 -68.664 -21 ATOM 3678 CDl LEU 559 -69.353 -20 ATOM 3679 CD2 LEU 559 -69.639 -22 ATOM 3680 C LEU 559 -65.777 -22 ATOM 3681 O LEU 559 -65.271 -22 ATOM 3682 N THR 560 -65.342 -20 ATOM 3683 CA THR 560 -64.186 -20 ATOM 3684 CB THR 560 -63.195 -19 ATOM 3685 OG1 THR 560 -63.826 -18 ATOM 3686 CG2 THR 560 -62.746 -20 ATOM 3687 C THR 560 -64.574 -19 ATOM 3688 O THR 560 -63.807 -19 ATOM 3689 N GLY 561 -65.757 -18 ATOM 3690 CA GLY 561 -66.217 -17 ATOM 3691 C GLY 561 -67.688 -17 ATOM 3692 0 GLY 561 -68.264 -17 ATOM 3693 N CYS 562 -68.296 -17 ATOM 3694 CA CYS 562 -69.694 -16 ATOM 3695 C CYS 562 -69.821 -15 ATOM 3696 0 CYS 562 -69.176 -15 ATOM 3697 CB CYS 562 -70.525 -17 ATOM 3698 SG CYS 562 -70.658 -19 ATOM 3699 N SER 563 -70.665 -14 ATOM 3700 CA SER 563 -70.980 -13 ATOM 3701 CB SER 563 -70.453 -12 ATOM 3702 OG SER 563 -69.037 -12 ATOM 3703 C SER 563 -72.484 -13 ATOM 3704 O SER 563 -73.270 -13 ATOM 3705 N SER 564 -72.883 -12 ATOM 3706 CA SER 564 -74.296 -11 ATOM 3707 CB SER 564 -74.798 -12 ATOM 3708 OG SER 564 -76.187 -12 ATOM 3709 C SER 564 -74.542 -10 ATOM 3710 O SER 564 -73.912 -9 ATOM 3711 N HIS 565 -75.458 -9 ATOM 3712 CA HIS 565 -75.896 -8 ATOM 3713 CB HIS 565 -75.342 -7 ATOM 3714 CG HIS 565 -76.129 -7 ATOM 3715 CD2 HIS 565 -77.193 -6 ATOM 3716 NDl HIS 565 -75.824 -7 ATOM 3717 CEl HIS 565 -76.664 -7 ATOM 3718 NE2 HIS 565 -77.505 -6 ATOM 3719 C HIS 565 -77.417 -8 ATOM 3720 0 HIS 565 -78.093 -9 ATOM 3721 N TRP 566 -77.952 -7 ATOM 3722 CA TRP 566 -79.395 -7
-35.766 1.00 68.17 B C -34.596 1.00 69.56 B C -33.472 1.00 68.69 B 0 -34.857 1.00 70.20 B N -34.818 1.00 63.77 B c -35.718 1.00 63.08 B 0 -33.828 1.00 61.44 B N -33.765 1.00 58.50 B c -33.169 1.00 56.70 B c -33.072 1.00 56.59 B 0 -32.775 1.00 54.74 B N -32.104 1.00 54.39 B c -32.654 1.00 56.06 B c -34.059 1.00 59.40 B c -34.631 1.00 60.00 B c -35.052 1.00 60.87 B N -36.175 1.00 60.41 B c -35.946 1.00 60.64 B N -30.597 1.00 52.41 B C -30.129 1.00 52.00 B 0 -29.843 1.00 50.33 B N -28.408 1.00 48.46 B C -27.989 1.00 48.10 B c -26.546 1.00 48.76 B c -28.913 1.00 47.38 B c -27.642 1.00 47.50 B c -28.080 1.00 48.38 B 0 -26.499 1.00 46.06 B N -25.674 1.00 45.93 B c -24.782 1.00 45.03 B c -23.833 1.00 47.58 B c -24.635 1.00 45.95 B c -22.847 1.00 46.31 B c -24.810 1.00 45.32 B c -23.988 1.00 46.56 B 0 -24.999 1.00 44.72 B N -24.267 1.00 43.84 B c -25.204 1.00 42.82 B c -25.792 1.00 42.05 B 0 -26.302 1.00 42.95 B c -23.167 1.00 43.79 B c -22.231 1.00 44.66 B 0 -23.281 1.00 44.15 B N -22.260 1.00 45.65 B c -22.363 1.00 48.91 B c -23.452 1.00 48.94 B 0 -21.223 1.00 52.04 B N -21.173 1.00 56.94 B c -20.622 1.00 57.36 B c -19.638 1.00 57.14 B 0 -20.286 1.00 60.25 B c -20.842 1.00 68.25 B s -21.254 1.00 59.16 B N -20.743 1.00 60.40 B c -21.697 1.00 59.60 B c -21.714 1.00 60.14 B 0 -20.570 1.00 61.68 B c -21.140 1.00 61.85 B 0 -19.780 1.00 63.51 B N -19.540 1.00 65.75 B c -18.424 1.00 65.21 B c -18.216 1.00 64.95 B 0 -19.156 1.00 67.58 B c -18.236 1.00 67.06 B 0 -19.862 1.00 70.45 B N -19.475 1.00 74.26 B c -20.444 1.00 74.10 B c -21.710 1.00 75.03 B c -22.019 1.00 75.03 B c -22.857 1.00 75.79 B N -23.817 1.00 75.02 B c -23.335 1.00 74.96 B N -19.447 1.00 76.76 B C -20.191 1.00 76.35 B 0 -18.582 1.00 80.24 B N -18.457 1.00 83.92 B C 227 WO 2009/026558 PCT/US2008/074097 ATOM 3723 CB TRP 566 -79.885 -7 ATOM 3724 CG TRP 566 -79.070 -7 ATOM 3725 CD2 TRP 566 -77.859 -8 ATOM 3726 CE2 TRP 566 -77.461 -7 ATOM 3727 CE3 TRP 566 -77.073 -9 ATOM 3728 CDl TRP 566 -79.348 -6 ATOM 3729 NEl TRP 566 -78.387 -6 ATOM 3730 CZ2 TRP 566 -76.314 -8 ATOM 3731 CZ3 TRP 566 -75.934 -9 ATOM 3732 CH2 TRP 566 -75.565 -9 ATOM 3733 C TRP 566 -79.835 -5 ATOM 3734 O TRP 566 -79.009 -4 ATOM 3735 N GLU 567 -81.146 -5 ATOM 3736 CA GLU 567 -81.711 -4 ATOM 3737 CB GLU 567 -82.770 -4 ATOM 3738 CG GLU 567 -82.799 -2 ATOM 3739 CD GLU 567 -81.568 -2 ATOM 3740 OE1 GLU 567 -80.732 -3 ATOM 3741 OE2 GLU 567 -81.436 -1 ATOM 3742 C GLU 567 -82.333 -3 ATOM 3743 0 GLU 567 -82.113 -2 ATOM 3744 N VAL 568 -83.Ill -4 ATOM 3745 CA VAL 568 -83.733 -4 ATOM 3746 CB VAL 568 -84.660 -5 ATOM 3747 CGI VAL 568 -85.738 -5 ATOM 3748 CG2 VAL 568 -83.847 -6 ATOM 3749 C VAL 568 -82.657 -4 ATOM 3750 O VAL 568 -81.478 -4 ATOM 3751 N GLU 569 -83.063 -3 ATOM 3752 CA GLU 569 -82.113 -3 ATOM 3753 CB GLU 569 -82.451 -2 ATOM 3754 CG GLU 569 -82.319 -1 ATOM 3755 CD GLU 569 -80.930 -0 ATOM 3756 OE1 GLU 569 -79.972 -0 ATOM 3757 OE2 GLU 569 -80.796 -1 ATOM 3758 C GLU 569 -82.088 -4 ATOM 3759 0 GLU 569 -81.021 -5 ATOM 3760 N ASP 570 -83.267 -5 ATOM 3761 CA ASP 570 -83.379 -6 ATOM 3762 CB ASP 570 -84.494 -5 ATOM 3763 CG ASP 570 -84.260 -4 ATOM 3764 OD1 ASP 570 -85.090 -4 ATOM 3765 OD2 ASP 570 -83.247 -3 ATOM 3766 C ASP 570 -83.652 -7 ATOM 3767 O ASP 570 -84.496 -7 ATOM 3768 N LEU 571 -82.927 -8 ATOM 3769 CA LEU 571 -83.060 -9 ATOM 3770 CB LEU 571 -81.836 -10 ATOM 3771 CG LEU 571 -81.609 -9 ATOM 3772 CDl LEU 571 -81.205 -8 ATOM 3773 CD2 LEU 571 -80.523 -10 ATOM 3774 C LEU 571 -83.215 -11 ATOM 3775 O LEU 571 -84.241 -11 ATOM 3776 N PRO 585 -72.292 -29 ATOM 3777 CD PRO 585 -72.479 -31 ATOM 3778 CA PRO 585 -70.992 -29 ATOM 3779 CB PRO 585 -70.252 -30 ATOM 3780 CG PRO 585 -71.337 -31 ATOM 3781 C PRO 585 -71.129 -2 8 ATOM 3782 O PRO 585 -71.931 -2 8 ATOM 3783 N ASN 586 -70.340 -27 ATOM 3784 CA ASN 586 -70.363 -26 ATOM 3785 CB ASN 586 -70.162 -26 ATOM 3786 CG ASN 586 -68.793 -27 ATOM 3787 OD1 ASN 586 -67.783 -26 ATOM 3788 ND2 ASN 586 -68.754 -28 ATOM 3789 C ASN 586 -71.659 -25 ATOM 3790 0 ASN 586 -72.162 -24 ATOM 3791 N GLN 587 -72.197 -25 ATOM 3792 CA GLN 587 -73.408 -2 4 ATOM 3793 CB GLN 587 -74.588 -25 ATOM 3794 CG GLN 587 -75.876 -24 ATOM 3795 CD GLN 587 -77.085 -2 5 ATOM 3796 OE1 GLN 587 -77.886 -25 ATOM 3797 NE2 GLN 587 -77.223 -25 ATOM 3798 C GLN 587 -73.263 -23 -17.181 1.00 82.87 B C -15.975 1.00 81.41 B C -15.564 1.00 80.85 B c -14.351 1.00 80.81 B c -16.103 1.00 80.36 B c -15.025 1.00 81.33 B c -14.043 1.00 81.30 B N -13.667 1.00 80.57 B c -15.423 1.00 80.05 B c -14.218 1.00 80.06 B c -18.459 1.00 87.50 B c -18.373 1.00 87.72 B 0 -18.555 1.00 91.79 B N -18.649 1.00 95.79 B c -19.749 1.00 96.18 B c -20.519 1.00 98.36 B c -21.384 1.00 99.33 B c -21.431 1.00 98.92 B 0 -22.019 1.00100.24 B 0 -17.328 1.00 98.41 B c -16.876 1.00 98.57 B 0 -16.714 1.00101.90 B N -15.428 1.00105.56 B c -14.971 1.00105.81 B c -16.016 1.00105.97 B c -14.728 1.00105.81 B c -14.371 1.00107.91 B c -14.625 1.00108.57 B 0 -13.187 1.00110.90 B N -12. 111 1.00113.78 B c -11.407 1.00114.54 B c -12.303 1.00116.01 B c -12.904 1.00116.56 B c -12.140 1.00116.54 B 0 -14.139 1.00116.94 B 0 -11.099 1.00115.27 B c -10.646 1.00115.42 B 0 -10.753 1.00116.99 B N -9.751 1.00118.36 B c -8.758 1.00119.50 B c -8.044 1.00120.50 B c -7.185 1.00120.98 B 0 -8.343 1.00120.72 B 0 -10.388 1.00118.64 B c -11.277 1.00118.66 B 0 -9.928 1.00118.81 B N -10.463 1.00118.86 B c -11.317 1.00118.99 B c -12.613 1.00118.90 B c -12.294 1.00119.28 B c -13.434 1.00118.88 B c -9.336 1.00118.75 B c -9.227 1.00118.42 B 0 -21.993 1.00 83.79 B N -22.411 1.00 84.05 B c -22.422 1.00 83.07 B c -22.939 1.00 83.40 B c -23.365 1.00 83.43 B c -23.496 1.00 81.48 B c -24.418 1.00 80.88 B 0 -23.365 1.00 80.01 B N -24.311 1.00 78.83 B c -25.749 1.00 79.79 B c -25.974 1.00 80.52 B c -26.031 1.00 79.27 B 0 -26.108 1.00 81.46 B N -24.243 1.00 77.08 B c -25.271 1.00 76.87 B 0 -23.040 1.00 75.05 B N -22.875 1.00 74.57 B c -22.512 1.00 74.98 B c -22.224 1.00 75.59 B c -22.114 1.00 76.09 B c -23.044 1.00 76.13 B 0 -20.973 1.00 75.12 B N -21.819 1.00 73.56 B c 228 WO 2009/026558 PCT/US2008/074097 ATOM 3799 0 GLN 587 -72.681 -23 ATOM 3800 N CYS 588 -73.796 -21 ATOM 3801 CA CYS 588 -73.872 -20 ATOM 3802 C CYS 588 -75.271 -20 ATOM 3803 0 CYS 588 -76.266 -20 ATOM 3804 CB CYS 588 -73.541 -19 ATOM 3805 SG CYS 588 -71.864 -19 ATOM 3806 N VAL 589 -75.348 -20 ATOM 3807 CA VAL 589 -76.629 -20 ATOM 3808 CB VAL 589 -76.974 -21 ATOM 3809 CGI VAL 589 -78.348 -21 ATOM 3810 CG2 VAL 589 -76.926 -22 ATOM 3811 C VAL 589 -76.612 -19 ATOM 3812 O VAL 589 -75.810 -18 ATOM 3813 N GLY 590 -77.503 -18 ATOM 3814 CA GLY 590 -77.608 -16 ATOM 3815 C GLY 590 -78.956 -16 ATOM 3816 0 GLY 590 -79.812 -17 ATOM 3817 N HIS 591 -79.143 -15 ATOM 3818 CA HIS 591 -80.426 -15 ATOM 3819 CB HIS 591 -80.329 -14 ATOM 3820 CG HIS 591 -81.482 -13 ATOM 3821 CD2 HIS 591 -81.585 -13 ATOM 3822 NDl HIS 591 -82.714 -13 ATOM 3823 CEl HIS 591 -83.527 -13 ATOM 3824 NE2 HIS 591 -82.867 -13 ATOM 3825 C HIS 591 -81.503 -15 ATOM 3826 0 HIS 591 -81.210 -15 ATOM 3827 N ARG 592 -82.749 -15 ATOM 3828 CA ARG 592 -83.861 -15 ATOM 3829 CB ARG 592 -85.141 -16 ATOM 3830 CG ARG 592 -85.501 -15 ATOM 3831 CD ARG 592 -86.947 -15 ATOM 3832 NE ARG 592 -87.177 -16 ATOM 3833 CZ ARG 592 -88.312 -17 ATOM 3834 NHl ARG 592 -88.435 -18 ATOM 3835 NH2 ARG 592 -89.325 -16 ATOM 3836 C ARG 592 -84.085 -14 ATOM 3837 O ARG 592 -84.473 -14 ATOM 3838 N GLU 593 -83.834 -13 ATOM 3839 CA GLU 593 -84.083 -11 ATOM 3840 CB GLU 593 -84.361 -10 ATOM 3841 CG GLU 593 -85.593 -11 ATOM 3842 CD GLU 593 -85.834 -10 ATOM 3843 OE1 GLU 593 -86.475 -9 ATOM 3844 OE2 GLU 593 -85.383 -10 ATOM 3845 C GLU 593 -82.917 -11 ATOM 3846 0 GLU 593 -83.001 -10 ATOM 3847 N ALA 594 -81.831 -11 ATOM 3848 CA ALA 594 -80.616 -11 ATOM 3849 CB ALA 594 -79.410 -11 ATOM 3850 C ALA 594 -80.394 -12 ATOM 3851 0 ALA 594 -80.829 -13 ATOM 3852 N SER 595 -79.718 -11 ATOM 3853 CA SER 595 -79.199 -11 ATOM 3854 CB SER 595 -78.882 -10 ATOM 3855 OG SER 595 -80.030 -9 ATOM 3856 C SER 595 -77.925 -12 ATOM 3857 O SER 595 -77.189 -12 ATOM 3858 N ILE 596 -77.669 -13 ATOM 3859 CA ILE 596 -76.505 -14 ATOM 3860 CB ILE 596 -76.932 -15 ATOM 3861 CG2 ILE 596 -77.525 -16 ATOM 3862 CGI ILE 596 -75.731 -16 ATOM 3863 CDl ILE 596 -75.266 -16 ATOM 3864 C ILE 596 -75.613 -14 ATOM 3865 0 ILE 596 -76.101 -14 ATOM 3866 N HIS 597 -74.304 -14 ATOM 3867 CA HIS 597 -73.350 -14 ATOM 3868 CB HIS 597 -72.680 -13 ATOM 3869 CG HIS 597 -73.646 -11 ATOM 3870 CD2 HIS 597 -74.065 -11 ATOM 3871 NDl HIS 597 -74.330 -11 ATOM 3872 CEl HIS 597 -75.128 -10 ATOM 3873 NE2 HIS 597 -74.987 -10 ATOM 3874 C HIS 597 -72.292 -15
-20.759 1.00 73.19 B O -22.118 1.00 72.91 B N -21.144 1.00 72.44 B C -20.551 1.00 73.33 B C -21.276 1.00 73.45 B 0 -21.796 1.00 70.56 B c -22.479 1.00 68.54 B s -19.234 1.00 74.61 B N -18.579 1.00 76.86 B c -17.618 1.00 76.35 B c -17.016 1.00 76.62 B c -18.355 1.00 76.25 B c -17.790 1.00 78.39 B c -16.874 1.00 78.41 B 0 -18.152 1.00 80.86 B N -17.427 1.00 83.83 B c -16.753 1.00 85.87 B c -16.854 1.00 86.28 B 0 -16.061 1.00 87.95 B N -15.452 1.00 89.48 B c -14.716 1.00 90.53 B c -13.803 1.00 91.97 B c -12.454 1.00 92.54 B c -14.262 1.00 92.28 B N -13.235 1.00 92.99 B c -12.126 1.00 92.92 B N -16.534 1.00 89.95 B C -17.700 1.00 89.23 B 0 -16.143 1.00 90.86 B N -17.088 1.00 91.76 B C -16.390 1.00 94.45 B c -15.163 1.00 98.10 B c -14.740 1.00101.13 B c -14.177 1.00103.71 B N -13.596 1.00105.10 B c -13.112 1.00105.47 B N -13.497 1.00105.79 B N -17.684 1.00 90.52 B C -18.845 1.00 89.74 B 0 -16.886 1.00 89.53 B N -17.310 1.00 88.86 B C -16.092 1.00 90.90 B c -15.292 1.00 93.06 B c -14.095 1.00 94.88 B c -14.270 1.00 95.59 B 0 -12.980 1.00 95.43 B 0 -18.102 1.00 86.91 B c -18.611 1.00 86.77 B 0 -18.206 1.00 84.52 B N -18.852 1.00 81.65 B c -17.961 1.00 81.53 B c -20.234 1.00 79.44 B c -20.508 1.00 79.69 B 0 -21.105 1.00 76.43 B N -22.345 1.00 73.80 B c -23.343 1.00 73.82 B c -23.621 1.00 74.77 B 0 -22.024 1.00 72.54 B c -21.108 1.00 72.16 B 0 -22.776 1.00 71.00 B N -22.527 1.00 68.81 B c -22.162 1.00 69.08 B c -23.376 1.00 69.30 B c -21.634 1.00 68.96 B c -20.276 1.00 68.21 B c -23.765 1.00 67.78 B c -24.892 1.00 67.52 B 0 -23.551 1.00 66.74 B N -24.653 1.00 65.51 B c -24.678 1.00 67.23 B c -24.586 1.00 69.06 B c -23.525 1.00 68.78 B c -25.680 1.00 69.46 B N -25.297 1.00 69.61 B c -23.993 1.00 69.86 B N -24.519 1.00 63.90 B C 229 WO 2009/026558 PCT/US2008/074097 ATOM 3875 0 HIS 597 -71.750 -15 ATOM 3876 N ALA 598 -72.000 -16 ATOM 3877 CA ALA 598 -71.035 -17 ATOM 3878 CB ALA 598 -71.733 -18 ATOM 3879 C ALA 598 -69.922 -17 ATOM 3880 0 ALA 598 -70.179 -16 ATOM 3881 N SER 599 -68.684 -17 ATOM 3882 CA SER 599 -67.548 -17 ATOM 3883 CB SER 599 -66.342 -16 ATOM 3884 OG SER 599 -65.192 -16 ATOM 3885 C SER 599 -67.212 -18 ATOM 3886 O SER 599 -66.904 -19 ATOM 3887 N CYS 600 -67.282 -18 ATOM 3888 CA CYS 600 -66.994 -19 ATOM 3889 C CYS 600 -65.816 -19 ATOM 3890 0 CYS 600 -65.784 -18 ATOM 3891 CB CYS 600 -68.218 -20 ATOM 3892 SG CYS 600 -69.778 -20 ATOM 3893 N CYS 601 -64.848 -20 ATOM 3894 CA CYS 601 -63.696 -20 ATOM 3895 C CYS 601 -63.475 -22 ATOM 3896 0 CYS 601 -63.589 -23 ATOM 3897 CB CYS 601 -62.420 -20 ATOM 3898 SG CYS 601 -62.321 -18 ATOM 3899 N HIS 602 -63.147 -22 ATOM 3900 CA HIS 602 -62.668 -23 ATOM 3901 CB HIS 602 -63.299 -23 ATOM 3902 CG HIS 602 -62.908 -2 4 ATOM 3903 CD2 HIS 602 -63.643 -25 ATOM 3904 NDl HIS 602 -61.615 -24 ATOM 3905 CEl HIS 602 -61.570 -25 ATOM 3906 NE2 HIS 602 -62.788 -26 ATOM 3907 C HIS 602 -61.156 -23 ATOM 3908 0 HIS 602 -60.658 -22 ATOM 3909 N ALA 603 -60.425 -24 ATOM 3910 CA ALA 603 -58.972 -24 ATOM 3911 CB ALA 603 -58.392 -23 ATOM 3912 C ALA 603 -58.414 -25 ATOM 3913 0 ALA 603 -58.907 -26 ATOM 3914 N PRO 604 -57.363 -25 ATOM 3915 CD PRO 604 -56.540 -24 ATOM 3916 CA PRO 604 -56.843 -27 ATOM 3917 CB PRO 604 -55.719 -27 ATOM 3918 CG PRO 604 -55.294 -25 ATOM 3919 C PRO 604 -56.344 -27 ATOM 3920 O PRO 604 -55.343 -27 ATOM 3921 N GLY 605 -57.046 -28 ATOM 3922 CA GLY 605 -5 6.616 -29 ATOM 3923 C GLY 605 -57.024 -28 ATOM 3924 0 GLY 605 -56.578 -28 ATOM 3925 N LEU 606 -57.871 -27 ATOM 3926 CA LEU 606 -58.380 -2 6 ATOM 3927 CB LEU 606 -59.100 -25 ATOM 3928 CG LEU 606 -59.707 -24 ATOM 3929 CDl LEU 606 -58.587 -24 ATOM 3930 CD2 LEU 606 -60.546 -23 ATOM 3931 C LEU 606 -59.352 -27 ATOM 3932 O LEU 606 -60.373 -28 ATOM 3933 N GLU 607 -59.044 -27 ATOM 3934 CA GLU 607 -60.027 -28 ATOM 3935 CB GLU 607 -59.688 -29 ATOM 3936 CG GLU 607 -58.375 -30 ATOM 3937 CD GLU 607 -58.294 -31 ATOM 3938 OE1 GLU 607 -57.200 -32 ATOM 3939 OE2 GLU 607 -59.325 -32 ATOM 3940 C GLU 607 -60.151 -27 ATOM 3941 0 GLU 607 -59.161 -27 ATOM 3942 N CYS 608 -61.384 -27 ATOM 3943 CA CYS 608 -61.677 -26 ATOM 3944 C CYS 608 -62.611 -27 ATOM 3945 0 CYS 608 -63.400 -28 ATOM 3946 CB CYS 608 -62.374 -25 ATOM 3947 SG CYS 608 -61.522 -24 ATOM 3948 N LYS 609 -62.526 -27 ATOM 3949 CA LYS 609 -63.435 -27 ATOM 3950 CB LYS 609 -62.791 -29 -23.440 1.00 64.34 B O -25.622 1.00 61.69 B N -25.606 1.00 59.24 B C -25.919 1.00 59.25 B C -26.610 1.00 57.16 B c -27.759 1.00 57.27 B 0 -26.172 1.00 55.41 B N -27.077 1.00 54.67 B c -26.349 1.00 54.38 B c -27.181 1.00 53.69 B 0 -27.586 1.00 54.57 B c -26.800 1.00 53.49 B 0 -28.901 1.00 55.25 B N -29.498 1.00 58.00 B c -30.457 1.00 58.00 B c -31.300 1.00 58.78 B 0 -30.259 1.00 59.36 B c -29.309 1.00 63.79 B s -30.330 1.00 57.59 B N -31.220 1.00 59.73 B c -31.892 1.00 59.37 B c -31.260 1.00 58.29 B 0 -30.461 1.00 61.31 B c -29.670 1.00 67.30 B s -33.177 1.00 59.49 B N -33.895 1.00 60.04 B c -35.293 1.00 62.97 B c -36.099 1.00 66.97 B c -36.565 1.00 68.22 B c -36.521 1.00 68.55 B N -37.211 1.00 68.47 B c -37.253 1.00 68.91 B N -34.005 1.00 59.13 B C -34.560 1.00 58.95 B 0 -33.462 1.00 57.63 B N -33.551 1.00 57.29 B C -32.478 1.00 57.06 B c -33.405 1.00 58.27 B c -32.611 1.00 57.05 B 0 -34.170 1.00 59.55 B N -34.914 1.00 60.80 B c -34.279 1.00 59.96 B c -35.308 1.00 60.62 B c -35.237 1.00 61.97 B c -32.954 1.00 59.56 B c -32.409 1.00 60.04 B 0 -32.445 1.00 58.14 B N -31.223 1.00 55.88 B c -29.969 1.00 54.81 B c -28.870 1.00 55.62 B 0 -30.126 1.00 52.76 B N -28.980 1.00 50.04 B c -29.445 1.00 48.66 B c -28.305 1.00 47.30 B c -27.437 1.00 47.38 B c -28.862 1.00 46.45 B c -28.179 1.00 50.49 B c -28.705 1.00 50.29 B 0 -26.905 1.00 49.74 B N -26.004 1.00 4 9.92 B c -25.689 1.00 51.37 B c -24.972 1.00 54.60 B c -24.346 1.00 56.01 B c -24.360 1.00 56.47 B 0 -23.836 1.00 57.69 B 0 -24.720 1.00 49.55 B c -24.179 1.00 49.44 B 0 -24.249 1.00 49.05 B N -23.050 1.00 49.93 B c -22.155 1.00 51.10 B c -22.641 1.00 51.03 B 0 -23.406 1.00 49.04 B c -24.553 1.00 51.08 B s -20.852 1.00 51.23 B N -19.901 1.00 52.84 B c -19.286 1.00 53.14 B c 230 WO 2009/026558 PCT/US2008/074097 ATOM 3951 CG LYS 609 -61.523 -28 ATOM 3952 CD LYS 609 -60.931 -30 ATOM 3953 CE LYS 609 -59.776 -30 ATOM 3954 NZ LYS 609 -59.273 -31 ATOM 3955 C LYS 609 -63.807 -26 ATOM 3956 0 LYS 609 -63.155 -25 ATOM 3957 N VAL 610 -64.859 -27 ATOM 3958 CA VAL 610 -65.302 -2 6 ATOM 3959 CB VAL 610 -66.830 -26 ATOM 3960 CGI VAL 610 -67.271 -25 ATOM 3961 CG2 VAL 610 -67.302 -25 ATOM 3962 C VAL 610 -64.856 -26 ATOM 3963 O VAL 610 -64.852 -28 ATOM 3964 N LYS 611 -64.472 -26 ATOM 3965 CA LYS 611 -64.239 -2 6 ATOM 3966 CB LYS 611 -62.755 -26 ATOM 3967 CG LYS 611 -61.822 -26 ATOM 3968 CD LYS 611 -60.861 -27 ATOM 3969 CE LYS 611 -59.980 -27 ATOM 3970 NZ LYS 611 -60.714 -27 ATOM 3971 C LYS 611 -65.042 -2 5 ATOM 3972 0 LYS 611 -65.139 -24 ATOM 3973 N GLU 612 -65.622 -25 ATOM 3974 CA GLU 612 -66.417 -25 ATOM 3975 CB GLU 612 -67.877 -25 ATOM 3976 CG GLU 612 -68.589 -25 ATOM 3977 CD GLU 612 -70.077 -25 ATOM 3978 OE1 GLU 612 -70.810 -25 ATOM 3979 OE2 GLU 612 -70.512 -26 ATOM 3980 C GLU 612 -65.901 -25 ATOM 3981 O GLU 612 -65.141 -26 ATOM 3982 N HIS 613 -66.327 -24 ATOM 3983 CA HIS 613 -66.140 -24 ATOM 3984 CB HIS 613 -64.726 -23 ATOM 3985 CG HIS 613 -64.399 -23 ATOM 3986 CD2 HIS 613 -64.782 -23 ATOM 3987 NDl HIS 613 -63.574 -24 ATOM 3988 CEl HIS 613 -63.462 -24 ATOM 3989 NE2 HIS 613 -64.185 -2 3 ATOM 3990 C HIS 613 -67.162 -23 ATOM 3991 0 HIS 613 -67.342 -22 ATOM 3992 N GLY 614 -67.840 -23 ATOM 3993 CA GLY 614 -68.806 -23 ATOM 3994 C GLY 614 -68.482 -22 ATOM 3995 0 GLY 614 -67.916 -23 ATOM 3996 N ILE 615 -68.829 -21 ATOM 3997 CA ILE 615 -68.696 -21 ATOM 3998 CB ILE 615 -67.545 -20 ATOM 3999 CG2 ILE 615 -67.478 -20 ATOM 4000 CGI ILE 615 -66.218 -21 ATOM 4001 CDl ILE 615 -65.019 -20 ATOM 4002 C ILE 615 -70.001 -21 ATOM 4003 0 ILE 615 -70.584 -20 ATOM 4004 N PRO 616 -70.480 -21 ATOM 4005 CD PRO 616 -69.870 -23 ATOM 4006 CA PRO 616 -71.741 -21 ATOM 4007 CB PRO 616 -71.878 -22 ATOM 4008 CG PRO 616 -71.022 -23 ATOM 4009 C PRO 616 -71.695 -20 ATOM 4010 O PRO 616 -72.555 -19 ATOM 4011 N ALA 617 -70.681 -19 ATOM 4012 CA ALA 617 -70.478 -18 ATOM 4013 CB ALA 617 -70.126 -18 ATOM 4014 C ALA 617 -69.369 -17 ATOM 4015 0 ALA 617 -68.188 -17 ATOM 4016 N PRO 618 -69.740 -17 ATOM 4017 CD PRO 618 -71.117 -16 ATOM 4018 CA PRO 618 -68.748 -16 ATOM 4019 CB PRO 618 -69.568 -15 ATOM 4020 CG PRO 618 -70.960 -15 ATOM 4021 C PRO 618 -68.052 -15 ATOM 4022 O PRO 618 -68.610 -14 ATOM 4023 N GLN 619 -66.829 -15 ATOM 4024 CA GLN 619 -66.071 -14 ATOM 4025 CB GLN 619 -64.819 -15 ATOM 4026 CG GLN 619 -63.990 -14 -18.501 1.00 56.59 B C -17.996 1.00 59.65 B C -17.035 1.00 62.05 B c -16.491 1.00 64.13 B N -18.808 1.00 53.60 B c -18.652 1.00 54.60 B 0 -18.059 1.00 53.79 B N -16.961 1.00 54.51 B c -16.947 1.00 53.63 B c -15.731 1.00 53.41 B c -18.218 1.00 53.06 B c -15.603 1.00 56.27 B c -15.371 1.00 56.36 B 0 -14.714 1.00 58.50 B N -13.308 1.00 60.09 B c -12.963 1.00 60.15 B c -14.002 1.00 62.60 B c -13.396 1.00 64.20 B c -12.319 1.00 63.58 B c -11.039 1.00 62.59 B N -12.449 1.00 61.71 B c -12.764 1.00 62.06 B 0 -11.369 1.00 63.68 B N -10.474 1.00 66.24 B c -10.484 1.00 67.02 B c -11.802 1.00 70.34 B c -11.685 1.00 72.40 B c -12.671 1.00 73.78 B 0 -10.600 1.00 73.79 B 0 -9.042 1.00 68.03 B c -8.675 1.00 66.96 B 0 -8.241 1.00 70.17 B N -6.798 1.00 72.95 B c -6.426 1.00 73.69 B c -4.975 1.00 74.96 B c -3.885 1.00 75.11 B c -4.512 1.00 76.02 B N -3.199 1.00 75.34 B c -2.793 1.00 75.59 B N -6.142 1.00 75.10 B C -6.557 1.00 74.72 B 0 -5.124 1.00 78.12 B N -4.404 1.00 81.74 B C -2.926 1.00 84.51 B c -2.376 1.00 84.08 B 0 -2.281 1.00 87.55 B N -0.836 1.00 90.95 B c -0.445 1.00 90.68 B c 1.070 1.00 90.91 B c -0.970 1.00 90.52 B c -0.596 1.00 91.21 B c -0.240 1.00 93.64 B c -0.734 1.00 93.43 B 0 0.829 1.00 96.49 B N 1.420 1.00 97.34 B c 1.490 1.00 98.31 B c 2.592 1.00 98.23 B c 2.137 1.00 97.91 B c 2.056 1.00100.07 B c 1.757 1.00100.25 B 0 2.875 1.00101.81 B N 3.440 1.00103.72 B c 4.920 1.00103.96 B c 2.690 1.00104.59 B c 3.006 1.00104.51 B 0 1.681 1.00105.43 B N 1.232 1.00105.79 B c 0.929 1.00105.78 B c -0.181 1.00106.12 B c 0.363 1.00106.24 B c 1.821 1.00105.78 B c 2.131 1.00105.85 B 0 2.228 1.00105.22 B N 3.158 1.00104.16 B c 3.610 1.00106.08 B c 4.651 1.00109.04 B c 231 WO 2009/026558 PCT/US2008/074097 ATOM 4027 CD GLN 619 -62.910 -15 ATOM 4028 OE1 GLN 619 -62.885 -15 ATOM 4029 NE2 GLN 619 -62.010 -16 ATOM 4030 C GLN 619 -65.675 -13 ATOM 4031 0 GLN 619 -65.431 -12 ATOM 4032 N GLY 620 -65.619 -13 ATOM 4033 CA GLY 62 0 -65.264 -12 ATOM 4034 C GLY 62 0 -64.971 -12 ATOM 4035 0 GLY 62 0 -65.153 -11 ATOM 4036 N GLN 621 -64.518 -13 ATOM 4037 CA GLN 621 -64.285 -14 ATOM 4038 CB GLN 621 -62.963 -13 ATOM 4039 CG GLN 621 -61.738 -14 ATOM 4040 CD GLN 621 -60.449 -13 ATOM 4041 OE1 GLN 621 -60.360 -12 ATOM 4042 NE2 GLN 621 -59.441 -14 ATOM 4043 C GLN 621 -64.261 -15 ATOM 4044 0 GLN 621 -63.759 -16 ATOM 4045 N VAL 622 -64.810 -16 ATOM 4046 CA VAL 622 -64.715 -17 ATOM 4047 CB VAL 622 -66.096 -18 ATOM 4048 CGI VAL 622 -65.987 -19 ATOM 4049 CG2 VAL 622 -67.099 -17 ATOM 4050 C VAL 622 -63.773 -17 ATOM 4051 O VAL 622 -63.844 -16 ATOM 4052 N THR 623 -62.889 -18 ATOM 4053 CA THR 623 -61.955 -18 ATOM 4054 CB THR 623 -60.535 -18 ATOM 4055 OG1 THR 623 -60.016 -19 ATOM 4056 CG2 THR 623 -60.539 -16 ATOM 4057 C THR 623 -61.868 -20 ATOM 4058 O THR 62 3 -62.154 -21 ATOM 4059 N VAL 62 4 -61.463 -20 ATOM 4060 CA VAL 624 -61.115 -21 ATOM 4061 CB VAL 624 -62.357 -22 ATOM 4062 CGI VAL 624 -62.927 -21 ATOM 4063 CG2 VAL 624 -61.979 -23 ATOM 4064 C VAL 62 4 -60.026 -21 ATOM 4065 O VAL 62 4 -60.034 -20 ATOM 4066 N ALA 625 -59.085 -22 ATOM 4067 CA ALA 625 -57.945 -22 ATOM 4068 CB ALA 62 5 -56.656 -22 ATOM 4069 C ALA 625 -57.869 -23 ATOM 4070 0 ALA 62 5 -58.319 -24 ATOM 4071 N CYS 62 6 -57.294 -23 ATOM 4072 CA CYS 62 6 -57.054 -24 ATOM 4073 C CYS 62 6 -55.829 -25 ATOM 4074 0 CYS 62 6 -54.831 -24 ATOM 4075 CB CYS 62 6 -56.840 -2 3 ATOM 4076 SG CYS 62 6 -58.258 -22 ATOM 4077 N GLU 627 -55.911 -26 ATOM 4078 CA GLU 627 -54.810 -27 ATOM 4079 CB GLU 627 -55.229 -28 ATOM 4080 CG GLU 627 -56.560 -2 9 ATOM 4081 CD GLU 627 -57.452 -30 ATOM 4082 OE1 GLU 627 -57.100 -31 ATOM 4083 OE2 GLU 627 -58.503 -29 ATOM 4084 C GLU 627 -53.576 -27 ATOM 4085 0 GLU 627 -53.669 -26 ATOM 4086 N GLU 62 8 -52.420 -27 ATOM 4087 CA GLU 628 -51.178 -27 ATOM 4088 CB GLU 628 -50.071 -28 ATOM 4089 CG GLU 62 8 -48.693 -28 ATOM 4090 CD GLU 62 8 -48.155 -26 ATOM 4091 OE1 GLU 62 8 -47.423 -26 ATOM 4092 OE2 GLU 62 8 -48.466 -25 ATOM 4093 C GLU 628 -51.377 -27 ATOM 4094 0 GLU 628 -51.897 -29 ATOM 4095 N GLY 62 9 -50.963 -27 ATOM 4096 CA GLY 62 9 -51.086 -27 ATOM 4097 C GLY 62 9 -52.260 -26 ATOM 4098 0 GLY 629 -52.297 -26 ATOM 4099 N TRP 630 -53.220 -26 ATOM 4100 CA TRP 630 -54.389 -25 ATOM 4101 CB TRP 630 -55.667 -26 ATOM 4102 CG TRP 630 -55.912 -27 5.243 1.00110.77 B C 6.451 1.00111.68 B O 4.394 1.00111.21 B N 2.532 1.00101.86 B C 3.237 1.00102.25 B O 1.204 1.00 98.47 B N 0.497 1.00 93.13 B C -0.964 1.00 89.75 B C -1.832 1.00 89.35 B 0 -1.236 1.00 85.41 B N -2.604 1.00 81.21 B c -3.122 1.00 80.76 B c -2.412 1.00 79.63 B c -3.080 1.00 80.09 B c -3.631 1.00 79.55 B 0 -3.036 1.00 79.53 B N -2.717 1.00 78.31 B c -1.833 1.00 77.75 B 0 -3.813 1.00 74.56 B N -4.135 1.00 70.71 B c -4.517 1.00 70.57 B c -4.772 1.00 70.29 B c -3.413 1.00 70.77 B c -5.323 1.00 68.02 B c -6.273 1.00 67.71 B 0 -5.272 1.00 65.11 B N -6.371 1.00 62.26 B c -6.005 1.00 62.27 B c -4.979 1.00 62.80 B 0 -5.515 1.00 61.70 B c -6.808 1.00 61.06 B c -6.037 1.00 60.46 B 0 -8.059 1.00 58.95 B N -8.570 1.00 56.86 B c -9.183 1.00 56.41 B c -10.326 1.00 56.31 B c -9.672 1.00 55.46 B c -9.634 1.00 55.91 B c -10.399 1.00 54.97 B 0 -9.674 1.00 55.07 B N -10.573 1.00 56.43 B c -9.766 1.00 55.50 B c -11.548 1.00 57.84 B c -11.241 1.00 58.31 B 0 -12.722 1.00 57.81 B N -13.692 1.00 59.13 B c -13.308 1.00 61.75 B c -12.845 1.00 62.27 B 0 -15.088 1.00 56.64 B c -15.751 1.00 57.44 B s -13.525 1.00 64.64 B N -13.241 1.00 67.51 B c -13.553 1.00 70.84 B c -12.944 1.00 7 6.92 B c -13.929 1.00 81.54 B c -14.322 1.00 83.33 B 0 -14.311 1.00 83.28 B 0 -14.061 1.00 67.30 B c -15.097 1.00 67.09 B 0 -13.587 1.00 67.21 B N -14.333 1.00 67.2 6 B c -13.638 1.00 71.29 B c -14.259 1.00 76.58 B c -14.105 1.00 80.28 B c -13.121 1.00 82.51 B 0 -14.965 1.00 81.67 B 0 -15.751 1.00 65.26 B c -15.943 1.00 65.44 B 0 -16.738 1.00 62.46 B N -18.123 1.00 58.55 B c -18.853 1.00 56.59 B c -20.085 1.00 56.28 B 0 -18.094 1.00 54.07 B N -18.670 1.00 52.31 B c -18.020 1.00 53.37 B c -18.298 1.00 56.24 B c 232 WO 2009/026558 PCT/US2008/074097 ATOM 4103 CD2 TRP 630 -56.828 -28 ATOM 4104 CE2 TRP 630 -56.728 -29 ATOM 4105 CE3 TRP 630 -57.724 -27 ATOM 4106 CDl TRP 630 -55.310 -28 ATOM 4107 NEl TRP 630 -55.794 -30 ATOM 4108 CZ2 TRP 630 -57.489 -30 ATOM 4109 CZ3 TRP 630 -58.482 -28 ATOM 4110 CH2 TRP 630 -58.357 -30 ATOM 4111 C TRP 630 -54.325 -24 ATOM 4112 O TRP 630 -53.696 -23 ATOM 4113 N THR 631 -54.987 -23 ATOM 4114 CA THR 631 -55.000 -22 ATOM 4115 CB THR 631 -54.472 -21 ATOM 4116 OGl THR 631 -53.126 -21 ATOM 4117 CG2 THR 631 -54.510 -19 ATOM 4118 C THR 631 -56.415 -21 ATOM 4119 O THR 631 -57.349 -21 ATOM 4120 N LEU 632 -56.573 -20 ATOM 4121 CA LEU 632 -57.866 -20 ATOM 4122 CB LEU 632 -57.799 -19 ATOM 4123 CG LEU 632 -59.077 -18 ATOM 4124 CDl LEU 632 -60.205 -19 ATOM 4125 CD2 LEU 632 -58.816 -17 ATOM 4126 C LEU 632 -58.232 -19 ATOM 4127 O LEU 632 -57.476 -18 ATOM 4128 N THR 633 -59.377 -19 ATOM 4129 CA THR 633 -59.849 -18 ATOM 4130 CB THR 633 -60.166 -19 ATOM 4131 OGl THR 633 -61.267 -20 ATOM 4132 CG2 THR 633 -58.958 -20 ATOM 4133 C THR 633 -61.113 -17 ATOM 4134 O THR 633 -61.408 -16 ATOM 4135 N GLY 634 -61.868 -18 ATOM 4136 CA GLY 634 -63.129 -17 ATOM 4137 C GLY 634 -63.344 -17 ATOM 4138 0 GLY 634 -62.980 -18 ATOM 4139 N CYS 635 -63.927 -16 ATOM 4140 CA CYS 635 -64.151 -16 ATOM 4141 C CYS 635 -65.479 -16 ATOM 4142 0 CYS 635 -65.802 -15 ATOM 4143 CB CYS 635 -63.019 -15 ATOM 4144 SG CYS 635 -63.191 -15 ATOM 4145 N SER 636 -66.245 -16 ATOM 4146 CA SER 636 -67.661 -16 ATOM 4147 CB SER 636 -68.390 -17 ATOM 4148 OG SER 636 -69.709 -16 ATOM 4149 C SER 636 -68.215 -16 ATOM 4150 O SER 636 -67.656 -17 ATOM 4151 N ALA 637 -69.310 -16 ATOM 4152 CA ALA 637 -70.052 -16 ATOM 4153 CB ALA 637 -70.318 -15 ATOM 4154 C ALA 637 -71.373 -17 ATOM 4155 0 ALA 637 -71.992 -16 ATOM 4156 N LEU 638 -71.803 -18 ATOM 4157 CA LEU 638 -73.124 -18 ATOM 4158 CB LEU 638 -73.332 -20 ATOM 4159 CG LEU 638 -72.627 -21 ATOM 4160 CDl LEU 638 -73.027 -22 ATOM 4161 CD2 LEU 638 -73.002 -21 ATOM 4162 C LEU 638 -74.195 -17 ATOM 4163 O LEU 638 -74.146 -17 ATOM 4164 N PRO 639 -75.180 -17 ATOM 4165 CD PRO 639 -75.359 -18 ATOM 4166 CA PRO 639 -76.228 -16 ATOM 4167 CB PRO 639 -76.986 -16 ATOM 4168 CG PRO 639 -76.738 -18 ATOM 4169 C PRO 639 -77.139 -16 ATOM 4170 O PRO 639 -77.156 -18 ATOM 4171 N GLY 640 -77.887 -15 ATOM 4172 CA GLY 640 -78.889 -16 ATOM 4173 C GLY 640 -78.395 -15 ATOM 4174 0 GLY 640 -78.954 -16 ATOM 4175 N THR 641 -77.345 -15 ATOM 4176 CA THR 641 -76.803 -14 ATOM 4177 CB THR 641 -75.305 -15 ATOM 4178 OGl THR 641 -75.106 -16 -19.253 1.00 56.84 B C -19.168 1.00 57.44 B C -20.170 1.00 56.63 B c -17.691 1.00 56.81 B c -18.206 1.00 57.15 B N -19.964 1.00 56.00 B c -20.962 1.00 58.10 B c -20.852 1.00 56.56 B c -18.487 1.00 50.00 B c -17.555 1.00 49.79 B 0 -19.378 1.00 46.86 B N -19.313 1.00 42.14 B c -20.628 1.00 41.03 B c -20.850 1.00 38.22 B 0 -20.568 1.00 39.04 B c -19.069 1.00 41.59 B c -19.777 1.00 41.97 B 0 -18.068 1.00 40.02 B N -17.804 1.00 39.61 B c -16.509 1.00 38.76 B c -16.057 1.00 42.02 B c -15.901 1.00 41.47 B c -14.731 1.00 41.91 B c -18.973 1.00 40.31 B c -19.311 1.00 39.62 B 0 -19.601 1.00 40.05 B N -20.676 1.00 40.37 B c -21.974 1.00 40.11 B c -21.740 1.00 42.19 B 0 -22.430 1.00 39.36 B c -20.267 1.00 40.80 B c -20.797 1.00 42.82 B 0 -19.335 1.00 41.84 B N -18.949 1.00 43.05 B c -17.454 1.00 44.20 B c -16.813 1.00 44.52 B 0 -16.892 1.00 46.22 B N -15.452 1.00 49.45 B c -15.176 1.00 50.61 B c -15.774 1.00 51.08 B 0 -14.770 1.00 49.68 B c -12.960 1.00 54.65 B s -14.261 1.00 52.89 B N -14 .186 1.00 56.15 B c -15.317 1.00 56.84 B c -15.483 1.00 59.24 B 0 -12.839 1.00 57.63 B c -12.187 1.00 57.25 B 0 -12.422 1.00 60.91 B N -11.253 1.00 64.91 B c -10.305 1.00 62.85 B c -11.704 1.00 68.14 B c -12.664 1.00 66.65 B 0 -11.016 1.00 72.27 B N -11.268 1.00 76.39 B c -10.447 1.00 76.34 B c -10.965 1.00 77.63 B c -10.120 1.00 77.21 B c -12.420 1.00 76.50 B c -10.907 1.00 79.19 B c -9.840 1.00 79.59 B 0 -11.797 1.00 81.71 B N -13.047 1.00 81.80 B c -11.609 1.00 84.07 B c -12.936 1.00 83.38 B c -13.494 1.00 82.31 B c -10.421 1.00 86.54 B c -9.904 1.00 86.12 B 0 -9.989 1.00 89.30 B N -8.958 1.00 92.85 B c -7.549 1.00 95.28 B c -6.583 1.00 95.56 B 0 -7.426 1.00 97.49 B N -6.115 1.00 99.35 B c -6.020 1.00100.06 B c -6.444 1.00100.46 B 0 233 WO 2009/026558 PCT/US2008/074097 ATOM 4179 CG2 THR 641 -74.817 -14 ATOM 4180 C THR 641 -76.969 -13 ATOM 4181 O THR 641 -77.280 -12 ATOM 4182 N SER 642 -76.758 -12 ATOM 4183 CA SER 642 -76.919 -10 ATOM 4184 CB SER 642 -78.311 -10 ATOM 4185 OG SER 642 -79.322 -10 ATOM 4186 C SER 642 -75.846 -10 ATOM 4187 O SER 642 -75.262 -9 ATOM 4188 N HIS 643 -75.587 -10 ATOM 4189 CA HIS 643 -74.555 -10 ATOM 4190 CB HIS 643 -74.722 -10 ATOM 4191 CG HIS 643 -75.936 -10 ATOM 4192 CD2 HIS 643 -76.772 -10 ATOM 4193 NDl HIS 643 -76.411 -9 ATOM 4194 CEl HIS 643 -77.485 -8 ATOM 4195 NE2 HIS 643 -77.726 -10 ATOM 4196 C HIS 643 -73.158 -10 ATOM 4197 0 HIS 643 -72.247 -10 ATOM 4198 N VAL 644 -73.012 -10 ATOM 4199 CA VAL 644 -71.728 -10 ATOM 4200 CB VAL 644 -71.815 -11 ATOM 4201 CGI VAL 644 -70.522 -11 ATOM 4202 CG2 VAL 644 -72.090 -13 ATOM 4203 C VAL 644 -71.298 -9 ATOM 4204 O VAL 644 -72.070 -8 ATOM 4205 N LEU 645 -70.061 -8 ATOM 4206 CA LEU 645 -69.520 -7 ATOM 4207 CB LEU 645 -68.409 -7 ATOM 4208 CG LEU 645 -68.789 -7 ATOM 4209 CDl LEU 645 -67.603 -6 ATOM 4210 CD2 LEU 645 -69.979 -6 ATOM 4211 C LEU 645 -68.971 -7 ATOM 4212 O LEU 645 -68.985 -6 ATOM 4213 N GLY 646 -68.493 -9 ATOM 4214 CA GLY 646 -67.971 -9 ATOM 4215 C GLY 646 -66.980 -10 ATOM 4216 0 GLY 646 -66.789 -11 ATOM 4217 N ALA 647 -66.342 -10 ATOM 4218 CA ALA 647 -65.407 -11 ATOM 4219 CB ALA 647 -66.143 -13 ATOM 4220 C ALA 64 7 -64.276 -11 ATOM 4221 0 ALA 647 -64.484 -10 ATOM 4222 N TYR 648 -63.081 -11 ATOM 4223 CA TYR 648 -61.950 -11 ATOM 4224 CB TYR 648 -61.315 -10 ATOM 4225 CG TYR 648 -61.108 -9 ATOM 4226 CDl TYR 648 -59.993 -10 ATOM 4227 CEl TYR 648 -59.825 -10 ATOM 4228 CD2 TYR 648 -62.051 -9 ATOM 4229 CE2 TYR 648 -61.891 -8 ATOM 4230 CZ TYR 648 -60.778 -9 ATOM 4231 OH TYR 648 -60.630 -9 ATOM 4232 C TYR 648 -60.905 -12 ATOM 4233 O TYR 648 -60.817 -13 ATOM 4234 N ALA 649 -60.112 -13 ATOM 4235 CA ALA 649 -59.012 -13 ATOM 4236 CB ALA 649 -58.743 -14 ATOM 4237 C ALA 649 -57.755 -13 ATOM 4238 0 ALA 649 -57.403 -12 ATOM 4239 N VAL 650 -57.089 -13 ATOM 4240 CA VAL 650 -55.743 -13 ATOM 4241 CB VAL 650 -55.659 -13 ATOM 4242 CGI VAL 650 -54.239 -12 ATOM 4243 CG2 VAL 650 -56.675 -12 ATOM 4244 C VAL 650 -54.814 -14 ATOM 4245 O VAL 650 -54.775 -15 ATOM 4246 N ASP 651 -54.068 -14 ATOM 4247 CA ASP 651 -53.278 -15 ATOM 4248 CB ASP 651 -52.219 -16 ATOM 4249 CG ASP 651 -51.177 -17 ATOM 4250 OD1 ASP 651 -51.113 -17 ATOM 4251 OD2 ASP 651 -50.420 -17 ATOM 4252 C ASP 651 -54.206 -16 ATOM 4253 O ASP 651 -55.093 -16 ATOM 4254 N ASN 652 -54.010 -17
-4.584 1.00100.75 B C -5.859 1.00 99.93 B C -4.741 1.00100.09 B 0 -6.907 1.00100.54 B N -6.847 1.00100.83 B c -6.311 1.00101.56 B c -7.233 1.00102.34 B 0 -6.000 1.00100.09 B c -6.421 1.00100.47 B 0 -4.813 1.00 98.31 B N -3.931 1.00 95.91 B c -2.519 1.00 98.80 B c -1.808 1.00102.15 B c -0.923 1.00103.19 B c -1.982 1.00103.40 B N -1.233 1.00103.99 B c -0.581 1.00104.35 B N -4.463 1.00 92.18 B C -3.707 1.00 92.08 B 0 -5.779 1.00 86.97 B N -6.450 1.00 81.49 B C -7.583 1.00 81.51 B c -8.383 1.00 80.44 B c -6.993 1.00 81.28 B c -7.042 1.00 77.33 B c -7.739 1.00 75.98 B 0 -6.756 1.00 72.69 B N -7.242 1.00 68.29 B c -6.307 1.00 68.02 B c -4.827 1.00 67.91 B c -4.015 1.00 67.93 B c -4.668 1.00 67.53 B c -8.657 1.00 65.15 B c -9.457 1.00 64.28 B 0 -8.957 1.00 61.10 B N -10.280 1.00 56.54 B c -10.276 1.00 53.72 B c -9.259 1.00 53.37 B 0 -11.417 1.00 50.95 B N -11.555 1.00 47.43 B c -12.073 1.00 46.90 B c -12.510 1.00 45.07 B c -13.471 1.00 45.31 B 0 -12.243 1.00 41.18 B N -13.132 1.00 40.43 B c -12.880 1.00 38.89 B c -11.418 1.00 37.05 B c -10.733 1.00 37.52 B c -9.381 1.00 37.90 B c -10.714 1.00 37.16 B c -9.370 1.00 38.07 B c -8.708 1.00 37.64 B c -7.362 1.00 40.14 B 0 -12.953 1.00 40.67 B c -11.896 1.00 40.70 B 0 -13.995 1.00 40.21 B N -13.936 1.00 40.94 B c -15.329 1.00 40.44 B c -13.395 1.00 41.98 B c -13.813 1.00 42.47 B 0 -12.460 1.00 41.96 B N -12.056 1.00 41.03 B c -10.528 1.00 41.39 B c -10.141 1.00 36.26 B c -10.115 1.00 38.03 B c -12.429 1.00 42.88 B c -11.746 1.00 43.57 B 0 -13.514 1.00 45.00 B N -14.084 1.00 47.26 B c -13.086 1.00 50.04 B c -13.721 1.00 55.64 B c -14.973 1.00 57.69 B 0 -12.965 1.00 57.35 B 0 -14.451 1.00 47.02 B c -15.288 1.00 45.87 B 0 -13.821 1.00 46.56 B N 234 WO 2009/026558 PCT/US2008/074097 ATOM 4255 CA ASN 652 -54.874 -19 ATOM 4256 CB ASN 652 -54.041 -2 0 ATOM 4257 CG ASN 652 -53.552 -20 ATOM 4258 OD1 ASN 652 -54.179 -20 ATOM 4259 ND2 ASN 652 -52.426 -21 ATOM 4260 C ASN 652 -55.900 -19 ATOM 4261 O ASN 652 -56.470 -20 ATOM 4262 N THR 653 -56.140 -18 ATOM 4263 CA THR 653 -57.173 -18 ATOM 4264 CB THR 653 -56.648 -18 ATOM 4265 OG1 THR 653 -55.569 -19 ATOM 4266 CG2 THR 653 -57.760 -18 ATOM 4267 C THR 653 -58.366 -17 ATOM 4268 O THR 653 -58.213 -16 ATOM 4269 N CYS 654 -59.556 -18 ATOM 4270 CA CYS 654 -60.790 -17 ATOM 4271 C CYS 654 -61.240 -16 ATOM 4272 0 CYS 654 -61.341 -17 ATOM 4273 CB CYS 654 -61.857 -18 ATOM 4274 SG CYS 654 -63.519 -17 ATOM 4275 N VAL 655 -61.502 -15 ATOM 4276 CA VAL 655 -61.840 -14 ATOM 4277 CB VAL 655 -60.806 -13 ATOM 4278 CGI VAL 655 -61.252 -13 ATOM 4279 CG2 VAL 655 -59.449 -14 ATOM 4280 C VAL 655 -63.221 -14 ATOM 4281 O VAL 655 -63.492 -13 ATOM 4282 N VAL 656 -64.098 -14 ATOM 4283 CA VAL 656 -65.419 -14 ATOM 4284 CB VAL 656 -66.527 -15 ATOM 4285 CGI VAL 656 -67.889 -14 ATOM 4286 CG2 VAL 656 -66.485 -15 ATOM 4287 C VAL 656 -65.512 -13 ATOM 4288 O VAL 656 -65.155 -13 ATOM 4289 N ARG 657 -65.984 -12 ATOM 4290 CA ARG 657 -66.028 -11 ATOM 4291 CB ARG 657 -65.441 -9 ATOM 4292 CG ARG 657 -63.976 -9 ATOM 4293 CD ARG 657 -63.099 -10 ATOM 4294 NE ARG 657 -63.292 -8 ATOM 4295 CZ ARG 657 -62.779 -7 ATOM 4296 NH1 ARG 657 -63.010 -6 ATOM 4297 NH2 ARG 657 -62.032 -7 ATOM 4298 C ARG 657 -67.446 -10 ATOM 4299 O ARG 657 -68.333 -10 ATOM 4300 N SER 658 -67.647 -11 ATOM 4301 CA SER 658 -68.945 -11 ATOM 4302 CB SER 658 -69.352 -12 ATOM 4303 OG SER 658 -68.362 -12 ATOM 4304 C SER 658 -68.876 -10 ATOM 4305 O SER 658 -67.807 -9 ATOM 4306 N ARG 659 -70.014 -9 ATOM 4307 CA ARG 659 -70.058 -8 ATOM 4308 CB ARG 659 -71.156 -7 ATOM 4309 CG ARG 659 -71.021 -6 ATOM 4310 CD ARG 659 -72.248 -5 ATOM 4311 NE ARG 659 -73.441 -5 ATOM 4312 CZ ARG 659 -74.593 -5 ATOM 4313 NH1 ARG 659 -74.716 -3 ATOM 4314 NH2 ARG 659 -75.624 -5 ATOM 4315 C ARG 659 -70.303 -8 ATOM 4316 O ARG 659 -69.628 -8 ATOM 4317 N ALA 671 -74.537 -18 ATOM 4318 CA ALA 671 -73.500 -19 ATOM 4319 CB ALA 671 -73.891 -20 ATOM 4320 C ALA 671 -73.234 -18 ATOM 4321 0 ALA 671 -74.154 -18 ATOM 4322 N VAL 672 -71.970 -18 ATOM 4323 CA VAL 672 -71.565 -18 ATOM 4324 CB VAL 672 -70.845 -17 ATOM 4325 CGI VAL 672 -70.430 -16 ATOM 4326 CG2 VAL 672 -71.759 -16 ATOM 4327 C VAL 672 -70.637 -19 ATOM 4328 O VAL 672 -69.829 -20 ATOM 4329 N THR 673 -70.760 -19 ATOM 4330 CA THR 673 -69.944 -2 0 -14.064 1.00 47.62 B C -14.269 1.00 46.87 B C -15.695 1.00 48.35 B c -16.633 1.00 47.24 B 0 -15.869 1.00 49.09 B N -12.969 1.00 47.56 B c -12.895 1.00 48.79 B 0 -12.118 1.00 46.14 B N -11.102 1.00 44.77 B c -9.704 1.00 44.11 B c -9.353 1.00 44.54 B 0 -8.670 1.00 42.08 B c -11.416 1.00 46.06 B c -11.769 1.00 46.42 B 0 -11.288 1.00 46.34 B N -11.481 1.00 47.21 B c -10.132 1.00 47.79 B c -9.161 1.00 48.70 B 0 -12.065 1.00 47.10 B c -12.264 1.00 49.57 B s -10.074 1.00 47.25 B N -8.821 1.00 46.56 B c -8.478 1.00 46.21 B c -7.252 1.00 45.65 B c -8.231 1.00 43.82 B c -8.914 1.00 48.25 B c -9.804 1.00 48.62 B 0 -7.995 1.00 50.22 B N -7.906 1.00 52.83 B c -7.912 1.00 52.93 B c -7.732 1.00 51.33 B c -9.227 1.00 50.98 B c -6.621 1.00 55.73 B c -5.544 1.00 55.45 B 0 -6.742 1.00 58.13 B N -5.602 1.00 62.52 B c -5.988 1.00 61.88 B c -6.376 1.00 61.18 B c -5.152 1.00 61.37 B c -4.232 1.00 61.93 B N -4.415 1.00 63.19 B c -3.527 1.00 63.51 B N -5.484 1.00 62.31 B N -5.082 1.00 65.59 B C -5.811 1.00 65.58 B 0 -3.813 1.00 70.15 B N -3.162 1.00 75.05 B C -2.488 1.00 75.03 B c -1.561 1.00 76.50 B 0 -2.118 1.00 77.90 B c -1.574 1.00 77.97 B 0 -1.837 1.00 81.25 B N -0.843 1.00 84.24 B c -1.185 1.00 86.82 B c -0.441 1.00 90.54 B c -0.625 1.00 93.57 B c -0.040 1.00 96.92 B N 0.150 1.00 98.47 B c -0.199 1.00 98.24 B N 0.691 1.00 99.04 B N 0.551 1.00 84.43 B C 1.510 1.00 85.18 B 0 -0.545 1.00 74.52 B N -1.186 1.00 75.31 B C -1.157 1.00 75.29 B c -2.628 1.00 75.10 B c -3.357 1.00 76.03 B 0 -3.035 1.00 73.34 B N -4.359 1.00 70.84 B c -4.262 1.00 71.44 B c -5.642 1.00 71.15 B c -3.605 1.00 70.69 B c -5.044 1.00 68.72 B c -4.385 1.00 68.45 B 0 -6.364 1.00 65.32 B N -7.114 1.00 62.53 B c 235 WO 2009/026558 PCT/US2008/074097 ATOM 4331 CB THR 673 -70.817 -21 ATOM 4332 OG1 THR 673 -71.524 -22 ATOM 4333 CG2 THR 673 -69.952 -22 ATOM 4334 C THR 673 -69.132 -19 ATOM 4335 O THR 673 -69.671 -19 ATOM 4336 N ALA 67 4 -67.830 -20 ATOM 4337 CA ALA 674 -66.935 -19 ATOM 4338 CB ALA 674 -65.567 -19 ATOM 4339 C ALA 67 4 -66.790 -20 ATOM 4340 0 ALA 67 4 -66.506 -21 ATOM 4341 N VAL 675 -66.974 -20 ATOM 4342 CA VAL 675 -66.941 -21 ATOM 4343 CB VAL 675 -68.256 -2 0 ATOM 4344 CGI VAL 675 -68.282 -22 ATOM 4345 CG2 VAL 675 -69.448 -21 ATOM 4346 C VAL 675 -65.778 -20 ATOM 4347 O VAL 675 -65.758 -19 ATOM 4348 N ALA 67 6 -64.817 -21 ATOM 4349 CA ALA 67 6 -63.688 -21 ATOM 4350 CB ALA 67 6 -62.389 -21 ATOM 4351 C ALA 67 6 -63.840 -22 ATOM 4352 0 ALA 67 6 -64.236 -23 ATOM 4353 N ILE 677 -63.518 -21 ATOM 4354 CA ILE 677 -63.322 -22 ATOM 4355 CB ILE 677 -64.044 -21 ATOM 4356 CG2 ILE 677 -63.786 -22 ATOM 4357 CGI ILE 677 -65.548 -21 ATOM 4358 CDl ILE 677 -66.349 -21 ATOM 4359 C ILE 677 -61.824 -22 ATOM 4360 0 ILE 677 -61.159 -21 ATOM 4361 N CYS 678 -61.303 -23 ATOM 4362 CA CYS 678 -59.877 -24 ATOM 4363 C CYS 678 -59.656 -24 ATOM 4364 0 CYS 678 -60.392 -25 ATOM 4365 CB CYS 678 -59.346 -24 ATOM 4366 SG CYS 678 -59.691 -24 ATOM 4367 N CYS 679 -58.641 -24 ATOM 4368 CA CYS 679 -58.335 -24 ATOM 4369 C CYS 679 -56.863 -25 ATOM 4370 0 CYS 679 -56.021 -24 ATOM 4371 CB CYS 679 -58.737 -23 ATOM 4372 SG CYS 679 -60.399 -23 ATOM 4373 N ARG 680 -56.574 -25 ATOM 4374 CA ARG 680 -55.214 -26 ATOM 4375 CB ARG 680 -54.573 -27 ATOM 4376 CG ARG 680 -55.435 -28 ATOM 4377 CD ARG 680 -54.577 -29 ATOM 4378 NE ARG 680 -55.302 -30 ATOM 4379 CZ ARG 680 -54.806 -32 ATOM 4380 NHl ARG 680 -55.532 -33 ATOM 4381 NH2 ARG 680 -53.583 -32 ATOM 4382 C ARG 680 -55.261 -2 6 ATOM 4383 O ARG 680 -56.339 -26 ATOM 4384 N SER 681 -54.093 -26 ATOM 4385 CA SER 681 -54.003 -27 ATOM 4386 CB SER 681 -53.377 -2 6 ATOM 4387 OG SER 681 -54.177 -25 ATOM 4388 C SER 681 -53.148 -28 ATOM 4389 O SER 681 -51.946 -28 ATOM 4390 N ARG 682 -53.764 -29 ATOM 4391 CA ARG 682 -53.031 -30 ATOM 4392 CB ARG 682 -54.005 -32 ATOM 4393 CG ARG 682 -54.534 -32 ATOM 4394 CD ARG 682 -55.114 -33 ATOM 4395 NE ARG 682 -54.231 -34 ATOM 4396 CZ ARG 682 -54.568 -36 ATOM 4397 NHl ARG 682 -53.691 -36 ATOM 4398 NH2 ARG 682 -55.777 -36 ATOM 4399 C ARG 682 -52.165 -31 ATOM 4400 O ARG 682 -52.319 -30 ATOM 4401 OXT ARG 682 -51.337 -31 TER 4402 ARG 682 ATOM 4403 CB GLU 1 -36.231 38 ATOM 4404 CG GLU 1 -35.182 39 ATOM 4405 CD GLU 1 -33.792 39 ATOM 4406 OE1 GLU 1 -33.555 38 -7.725 1.00 63.63 B C -6.679 1.00 64.64 B O -8.473 1.00 62.74 B c -8.231 1.00 59.50 B c -9.077 1.00 58.78 B 0 -8.221 1.00 56.52 B N -9.264 1.00 54.91 B c -8.666 1.00 53.50 B c -10.379 1.00 53.38 B c -10.121 1.00 52.02 B 0 -11.616 1.00 50.64 B N -12.776 1.00 49.05 B c -13.583 1.00 48.94 B c -14.685 1.00 46.82 B c -12.653 1.00 47.81 B c -13.701 1.00 47.76 B c -14.291 1.00 47.79 B 0 -13.828 1.00 46.75 B N -14.736 1.00 45.42 B c -14.037 1.00 43.18 B c -15.996 1.00 46.23 B c -15.932 1.00 47.47 B 0 -17.142 1.00 45.06 B N -18.358 1.00 42.84 B c -19.559 1.00 41.75 B c -20.834 1.00 38.64 B c -19.287 1.00 41.12 B c -20.430 1.00 42.32 B c -18.622 1.00 42.86 B c -18.733 1.00 43.27 B 0 -18.701 1.00 44.51 B N -18.896 1.00 46.16 B c -20.248 1.00 46.08 B c -20.615 1.00 46.07 B 0 -17.800 1.00 48.42 B c -16.096 1.00 55.45 B s -20.981 1.00 46.30 B N -22.273 1.00 48.35 B c -22.441 1.00 50.02 B c -21.646 1.00 49.93 B 0 -23.415 1.00 47.56 B c -23.340 1.00 48.97 B s -23.501 1.00 52.89 B N -23.944 1.00 57.75 B c -23.100 1.00 58.25 B c -22.933 1.00 61.86 B c -22.813 1.00 64.43 B c -22.205 1.00 68.80 B N -22.065 1.00 70.93 B c -21.497 1.00 71.39 B N -22.501 1.00 73.17 B N -25.404 1.00 60.89 B C -25.970 1.00 59.44 B 0 -26.017 1.00 66.22 B N -27.367 1.00 72.84 B C -28.317 1.00 73.28 B c -28.429 1.00 75.41 B 0 -27.357 1.00 76.77 B c -27.096 1.00 77.43 B 0 -27.644 1.00 81.26 B N -27.694 1.00 85.36 B c -27.634 1.00 88.32 B c -26.237 1.00 92.63 B c -26.167 1.00 96.94 B c -26.789 1.00100.46 B N -27.043 1.00102.13 B c -27.616 1.00102.64 B N -26.724 1.00102.84 B N -28.953 1.00 86.02 B C -29.860 1.00 85.88 B 0 -29.016 1.00 86.99 B 0 B 6.129 1.00 73.54 L c 5.116 1.00 77.83 L c 5.713 1.00 80.96 L c 6.736 1.00 81.61 L 0 236 WO 2009/026558 PCT/US2008/074097 ATOM 4407 OE2 GLU 1 -32.939 39 ATOM 4408 C GLU 1 -37.606 37 ATOM 4409 0 GLU 1 -36.842 36 ATOM 4410 N GLU 1 -38.659 38 ATOM 4411 CA GLU 1 -37.610 38 ATOM 4412 N SER 2 -38.458 36 ATOM 4413 CA SER 2 -38.645 34 ATOM 4414 CB SER 2 -39.040 33 ATOM 4415 OG SER 2 -40.188 34 ATOM 4416 C SER 2 -39.713 35 ATOM 4417 O SER 2 -40.693 35 ATOM 4418 N VAL 3 -39.514 34 ATOM 4419 CA VAL 3 -40.437 34 ATOM 4420 CB VAL 3 -39.850 33 ATOM 4421 CGI VAL 3 -40.818 33 ATOM 4422 CG2 VAL 3 -38.519 34 ATOM 4423 C VAL 3 -41.798 33 ATOM 4424 O VAL 3 -42.831 34 ATOM 4425 N LEU 4 -41.796 32 ATOM 4426 CA LEU 4 -43.039 32 ATOM 4427 CB LEU 4 -42.943 30 ATOM 4428 CG LEU 4 -42.440 30 ATOM 4429 CDl LEU 4 -42.428 28 ATOM 4430 CD2 LEU 4 -43.339 30 ATOM 4431 C LEU 4 -43.312 32 ATOM 4432 O LEU 4 -42.414 32 ATOM 4433 N THR 5 -44.554 33 ATOM 4434 CA THR 5 -44.870 33 ATOM 4435 CB THR 5 -45.693 34 ATOM 4436 OG1 THR 5 -44.944 35 ATOM 4437 CG2 THR 5 -45.998 35 ATOM 4438 C THR 5 -45.637 32 ATOM 4439 O THR 5 -46.701 32 ATOM 4440 N GLN 6 -45.088 32 ATOM 4441 CA GLN 6 -45.755 31 ATOM 4442 CB GLN 6 -44.886 30 ATOM 4443 CG GLN 6 -44.498 29 ATOM 4444 CD GLN 6 -43.610 28 ATOM 4445 OE1 GLN 6 -42.530 28 ATOM 4446 NE2 GLN 6 -44.061 27 ATOM 4447 C GLN 6 -45.959 32 ATOM 4448 0 GLN 6 -45.203 33 ATOM 4449 N PRO 7 -46.963 32 ATOM 4450 CD PRO 7 -48.008 31 ATOM 4451 CA PRO 7 -47.036 32 ATOM 4452 CB PRO 7 -48.356 32 ATOM 4453 CG PRO 7 -48.581 31 ATOM 4454 C PRO 7 -45.835 32 ATOM 4455 O PRO 7 -45.385 31 ATOM 4456 N PRO 8 -45.295 33 ATOM 4457 CD PRO 8 -45.722 34 ATOM 4458 CA PRO 8 -44.112 33 ATOM 4459 CB PRO 8 -43.814 34 ATOM 4460 CG PRO 8 -44.501 35 ATOM 4461 C PRO 8 -44.371 32 ATOM 4 4 62 O PRO 8 -43.480 31 ATOM 4463 N SER 9 -45.591 32 ATOM 4464 CA SER 9 -45.886 31 ATOM 4465 CB SER 9 -45.491 31 ATOM 4466 OG SER 9 -46.262 32 ATOM 4467 C SER 9 -47.349 30 ATOM 4468 O SER 9 -48.225 31 ATOM 4469 N VAL 10 -47.598 29 ATOM 4470 CA VAL 10 -48.952 29 ATOM 4471 CB VAL 10 -49.503 28 ATOM 4472 CGI VAL 10 -49.559 28 ATOM 4473 CG2 VAL 10 -48.621 26 ATOM 4474 C VAL 10 -48.888 28 ATOM 4475 O VAL 10 -47.809 27 ATOM 4476 N SER 11 -50.035 28 ATOM 4477 CA SER 11 -50.049 27 ATOM 4478 CB SER 11 -49.688 28 ATOM 4479 OG SER 11 -50.592 29 ATOM 4480 C SER 11 -51.397 26 ATOM 4481 O SER 11 -52.418 27 ATOM 4482 N GLY 12 -51.381 25
5.159 1.00 81.99 L O 4.782 1.00 68.14 L C 3.836 1.00 68.19 L 0 6.573 1.00 71.43 L N 5.515 1.00 70.62 L c 5.230 1.00 64.55 L N 4.540 1.00 60.66 L C 5.545 1.00 60.92 L c 6.293 1.00 59.32 L 0 3.450 1.00 57.06 L c 3.607 1.00 55.88 L 0 2.346 1.00 52.88 L N 1.212 1.00 48.89 L c -0.013 1.00 49.36 L c -1.170 1.00 49.74 L c -0.420 1.00 48.94 L c 1.562 1.00 45.34 L c 1.057 1.00 46.42 L 0 2.419 1.00 40.20 L N 2.919 1.00 36.80 L c 2.932 1.00 35.15 L c 1.639 1.00 35.77 L c 1.799 1.00 33.82 L c 0.473 1.00 33.23 L c 4.330 1.00 34.95 L c 5.167 1.00 34.99 L 0 4.599 1.00 34.09 L N 5.880 1.00 33.56 L c 5.686 1.00 34.89 L c 4.883 1.00 36.65 L 0 7.037 1.00 33.40 L c 6.790 1.00 33.35 L c 6.421 1.00 33.73 L 0 7.979 1.00 32.27 L N 9.014 1.00 32.42 L c 9.440 1.00 31.42 L c 8.353 1.00 29.42 L c 8.891 1.00 29.99 L c 8.362 1.00 30.78 L 0 9.956 1.00 26.07 L N 10.241 1.00 33.06 L c 10.462 1.00 33.60 L 0 11.074 1.00 32.74 L N 10.922 1.00 32.27 L c 12.369 1.00 33.15 L c 12.963 1.00 32.34 L c 12.312 1.00 33.16 L c 13.241 1.00 33.91 L c 13.237 1.00 34.46 L 0 13.994 1.00 35.09 L N 14.069 1.00 34.70 L c 14.825 1.00 34.71 L c 15.494 1.00 36.39 L c 14.617 1.00 38.46 L c 15.858 1.00 33.60 L c 16.188 1.00 33.87 L 0 16.373 1.00 32.78 L N 17.409 1.00 34.68 L c 18.776 1.00 36.06 L c 19.072 1.00 40.67 L 0 17.439 1.00 32.15 L c 16.988 1.00 33.49 L 0 17.967 1.00 29.27 L N 18.237 1.00 28.93 L c 17.101 1.00 29.21 L c 15.784 1.00 32.11 L c 16.952 1.00 29.17 L c 19.513 1.00 28.40 L c 19.925 1.00 29.78 L 0 20.143 1.00 27.75 L N 21.377 1.00 30.00 L c 22.550 1.00 30.66 L c 22.626 1.00 33.85 L 0 21.621 1.00 27.91 L c 21.105 1.00 27.57 L 0 22.404 1.00 27.56 L N 237 WO 2009/026558 PCT/US2008/074097 ATOM 4483 CA GLY 12 -52.605 24 ATOM 4484 C GLY 12 -52.322 24 ATOM 4485 0 GLY 12 -51.165 23 ATOM 4486 N ALA 13 -53.375 23 ATOM 4487 CA ALA 13 -53.259 22 ATOM 4488 CB ALA 13 -54.372 22 ATOM 4489 C ALA 13 -53.345 21 ATOM 4490 0 ALA 13 -53.861 20 ATOM 4491 N PRO 14 -52.839 20 ATOM 4492 CD PRO 14 -52.181 20 ATOM 4493 CA PRO 14 -52.938 18 ATOM 4494 CB PRO 14 -52.425 17 ATOM 4495 CG PRO 14 -51.520 18 ATOM 4496 C PRO 14 -54.382 18 ATOM 4497 O PRO 14 -55.303 18 ATOM 4498 N GLY 15 -54.575 17 ATOM 4499 CA GLY 15 -55.907 17 ATOM 4500 C GLY 15 -56.561 18 ATOM 4501 0 GLY 15 -57.538 18 ATOM 4502 N GLN 16 -56.037 19 ATOM 4503 CA GLN 16 -56.621 20 ATOM 4504 CB GLN 16 -56.273 22 ATOM 4505 CG GLN 16 -56.942 22 ATOM 4506 CD GLN 16 -56.922 23 ATOM 4507 OE1 GLN 16 -55.867 24 ATOM 4508 NE2 GLN 16 -58.094 24 ATOM 4509 C GLN 16 -56.155 20 ATOM 4510 0 GLN 16 -55.245 19 ATOM 4511 N ARG 17 -56.798 21 ATOM 4512 CA ARG 17 -56.407 21 ATOM 4513 CB ARG 17 -57.628 20 ATOM 4514 CG ARG 17 -57.375 21 ATOM 4515 CD ARG 17 -58.629 20 ATOM 4516 NE ARG 17 -58.384 20 ATOM 4517 CZ ARG 17 -58.443 22 ATOM 4518 NHl ARG 17 -58.737 23 ATOM 4519 NH2 ARG 17 -58.214 22 ATOM 4520 C ARG 17 -55.853 22 ATOM 4521 O ARG 17 -56.492 23 ATOM 4522 N VAL 18 -54.664 22 ATOM 4523 CA VAL 18 -54.095 23 ATOM 4524 CB VAL 18 -52.847 24 ATOM 4525 CGI VAL 18 -53.234 24 ATOM 4526 CG2 VAL 18 -51.771 23 ATOM 4527 C VAL 18 -53.706 23 ATOM 4528 O VAL 18 -53.442 22 ATOM 4529 N THR 19 -53.680 25 ATOM 4530 CA THR 19 -53.253 25 ATOM 4531 CB THR 19 -54.419 25 ATOM 4532 OG1 THR 19 -54.922 26 ATOM 4533 CG2 THR 19 -55.549 24 ATOM 4534 C THR 19 -52.109 26 ATOM 4535 O THR 19 -51.977 27 ATOM 4536 N ILE 20 -51.282 25 ATOM 4537 CA ILE 20 -50.173 26 ATOM 4538 CB ILE 20 -48.827 26 ATOM 4539 CG2 ILE 20 -47.670 26 ATOM 4540 CGI ILE 20 -48.706 25 ATOM 4541 CDl ILE 20 -47.458 24 ATOM 4542 C ILE 20 -50.295 27 ATOM 4543 0 ILE 20 -50.325 26 ATOM 4544 N SER 21 -50.375 28 ATOM 4545 CA SER 21 -50.526 28 ATOM 4546 CB SER 21 -51.455 29 ATOM 4547 OG SER 21 -50.847 31 ATOM 4548 C SER 21 -49.187 29 ATOM 4549 O SER 21 -48.208 29 ATOM 4550 N CYS 22 -49.159 28 ATOM 4551 CA CYS 22 -47.970 29 ATOM 4552 C CYS 22 -48.488 29 ATOM 4553 0 CYS 22 -49.257 29 ATOM 4554 CB CYS 22 -47.295 27 ATOM 4555 SG CYS 22 -45.777 28 ATOM 4556 N THR 23 -48.099 31 ATOM 4557 CA THR 23 -48.563 31 ATOM 4558 CB THR 23 -49.375 33 22.836 1.00 25.58 L C 24.004 1.00 27.45 L C 24.271 1.00 26.91 L 0 24.706 1.00 26.20 L N 25.762 1.00 27.69 L c 26.804 1.00 27.24 L c 25.171 1.00 26.76 L c 24.071 1.00 27.16 L 0 25.900 1.00 2 6.62 L N 27.219 1.00 26.21 L c 25.408 1.00 25.50 L c 26.587 1.00 27.17 L c 27.343 1.00 24.03 L c 25.046 1.00 26.24 L c 25.816 1.00 25.55 L 0 23.864 1.00 25.21 L N 23.432 1.00 25.03 L c 22.464 1.00 26.75 L c 21.794 1.00 28.23 L 0 22.382 1.00 25.53 L N 21.502 1.00 25.79 L c 22.001 1.00 25.68 L c 23.327 1.00 27.59 L c 23.606 1.00 30.78 L c 23.878 1.00 30.95 L 0 23.540 1.00 27.50 L N 20.064 1.00 25.94 L c 19.772 1.00 24.98 L 0 19.161 1.00 28.78 L N 17.756 1.00 29.05 L c 16.876 1.00 31.19 L c 15.385 1.00 32.39 L c 14.577 1.00 32.91 L c 13.140 1.00 36.49 L N 12.466 1.00 39.15 L c 13.098 1.00 40.18 L N 11.160 1.00 39.44 L N 17.430 1.00 29.77 L C 17.716 1.00 30.44 L 0 16.845 1.00 28.97 L N 16.439 1.00 30.60 L C 17.288 1.00 32.96 ' L c 18.756 1.00 32.49 L c 17.108 1.00 34.57 L c 14.967 1.00 30.86 L c 14.418 1.00 31.31 L 0 14.322 1.00 30.68 L N 12.937 1.00 30.55 L c 12.003 1.00 33.05 L c 12.412 1.00 37.51 L 0 12.057 1.00 30.05 L c 12.772 1.00 30.41 L c 13.535 1.00 31.46 L 0 11.766 1.00 30.36 L N 11.430 1.00 28.18 L c 11.700 1.00 28.17 L c 11.207 1.00 24.45 L c 13.199 1.00 30.05 L c 13.567 1.00 27.37 L c 9.944 1.00 31.43 L c 9.119 1.00 31.91 L 0 9.600 1.00 31.04 L N 8.206 1.00 31.99 L c 8.086 1.00 32.54 L c 8.642 1.00 34.59 L 0 7.567 1.00 32.68 L c 8.248 1.00 32.74 L 0 6.245 1.00 33.22 L N 5.456 1.00 35.47 L c 4.222 1.00 36.21 L c 3.447 1.00 37.64 L 0 5.053 1.00 33.85 L c 4.037 1.00 40.59 L s 4 . 033 1.00 35.52 L N 2.849 1.00 36.01 L c 3.218 1.00 36.77 L c 238 WO 2009/026558 PCT/US2008/074097 ATOM 4559 OG1 THR 23 -48.493 34 ATOM 4560 CG2 THR 23 -50.408 32 ATOM 4561 C THR 23 -47.399 32 ATOM 4562 O THR 23 -46.386 32 ATOM 4563 N GLY 24 -47.549 32 ATOM 4564 CA GLY 24 -46.526 32 ATOM 4565 C GLY 24 -47.058 33 ATOM 4566 0 GLY 24 -47.847 34 ATOM 4567 N SER 25 -46.622 33 ATOM 4568 CA SER 25 -46.957 33 ATOM 4569 CB SER 25 -45.879 35 ATOM 4570 OG SER 25 -44.723 34 ATOM 4571 C SER 25 -47.065 33 ATOM 4572 O SER 25 -46.973 31 ATOM 4573 N SER 26 -47.240 33 ATOM 4574 CA SER 26 -47.413 33 ATOM 4575 CB SER 26 -47.955 34 ATOM 4576 OG SER 26 -47.059 35 ATOM 4577 C SER 26 -46.113 32 ATOM 4578 O SER 26 -46.125 31 ATOM 4579 N SER 27 -44.988 33 ATOM 4580 CA SER 27 -43.725 32 ATOM 4581 CB SER 27 -42.586 33 ATOM 4582 OG SER 27 -42.376 33 ATOM 4583 C SER 27 -43.359 31 ATOM 4584 O SER 27 -42.387 30 ATOM 4585 N ASN 28 -44.126 30 ATOM 4586 CA ASN 28 -43.899 29 ATOM 4587 CB ASN 28 -43.209 29 ATOM 4588 CG ASN 28 -43.767 30 ATOM 4589 OD1 ASN 28 -44.919 30 ATOM 4590 ND2 ASN 28 -42.943 31 ATOM 4591 C ASN 28 -45.150 28 ATOM 4592 0 ASN 28 -45.499 27 ATOM 4593 N ILE 29 -45.830 28 ATOM 4594 CA ILE 29 -47.009 28 ATOM 4595 CB ILE 29 -47.614 28 ATOM 4596 CG2 ILE 29 -48.921 27 ATOM 4597 CGI ILE 29 -46.613 27 ATOM 4598 CDl ILE 29 -47.137 28 ATOM 4599 C ILE 29 -48.063 28 ATOM 4600 0 ILE 29 -48.703 27 ATOM 4601 N GLY 30 -48.230 29 ATOM 4602 CA GLY 30 -49.224 29 ATOM 4603 C GLY 30 -48.821 29 ATOM 4604 0 GLY 30 -49.600 29 ATOM 4605 N ALA 31 -47.612 28 ATOM 4606 CA ALA 31 -47.131 28 ATOM 4607 CB ALA 31 -45.687 28 ATOM 4608 C ALA 31 -47.233 26 ATOM 4609 0 ALA 31 -46.697 26 ATOM 4610 N GLY 32 -47.907 26 ATOM 4611 CA GLY 32 -48.112 24 ATOM 4612 C GLY 32 -47.097 23 ATOM 4613 0 GLY 32 -47.106 22 ATOM 4614 N TYR 33 -46.213 24 ATOM 4615 CA TYR 33 -45.240 23 ATOM 4616 CB TYR 33 -43.951 24 ATOM 4617 CG TYR 33 -43.300 24 ATOM 4618 CDl TYR 33 -42.695 23 ATOM 4619 CEl TYR 33 -42.170 24 ATOM 4620 CD2 TYR 33 -43.356 26 ATOM 4 621 CE2 TYR 33 -42.834 26 ATOM 4622 CZ TYR 33 -42.247 25 ATOM 4623 OH TYR 33 -41.747 25 ATOM 4 62 4 C TYR 33 -45.835 23 ATOM 4625 O TYR 33 -46.581 24 ATOM 4 62 6 N ASP 34 -45.526 22 ATOM 4627 CA ASP 34 -46.046 21 ATOM 4628 CB ASP 34 -45.809 20 ATOM 4629 CG ASP 34 -46.733 19 ATOM 4630 OD1 ASP 34 -46.567 18 ATOM 4631 OD2 ASP 34 -47.618 19 ATOM 4632 C ASP 34 -45.377 22 ATOM 4633 O ASP 34 -44.238 22 ATOM 4634 N VAL 35 -46.090 22
3.725 1.00 43.95 L O 4.285 1.00 35.35 L C 1.953 1.00 35.25 L c 2.418 1.00 33.54 L 0 0.663 1.00 33.91 L N -0.295 1.00 34.67 L c -1.373 1.00 35.72 L c -1.100 1.00 35.18 L 0 -2.604 1.00 36.22 L N -3.717 1.00 38.10 L c -3.880 1.00 36.60 L c -4.495 1.00 38.31 L 0 -5.012 1.00 38.80 L c -5. Oil 1.00 37.63 L 0 -6.118 1.00 39.46 L N -7.425 1.00 39.78 L c -8.423 1.00 40.90 L c -8.537 1.00 42.25 L 0 -7.966 1.00 38.37 L c -8.965 1.00 40.32 L 0 -7.325 1.00 37.56 L N -7.756 1.00 36.90 L c -7.636 1.00 37.67 L c -6.290 1.00 46.23 L 0 -7.003 1.00 34.65 L c -7.356 1.00 34.64 L 0 -5.972 1.00 32.35 L N -5.288 1.00 31.77 L c -3.930 1.00 29.14 L c -3.162 1.00 29.35 L c -2.717 1.00 30.17 L 0 -2.986 1.00 27.56 L N -5.101 1.00 32.18 L c -5.971 1.00 33.39 L 0 -3.974 1.00 31.68 L N -3.703 1.00 34.34 L c -2.323 1.00 34.09 L c -2.126 1.00 33.22 L c -1.221 1.00 32.59 L c 0.186 1.00 33.16 L c -4.786 1.00 36.40 L c -5.241 1.00 37.01 L 0 -5.202 1.00 36.65 L N -6.212 1.00 37.76 L c -7.630 1.00 39.98 L c -8.562 1.00 41.54 L 0 -7.800 1.00 39.82 L N -9.119 1.00 38.00 L c -9.313 1.00 34.50 L c -9.305 1.00 39.19 L c -10.268 1.00 40.14 L 0 -8.377 1.00 39.51 L N -8.526 1.00 39.02 L c -7.825 1.00 39.80 L c -8.004 1.00 42.17 L 0 -7.029 1.00 36.85 L N -6.297 1.00 35.51 L c -6.092 1.00 34.69 L c -7.410 1.00 34.74 L c -8.198 1.00 33.78 L c -9.443 1.00 34.40 L c -7.903 1.00 35.64 L c -9.149 1.00 34.16 L c -9.913 1.00 35.08 L c -11.157 1.00 38.62 L 0 -4.962 1.00 32.94 L c -4.340 1.00 33.35 L 0 -4.544 1.00 29.96 L N -3.288 1.00 28.49 L c -3.221 1.00 30.81 L c -4.136 1.00 34.47 L c -4.189 1.00 36.39 L 0 -4.793 1.00 32.29 L 0 -2.073 1.00 27.51 L c -2.151 1.00 25.64 L 0 -0.954 1.00 26.98 L N 239 WO 2009/026558 PCT/US2008/074097 ATOM 4635 CA VAL 35 -45.523 22 ATOM 4636 CB VAL 35 -46.543 23 ATOM 4637 CGI VAL 35 -45.970 23 ATOM 4638 CG2 VAL 35 -46.897 24 ATOM 4639 C VAL 35 -45.143 21 ATOM 4640 O VAL 35 -45.925 20 ATOM 4641 N HIS 36 -43.943 21 ATOM 4642 CA HIS 36 -43.556 20 ATOM 4643 CB HIS 36 -42.284 19 ATOM 4644 CG HIS 36 -42.256 19 ATOM 4645 CD2 HIS 36 -41.509 19 ATOM 4646 NDl HIS 36 -43.056 18 ATOM 4647 CEl HIS 36 -42.801 18 ATOM 4648 NE2 HIS 36 -41.866 19 ATOM 4649 C HIS 36 -43.309 20 ATOM 4650 0 HIS 36 -42.879 22 ATOM 4651 N TRP 37 -43.575 20 ATOM 4652 CA TRP 37 -43.456 20 ATOM 4653 CB TRP 37 -44.807 20 ATOM 4654 CG TRP 37 -45.845 21 ATOM 4655 CD2 TRP 37 -46.188 22 ATOM 4656 CE2 TRP 37 -47.265 23 ATOM 4657 CE3 TRP 37 -45.693 23 ATOM 4658 CDl TRP 37 -46.704 21 ATOM 4659 NEl TRP 37 -47.559 22 ATOM 4660 CZ2 TRP 37 -47.856 24 ATOM 4661 CZ3 TRP 37 -46.280 24 ATOM 4662 CH2 TRP 37 -47.352 25 ATOM 4663 C TRP 37 -42.437 19 ATOM 4664 O TRP 37 -42.348 18 ATOM 4665 N TYR 38 -41.678 20 ATOM 4666 CA TYR 38 -40.661 19 ATOM 4667 CB TYR 38 -39.286 20 ATOM 4668 CG TYR 38 -39.001 20 ATOM 4669 CDl TYR 38 -39.377 21 ATOM 4670 CEl TYR 38 -39.164 20 ATOM 4 671 CD2 TYR 38 -38.394 18 ATOM 4 672 CE2 TYR 38 -38.174 18 ATOM 4673 CZ TYR 38 -38.566 19 ATOM 4674 OH TYR 38 -38.362 19 ATOM 4675 C TYR 38 -40.911 20 ATOM 4676 O TYR 38 -41.383 21 ATOM 4677 N GLN 39 -40.596 19 ATOM 4678 CA GLN 39 -40.677 19 ATOM 4679 CB GLN 39 -41.471 18 ATOM 4680 CG GLN 39 -41.665 18 ATOM 4681 CD GLN 39 -42.299 17 ATOM 4682 OE1 GLN 39 -41.752 16 ATOM 4683 NE2 GLN 39 -43.461 17 ATOM 4684 C GLN 39 -39.262 19 ATOM 4685 0 GLN 39 -38.481 18 ATOM 4686 N GLN 40 -38.921 20 ATOM 4687 CA GLN 40 -37.609 20 ATOM 4688 CB GLN 40 -36.766 21 ATOM 4689 CG GLN 40 -35.331 21 ATOM 4690 CD GLN 40 -34.505 22 ATOM 4691 OE1 GLN 40 -35.014 23 ATOM 4692 NE2 GLN 40 -33.226 22 ATOM 4693 C GLN 40 -37.769 20 ATOM 4694 0 GLN 40 -38.186 21 ATOM 4695 N LEU 41 -37.450 19 ATOM 4696 CA LEU 41 -37.465 19 ATOM 4697 CB LEU 41 -37.397 17 ATOM 4698 CG LEU 41 -38.540 17 ATOM 4699 CDl LEU 41 -38.322 15 ATOM 4700 CD2 LEU 41 -39.866 17 ATOM 4701 C LEU 41 -36.268 20 ATOM 4702 O LEU 41 -35.249 20 ATOM 4703 N PRO 42 -36.374 20 ATOM 4704 CD PRO 42 -37.515 20 ATOM 4705 CA PRO 42 -35.270 21 ATOM 4706 CB PRO 42 -35.733 21 ATOM 4707 CG PRO 42 -37.239 21 ATOM 4708 C PRO 42 -33.955 20 ATOM 4709 O PRO 42 -33.887 19 ATOM 4710 N GLY 43 -32.924 21
0.326 1.00 28.45 L C 1.139 1.00 27.84 L C 2.497 1.00 25.77 L c 0.375 1.00 29.67 L c 1 .136 1.00 28.31 L c 1.237 1.00 28.31 L 0 1.706 1.00 27.34 L N 2.623 1.00 27.59 L c 2.131 1.00 26.50 L c 0.653 1.00 27.79 L c -0.327 1.00 25.62 L c 0.032 1.00 27.57 L N -1.264 1.00 27.14 L c -1.508 1.00 27.36 L N 4.009 1.00 28.07 L C 4 . 127 1.00 28.94 L 0 5.051 1.00 25.76 L N 6.426 1.00 24.75 L C 7.145 1.00 22.85 L c 6.588 1.00 25.11 L c 7.082 1.00 23.55 L c 6.301 1.00 24.06 L c 8 . 111 1.00 25.38 L c 5.544 1.00 22.14 L c 5.370 1.00 24.91 L N 6.520 1.00 23.30 L c 8.330 1.00 24.69 L c 7.537 1.00 26.88 L c 7.220 1.00 26.46 L c 7.099 1.00 25.56 L 0 8.042 1.00 25.83 L N 8.883 1.00 25.04 L c 8.462 1.00 24.09 L c 7.010 1.00 26.55 L c 6.026 1.00 25.25 L c 4.686 1.00 26.99 L c 6.617 1.00 25.37 L c 5.278 1.00 25.45 L c 4.317 1.00 26.83 L c 2.981 1.00 27.05 L 0 10.342 1.00 27.08 L c 10.673 1.00 25.71 L 0 11.204 1.00 27.12 L N 12.644 1.00 26.88 L c 13.262 1.00 26.61 L c 14.767 1.00 27.00 L c 15.326 1.00 28.70 L c 15.179 1.00 28.98 L 0 15.965 1.00 25.31 L N 13.190 1.00 27.65 L c 12.855 1.00 27.35 L 0 14.022 1.00 26.72 L N 14.660 1.00 29.84 L c 14.172 1.00 28.79 L c 14.685 1.00 30.78 L c 14.157 1.00 31.87 L c 13.984 1.00 30.96 L 0 13.900 1.00 26.76 L N 16.175 1.00 31.91 L c 16.729 1.00 30.67 L 0 16.839 1.00 36.61 L N 18.294 1.00 40.30 L c 18.779 1.00 40.69 L c 18.289 1.00 45.02 L c 18.778 1.00 47.42 L c 18.790 1.00 45.56 L c 18.813 1.00 41.26 L c 18.131 1.00 40.76 L 0 20.031 1.00 44.22 L N 20.961 1.00 44.68 L c 20.584 1.00 45.94 L c 22.006 1.00 45.06 L c 21.942 1.00 45.70 L c 20.561 1.00 47.33 L c 21.042 1.00 47.47 L 0 19.976 1.00 48.07 L N 240 WO 2009/026558 PCT/US2008/074097 ATOM 4711 CA GLY 43 -31.632 20.626 19.902 1.00 49.97 L C ATOM 4712 C GLY 43 -31.587 19.359 19.058 1.00 51.95 L C ATOM 4713 0 GLY 43 -30.963 18.374 19.455 1.00 54.06 L 0 ATOM 4714 N THR 44 -32.245 19.373 17.899 1.00 49.25 L N ATOM 4715 CA THR 44 -32.135 18.274 16.947 1.00 44.82 L c ATOM 4716 CB THR 44 -33.288 17.256 17. 111 1.00 46.65 L c ATOM 4717 OG1 THR 44 -34.531 17.869 16.741 1.00 48.05 L 0 ATOM 4718 CG2 THR 44 -33.384 16.781 18.558 1.00 46.96 L c ATOM 4719 C THR 44 -32.171 18.812 15.519 1.00 41.95 L c ATOM 4720 O THR 44 -32.424 19.994 15.294 1.00 41.93 L 0 ATOM 4721 N ALA 45 -31.912 17.939 14.556 1.00 39.35 L N ATOM 4722 CA ALA 45 -32.058 18.293 13.150 1.00 37.05 L c ATOM 4723 CB ALA 45 -31.294 17.312 12.285 1.00 37.54 L c ATOM 4724 C ALA 45 -33.533 18.269 12.774 1.00 35.57 L c ATOM 4725 O ALA 45 -34.326 17.537 13.369 1.00 34.35 L 0 ATOM 4726 N PRO 46 -33.918 19.070 11.774 1.00 33.17 L N ATOM 4727 CD PRO 46 -33.124 20.113 11.103 1.00 33.74 L c ATOM 4728 CA PRO 46 -35.280 18.991 11.245 1.00 32.23 L c ATOM 4729 CB PRO 46 -35.279 20.002 10.096 1.00 32.13 L c ATOM 4730 CG PRO 46 -34.178 20.960 10.444 1.00 34.08 L c ATOM 4731 C PRO 46 -35.558 17.582 10.755 1.00 31.89 L c ATOM 4732 O PRO 46 -34.652 16.894 10.283 1.00 32.49 L 0 ATOM 4733 N LYS 47 -36.803 17.141 10.873 1.00 31.47 L N ATOM 4734 CA LYS 47 -37.210 15.914 10.200 1.00 33.45 L c ATOM 4735 CB LYS 47 -37.460 14.790 11.215 1.00 35.12 L c ATOM 4736 CG LYS 47 -38.870 14.755 11.764 1.00 41.61 L c ATOM 4737 CD LYS 47 -39.162 13.420 12.443 1.00 47.61 L c ATOM 4738 CE LYS 47 -40.662 13.196 12.597 1.00 50.11 L c ATOM 4739 NZ LYS 47 -40.987 11.855 13.161 1.00 52.03 L N ATOM 4740 C LYS 47 -38.475 16.169 9.387 1.00 30.96 L c ATOM 4741 0 LYS 47 -39.262 17.059 9.712 1.00 28.92 L 0 ATOM 4742 N LEU 48 -38.661 15.381 8.332 1.00 30.98 L N ATOM 4743 CA LEU 48 -39.814 15.526 7.448 1.00 29.23 L c ATOM 4744 CB LEU 48 -39.668 14.589 6.245 1.00 29.31 L c ATOM 4745 CG LEU 48 -40.813 14.640 5.230 1.00 30.45 L c ATOM 4746 CDl LEU 48 -40.989 16.074 4.740 1.00 28.18 L c ATOM 4747 CD2 LEU 48 -40.515 13.697 4.068 1.00 28.52 L c ATOM 4748 C LEU 48 -41.084 15.182 8.208 1.00 27.62 L c ATOM 4749 O LEU 48 -41.135 14.160 8.882 1.00 29.03 L 0 ATOM 4750 N LEU 49 -42.105 16.028 8.091 1.00 26.47 L N ATOM 4751 CA LEU 49 -43.375 15.826 8.793 1.00 25.82 L c ATOM 4752 CB LEU 49 -43.688 17.046 9.664 1.00 24.24 L c ATOM 4753 CG LEU 49 -44.941 16.965 10.538 1.00 24.60 L c ATOM 4754 CDl LEU 49 -44.685 15.971 11.675 1.00 18.36 L c ATOM 4755 CD2 LEU 49 -45.295 18.353 11.086 1.00 20.80 L c ATOM 4756 C LEU 49 -44.544 15.589 7.825 1.00 28.13 L c ATOM 4757 O LEU 49 -45.342 14.669 8.007 1.00 29.97 L 0 ATOM 4758 N ILE 50 -44.648 16.438 6.808 1.00 26.87 L N ATOM 4759 CA ILE 50 -45.665 16.312 5.770 1.00 27.06 L c ATOM 4760 CB ILE 50 -46.783 17.382 5.917 1.00 26.55 L c ATOM 4761 CG2 ILE 50 -47.716 17.325 4.697 1.00 25.11 L c ATOM 4762 CGI ILE 50 -47.569 17.184 7.215 1.00 24.89 L c ATOM 4763 CDl ILE 50 -48.447 15.944 7.230 1.00 26.04 L c ATOM 4764 C ILE 50 -44.968 16.569 4 . 432 1.00 28.76 L c ATOM 4765 0 ILE 50 -44.224 17.547 4.293 1.00 26.93 L 0 ATOM 4766 N SER 51 -45.201 15.707 3.449 1.00 26.34 L N ATOM 4767 CA SER 51 -44.674 15.963 2.114 1.00 27.63 L c ATOM 4768 CB SER 51 -43.760 14.821 1.670 1.00 26.45 L c ATOM 4769 OG SER 51 -44.481 13.605 1.599 1.00 28.18 L 0 ATOM 4770 C SER 51 -45.823 16.112 1. 124 1.00 28.06 L c ATOM 4771 O SER 51 -46.910 15.553 1.325 1.00 27.05 L 0 ATOM 4772 N GLY 52 -45.579 16.868 0.059 1.00 28.20 L N ATOM 4773 CA GLY 52 -46.568 16.999 -0.999 1.00 28.39 L c ATOM 4774 C GLY 52 -47.898 17.525 -0.495 1.00 28.92 L c ATOM 4775 0 GLY 52 -48.950 16.985 -0.838 1.00 28.40 L 0 ATOM 4776 N ASN 53 -47.845 18.571 0.328 1.00 26.76 L N ATOM 4777 CA ASN 53 -49.044 19.222 0.868 1.00 28.99 L c ATOM 4778 CB ASN 53 -50.080 19.496 -0.239 1.00 27.64 L c ATOM 4779 CG ASN 53 -49.514 20.313 -1.391 1.00 31.12 L c ATOM 4780 OD1 ASN 53 -48.790 21.288 -1.184 1.00 30.52 L 0 ATOM 4781 ND2 ASN 53 -49.846 19.914 -2.617 1.00 28.74 L N ATOM 4782 C ASN 53 -49.737 18.448 1.986 1.00 28.32 L c ATOM 4783 0 ASN 53 -50.223 19.047 2.947 1.00 26.59 L 0 ATOM 4784 N SER 54 -49.814 17.128 1.862 1.00 30.28 L N ATOM 4785 CA SER 54 -50.744 16.385 2.713 1.00 32.77 L c ATOM 4786 CB SER 54 -52.149 16.428 2.105 1.00 31.85 L c 241 WO 2009/026558 PCT/US2008/074097 ATOM 4787 OG SER 54 -52.154 15 ATOM 4788 C SER 54 -50.386 14 ATOM 4789 O SER 54 -51.165 14 ATOM 4790 N ASN 55 -49.232 14 ATOM 4791 CA ASN 55 -48.818 13 ATOM 4792 CB ASN 55 -48.020 12 ATOM 4793 CG ASN 55 -48.839 12 ATOM 4794 OD1 ASN 55 -49.720 11 ATOM 4795 ND2 ASN 55 -48.553 13 ATOM 4796 C ASN 55 -47.983 12 ATOM 4797 0 ASN 55 -47.071 13 ATOM 4798 N ARG 56 -48.300 11 ATOM 4799 CA ARG 56 -47.554 11 ATOM 4800 CB ARG 56 -48.506 11 ATOM 4801 CG ARG 56 -49.371 12 ATOM 4802 CD ARG 56 -50.289 11 ATOM 4803 NE ARG 56 -51.374 11 ATOM 4804 CZ ARG 56 -51.380 9 ATOM 4805 NH1 ARG 56 -52.404 8 ATOM 4806 NH2 ARG 56 -50.363 9 ATOM 4807 C ARG 56 -46.539 10 ATOM 4808 O ARG 56 -46.886 9 ATOM 4809 N PRO 57 -45.267 10 ATOM 4810 CD PRO 57 -44.712 12 ATOM 4811 CA PRO 57 -44.244 9 ATOM 4812 CB PRO 57 -42.968 10 ATOM 4813 CG PRO 57 -43.240 11 ATOM 4814 C PRO 57 -44.613 8 ATOM 4815 O PRO 57 -45.359 8 ATOM 4816 N SER 58 -44.091 7 ATOM 4817 CA SER 58 -44.130 6 ATOM 4818 CB SER 58 -43.252 5 ATOM 4819 OG SER 58 -43.995 4 ATOM 4820 C SER 58 -43.621 6 ATOM 4821 O SER 58 -42.569 7 ATOM 4822 N GLY 59 -44.363 6 ATOM 4823 CA GLY 59 -43.914 7 ATOM 4824 C GLY 59 -44.533 8 ATOM 4825 0 GLY 59 -44.383 8 ATOM 4826 N VAL 60 -45.225 9 ATOM 4827 CA VAL 60 -45.922 10 ATOM 4828 CB VAL 60 -45.788 11 ATOM 4829 CGI VAL 60 -46.661 12 ATOM 4830 CG2 VAL 60 -44.329 11 ATOM 4831 C VAL 60 -47.398 10 ATOM 4832 O VAL 60 -48.119 9 ATOM 4833 N PRO 61 -47.866 10 ATOM 4834 CD PRO 61 -47.074 10 ATOM 4835 CA PRO 61 -49.233 10 ATOM 4836 CB PRO 61 -49.262 10 ATOM 4837 CG PRO 61 -47.829 10 ATOM 4838 C PRO 61 -50.271 10 ATOM 4839 O PRO 61 -49.997 11 ATOM 4840 N ASP 62 -51.464 10 ATOM 4841 CA ASP 62 -52.509 10 ATOM 4842 CB ASP 62 -53.630 9 ATOM 4843 CG ASP 62 -54.249 9 ATOM 4844 OD1 ASP 62 -53.929 9 ATOM 4845 OD2 ASP 62 -55.063 8 ATOM 4846 C ASP 62 -53.085 12 ATOM 4847 O ASP 62 -53.968 12 ATOM 4848 N ARG 63 -52.579 12 ATOM 4849 CA ARG 63 -52.920 13 ATOM 4850 CB ARG 63 -52.253 13 ATOM 4851 CG ARG 63 -52.537 12 ATOM 4852 CD ARG 63 -52.038 12 ATOM 4853 NE ARG 63 -50.578 12 ATOM 4854 CZ ARG 63 -49.811 13 ATOM 4855 NH1 ARG 63 -50.373 14 ATOM 4856 NH2 ARG 63 -48.499 13 ATOM 4857 C ARG 63 -52.455 14 ATOM 4858 O ARG 63 -53.024 15 ATOM 4859 N PHE 64 -51.417 14 ATOM 4860 CA PHE 64 -50.875 15 ATOM 4861 CB PHE 64 -49.348 15 ATOM 4 8 62 CG PHE 64 -48.608 15 0.842 1.00 36.17 L O 3.008 1.00 31.72 L C 3.659 1.00 32.86 L 0 2.533 1.00 31.26 L N 2.775 1.00 32.61 L c 1.582 1.00 32.07 L c 0.298 1.00 35.95 L c 0.134 1.00 36.33 L 0 -0.616 1.00 34.48 L N 4 . 051 1.00 32.40 L c 4.305 1.00 31.40 L 0 4 .844 1.00 34.00 L N 6.061 1.00 35.54 L c 7.182 1.00 36.63 L c 7.723 1.00 42.78 L c 8.846 1.00 46.38 L c 8.356 1.00 49.53 L N 8.449 1.00 54.19 L c 7.971 1.00 55.69 L N 9.025 1.00 53.47 L N 5.822 1.00 35.53 L C 5.353 1.00 35.07 L 0 6.154 1.00 36.46 L N 6.516 1.00 35.66 L C 6.163 1.00 37.45 L c 6.581 1.00 36.26 L c 6.281 1.00 37.45 L c 7.167 1.00 39.29 L c 8.121 1.00 37.09 L 0 6.944 1.00 40.87 L N 7.965 1.00 43.46 L c 7.557 1.00 43.89 L c 6.803 1.00 51.42 L 0 9.285 1.00 41.83 L c 9.338 1.00 43.28 L 0 10.353 1.00 40.66 L N 11.658 1.00 40.19 L c 12.118 1.00 40.38 L c 13.278 1.00 44.27 L 0 11.228 1.00 38.65 L N 11.627 1.00 36.24 L c 10.550 1.00 36.26 L c 10.917 1.00 33.36 L c 10.425 1.00 31.61 L c 11.882 1.00 36.29 L c 10.992 1.00 36.29 L 0 13.113 1.00 36.76 L N 14.165 1.00 37.16 L c 13.560 1.00 36.64 L c 15.010 1.00 37.12 L c 15.415 1.00 38.26 L c 12.714 1.00 38.15 L c 12.193 1.00 36.93 L 0 12.594 1.00 37.72 L N 11.779 1.00 39.64 L c 11.491 1.00 45.58 L c 12.763 1.00 52.82 L c 13.877 1.00 54.52 L 0 12.642 1.00 57.04 L 0 12.440 1.00 36.85 L c 11.887 1.00 35.85 L 0 13.623 1.00 33.17 L N 14.275 1.00 33.59 L c 15.658 1.00 34.57 L c 16.546 1.00 40.31 L c 17.983 1.00 41.07 L c 18.119 1.00 39.33 L N 18.221 1.00 36.57 L c 18.188 1.00 34.87 L N 18.394 1.00 34.48 L N 13.413 1.00 30.38 L C 13.483 1.00 28.85 L 0 12.613 1.00 27.74 L N 11.736 1.00 29.98 L C 11.621 1.00 26.68 L c 12.911 1.00 28.95 L c 242 WO 2009/026558 PCT/US2008/074097 ATOM 4 8 63 CD1 PHE 64 -48.214 17 ATOM 4864 CD2 PHE 64 -48.295 14 ATOM 4865 CEl PHE 64 -47.518 17 ATOM 4866 CE2 PHE 64 -47.599 14 ATOM 4 8 67 CZ PHE 64 -47.211 16 ATOM 4868 C PHE 64 -51.487 15 ATOM 4869 O PHE 64 -51.518 14 ATOM 4870 N SER 65 -51.963 16 ATOM 4871 CA SER 65 -52.463 16 ATOM 4872 CB SER 65 -53.980 16 ATOM 4873 OG SER 65 -54.665 17 ATOM 4874 C SER 65 -52.135 18 ATOM 4875 O SER 65 -51.937 19 ATOM 4876 N GLY 66 -52.077 18 ATOM 4877 CA GLY 66 -51.749 19 ATOM 4878 C GLY 66 -52.688 19 ATOM 4879 0 GLY 66 -53.314 18 ATOM 4880 N SER 67 -52.793 20 ATOM 4881 CA SER 67 -53.540 21 ATOM 4882 CB SER 67 -55.018 21 ATOM 4883 OG SER 67 -55.168 22 ATOM 4884 C SER 67 -52.954 22 ATOM 4885 O SER 67 -52.248 23 ATOM 4886 N LYS 68 -53.252 22 ATOM 4887 CA LYS 68 -52.826 23 ATOM 4888 CB LYS 68 -51.729 23 ATOM 4889 CG LYS 68 -51.463 24 ATOM 4890 CD LYS 68 -50.479 23 ATOM 4891 CE LYS 68 -50.427 24 ATOM 4892 NZ LYS 68 -49.320 24 ATOM 4893 C LYS 68 -54.004 24 ATOM 4894 O LYS 68 -54.869 23 ATOM 4895 N SER 69 -54.026 25 ATOM 4896 CA SER 69 -55.090 26 ATOM 4897 CB SER 69 -56.310 26 ATOM 4898 OG SER 69 -57.267 27 ATOM 4899 C SER 69 -54.635 27 ATOM 4900 O SER 69 -54.309 28 ATOM 4901 N GLY 70 -54.616 27 ATOM 4902 CA GLY 70 -54.209 29 ATOM 4903 C GLY 70 -52.744 29 ATOM 4904 0 GLY 70 -51.877 28 ATOM 4905 N THR 71 -52.460 30 ATOM 4906 CA THR 71 -51.083 30 ATOM 4907 CB THR 71 -50.801 32 ATOM 4908 OG1 THR 71 -51.714 33 ATOM 4909 CG2 THR 71 -50.953 32 ATOM 4910 C THR 71 -50.732 30 ATOM 4911 O THR 71 -49.700 30 ATOM 4912 N SER 72 -51.590 29 ATOM 4913 CA SER 72 -51.303 29 ATOM 4914 CB SER 72 -52.187 30 ATOM 4915 OG SER 72 -53.541 29 ATOM 4916 C SER 72 -51.471 27 ATOM 4917 O SER 72 -52.095 27 ATOM 4918 N ALA 73 -50.880 27 ATOM 4919 CA ALA 73 -50.997 26 ATOM 4 92 0 CB ALA 73 -49.767 25 ATOM 4 921 C ALA 73 -51.154 26 ATOM 4922 0 ALA 73 -50.896 27 ATOM 4923 N SER 74 -51.583 24 ATOM 4924 CA SER 74 -51.886 24 ATOM 4925 CB SER 74 -53.375 25 ATOM 4 92 6 OG SER 74 -53.697 25 ATOM 4927 C SER 74 -51.510 23 ATOM 4928 O SER 74 -51.747 22 ATOM 4929 N LEU 75 -50.902 23 ATOM 4930 CA LEU 75 -50.638 22 ATOM 4931 CB LEU 75 -49.192 22 ATOM 4932 CG LEU 75 -48.781 21 ATOM 4933 CDl LEU 75 -48.627 19 ATOM 4934 CD2 LEU 75 -47.456 21 ATOM 4935 C LEU 75 -51.607 22 ATOM 4936 O LEU 75 -51.767 23 ATOM 4937 N ALA 76 -52.263 21 ATOM 4938 CA ALA 76 -53.173 21 13.247 1.00 27.02 L C 13.780 1.00 27.70 L C 14.431 1.00 27.84 L c 14.967 1.00 28.68 L c 15.291 1.00 27.70 L c 10.340 1.00 30.00 L c 9.744 1.00 29.23 L 0 9.819 1.00 29.23 L N 8.445 1.00 31.26 L c 8.413 1.00 30.43 L c 9.032 1.00 32.55 L 0 7.787 1.00 31.18 L c 8.470 1.00 31.63 L 0 6.460 1.00 30.29 L N 5.746 1.00 32.02 L c 4.585 1.00 34.44 L c 4.064 1.00 35.30 L 0 4 . 174 1.00 35.63 L N 2.971 1.00 37.94 L c 3.304 1.00 37.38 L c 4.280 1.00 39.96 L 0 2.300 1.00 39.49 L c 2.936 1.00 39.23 L 0 1.012 1.00 40.52 L N 0.236 1.00 42.33 L c -0.755 1.00 42.24 L c -1.831 1.00 44.74 L c -2.890 1.00 46.29 L c -4.088 1.00 47.53 L c -5.037 1.00 44 . 81 L N -0.531 1.00 42.80 L c -1.026 1.00 41.34 L 0 -0.640 1.00 43.73 L N -1.366 1.00 44.46 L c -0.458 1.00 46.75 L c -1.036 1.00 51.75 L 0 -1.867 1.00 43.71 L c -1.074 1.00 42.73 L 0 -3.186 1.00 43.48 L N -3.749 1.00 41.87 L c -3.470 1.00 42.01 L c -3.871 1.00 42.41 L 0 -2.775 1.00 40.06 L N -2.443 1.00 40.11 L c -2.712 1.00 40.96 L c -1.951 1.00 40.94 L 0 -4.201 1.00 39.96 L c -0.981 1.00 39.88 L c -0.487 1.00 40.96 L 0 -0.285 1.00 37.34 L N 1.100 1.00 37.58 L c 2.041 1.00 38.75 L c 1.940 1.00 43.69 L 0 1.392 1.00 36.49 L c 0.619 1.00 34.73 L 0 2.500 1.00 33.01 L N 2.950 1.00 31.45 L c 2.543 1.00 30.50 L c 4.463 1.00 31.13 L c 5.132 1.00 30.70 L 0 5.006 1.00 30.38 L N 6.421 1.00 32.16 L c 6.627 1.00 32.93 L c 8.002 1.00 40.40 L 0 7.001 1.00 30.96 L c 6.379 1.00 32.04 L 0 8.184 1.00 31.07 L N 8.928 1.00 29.53 L c 9.441 1.00 26.68 L c 10.362 1.00 28.53 L c 9.553 1.00 23.41 L c 11.059 1.00 24.35 L c 10.107 1.00 31.37 L c 10.827 1.00 30.48 L 0 10.300 1.00 30.74 L N 11.425 1.00 30.46 L c 243 WO 2009/026558 PCT/US2008/074097 ATOM 4939 CB ALA 76 -54.600 20 ATOM 4940 C ALA 76 -52.737 19 ATOM 4941 O ALA 76 -52.334 18 ATOM 4942 N ILE 77 -52.822 20 ATOM 4943 CA ILE 77 -52.447 19 ATOM 4944 CB ILE 77 -51.234 19 ATOM 4945 CG2 ILE 77 -50.800 18 ATOM 4946 CGI ILE 77 -50.085 19 ATOM 4947 CDl ILE 77 -48.913 20 ATOM 4948 C ILE 77 -53.630 18 ATOM 4949 0 ILE 77 -54.000 19 ATOM 4950 N THR 78 -54.231 17 ATOM 4951 CA THR 78 -55.314 17 ATOM 4952 CB THR 78 -56.425 16 ATOM 4953 OG1 THR 78 -55.877 15 ATOM 4954 CG2 THR 78 -57.014 17 ATOM 4955 C THR 78 -54.750 16 ATOM 4956 O THR 78 -53.631 16 ATOM 4957 N GLY 79 -55.514 16 ATOM 4958 CA GLY 79 -55.052 15 ATOM 4959 C GLY 79 -53.649 16 ATOM 4960 0 GLY 79 -52.798 15 ATOM 4961 N LEU 80 -53.406 17 ATOM 4962 CA LEU 80 -52.082 18 ATOM 4963 CB LEU 80 -52.200 19 ATOM 4964 CG LEU 80 -50.929 20 ATOM 4965 CDl LEU 80 -50.314 20 ATOM 4966 CD2 LEU 80 -51.271 21 ATOM 4967 C LEU 80 -51.443 17 ATOM 4968 O LEU 80 -52.080 17 ATOM 4969 N GLN 81 -50.187 16 ATOM 4970 CA GLN 81 -49.425 16 ATOM 4971 CB GLN 81 -48.930 14 ATOM 4972 CG GLN 81 -50.027 13 ATOM 4973 CD GLN 81 -50.816 13 ATOM 4974 OE1 GLN 81 -50.313 12 ATOM 4975 NE2 GLN 81 -52.061 13 ATOM 4976 C GLN 81 -48.213 16 ATOM 4977 0 GLN 81 -47.676 17 ATOM 4978 N ALA 82 -47.772 16 ATOM 4979 CA ALA 82 -46.587 17 ATOM 4980 CB ALA 82 -46.257 16 ATOM 4981 C ALA 82 -45.359 17 ATOM 4982 O ALA 82 -44.597 18 ATOM 4983 N GLU 83 -45.153 16 ATOM 4984 CA GLU 83 -43.982 15 ATOM 4985 CB GLU 83 -43.768 14 ATOM 4986 CG GLU 83 -44.991 13 ATOM 4987 CD GLU 83 -45.924 13 ATOM 4988 OE1 GLU 83 -46.852 12 ATOM 4989 OE2 GLU 83 -45.741 13 ATOM 4990 C GLU 83 -44.070 16 ATOM 4991 0 GLU 83 -43.115 16 ATOM 4992 N ASP 84 -45.206 17 ATOM 4993 CA ASP 84 -45.370 18 ATOM 4994 CB ASP 84 -46.851 18 ATOM 4995 CG ASP 84 -47.539 17 ATOM 4996 OD1 ASP 84 -46.859 16 ATOM 4997 OD2 ASP 84 -48.763 16 ATOM 4998 C ASP 84 -44.737 19 ATOM 4999 O ASP 84 -44.653 20 ATOM 5000 N GLU 85 -44.309 19 ATOM 5001 CA GLU 85 -43.660 21 ATOM 5002 CB GLU 85 -43.317 21 ATOM 5003 CG GLU 85 -42.876 22 ATOM 5004 CD GLU 85 -43.034 23 ATOM 5005 OE1 GLU 85 -42.004 23 ATOM 5006 OE2 GLU 85 -44.182 23 ATOM 5007 C GLU 85 -42.391 21 ATOM 5008 0 GLU 85 -41.542 20 ATOM 5009 N ALA 86 -42.269 22 ATOM 5010 CA ALA 86 -41.217 22 ATOM 5011 CB ALA 86 -41.295 20 ATOM 5012 C ALA 86 -41.378 23 ATOM 5013 O ALA 86 -42.335 24 ATOM 5014 N ASP 87 -40.437 23
10.930 1.00 27.72 L C 12.316 1.00 30.96 L C 11.833 1.00 31.40 L 0 13.624 1.00 31.12 L N 14.612 1.00 31.39 L c 15.440 1.00 32.11 L c 16.412 1.00 31.86 L c 14.505 1.00 33.01 L c 15.210 1.00 31.72 L c 15.550 1.00 31.92 L c 16.271 1.00 33.01 L 0 15.538 1.00 32.75 L N 16.474 1.00 34.22 L c 15.808 1.00 36.19 L c 15.369 1.00 37.55 L 0 14.610 1.00 33.93 L c 17.652 1.00 33.72 L c 17.582 1.00 35.50 L 0 18.735 1.00 33.77 L N 19.891 1.00 31.44 L c 20.312 1.00 30.87 L c 20.543 1.00 31.97 L 0 20.410 1.00 29.82 L N 20.731 1.00 30.55 L c 21.088 1.00 31.73 L c 21.084 1.00 31.97 L c 19.690 1.00 31.53 L c 21.495 1.00 33.68 L c 21.894 1.00 31.41 L c 22.924 1.00 28.69 L 0 21.718 1.00 33.22 L N 22.769 1.00 35.00 L c 22.277 1.00 36.97 L c 21.874 1.00 46.26 L c 23.066 1.00 52.65 L c 23.858 1.00 56.12 L 0 23.203 1.00 54.96 L N 23.190 1.00 34.68 L c 22.395 1.00 32.67 L 0 24.431 1.00 34.64 L N 24.966 1.00 35.20 L c 26.356 1.00 36.44 L c 24.069 1.00 34.25 L c 23.923 1.00 35.41 L 0 23.475 1.00 33.73 L N 22.629 1.00 36.46 L c 22.371 1.00 37.92 L c 21.844 1.00 48.23 L c 22.957 1.00 55.83 L c 22.641 1.00 60.92 L 0 24.140 1.00 54.46 L 0 21.295 1.00 35.87 L c 20.518 1.00 36.46 L 0 21.040 1.00 33.53 L N 19.830 1.00 32.04 L c 19.482 1.00 29.82 L c 19.156 1.00 33.55 L c 18.667 1.00 33.27 L 0 19.390 1.00 31.73 L 0 19.979 1.00 32.06 L c 19.003 1.00 30.80 L 0 21.191 1.00 29.59 L N 21.389 1.00 31.50 L c 22.870 1.00 33.60 L c 23.172 1.00 38.51 L c 24.641 1.00 43.82 L c 25.290 1.00 47.43 L 0 25.150 1.00 42.38 L 0 20.549 1.00 29.61 L c 20.688 1.00 32.34 L 0 19.664 1.00 26.98 L N 18.656 1.00 26.63 L c 17.850 1.00 27.34 L c 17.725 1.00 27.49 L c 17.844 1.00 28.13 L 0 16.803 1.00 28.02 L N 244 WO 2009/026558 PCT/US2008/074097 ATOM 5015 CA ASP 87 -40.565 24 ATOM 5016 CB ASP 87 -39.227 25 ATOM 5017 CG ASP 87 -38.845 26 ATOM 5018 OD1 ASP 87 -39.736 26 ATOM 5019 OD2 ASP 87 -37.653 26 ATOM 5020 C ASP 87 -41.007 23 ATOM 5021 O ASP 87 -40.577 22 ATOM 5022 N TYR 88 -41.874 24 ATOM 5023 CA TYR 88 -42.396 23 ATOM 5024 CB TYR 88 -43.904 23 ATOM 5025 CG TYR 88 -44.269 22 ATOM 5026 CDl TYR 88 -44.328 22 ATOM 5027 CEl TYR 88 -44.617 21 ATOM 5028 CD2 TYR 88 -44.514 21 ATOM 5029 CE2 TYR 88 -44.802 20 ATOM 5030 CZ TYR 88 -44.849 20 ATOM 5031 OH TYR 88 -45.104 19 ATOM 5032 C TYR 88 -42.117 24 ATOM 5033 O TYR 88 -42.384 26 ATOM 5034 N TYR 89 -41.580 24 ATOM 5035 CA TYR 89 -41.213 25 ATOM 5036 CB TYR 89 -39.698 24 ATOM 5037 CG TYR 89 -38.873 25 ATOM 5038 CDl TYR 89 -38.414 24 ATOM 5039 CEl TYR 89 -37.671 25 ATOM 5040 CD2 TYR 89 -38.566 26 ATOM 5041 CE2 TYR 89 -37.829 27 ATOM 5042 CZ TYR 89 -37.384 26 ATOM 5043 OH TYR 89 -36.651 27 ATOM 5044 C TYR 89 -41.935 24 ATOM 5045 O TYR 89 -41.986 23 ATOM 5046 N CYS 90 -42.493 25 ATOM 5047 CA CYS 90 -42.966 25 ATOM 5048 C CYS 90 -41.898 25 ATOM 5049 0 CYS 90 -40.957 26 ATOM 5050 CB CYS 90 -44.270 25 ATOM 5051 SG CYS 90 -44.257 27 ATOM 5052 N GLN 91 -42.036 24 ATOM 5053 CA GLN 91 -41.044 24 ATOM 5054 CB GLN 91 -39.966 23 ATOM 5055 CG GLN 91 -38.890 23 ATOM 5056 CD GLN 91 -38.225 22 ATOM 5057 OE1 GLN 91 -38.893 21 ATOM 5058 NE2 GLN 91 -36.896 22 ATOM 5059 C GLN 91 -41.718 24 ATOM 5060 0 GLN 91 -42.679 23 ATOM 5061 N SER 92 -41.210 25 ATOM 5062 CA SER 92 -41.704 25 ATOM 5063 CB SER 92 -43.013 25 ATOM 5064 OG SER 92 -43.443 26 ATOM 5065 C SER 92 -40.668 25 ATOM 50 66 O SER 92 -39.914 26 ATOM 5067 N TYR 93 -40.627 25 ATOM 5068 CA TYR 93 -39.728 25 ATOM 5069 CB TYR 93 -39.677 24 ATOM 5070 CG TYR 93 -38.685 25 ATOM 5071 CDl TYR 93 -37.317 24 ATOM 5072 CEl TYR 93 -36.406 25 ATOM 5073 CD2 TYR 93 -39.120 25 ATOM 5074 CE2 TYR 93 -38.220 25 ATOM 5075 CZ TYR 93 -36.865 25 ATOM 5076 OH TYR 93 -35.969 26 ATOM 5077 C TYR 93 -40.233 26 ATOM 5078 O TYR 93 -41.441 27 ATOM 5079 N ASP 94 -39.303 27 ATOM 5080 CA ASP 94 -39.652 29 ATOM 5081 CB ASP 94 -39.229 30 ATOM 5082 CG ASP 94 -39.679 31 ATOM 5083 OD1 ASP 94 -40.570 32 ATOM 5084 OD2 ASP 94 -39.138 32 ATOM 5085 C ASP 94 -38.932 29 ATOM 5086 O ASP 94 -37.701 29 ATOM 5087 N SER 95 -39.694 29 ATOM 5088 CA SER 95 -39.098 29 ATOM 5089 CB SER 95 -40.176 29 ATOM 5090 OG SER 95 -41.217 30 15.750 1.00 29.17 L C 15.534 1.00 31.60 L C 16.712 1.00 36.68 L c 17.260 1.00 40.12 L 0 17.095 1.00 38.12 L 0 14.458 1.00 28.96 L c 14.164 1.00 26.69 L 0 13.699 1.00 26.76 L N 12.462 1.00 27.47 L c 12.576 1.00 25.61 L c 13.607 1.00 23.78 L c 14.965 1.00 24.12 L c 15.920 1.00 22.16 L c 13.231 1.00 22.59 L c 14.166 1.00 22.72 L c 15.511 1.00 22.94 L c 16.437 1.00 21.22 L 0 11.298 1.00 26.66 L c 11.379 1.00 29.21 L 0 10.219 1.00 27.15 L N 9.044 1.00 25.90 L c 8.814 1.00 26.15 L c 9.931 1.00 28.08 L c 10.992 1.00 28.94 L c 12.027 1.00 27.99 L c 9.934 1.00 27.68 L c 10.962 1.00 28.70 L c 12.006 1.00 30.96 L c 13.031 1.00 32.52 L 0 7.811 1.00 26.61 L c 7.584 1.00 24.13 L 0 7 . Oil 1.00 26.60 L N 5.694 1.00 25.92 L c 4.644 1.00 27.13 L c 4.877 1.00 27.83 L 0 5.342 1.00 29.34 L c 5.342 1.00 38.10 L s 3.488 1.00 28.80 L N 2.429 1.00 28.24 L c 2.595 1.00 27.60 L c 1.525 1.00 29.58 L c 1.351 1.00 33.53 L c 1.360 1.00 30.27 L 0 1 . 198 1.00 35.14 L N 1.078 1.00 29.35 L c 0.946 1.00 29.91 L 0 0.076 1.00 29.56 L N -1.293 1.00 31.14 L c -1.451 1.00 32.55 L c -2.802 1.00 34.97 L 0 -2.285 1.00 30.79 L c -1.979 1.00 30.97 L 0 -3.473 1.00 29.05 L N -4.507 1.00 29.06 L c -5.698 1.00 28.59 L c -6.783 1.00 30.48 L c -6.609 1.00 31.57 L c -7.599 1.00 30.71 L c -7.983 1.00 31.67 L c -8.984 1.00 30.85 L c -8.783 1.00 33.32 L c -9.760 1.00 32.49 L 0 -4.958 1.00 29.39 L c -5.017 1.00 27.21 L 0 -5.248 1.00 29.82 L N -5.780 1.00 31.94 L c -4.811 1.00 34.22 L c -5.256 1.00 39.09 L c -4.589 1.00 38.37 L 0 -6.272 1.00 41.24 L 0 -7.110 1.00 33.39 L c -7.157 1.00 32.83 L 0 -8.189 1.00 32.19 L N -9.519 1.00 35.46 L c -10.598 1.00 33.41 L c -10.442 1.00 37.34 L 0 245 WO 2009/026558 PCT/US2008/074097 ATOM 5091 c SER 95 -38.274 30 ATOM 5092 0 SER 95 -37.381 30 ATOM 5093 N SER 96 -38.547 31 ATOM 5094 CA SER 96 -37.712 33 ATOM 5095 CB SER 96 -38.461 34 ATOM 5096 OG SER 96 -38.428 34 ATOM 5097 C SER 96 -36.378 32 ATOM 5098 O SER 96 -35.411 33 ATOM 5099 N LEU 97 -36.317 32 ATOM 5100 CA LEU 97 -35.085 32 ATOM 5101 CB LEU 97 -35.403 32 ATOM 5102 CG LEU 97 -36.119 33 ATOM 5103 CD1 LEU 97 -36.377 33 ATOM 5104 CD2 LEU 97 -35.271 34 ATOM 5105 C LEU 97 -34.330 30 ATOM 5106 O LEU 97 -33.166 30 ATOM 5107 N SER 98 -35.005 29 ATOM 5108 CA SER 98 -34.432 28 ATOM 5109 CB SER 98 -33.228 28 ATOM 5110 OG SER 98 -33.610 29 ATOM 5111 C SER 98 -34.018 27 ATOM 5112 O SER 98 -33.073 26 ATOM 5113 N GLY 99 -34.728 27 ATOM 5114 CA GLY 99 -34.422 27 ATOM 5115 C GLY 99 -35.657 26 ATOM 5116 0 GLY 99 -36.657 27 ATOM 5117 N SER 100 -35.588 25 ATOM 5118 CA SER 100 -36.707 25 ATOM 5119 CB SER 100 -36.765 23 ATOM 5120 OG SER 100 -37.335 23 ATOM 5121 C SER 100 -36.563 26 ATOM 5122 O SER 100 -35.908 25 ATOM 5123 N VAL 101 -37.197 27 ATOM 5124 CA VAL 101 -37.020 28 ATOM 5125 CB VAL 101 -37.142 29 ATOM 5126 CGI VAL 101 -36.015 29 ATOM 5127 CG2 VAL 101 -38.501 29 ATOM 5128 C VAL 101 -38.002 27 ATOM 5129 O VAL 101 -39.047 27 ATOM 5130 N PHE 102 -37.652 28 ATOM 5131 CA PHE 102 -38.362 27 ATOM 5132 CB PHE 102 -37.361 27 ATOM 5133 CG PHE 102 -36.680 26 ATOM 5134 CD1 PHE 102 -35.472 26 ATOM 5135 CD2 PHE 102 -37.259 24 ATOM 5136 CEl PHE 102 -34.853 24 ATOM 5137 CE2 PHE 102 -36.645 23 ATOM 5138 CZ PHE 102 -35.439 23 ATOM 5139 C PHE 102 -39.158 29 ATOM 5140 O PHE 102 -38.750 30 ATOM 5141 N GLY 103 -40.292 28 ATOM 5142 CA GLY 103 -40.949 29 ATOM 5143 C GLY 103 -40.094 30 ATOM 5144 0 GLY 103 -39.068 29 ATOM 5145 N GLY 104 -40.513 31 ATOM 5146 CA GLY 104 -39.722 31 ATOM 5147 C GLY 104 -39.801 30 ATOM 5148 0 GLY 104 -39.038 31 ATOM 5149 N GLY 105 -40.715 29 ATOM 5150 CA GLY 105 -40.796 29 ATOM 5151 C GLY 105 -41.890 29 ATOM 5152 0 GLY 105 -42.133 30 ATOM 5153 N THR 106 -42.557 28 ATOM 5154 CA THR 106 -43.546 28 ATOM 5155 CB THR 106 -44.950 28 ATOM 5156 OG1 THR 106 -45.338 28 ATOM 5157 CG2 THR 106 -45.950 28 ATOM 5158 C THR 106 -43.170 27 ATOM 5159 O THR 106 -42.953 26 ATOM 5160 N LYS 107 -43.099 28 ATOM 5161 CA LYS 107 -42.788 27 ATOM 5162 CB LYS 107 -42.130 28 ATOM 5163 CG LYS 107 -41.064 28 ATOM 5164 CD LYS 107 -41.600 27 ATOM 5165 CE LYS 107 -40.472 26 ATOM 5166 NZ LYS 107 -40.985 25
-9.811 1.00 35.42 L C -10.651 1.00 38.68 L O -9.132 1.00 37.35 L N -9.343 1.00 39.64 L C -8.947 1.00 38.48 L C -7.548 1.00 48.03 L 0 -8.589 1.00 40.42 L c -8.951 1.00 41.72 L 0 -7.552 1.00 40.63 L N -6.776 1.00 39.89 L c -5.278 1.00 39.69 L c -4.752 1.00 41.84 L c -3.257 1.00 40.69 L c -5.034 1.00 39.18 L c -7.142 1.00 40.12 L c -6.775 1.00 38.81 L 0 -7.862 1.00 40.10 L N -8.247 1.00 39.46 L c -9.169 1.00 39.43 L c -10.354 1.00 42.81 L 0 -7.045 1.00 38.54 L c -7.123 1.00 38.98 L 0 -5.934 1.00 37.42 L N -4.762 1.00 35.97 L c -3.940 1.00 36.31 L c -4.065 1.00 35.39 L 0 -3.100 1.00 36.91 L N -2.246 1.00 37.76 L c -2.076 1.00 39.33 L c -3.212 1.00 39.19 L 0 -0.885 1.00 38.62 L c 0.012 1.00 40.69 L 0 -0.735 1.00 35.61 L N 0.428 1.00 34.08 L c 0.033 1.00 34.68 L c -0.932 1.00 37.67 L c -0.605 1.00 30.50 L c 1.563 1.00 33.19 L c 1.362 1.00 31.98 L 0 2.755 1.00 30.75 L N 3.985 1.00 29.44 L c 5.053 1.00 28.91 L c 4.742 1.00 27.81 L c 4.070 1.00 26.76 L c 5.110 1.00 26.32 L c 3.764 1.00 26.61 L c 4.809 1.00 25.33 L c 4.133 1.00 25.96 L c 4.521 1.00 28.98 L c 4.372 1.00 31.15 L 0 5.154 1.00 28.82 L N 5.956 1.00 27.61 L c 7.153 1.00 28.18 L c 7.419 1.00 27.21 L 0 7.877 1.00 29.41 L N 8.987 1.00 30.21 L c 10.245 1.00 31.93 L c 11.186 1.00 31.09 L 0 10.262 1.00 31.73 L N 11.385 1.00 30.36 L c 12.360 1.00 30.83 L c 12.597 1.00 30.41 L 0 12.924 1.00 30.56 L N 13.969 1.00 30.39 L c 13.538 1.00 30.35 L c 12.354 1.00 32.39 L 0 14.635 1.00 30.52 L c 15.219 1.00 30.74 L c 15.167 1.00 30.35 L 0 16.341 1.00 31.45 L N 17.623 1.00 33.01 L c 18.540 1.00 38.62 L c 19.485 1.00 44.72 L c 20.334 1.00 49.04 L c 20.831 1.00 51.13 L c 21.262 1.00 50.21 L N 246 WO 2009/026558 PCT/US2008/074097 ATOM 5167 c LYS 107 -44.107 27 ATOM 5168 0 LYS 107 -44.979 28 ATOM 5169 N LEU 108 -44.273 26 ATOM 5170 CA LEU 108 -45.486 25 ATOM 5171 CB LEU 108 -45.970 24 ATOM 5172 CG LEU 108 -47.289 23 ATOM 5173 CDl LEU 108 -47.883 22 ATOM 5174 CD2 LEU 108 -47.058 23 ATOM 5175 C LEU 108 -45.256 25 ATOM 5176 O LEU 108 -44.342 24 ATOM 5177 N THR 109 -46.112 25 ATOM 5178 CA THR 109 -45.992 25 ATOM 5179 CB THR 109 -45.942 27 ATOM 5180 OG1 THR 109 -44.728 27 ATOM 5181 CG2 THR 109 -45.991 26 ATOM 5182 C THR 109 -47.173 24 ATOM 5183 O THR 109 -48.326 25 ATOM 5184 N VAL 110 -46.890 23 ATOM 5185 CA VAL 110 -47.952 23 ATOM 5186 CB VAL 110 -47.589 21 ATOM 5187 CGI VAL 110 -48.696 20 ATOM 5188 CG2 VAL 110 -47.391 21 ATOM 5189 C VAL 110 -48.247 23 ATOM 5190 O VAL 110 -47.389 23 ATOM 5191 N LEU 111 -49.470 24 ATOM 5192 CA LEU 111 -49.831 24 ATOM 5193 CB LEU 111 -50.785 25 ATOM 5194 CG LEU 111 -50.233 27 ATOM 5195 CDl LEU 111 -51.313 28 ATOM 5196 CD2 LEU 111 -49.029 27 ATOM 5197 C LEU 111 -50.492 23 ATOM 5198 O LEU 111 -50.631 22 ATOM 5199 N GLY 112 -50.893 24 ATOM 5200 CA GLY 112 -51.772 23 ATOM 5201 C GLY 112 -51.139 23 ATOM 5202 0 GLY 112 -51.853 22 ATOM 5203 N GLN 113 -49.815 23 ATOM 5204 CA GLN 113 -49.186 22 ATOM 5205 CB GLN 113 -47.725 22 ATOM 52 0 6 CG GLN 113 -46.732 23 ATOM 5207 CD GLN 113 -45.326 22 ATOM 5208 OE1 GLN 113 -44.513 22 ATOM 5209 NE2 GLN 113 -45.034 22 ATOM 5210 C GLN 113 -49.282 23 ATOM 5211 0 GLN 113 -49.377 24 ATOM 5212 N PRO 114 -49.282 22 ATOM 5213 CD PRO 114 -49.223 21 ATOM 5214 CA PRO 114 -49.519 23 ATOM 5215 CB PRO 114 -49.539 22 ATOM 5216 CG PRO 114 -49.909 21 ATOM 5217 C PRO 114 -48.458 24 ATOM 5218 O PRO 114 -47.285 24 ATOM 5219 N LYS 115 -48.874 25 ATOM 5220 CA LYS 115 -47.916 27 ATOM 5221 CB LYS 115 -48.634 28 ATOM 5222 CG LYS 115 -47.748 29 ATOM 5223 CD LYS 115 -47.982 30 ATOM 5224 CE LYS 115 -49.028 31 ATOM 5225 NZ LYS 115 -48.997 32 ATOM 5226 C LYS 115 -46.879 26 ATOM 5227 0 LYS 115 -47.206 25 ATOM 5228 N ALA 116 -45.630 26 ATOM 5229 CA ALA 116 -44.570 26 ATOM 5230 CB ALA 116 -43.738 25 ATOM 5231 C ALA 116 -43.678 27 ATOM 5232 O ALA 116 -43.179 28 ATOM 5233 N ALA 117 -43.487 27 ATOM 5234 CA ALA 117 -42.664 29 ATOM 5235 CB ALA 117 -43.008 29 ATOM 5236 C ALA 117 -41.188 28 ATOM 5237 O ALA 117 -40.818 27 ATOM 5238 N PRO 118 -40.329 29 ATOM 5239 CD PRO 118 -40.679 31 ATOM 5240 CA PRO 118 -38.902 29 ATOM 5241 CB PRO 118 -38.394 30 ATOM 5242 CG PRO 118 -39.339 31 18.230 1.00 31.74 L C 18.538 1.00 32.77 L O 18.393 1.00 28.38 L N 19.037 1.00 30.04 L C 18.351 1.00 26.99 L C 18.861 1.00 29.30 L c 17.802 1.00 29.60 L c 20.150 1.00 31.06 L c 20.515 1.00 29.02 L c 20.871 1.00 31.80 L 0 21.367 1.00 30.44 L N 22.812 1.00 32.72 L c 23.535 1.00 33.32 L c 23.190 1.00 39.35 L 0 25.030 1.00 36.60 L c 23.352 1.00 31.37 L c 23.056 1.00 32.44 L 0 24.141 1.00 29.28 L N 24.759 1.00 30.60 L c 24.843 1.00 31.58 L c 25.564 1.00 31.21 L c 23.437 1.00 29.51 L c 26.163 1.00 32.83 L c 27.041 1.00 32.80 L 0 26.364 1.00 34 .22 L N 27.581 1.00 34.04 L c 27.247 1.00 34.30 L c 26.294 1.00 39.19 L c 25.964 1.00 37.22 L c 26.934 1.00 38.67 L c 28.598 1.00 34.06 L c 28.376 1.00 34.37 L 0 29.724 1.00 33.66 L N 30.632 1.00 32.43 L c 31.903 1.00 32.20 L c 32.838 1.00 32.07 L 0 31.965 1.00 31.98 L N 33.145 1.00 33.88 L c 32.853 1.00 34.74 L c 32.993 1.00 38.41 L c 32.653 1.00 42.73 L c 33.543 1.00 42.57 L 0 31.354 1.00 42.20 L N 34.354 1.00 32.67 L c 34.208 1.00 30.96 L 0 35.568 1.00 32.80 L N 35.868 1.00 33.24 L c 36.777 1.00 32.36 L c 37.902 1.00 32.38 L c 37.213 1.00 34.37 L c 37.007 1.00 30.82 L c 36.677 1.00 26.86 L 0 37.569 1.00 31.80 L N 37.930 1.00 34.33 L c 38.583 1.00 36.99 L c 38.753 1.00 44.60 L c 40.084 1.00 48.66 L c 39.966 1.00 50.81 L c 41.157 1.00 52.88 L N 38.897 1.00 33.33 L c 39.736 1.00 30.94 L 0 38.762 1.00 32.81 L N 39.697 1.00 33.88 L c 39.111 1.00 30.45 L c 40.012 1.00 33.75 L c 39.105 1.00 33.41 L 0 41.300 1.00 34.49 L N 41.733 1.00 34.10 L c 43.181 1.00 34.76 L c 41.622 1.00 34.26 L c 41.781 1.00 34.36 L 0 41.331 1.00 34.24 L N 41.151 1.00 33.58 L c 41.114 1.00 35.01 L c 40.517 1.00 34.92 L c 41.039 1.00 34.58 L c 247 WO 2009/026558 PCT/US2008/074097 ATOM 5243 c PRO 118 -38.172 29, ATOM 5244 0 PRO 118 -38.483 29, ATOM 5245 N SER 119 -37.212 28 , ATOM 5246 CA SER 119 -36.175 28 ATOM 5247 CB SER 119 -35.621 26 ATOM 5248 OG SER 119 -36.607 25, ATOM 5249 C SER 119 -35.055 29 ATOM 5250 O SER 119 -34.615 29 ATOM 5251 N VAL 120 -34.597 29 ATOM 5252 CA VAL 120 -33.478 30 ATOM 5253 CB VAL 120 -33.889 32 ATOM 5254 CGI VAL 120 -32.680 33 ATOM 5255 CG2 VAL 120 -34.995 32 ATOM 5256 C VAL 120 -32.338 30 ATOM 5257 O VAL 120 -32.543 30 ATOM 5258 N THR 121 -31.134 30 ATOM 5259 CA THR 121 -29.961 30 ATOM 5260 CB THR 121 -29.413 28 ATOM 5261 OG1 THR 121 -28.028 28 ATOM 5262 CG2 THR 121 -30.191 27 ATOM 5263 C THR 121 -28.900 31 ATOM 5264 O THR 121 -28.695 31 ATOM 5265 N LEU 122 -28.253 31 ATOM 52 66 CA LEU 122 -27.357 32 ATOM 5267 CB LEU 122 -27.971 34 ATOM 5268 CG LEU 122 -27.093 35 ATOM 5269 CDl LEU 122 -26.790 35 ATOM 5270 CD2 LEU 122 -27.815 36 ATOM 5271 C LEU 122 -25.979 32 ATOM 5272 O LEU 122 -25.873 32 ATOM 5273 N PHE 123 -24.934 32 ATOM 5274 CA PHE 123 -23.563 32 ATOM 5275 CB PHE 123 -22.803 31 ATOM 5276 CG PHE 123 -23.292 30 ATOM 5277 CDl PHE 123 -24.108 29 ATOM 5278 CD2 PHE 123 -22.919 29 ATOM 5279 CEl PHE 123 -24.545 28 ATOM 5280 CE2 PHE 123 -23.351 28 ATOM 5281 CZ PHE 123 -24.165 27 ATOM 5282 C PHE 123 -22.822 33 ATOM 5283 O PHE 123 -22.887 34 ATOM 5284 N PRO 124 -22.085 34 ATOM 5285 CD PRO 124 -22.022 33 ATOM 5286 CA PRO 124 -21.179 35 ATOM 5287 CB PRO 124 -20.827 35 ATOM 5288 CG PRO 124 -20.911 33 ATOM 5289 C PRO 124 -19.952 35 ATOM 5290 O PRO 124 -19.764 33 ATOM 5291 N PRO 125 -19.100 36 ATOM 5292 CD PRO 125 -19.242 37 ATOM 5293 CA PRO 125 -17.823 35 ATOM 5294 CB PRO 125 -17.180 37 ATOM 5295 CG PRO 125 -18.291 38 ATOM 5296 C PRO 125 -16.961 34 ATOM 5297 O PRO 125 -16.917 34 ATOM 5298 N SER 126 -16.281 33 ATOM 5299 CA SER 126 -15.335 33 ATOM 5300 CB SER 126 -14.937 31 ATOM 5301 OG SER 126 -14.250 32 ATOM 5302 C SER 126 -14.093 33 ATOM 5303 O SER 126 -13.777 34 ATOM 5304 N SER 127 -13.383 33 ATOM 5305 CA SER 127 -12.176 34 ATOM 5306 CB SER 127 -11.653 33 ATOM 5307 OG SER 127 -11.268 32 ATOM 5308 C SER 127 -11.100 34 ATOM 5309 O SER 127 -10.301 34 ATOM 5310 N GLU 128 -11.099 32 ATOM 5311 CA GLU 128 -10.172 32 ATOM 5312 CB GLU 128 -10.288 31 ATOM 5313 CG GLU 128 -9.137 31 ATOM 5314 CD GLU 128 -9.217 29 ATOM 5315 OE1 GLU 128 -8.448 29 ATOM 5316 OE2 GLU 128 -10.041 28 ATOM 5317 C GLU 128 -10.396 33 ATOM 5318 O GLU 128 -9.436 34 42.403 1.00 37.33 L C 4 3.4 67 1.00 37.79 L O 42.295 1.00 37.11 L N 43.304 1.00 37.74 L C 43.312 1.00 36.71 L C 43.742 1.00 45.31 L 0 42.951 1.00 37.01 L c 41.799 1.00 38.07 L 0 43.944 1.00 35.51 L N 43.758 1.00 35.22 L c 44.059 1.00 34.18 L c 43.933 1.00 30.75 L c 43.103 1.00 33.05 L c 44.684 1.00 36.13 L c 45.879 1.00 35.93 L 0 44.134 1.00 35.67 L N 44.975 1.00 36.07 L c 45.022 1.00 38.17 L c 44.670 1.00 43.48 L 0 44.092 1.00 38.07 L c 44.518 1.00 35.24 L c 43.321 1.00 33.07 L 0 45.490 1.00 34.06 L N 45.220 1.00 34.60 L c 45.762 1.00 31.62 L c 45.764 1.00 33.67 L c 44.337 1.00 31.18 L c 46.519 1.00 34.33 L c 45.852 1.00 35.18 L c 47.048 1.00 35.07 L 0 45.040 1.00 34.10 L N 45.503 1.00 33.60 L c 44.598 1.00 32.81 L c 44.673 1.00 33.31 L c 43.680 1.00 31.54 L c 45.726 1.00 31.90 L c 43.731 1.00 32.77 L c 45.783 1.00 31.56 L c 44.784 1.00 32.86 L c 45.507 1.00 34.23 L c 44.541 1.00 33.21 L 0 46.595 1.00 34.60 L N 47.802 1.00 33.97 L c 46.681 1.00 33.22 L c 48.162 1.00 32.92 L c 48.613 1.00 32.54 L c 45.815 1.00 33.35 L c 45.318 1.00 32.14 L 0 45.624 1.00 34.18 L N 46.084 1.00 34.13 L c 44.937 1.00 33.64 L c 44.894 1.00 34.39 L c 45.187 1.00 35.53 L c 45.732 1.00 35.03 L c 46.962 1.00 35.09 L 0 45.035 1.00 34.42 L N 45.691 1.00 34.25 L c 44.744 1.00 32.73 L c 43.621 1.00 32.43 L 0 46.084 1.00 35.04 L c 45.461 1.00 33.38 L 0 47.110 1.00 35.77 L N 47.534 1.00 37.95 L c 48.864 1.00 39.02 L c 48.731 1.00 45.05 L 0 46.452 1.00 36.52 L c 46.276 1.00 35.94 L 0 45.703 1.00 36.21 L N 44.590 1.00 38.71 L c 43.975 1.00 40.30 L c 43.054 1.00 44.77 L c 42.538 1.00 48.56 L c 41.610 1.00 48.39 L 0 43.061 1.00 49.98 L 0 43.514 1.00 40.21 L c 43.025 1.00 39.54 L 0 248 WO 2009/026558 PCT/US2008/074097 ATOM 5319 N GLU 129 -11.652 34 ATOM 5320 CA GLU 129 -11.927 35 ATOM 5321 CB GLU 129 -13.406 35 ATOM 5322 CG GLU 129 -13.717 36 ATOM 5323 CD GLU 129 -15.192 36 ATOM 5324 OE1 GLU 129 -15.469 36 ATOM 5325 OE2 GLU 129 -16.072 36 ATOM 5326 C GLU 129 -11.560 36 ATOM 5327 0 GLU 129 -11.107 37 ATOM 5328 N LEU 130 -11.759 36 ATOM 5329 CA LEU 130 -11.361 38 ATOM 5330 CB LEU 130 -11.837 38 ATOM 5331 CG LEU 130 -13.358 38 ATOM 5332 CDl LEU 130 -13.723 38 ATOM 5333 CD2 LEU 130 -13.832 39 ATOM 5334 C LEU 130 -9.844 38 ATOM 5335 O LEU 130 -9.401 39 ATOM 5336 N GLN 131 -9.056 37 ATOM 5337 CA GLN 131 -7.606 37 ATOM 5338 CB GLN 131 -6.950 35 ATOM 5339 CG GLN 131 -6.260 35 ATOM 5340 CD GLN 131 -5.469 37 ATOM 5341 OE1 GLN 131 -5.756 37 ATOM 5342 NE2 GLN 131 -4.470 37 ATOM 5343 C GLN 131 -7.248 37 ATOM 5344 0 GLN 131 -6.261 38 ATOM 5345 N ALA 132 -8.039 37 ATOM 5346 CA ALA 132 -7.868 37 ATOM 5347 CB ALA 132 -8.552 36 ATOM 5348 C ALA 132 -8.435 38 ATOM 5349 O ALA 132 -8.516 39 ATOM 5350 N ASN 133 -8.845 39 ATOM 5351 CA ASN 133 -9.273 40 ATOM 5352 CB ASN 133 -8.155 41 ATOM 5353 CG ASN 133 -8.282 43 ATOM 5354 OD1 ASN 133 -8.791 43 ATOM 5355 ND2 ASN 133 -7.821 44 ATOM 5356 C ASN 133 -10.581 41 ATOM 5357 0 ASN 133 -10.751 42 ATOM 5358 N LYS 134 -11.494 40 ATOM 5359 CA LYS 134 -12.830 40 ATOM 5360 CB LYS 134 -12.955 39 ATOM 5361 CG LYS 134 -11.819 39 ATOM 5362 CD LYS 134 -11.935 40 ATOM 5363 CE LYS 134 -11.460 40 ATOM 5364 NZ LYS 134 -10.414 39 ATOM 5365 C LYS 134 -13.854 39 ATOM 5366 0 LYS 134 -13.510 39 ATOM 5367 N ALA 135 -15.112 40 ATOM 5368 CA ALA 135 -16.199 39 ATOM 5369 CB ALA 135 -16.485 40 ATOM 5370 C ALA 135 -17.465 39 ATOM 5371 O ALA 135 -17.928 40 ATOM 5372 N THR 136 -18.019 38 ATOM 5373 CA THR 136 -19.223 37 ATOM 5374 CB THR 136 -18.910 36 ATOM 5375 OG1 THR 136 -17.877 37 ATOM 5376 CG2 THR 136 -20.149 36 ATOM 5377 C THR 136 -20.234 37 ATOM 5378 O THR 136 -19.952 36 ATOM 5379 N LEU 137 -21.410 37 ATOM 5380 CA LEU 137 -22.527 37 ATOM 5381 CB LEU 137 -23.417 38 ATOM 5382 CG LEU 137 -22.746 39 ATOM 5383 CDl LEU 137 -23.790 40 ATOM 5384 CD2 LEU 137 -21.929 38 ATOM 5385 C LEU 137 -23.332 36 ATOM 5386 O LEU 137 -23.562 36 ATOM 5387 N VAL 138 -23.748 35 ATOM 5388 CA VAL 138 -24.366 34 ATOM 5389 CB VAL 138 -23.496 33 ATOM 5390 CGI VAL 138 -24.158 32 ATOM 5391 CG2 VAL 138 -22.096 33 ATOM 5392 C VAL 138 -25.736 33 ATOM 5393 O VAL 138 -25.851 33 ATOM 5394 N CYS 139 -26.772 34
43.147 1.00 40.30 L N 42.142 1.00 38.87 L C 41.720 1.00 39.30 L C 40.653 1.00 40.41 L c 40.261 1.00 42.41 L c 39.081 1.00 44 . 06 L 0 41.117 1.00 40.48 L 0 42.681 1.00 38.41 L c 41.933 1.00 36.76 L 0 43.979 1.00 37.71 L N 44.599 1.00 38.42 L c 46.053 1.00 36.50 L c 46.237 1.00 36.84 L c 47.713 1.00 34.95 L c 45.657 1.00 33.05 L c 44.515 1.00 40.34 L c 44 .243 1.00 40.94 L 0 44.730 1.00 41.55 L N 44.532 1.00 43.80 L c 44.844 1.00 43.76 L c 46.191 1.00 47.33 L c 46.514 1.00 47.15 L c 47.497 1.00 49.05 L 0 45.692 1.00 45.39 L N 43.105 1.00 45.27 L c 42.876 1.00 46.89 L 0 42.147 1.00 45.27 L N 40.743 1.00 43.98 L c 39.841 1.00 43.38 L c 40.474 1.00 43.57 L c 39.327 1.00 42.33 L 0 41.537 1.00 43.82 L N 41.433 1.00 46.95 L c 40.792 1.00 48.35 L c 41.101 1.00 50.92 L c 42.158 1.00 51.72 L 0 40.179 1.00 51.45 L N 40.642 1.00 46.81 L c 39.929 1.00 47.08 L 0 40.768 1.00 46.18 L N 40.186 1.00 45.08 L c 38.946 1.00 46.32 L c 37.947 1.00 49.14 L c 37.107 1.00 55.33 L c 35.673 1.00 58.41 L c 35.603 1.00 59.23 L N 41.218 1.00 44.89 L c 42.181 1.00 45.02 L 0 41.013 1.00 43.12 L N 41.845 1.00 42.34 L c 42.986 1.00 40.89 L c 41.019 1.00 41.64 L c 40.299 1.00 42.40 L 0 41 .129 1.00 41.17 L N 40.392 1.00 36.95 L c 39.301 1.00 36.17 L c 38.448 1.00 34.77 L 0 38.460 1.00 35.99 L c 41.349 1.00 35.86 L c 42.003 1.00 35.40 L 0 41.434 1.00 35.37 L N 42.140 1.00 34.20 L c 42.758 1.00 36.75 L c 43.798 1.00 40.79 L c 44.597 1.00 41.82 L c 44.725 1.00 42.69 L c 41.160 1.00 34.75 L c 40.013 1.00 33.76 L 0 41.616 1.00 33.20 L N 40.741 1.00 33.86 L c 40.627 1.00 33.39 L c 39.679 1.00 31.94 L c 40.155 1.00 28.69 L c 41.261 1.00 34.92 L c 42.303 1.00 35.11 L 0 40.528 1.00 34.33 L N 249 WO 2009/026558 PCT/US2008/074097 ATOM 5395 CA CYS 139 -28.145 34 ATOM 5396 C CYS 139 -28.755 33 ATOM 5397 0 CYS 139 -28.914 33 ATOM 5398 CB CYS 139 -28.963 35 ATOM 5399 SG CYS 139 -30.606 35 ATOM 5400 N LEU 140 -29.092 31 ATOM 5401 CA LEU 140 -29.556 30 ATOM 5402 CB LEU 140 -28.722 29 ATOM 5403 CG LEU 140 -27.225 29 ATOM 5404 CDl LEU 140 -26.500 28 ATOM 5405 CD2 LEU 140 -26.981 29 ATOM 5406 C LEU 140 -31.024 30 ATOM 5407 O LEU 140 -31.432 30 ATOM 5408 N ILE 141 -31.808 30 ATOM 5409 CA ILE 141 -33.266 30 ATOM 5410 CB ILE 141 -33.873 31 ATOM 5411 CG2 ILE 141 -35.333 31 ATOM 5412 CGI ILE 141 -33.095 32 ATOM 5413 CDl ILE 141 -33.396 34 ATOM 5414 C ILE 141 -33.784 29 ATOM 5415 0 ILE 141 -33.506 28 ATOM 5416 N SER 142 -34.533 28 ATOM 5417 CA SER 142 -34.925 27 ATOM 5418 CB SER 142 -33.897 25 ATOM 5419 OG SER 142 -33.838 25 ATOM 5420 C SER 142 -36.315 26 ATOM 5421 0 SER 142 -36.918 27 ATOM 5422 N ASP 143 -36.820 25 ATOM 5423 CA ASP 143 -38.075 24 ATOM 5424 CB ASP 143 -37.980 24 ATOM 5425 CG ASP 143 -36.947 23 ATOM 5426 OD1 ASP 143 -36.195 22 ATOM 5427 OD2 ASP 143 -36.886 22 ATOM 5428 C ASP 143 -39.301 25 ATOM 5429 0 ASP 143 -40.216 25 ATOM 5430 N PHE 144 -39.340 26 ATOM 5431 CA PHE 144 -40.513 27 ATOM 5432 CB PHE 144 -40.120 29 ATOM 5433 CG PHE 144 -39.148 29 ATOM 5434 CDl PHE 144 -39.606 30 ATOM 5435 CD2 PHE 144 -37.776 29 ATOM 5436 CEl PHE 144 -38.712 31 ATOM 5437 CE2 PHE 144 -36.874 30 ATOM 5438 CZ PHE 144 -37.345 30 ATOM 5439 C PHE 144 -41.360 27 ATOM 5440 0 PHE 144 -40.859 27 ATOM 5441 N TYR 145 -42.658 27 ATOM 5442 CA TYR 145 -43.570 27 ATOM 5443 CB TYR 145 -44.099 26 ATOM 5444 CG TYR 145 -44.958 26 ATOM 5445 CDl TYR 145 -46.301 26 ATOM 5446 CEl TYR 145 -47.053 26 ATOM 5447 CD2 TYR 145 -44.399 26 ATOM 5448 CE2 TYR 145 -45.144 26 ATOM 5449 CZ TYR 145 -46.466 26 ATOM 5450 OH TYR 145 -47.196 26 ATOM 5451 C TYR 145 -44.735 28 ATOM 5452 0 TYR 145 -45.261 28 ATOM 5453 N PRO 146 -45.168 29 ATOM 5454 CD PRO 146 -46.411 30 ATOM 5455 CA PRO 146 -44.607 29 ATOM 5456 CB PRO 146 -45.686 30 ATOM 5457 CG PRO 146 -46.458 31 ATOM 5458 C PRO 146 -43.247 30 ATOM 5459 0 PRO 146 -42.752 30 ATOM 5460 N GLY 147 -42.668 30 ATOM 5461 CA GLY 147 -41.256 30 ATOM 5462 C GLY 147 -40.878 32 ATOM 5463 0 GLY 147 -39.990 32 ATOM 5464 N ALA 148 -41.533 33 ATOM 5465 CA ALA 148 -41.119 34 ATOM 5466 CB ALA 148 -42.205 35 ATOM 5467 C ALA 148 -40.826 34 ATOM 5468 0 ALA 148 -41.658 34 ATOM 5469 N VAL 149 -39.638 35 ATOM 5470 CA VAL 149 -39.300 36 40.937 1.00 34.32 L C 40.009 1.00 32.61 L C 38.816 1.00 32.03 L 0 40.868 1.00 36.04 L c 41.630 1.00 39.55 L s 40.559 1.00 30.81 L N 39.745 1.00 32.77 L c 40.041 1.00 32.67 L c 39.777 1.00 33.78 L c 40.172 1.00 31.83 L c 38.302 1.00 30.83 L c 40.018 1.00 33.03 L c 41.169 1.00 32.85 L 0 38.946 1.00 33.23 L N 39.040 1.00 33.94 L c 38.419 1.00 33.58 L c 38.822 1.00 34.21 L c 38.899 1.00 32.33 L c 38.106 1.00 32.35 L c 38.277 1.00 33.63 L c 37.088 1.00 36.23 L 0 38.947 1.00 32.80 L N 38.327 1.00 33.50 L c 38.651 1.00 34.71 L c 40.040 1.00 39.34 L 0 38.720 1.00 33.10 L c 39.664 1.00 31.05 L 0 37.963 1.00 33.73 L N 38.266 1.00 35.27 L c 39.613 1.00 37.99 L c 39.606 1.00 46.04 L c 40.601 1.00 49.81 L 0 38.604 1.00 46.96 L 0 38.277 1.00 35.39 L c 39.075 1.00 35.57 L 0 37.408 1.00 32.40 L N 37.392 1.00 33.33 L c 37.632 1.00 32.73 L c 36.624 1.00 32.95 L c 35.529 1.00 32.15 L c 36.820 1.00 32.00 L c 34.649 1.00 32.86 L c 35.946 1.00 31.42 L c 34.859 1.00 31.87 L c 36.126 1.00 33.15 L c 35.051 1.00 31.11 L 0 36.277 1.00 32.99 L N 35.146 1.00 35.64 L c 34.814 1.00 35.95 L c 33.567 1.00 40.08 L c 33.623 1.00 40.50 L c 32.471 1.00 42.12 L c 32.316 1.00 39.32 L c 31.158 1.00 41.02 L c 31.240 1.00 42.27 L c 30.089 1.00 43.82 L 0 35.499 1.00 35.38 L c 36.609 1.00 37.77 L 0 34.562 1.00 35.04 L N 34.759 1.00 34.49 L c 33.217 1.00 36.14 L c 32.480 1.00 33.39 L c 33.550 1.00 35.09 L c 33.179 1.00 38.56 L c 34.200 1.00 38.92 L 0 31.981 1.00 38.91 L N 31.843 1.00 40.73 L c 31.670 1.00 41.71 L c 30.886 1.00 45.13 L 0 32.399 1.00 41.10 L N 32.410 1.00 42.96 L c 31.801 1.00 42.15 L c 33.838 1.00 43.29 L c 34.730 1.00 43.64 L 0 34.047 1.00 42.89 L N 35.315 1.00 43.55 L c 250 WO 2009/026558 PCT/US2008/074097 ATOM 5471 CB VAL 149 -38.333 35 ATOM 5472 CGI VAL 149 -39.040 34 ATOM 5473 CG2 VAL 149 -37.126 34 ATOM 5474 C VAL 149 -38.606 37 ATOM 5475 O VAL 149 -38.039 37 ATOM 5476 N THR 150 -38.651 38 ATOM 5477 CA THR 150 -37.788 39 ATOM 5478 CB THR 150 -38.603 40 ATOM 5479 OG1 THR 150 -39.451 40 ATOM 5480 CG2 THR 150 -39.455 40 ATOM 5481 C THR 150 -36.871 39 ATOM 5482 O THR 150 -37.286 39 ATOM 5483 N VAL 151 -35.623 39 ATOM 5484 CA VAL 151 -34.645 39 ATOM 5485 CB VAL 151 -33.424 39 ATOM 5486 CGI VAL 151 -32.524 38 ATOM 5487 CG2 VAL 151 -33.885 37 ATOM 5488 C VAL 151 -34.162 41 ATOM 5489 O VAL 151 -33.789 42 ATOM 5490 N ALA 152 -34.164 41 ATOM 5491 CA ALA 152 -33.621 42 ATOM 5492 CB ALA 152 -34.750 43 ATOM 5493 C ALA 152 -32.581 42 ATOM 5494 O ALA 152 -32.771 41 ATOM 5495 N TRP 153 -31.489 43 ATOM 5496 CA TRP 153 -30.434 43 ATOM 5497 CB TRP 153 -29.068 43 ATOM 5498 CG TRP 153 -28.835 41 ATOM 5499 CD2 TRP 153 -28.153 40 ATOM 5500 CE2 TRP 153 -28.095 39 ATOM 5501 CE3 TRP 153 -27.584 40 ATOM 5502 CDl TRP 153 -29.158 41 ATOM 5503 NEl TRP 153 -28.714 40 ATOM 5504 CZ2 TRP 153 -27.487 38 ATOM 5505 CZ3 TRP 153 -26.982 39 ATOM 5506 CH2 TRP 153 -26.938 38 ATOM 5507 C TRP 153 -30.425 44 ATOM 5508 0 TRP 153 -30.656 45 ATOM 5509 N LYS 154 -30.158 44 ATOM 5510 CA LYS 154 -30.028 45 ATOM 5511 CB LYS 154 -31.100 45 ATOM 5512 CG LYS 154 -32.529 45 ATOM 5513 CD LYS 154 -32.750 46 ATOM 5514 CE LYS 154 -34.157 46 ATOM 5515 NZ LYS 154 -35.197 46 ATOM 5516 C LYS 154 -28.649 45 ATOM 5517 0 LYS 154 -28.189 44 ATOM 5518 N ALA 155 -27.998 46 ATOM 5519 CA ALA 155 -26.844 46 ATOM 5520 CB ALA 155 -25.912 47 ATOM 5521 C ALA 155 -27.352 47 ATOM 5522 0 ALA 155 -27.797 48 ATOM 5523 N ASP 156 -27.292 46 ATOM 5524 CA ASP 156 -27.989 46 ATOM 5525 CB ASP 156 -27.503 48 ATOM 5526 CG ASP 156 -26.129 48 ATOM 5527 OD1 ASP 156 -25.959 47 ATOM 5528 OD2 ASP 156 -25.220 48 ATOM 5529 C ASP 156 -29.492 46 ATOM 5530 0 ASP 156 -30.177 45 ATOM 5531 N SER 157 -30.004 48 ATOM 5532 CA SER 157 -31.422 48 ATOM 5533 CB SER 157 -32.119 48 ATOM 5534 OG SER 157 -32.192 48 ATOM 5535 C SER 157 -31.650 49 ATOM 5536 0 SER 157 -32.765 49 ATOM 5537 N SER 158 -30.591 49 ATOM 5538 CA SER 158 -30.677 50 ATOM 5539 CB SER 158 -29.621 51 ATOM 5540 OG SER 158 -29.610 51 ATOM 5541 C SER 158 -30.488 49 ATOM 5542 0 SER 158 -29.701 48 ATOM 5543 N PRO 159 -31.215 49 ATOM 5544 CD PRO 159 -32.254 50 ATOM 5545 CA PRO 159 -31.157 49 ATOM 5546 CB PRO 159 -32.184 49 36.159 1.00 42.09 L C 36.679 1.00 40.84 L C 35.318 1.00 40.82 L c 35.027 1.00 44.09 L c 33.951 1.00 44.44 L 0 35.990 1.00 44.32 L N 35.947 1.00 45.76 L c 35.969 1.00 47.68 L c 37.124 1.00 50.74 L 0 34.710 1.00 48.08 L c 37.159 1.00 44.03 L c 38 .251 1.00 42.08 L 0 36.960 1.00 43.16 L N 38.034 1.00 43.36 L c 37.659 1.00 43.35 L c 38.880 1.00 42.41 L c 37.119 1.00 41.25 L c 38.343 1.00 43.86 L c 37.442 1.00 44.90 L 0 39.623 1.00 44.46 L N 40.067 1.00 46.25 L c 40.590 1.00 44.32 L c 41.167 1.00 46.44 L c 42.041 1.00 45.37 L 0 41.121 1.00 46.96 L N 42.124 1.00 48.34 L c 41.445 1.00 46.62 L c 40.692 1.00 44.35 L c 41.174 1.00 43.29 L c 40.106 1.00 42.33 L c 42.403 1.00 41.90 L c 39.390 1.00 43.20 L c 39.030 1.00 41.75 L N 40.231 1.00 41.82 L c 42.525 1.00 40.30 L c 41.443 1.00 41.25 L c 43.055 1.00 50.76 L c 42.619 1.00 51.60 L 0 44.337 1.00 53.56 L N 45.311 1.00 55.91 L c 46.400 1.00 57.60 L c 45.893 1.00 61.06 L c 45.026 1.00 64.51 L c 44.439 1.00 65.49 L c 45.509 1.00 67.42 L N 45.974 1.00 56.74 L c 46.490 1.00 55.15 L 0 45.952 1.00 57.64 L N 46.809 1.00 59.43 L c 46.147 1.00 58.00 L c 48.142 1.00 60.59 L c 48.228 1.00 60.44 L 0 49.176 1.00 62.39 L N 50.426 1.00 65.83 L c 51.032 1.00 67.21 L c 51.654 1.00 69.56 L c 52.554 1.00 70.11 L 0 51.239 1.00 71.44 L 0 50.195 1.00 67.34 L c 50.179 1.00 68.08 L 0 50.012 1.00 68.19 L N 49.739 1.00 69.31 L c 50.954 1.00 70.08 L c 52.025 1.00 71.57 L 0 48.513 1.00 69.35 L c 48.265 1.00 69.73 L 0 47.747 1.00 68.83 L N 46.580 1.00 69.49 L c 46.679 1.00 70.91 L c 47.986 1.00 73.20 L 0 45.285 1.00 69.20 L c 45.225 1.00 69.63 L 0 44.229 1.00 68.97 L N 44.259 1.00 69.29 L c 42.926 1.00 68.40 L c 42.083 1.00 68.16 L c 251 WO 2009/026558 PCT/US2008/074097 ATOM 5547 CG PRO 159 -33.113 50 ATOM 5548 C PRO 159 -29.771 49 ATOM 5549 O PRO 159 -29.129 50 ATOM 5550 N VAL 160 -29.317 48 ATOM 5551 CA VAL 160 -28.076 48 ATOM 5552 CB VAL 160 -27.268 46 ATOM 5553 CGI VAL 160 -25.984 46 ATOM 5554 CG2 VAL 160 -26.970 46 ATOM 5555 C VAL 160 -28.415 47 ATOM 5556 O VAL 160 -29.066 47 ATOM 5557 N LYS 161 -27.968 48 ATOM 5558 CA LYS 161 -28.304 48 ATOM 5559 CB LYS 161 -28.436 50 ATOM 5560 CG LYS 161 -29.469 51 ATOM 5561 CD LYS 161 -30.885 50 ATOM 5562 CE LYS 161 -31.912 51 ATOM 5563 NZ LYS 161 -33.299 51 ATOM 5564 C LYS 161 -27.254 48 ATOM 5565 0 LYS 161 -27.562 47 ATOM 5566 N ALA 162 -26.012 48 ATOM 5567 CA ALA 162 -24.935 48 ATOM 5568 CB ALA 162 -23.839 49 ATOM 5569 C ALA 162 -24.344 46 ATOM 5570 O ALA 162 -24.505 46 ATOM 5571 N GLY 163 -23.663 46 ATOM 5572 CA GLY 163 -22.992 45 ATOM 5573 C GLY 163 -23.885 43 ATOM 5574 0 GLY 163 -23.441 42 ATOM 5575 N VAL 164 -25.137 43 ATOM 5576 CA VAL 164 -26.079 42 ATOM 5577 CB VAL 164 -27.466 43 ATOM 5578 CGI VAL 164 -28.429 42 ATOM 5579 CG2 VAL 164 -27.365 43 ATOM 5580 C VAL 164 -26.237 42 ATOM 5581 O VAL 164 -26.474 42 ATOM 5582 N GLU 165 -26.106 40 ATOM 5583 CA GLU 165 -26.428 40 ATOM 5584 CB GLU 165 -25.143 39 ATOM 5585 CG GLU 165 -24.375 41 ATOM 5586 CD GLU 165 -23.153 40 ATOM 5587 OE1 GLU 165 -23.033 41 ATOM 5588 OE2 GLU 165 -22.312 39 ATOM 5589 C GLU 165 -27.238 38 ATOM 5590 0 GLU 165 -26.797 38 ATOM 5591 N THR 166 -28.430 38 ATOM 5592 CA THR 166 -29.392 37 ATOM 5593 CB THR 166 -30.700 38 ATOM 5594 OG1 THR 166 -30.414 39 ATOM 5595 CG2 THR 166 -31.691 37 ATOM 5596 C THR 166 -29.719 36 ATOM 5597 O THR 166 -29.941 37 ATOM 5598 N THR 167 -29.749 35 ATOM 5599 CA THR 167 -30.116 34 ATOM 5600 CB THR 167 -29.722 33 ATOM 5601 OG1 THR 167 -30.455 32 ATOM 5602 CG2 THR 167 -28.233 33 ATOM 5603 C THR 167 -31.627 34 ATOM 5604 O THR 167 -32.373 35 ATOM 5605 N THR 168 -32.078 34 ATOM 5606 CA THR 168 -33.509 34 ATOM 5607 CB THR 168 -33.852 34 ATOM 5608 OG1 THR 168 -33.082 33 ATOM 5609 CG2 THR 168 -33.535 35 ATOM 5610 C THR 168 -33.922 32 ATOM 5611 O THR 168 -33.178 31 ATOM 5612 N PRO 169 -35.116 32 ATOM 5613 CD PRO 169 -36.045 33 ATOM 5614 CA PRO 169 -35.595 31 ATOM 5615 CB PRO 169 -37.008 31 ATOM 5616 CG PRO 169 -36.956 33 ATOM 5617 C PRO 169 -35.571 30 ATOM 5618 O PRO 169 -35.869 30 ATOM 5619 N SER 170 -35.207 29 ATOM 5620 CA SER 170 -35.041 28 ATOM 5621 CB SER 170 -33.561 27 ATOM 5622 OG SER 170 -33.297 26 43.082 1.00 69.30 L C 42.294 1.00 68.38 L C 42.249 1.00 68.62 L 0 41.804 1.00 67.89 L N 41.047 1.00 67.89 L c 41.426 1.00 67.44 L c 40.614 1.00 66.24 L c 42.917 1.00 66.87 L c 39.566 1.00 68.75 L c 39.128 1.00 70.43 L 0 38.796 1.00 68.73 L N 37.378 1.00 68.60 L c 36.927 1.00 73.13 L c 37.711 1.00 77.34 L c 37.505 1.00 80.36 L c 38.294 1.00 82.15 L c 38.144 1.00 82.95 L N 36.523 1.00 65.92 L c 35.787 1.00 65.61 L 0 36.634 1.00 61.33 L N 35.763 1.00 57.37 L c 35.699 1.00 57.49 L c 36.219 1.00 53.70 L c 37.368 1.00 51.79 L 0 35.303 1.00 50.45 L N 35.646 1.00 49.48 L c 35.674 1.00 48.47 L c 36.078 1.00 49.78 L 0 35.252 1.00 44.89 L N 35.282 1.00 42.87 L c 35.757 1.00 41.38 L c 35.757 1.00 40.11 L c 37.146 1.00 40.00 L c 33.920 1.00 42.51 L c 32.926 1.00 43.92 L 0 33.874 1.00 41.72 L N 32.664 1.00 43.48 L c 31.911 1.00 45.09 L c 31.483 1.00 50.70 L c 30.637 1.00 54.19 L c 29.542 1.00 54.85 L 0 31.070 1.00 55.72 L 0 32.984 1.00 42.87 L c 33.752 1.00 42.63 L 0 32.394 1.00 41.04 L N 32.681 1.00 40.42 L c 33.233 1.00 40.61 L c 34.406 1.00 41.13 L 0 33.580 1.00 40.33 L c 31.415 1.00 40.37 L c 30.360 1.00 42.10 L 0 31.513 1.00 41.03 L N 30.365 1.00 40.58 L c 30.567 1.00 39.43 L c 31.671 1.00 39.95 L 0 30.832 1.00 38.27 L c 30.149 1.00 41.37 L c 31.010 1.00 41.43 L 0 28.996 1.00 41.45 L N 28.760 1.00 42.31 L c 27.256 1.00 44 . 42 L c 26.522 1.00 48.18 L 0 26.732 1.00 44.90 L c 29.259 1.00 40.42 L c 29.112 1.00 40.27 L 0 29.858 1.00 40.18 L N 30.151 1.00 40.79 L c 30.400 1.00 41.42 L c 30.879 1.00 39.94 L c 31.200 1.00 41.04 L c 29.364 1.00 42.24 L c 28.193 1.00 45.17 L 0 29.805 1.00 42.33 L N 28.907 1.00 43.07 L c 28.562 1.00 42.97 L c 27.950 1.00 50.77 L 0 252 WO 2009/026558 PCT/US2008/074097 ATOM 5623 c SER 170 -35.566 26 ATOM 5624 0 SER 170 -35.396 26 ATOM 5625 N LYS 171 -36.211 25 ATOM 5626 CA LYS 171 -36.836 24 ATOM 5627 CB LYS 171 -37.741 24 ATOM 5628 CG LYS 171 -39.099 24 ATOM 5629 CD LYS 171 -40.179 23 ATOM 5630 CE LYS 171 -41.558 24 ATOM 5631 NZ LYS 171 -42.624 23 ATOM 5632 C LYS 171 -35.805 23 ATOM 5633 0 LYS 171 -34.858 23 ATOM 5634 N GLN 172 -36.007 23 ATOM 5635 CA GLN 172 -35.185 22 ATOM 5636 CB GLN 172 -35.218 22 ATOM 5637 CG GLN 172 -34.806 23 ATOM 5638 CD GLN 172 -35.245 23 ATOM 5639 OE1 GLN 172 -34.665 24 ATOM 5640 NE2 GLN 172 -36.273 22 ATOM 5641 C GLN 172 -35.736 20 ATOM 5642 0 GLN 172 -36.790 20 ATOM 5643 N SER 173 -35.031 19 ATOM 5644 CA SER 173 -35.463 18 ATOM 5645 CB SER 173 -34.335 17 ATOM 5646 OG SER 173 -34.118 17 ATOM 5647 C SER 173 -36.715 17 ATOM 5648 O SER 173 -37.363 16 ATOM 5649 N ASN 174 -37.058 18 ATOM 5650 CA ASN 174 -38.284 18 ATOM 5651 CB ASN 174 -38.067 18 ATOM 5652 CG ASN 174 -37.959 19 ATOM 5653 OD1 ASN 174 -37.810 20 ATOM 5654 ND2 ASN 174 -38.036 20 ATOM 5655 C ASN 174 -39.426 19 ATOM 5656 0 ASN 174 -40.484 19 ATOM 5657 N ASN 175 -39.188 19 ATOM 5658 CA ASN 175 -40.231 20 ATOM 5659 CB ASN 175 -41.476 19 ATOM 5660 CG ASN 175 -42.214 20 ATOM 5661 OD1 ASN 175 -43.406 20 ATOM 5662 ND2 ASN 175 -41.502 20 ATOM 5663 C ASN 175 -40.621 21 ATOM 5664 0 ASN 175 -41.609 22 ATOM 5665 N LYS 176 -39.847 22 ATOM 5666 CA LYS 176 -39.974 23 ATOM 5667 CB LYS 176 -39.993 23 ATOM 5668 CG LYS 176 -41.086 22 ATOM 5669 CD LYS 176 -41.149 22 ATOM 5670 CE LYS 176 -41.815 21 ATOM 5671 NZ LYS 176 -42.250 21 ATOM 5672 C LYS 176 -38.802 24 ATOM 5673 0 LYS 176 -37.914 24 ATOM 5674 N TYR 177 -38.804 25 ATOM 5675 CA TYR 177 -37.856 26 ATOM 5676 CB TYR 177 -38.582 28 ATOM 5677 CG TYR 177 -39.386 27 ATOM 5678 CDl TYR 177 -38.803 28 ATOM 5679 CEl TYR 177 -39.535 28 ATOM 5680 CD2 TYR 177 -40.732 27 ATOM 5681 CE2 TYR 177 -41.477 27 ATOM 5682 CZ TYR 177 -40.870 27 ATOM 5683 OH TYR 177 -41.600 27 ATOM 5684 C TYR 177 -36.682 27 ATOM 5685 O TYR 177 -36.783 26 ATOM 5686 N ALA 178 -35.571 27 ATOM 5687 CA ALA 178 -34.397 27 ATOM 5688 CB ALA 178 -33.345 26 ATOM 5689 C ALA 178 -33.804 29 ATOM 5690 O ALA 178 -33.840 29 ATOM 5691 N ALA 179 -33.252 30 ATOM 5692 CA ALA 179 -32.551 31 ATOM 5693 CB ALA 179 -33.519 32 ATOM 5694 C ALA 179 -31.450 31 ATOM 5695 O ALA 179 -31.486 30 ATOM 5696 N SER 180 -30.468 32 ATOM 5697 CA SER 180 -29.469 32 ATOM 5698 CB SER 180 -28.191 31 29.582 1.00 43.51 L C 30.790 1.00 43.82 L O 28.809 1.00 43.46 L N 29.359 1.00 44.64 L C 28.317 1.00 46.55 L C 28.140 1.00 51.02 L c 28.923 1.00 52.77 L c 28.315 1.00 54.67 L c 28.902 1.00 54.14 L N 29.833 1.00 44 . 02 L c 29.119 1.00 43.67 L 0 31.041 1.00 44.49 L N 31.583 1.00 46.21 L c 33.116 1.00 45.47 L c 33.714 1.00 49.31 L c 35.167 1.00 49.94 L c 35.909 1.00 52.52 L 0 35.570 1.00 51.29 L N 31.093 1.00 45.91 L c 30.461 1.00 46.76 L 0 31.396 1.00 46.60 L N 30.961 1.00 48.58 L c 31.157 1.00 49.25 L c 32.535 1.00 52.49 L 0 31.711 1.00 48.45 L c 31.307 1.00 48.69 L 0 32.799 1.00 47.11 L N 33.526 1.00 47.32 L c 35.032 1.00 48.35 L c 35.483 1.00 51.01 L c 34.666 1.00 50.68 L 0 36.794 1.00 52.49 L N 33.093 1.00 47.13 L c 33.721 1.00 47.39 L 0 32.028 1.00 46.42 L N 31.378 1.00 46.60 L c 31.148 1.00 49.67 L c 29.886 1.00 56.34 L c 29.920 1.00 58.64 L 0 28.757 1.00 57.45 L N 32.126 1.00 44.32 L c 31.789 1.00 42.56 L 0 33.144 1.00 42.39 L N 33.753 1.00 40.88 L c 35.281 1.00 41.57 L c 35.806 1.00 43.43 L c 37.330 1.00 46.57 L c 37.867 1.00 48.69 L c 39.295 1.00 52.64 L N 33.290 1.00 39.00 L c 32.580 1.00 36.87 L 0 33.686 1.00 37.05 L N 33.143 1.00 37.79 L c 32.787 1.00 40.04 L c 31.509 1.00 42.10 L c 30.285 1.00 4 3.92 L c 29.114 1.00 46.21 L c 31.527 1.00 43.08 L c 30.361 1.00 46.97 L c 29.153 1.00 47.58 L c 27.987 1.00 48.95 L 0 34.065 1.00 36.65 L c 35.291 1.00 35.52 L 0 33.458 1.00 34.98 L N 34.205 1.00 34.14 L c 34.220 1.00 33.79 L c 33.599 1.00 34.93 L c 32.380 1.00 34.79 L 0 34.461 1.00 32.77 L N 34.019 1.00 31.61 L c 33.943 1.00 30.08 L c 35.024 1.00 32.24 L c 36.148 1.00 31.98 L 0 34.629 1.00 32.46 L N 35.585 1.00 34.62 L c 35.475 1.00 34.30 L c 253 WO 2009/026558 PCT/US2008/074097 ATOM 5699 OG SER 180 -27.821 31 ATOM 5700 C SER 180 -29.149 34 ATOM 5701 O SER 180 -29.371 34 ATOM 5702 N SER 181 -28.648 34 ATOM 5703 CA SER 181 -28.306 36 ATOM 5704 CB SER 181 -29.420 37 ATOM 5705 OG SER 181 -29.219 38 ATOM 5706 C SER 181 -26.975 36 ATOM 5707 O SER 181 -26.740 36 ATOM 5708 N TYR 182 -26.110 37 ATOM 5709 CA TYR 182 -24.768 37 ATOM 5710 CB TYR 182 -23.739 37 ATOM 5711 CG TYR 182 -23.721 35 ATOM 5712 CDl TYR 182 -24.573 34 ATOM 5713 CE1 TYR 182 -24.556 33 ATOM 5714 CD2 TYR 182 -22.850 34 ATOM 5715 CE2 TYR 182 -22.823 33 ATOM 5716 CZ TYR 182 -23.675 32 ATOM 5717 OH TYR 182 -23.624 31 ATOM 5718 C TYR 182 -24.576 39 ATOM 5719 O TYR 182 -24.817 39 ATOM 5720 N LEU 183 -24.136 39 ATOM 5721 CA LEU 183 -23.780 40 ATOM 5722 CB LEU 183 -24.485 41 ATOM 5723 CG LEU 183 -24.120 42 ATOM 5724 CDl LEU 183 -24.315 43 ATOM 5725 CD2 LEU 183 -24.983 42 ATOM 5726 C LEU 183 -22.269 40 ATOM 5727 O LEU 183 -21.681 40 ATOM 5728 N SER 184 -21.648 41 ATOM 5729 CA SER 184 -20.215 41 ATOM 5730 CB SER 184 -19.639 42 ATOM 5731 OG SER 184 -19.775 40 ATOM 5732 C SER 184 -19.913 43 ATOM 5733 O SER 184 -20.460 44 ATOM 5734 N LEU 185 -19.036 42 ATOM 5735 CA LEU 185 -18.597 44 ATOM 5736 CB LEU 185 -19.093 43 ATOM 5737 CG LEU 185 -20.592 43 ATOM 5738 CDl LEU 185 -20.840 43 ATOM 5739 CD2 LEU 185 -21.267 45 ATOM 5740 C LEU 185 -17.069 44 ATOM 5741 O LEU 185 -16.414 43 ATOM 5742 N THR 186 -16.502 45 ATOM 5743 CA THR 186 -15.103 45 ATOM 5744 CB THR 186 -14.512 46 ATOM 5745 OG1 THR 186 -15.145 47 ATOM 5746 CG2 THR 186 -14.720 47 ATOM 5747 C THR 186 -15.067 44 ATOM 5748 O THR 186 -16.047 44 ATOM 5749 N PRO 187 -13.937 44 ATOM 5750 CD PRO 187 -12.753 43 ATOM 5751 CA PRO 187 -13.813 43 ATOM 5752 CB PRO 187 -12.374 43 ATOM 5753 CG PRO 187 -12.048 42 ATOM 5754 C PRO 187 -14.098 44 ATOM 5755 O PRO 187 -14.677 44 ATOM 5756 N GLU 188 -13.707 45 ATOM 5757 CA GLU 188 -13.931 47 ATOM 5758 CB GLU 188 -13.236 48 ATOM 5759 CG GLU 188 -11.728 48 ATOM 5760 CD GLU 188 -11.354 47 ATOM 5761 OE1 GLU 188 -10.157 47 ATOM 5762 OE2 GLU 188 -12.252 47 ATOM 5763 C GLU 188 -15.424 47 ATOM 5764 O GLU 188 -15.875 47 ATOM 5765 N GLN 189 -16.186 47 ATOM 5766 CA GLN 189 -17.634 47 ATOM 5767 CB GLN 189 -18.266 47 ATOM 5768 CG GLN 189 -17.986 48 ATOM 5769 CD GLN 189 -18.586 48 ATOM 5770 OE1 GLN 189 -18.126 47 ATOM 5771 NE2 GLN 189 -19.623 49 ATOM 5772 C GLN 189 -18.245 46 ATOM 5773 0 GLN 189 -19.102 46 ATOM 5774 N TRP 190 -17.803 45
34.130 1.00 36.12 L O 35.401 1.00 35.73 L C 34.328 1.00 36.20 L 0 36.464 1.00 35.66 L N 36.428 1.00 35.32 L c 37.085 1.00 35.39 L c 36.863 1.00 35.35 L 0 37.134 1.00 34.93 L c 38.246 1.00 34.66 L 0 36.474 1.00 34.88 L N 36.970 1.00 34.05 L c 35.936 1.00 33.06 L c 35.710 1.00 33.67 L c 34.787 1.00 33.90 L c 34.580 1.00 32.99 L c 36.422 1.00 34.60 L c 36.226 1.00 33.92 L c 35.304 1.00 34.85 L c 35.101 1.00 35.11 L 0 37.246 1.00 35.65 L c 36.373 1.00 34.81 L 0 38.456 1.00 35.39 L N 38.778 1.00 36.48 L c 40.062 1.00 36.53 L c 40.611 1.00 38.34 L c 39.541 1.00 38.29 L c 41.831 1.00 37.55 L c 38.946 1.00 37.69 L c 39.847 1.00 38.05 L 0 38.067 1.00 38.46 L N 38.142 1.00 40.81 L c 36.741 1.00 39.79 L c 35.960 1.00 42.53 L 0 38.992 1.00 42.63 L c 38.759 1.00 44.23 L 0 39.977 1.00 44.38 L N 40.854 1.00 44 .18 L c 42.276 1.00 43.90 L c 42.518 1.00 45.77 L c 43.987 1.00 43.80 L c 42.125 1.00 46.33 L c 40.879 1.00 45.19 L c 40.556 1.00 45.27 L 0 41.271 1.00 44.94 L N 41.691 1.00 44.94 L c 41.708 1.00 44.97 L c 42.742 1.00 47.27 L 0 40.367 1.00 42.76 L c 43.115 1.00 44.48 L c 43.859 1.00 43.11 L 0 43.515 1.00 44.61 L N 42.702 1.00 43.46 L c 44.890 1.00 45.61 L c 44.959 1.00 43.07 L c 43.546 1.00 44 . 14 L c 45.917 1.00 47.37 L c 46.973 1.00 47.85 L 0 45.597 1.00 49.99 L N 46.500 1.00 54.63 L c 45.963 1.00 57.78 L c 45.779 1.00 64.11 L c 44.562 1.00 67.50 L c 44.411 1.00 70.08 L 0 43.756 1.00 69.12 L 0 46.695 1.00 54.97 L c 47.818 1.00 54.27 L 0 45.602 1.00 54.96 L N 45.688 1.00 54.99 L c 44.297 1.00 57.33 L c 43.461 1.00 59.74 L c 42.076 1.00 62.10 L c 41.244 1.00 62.33 L 0 41.819 1.00 63.40 L N 46.533 1.00 54.40 L c 47.379 1.00 54.55 L 0 46.298 1.00 53.18 L N 254 WO 2009/026558 PCT/US2008/074097 ATOM 5775 CA TRP 190 -18.328 43 ATOM 5776 CB TRP 190 -17.647 42 ATOM 5777 CG TRP 190 -17.835 41 ATOM 5778 CD2 TRP 190 -19.078 40 ATOM 5779 CE2 TRP 190 -18.767 39 ATOM 5780 CE3 TRP 190 -20.420 41 ATOM 5781 CD1 TRP 190 -16.853 40 ATOM 5782 NEl TRP 190 -17.403 39 ATOM 5783 CZ2 TRP 190 -19.749 39 ATOM 5784 CZ3 TRP 190 -21.395 40 ATOM 5785 CH2 TRP 190 -21.054 39 ATOM 5786 C TRP 190 -18.122 44 ATOM 5787 O TRP 190 -19.014 43 ATOM 5788 N LYS 191 -16.949 44 ATOM 5789 CA LYS 191 -16.606 44 ATOM 5790 CB LYS 191 -15.087 44 ATOM 5791 CG LYS 191 -14.517 43 ATOM 5792 CD LYS 191 -13.238 42 ATOM 5793 CE LYS 191 -12.009 43 ATOM 5794 NZ LYS 191 -11.653 42 ATOM 5795 C LYS 191 -17.142 45 ATOM 5796 0 LYS 191 -17.204 46 ATOM 5797 N SER 192 -17.545 46 ATOM 5798 CA SER 192 -17.975 48 ATOM 5799 CB SER 192 -17.613 49 ATOM 5800 OG SER 192 -18.392 49 ATOM 5801 C SER 192 -19.467 48 ATOM 5802 O SER 192 -19.935 49 ATOM 5803 N HIS 193 -20.217 47 ATOM 5804 CA HIS 193 -21.638 47 ATOM 5805 CB HIS 193 -22.485 46 ATOM 5806 CG HIS 193 -22.486 48 ATOM 5807 CD2 HIS 193 -23.325 49 ATOM 5808 ND1 HIS 193 -21.535 48 ATOM 5809 CEl HIS 193 -21.789 49 ATOM 5810 NE2 HIS 193 -22.870 49 ATOM 5811 C HIS 193 -21.924 46 ATOM 5812 0 HIS 193 -21.148 45 ATOM 5813 N ARG 194 -23.040 46 ATOM 5814 CA ARG 194 -23.416 45 ATOM 5815 CB ARG 194 -24.500 45 ATOM 5816 CG ARG 194 -23.971 46 ATOM 5817 CD ARG 194 -23.055 46 ATOM 5818 NE ARG 194 -22.122 47 ATOM 5819 CZ ARG 194 -21.136 46 ATOM 5820 NH1 ARG 194 -20.332 47 ATOM 5821 NH2 ARG 194 -20.953 45 ATOM 5822 C ARG 194 -23.916 44 ATOM 5823 O ARG 194 -23.696 42 ATOM 5824 N SER 195 -24.595 44 ATOM 5825 CA SER 195 -25.120 42 ATOM 5826 CB SER 195 -26.280 42 ATOM 5827 OG SER 195 -27.376 43 ATOM 5828 C SER 195 -25.581 43 ATOM 5829 O SER 195 -25.760 44 ATOM 5830 N TYR 196 -25.757 42 ATOM 5831 CA TYR 196 -26.331 42 ATOM 5832 CB TYR 196 -25.279 41 ATOM 5833 CG TYR 196 -24.395 43 ATOM 5834 CD1 TYR 196 -24.664 43 ATOM 5835 CEl TYR 196 -23.850 44 ATOM 5836 CD2 TYR 196 -23.279 43 ATOM 5837 CE2 TYR 196 -22.451 44 ATOM 5838 CZ TYR 196 -22.742 45 ATOM 5839 OH TYR 196 -21.920 46 ATOM 5840 C TYR 196 -27.493 41 ATOM 5841 O TYR 196 -27.504 40 ATOM 5842 N SER 197 -28.480 41 ATOM 5843 CA SER 197 -29.666 40 ATOM 5844 CB SER 197 -30.846 41 ATOM 5845 OG SER 197 -30.752 41 ATOM 5846 C SER 197 -30.043 40 ATOM 5847 O SER 197 -29.923 41 ATOM 5848 N CYS 198 -30.490 39 ATOM 5849 CA CYS 198 -31.085 38 ATOM 5850 C CYS 198 -32.590 38 47.031 1.00 52.69 L C 46.555 1.00 47.71 L C 47.469 1.00 43.39 L c 47.852 1.00 42.46 L c 48.690 1.00 41.15 L c 47.568 1.00 40.32 L c 48.076 1.00 42.75 L c 48.810 1.00 40.87 L N 49.246 1.00 39.96 L c 48.123 1.00 39.31 L c 48.951 1.00 37.86 L c 48.532 1.00 55.45 L c 49.325 1.00 56.54 L 0 48.922 1.00 57.84 L N 50.337 1.00 61.22 L c 50.514 1.00 63.09 L c 50.141 1.00 68.04 L c 50.908 1.00 71.58 L c 50.217 1.00 73.94 L c 48.975 1.00 75.18 L N 51.037 1.00 61.69 L c 52.264 1.00 61.30 L 0 50.259 1.00 62.65 L N 50.824 1.00 63.95 L c 49.874 1.00 64.65 L c 48.692 1.00 67.19 L 0 51.161 1.00 64.72 L c 51.673 1.00 66.00 L 0 50.874 1.00 63.86 L N 51.216 1.00 61.95 L c 49.970 1.00 61.37 L c 48.988 1.00 61.60 L c 48.841 1.00 61.56 L c 47.998 1.00 61.98 L N 47.283 1.00 62.58 L c 47.773 1.00 62.31 L N 52.2 60 1.00 62.02 L C 52.428 1.00 62.20 L 0 52.965 1.00 62.45 L N 53.991 1.00 63.53 L C 54.902 1.00 68.20 L c 55.941 1.00 75.45 L c 56.922 1.00 80.85 L c 57.584 1.00 85.64 L N 58.386 1.00 87.72 L c 58.947 1.00 88.22 L N 58.629 1.00 88.28 L N 53.369 1.00 61.25 L C 53.910 1.00 60.80 L 0 52.232 1.00 57.80 L N 51.562 1.00 55.09 L C 52.369 1.00 55.10 L c 52.411 1.00 57.11 L 0 50.142 1.00 52.03 L c 49.748 1.00 51.53 L 0 49.374 1.00 48.88 L N 48.044 1.00 45.63 L c 46.989 1.00 44.45 L c 46.626 1.00 44.49 L c 45.501 1.00 43.92 L c 45.140 1.00 46.40 L c 47.390 1.00 45.08 L c 47.035 1.00 45.84 L c 45.907 1.00 47.07 L c 45.516 1.00 48.23 L 0 47.946 1.00 44.90 L c 48.614 1.00 44.93 L 0 47.126 1.00 44.07 L N 47.001 1.00 44.08 L c 47.727 1.00 43.76 L c 49.125 1.00 46.25 L 0 45.556 1.00 43.65 L c 44.687 1.00 42.68 L 0 45.311 1.00 42.68 L N 44.037 1.00 43.42 L c 44.260 1.00 42.81 L c 255 WO 2009/026558 PCT/US2008/074097 ATOM 5851 0 CYS 198 -33.036 38 ATOM 5852 CB CYS 198 -30.516 37 ATOM 5853 SG CYS 198 -31.115 37 ATOM 5854 N GLN 199 -33.368 39 ATOM 5855 CA GLN 199 -34.826 39 ATOM 5856 CB GLN 199 -35.370 41 ATOM 5857 CG GLN 199 -34.995 41 ATOM 5858 CD GLN 199 -35.634 42 ATOM 5859 OE1 GLN 199 -35.855 43 ATOM 5860 NE2 GLN 199 -35.935 43 ATOM 5861 C GLN 199 -35.462 39 ATOM 5862 0 GLN 199 -35.324 39 ATOM 5863 N VAL 200 -36.160 37 ATOM 5864 CA VAL 200 -36.772 37 ATOM 5865 CB VAL 200 -36.363 35 ATOM 58 66 CGI VAL 200 -37.035 35 ATOM 5867 CG2 VAL 200 -34.842 35 ATOM 5868 C VAL 200 -38.284 37 ATOM 5869 O VAL 200 -38.897 36 ATOM 5870 N THR 201 -38.880 38 ATOM 5871 CA THR 201 -40.323 38 ATOM 5872 CB THR 201 -40.698 39 ATOM 5873 OG1 THR 201 -40.139 40 ATOM 5874 CG2 THR 201 -42.218 39 ATOM 5875 C THR 201 -40.935 37 ATOM 5876 O THR 201 -40.502 37 ATOM 5877 N HIS 202 -41.942 36 ATOM 5878 CA HIS 202 -42.586 35 ATOM 5879 CB HIS 202 -42.032 34 ATOM 5880 CG HIS 202 -42.664 33 ATOM 5881 CD2 HIS 202 -42.498 32 ATOM 5882 ND1 HIS 202 -43.575 32 ATOM 5883 CEl HIS 202 -43.941 31 ATOM 5884 NE2 HIS 202 -43.301 31 ATOM 5885 C HIS 202 -44.081 35 ATOM 5886 0 HIS 202 -44.516 35 ATOM 5887 N GLU 203 -44.862 35 ATOM 5888 CA GLU 203 -46.310 36 ATOM 5889 CB GLU 203 -46.907 34 ATOM 5890 CG GLU 203 -46.537 33 ATOM 5891 CD GLU 203 -47.209 33 ATOM 5892 OE1 GLU 203 -46.488 34 ATOM 5893 OE2 GLU 203 -48.460 33 ATOM 5894 C GLU 203 -46.676 36 ATOM 5895 O GLU 203 -47.514 36 ATOM 5896 N GLY 203 -46.031 38 ATOM 5897 CA GLY 203 -46.380 39 ATOM 5898 C GLY 203 -45.999 38 ATOM 5899 0 GLY 203 -46.399 39 ATOM 5900 N SER 205 -45.243 37 ATOM 5901 CA SER 205 -44.651 37 ATOM 5902 CB SER 205 -45.060 35 ATOM 5903 OG SER 205 -46.365 35 ATOM 5904 C SER 205 -43.135 37 ATOM 5905 O SER 205 -42.511 36 ATOM 5906 N THR 206 -42.548 37 ATOM 5907 CA THR 206 -41.107 38 ATOM 5908 CB THR 206 -40.781 39 ATOM 5909 OG1 THR 206 -41.343 40 ATOM 5910 CG2 THR 206 -39.279 39 ATOM 5911 C THR 206 -40.415 37 ATOM 5912 O THR 206 -40.846 36 ATOM 5913 N VAL 207 -39.351 36 ATOM 5914 CA VAL 207 -38.490 35 ATOM 5915 CB VAL 207 -38.309 34 ATOM 5916 CGI VAL 207 -37.331 33 ATOM 5917 CG2 VAL 207 -39.642 33 ATOM 5918 C VAL 207 -37.120 36 ATOM 5919 O VAL 207 -36.562 36 ATOM 5920 N GLU 208 -36.582 36 ATOM 5921 CA GLU 208 -35.353 37 ATOM 5922 CB GLU 208 -35.661 38 ATOM 5923 CG GLU 208 -34.455 39 ATOM 5924 CD GLU 208 -34.835 40 ATOM 5925 OE1 GLU 208 -34.754 41 ATOM 5926 OE2 GLU 208 -35.218 40 45.089 1.00 41.88 L O 43.548 1.00 42.55 L C 41.887 1.00 48.59 L s 43.532 1.00 42.44 L N 43.650 1.00 43.18 L c 43.922 1.00 45.67 L c 45.290 1.00 53.84 L c 45.584 1.00 56.85 L c 44.681 1.00 60.04 L 0 46.852 1.00 58.12 L N 42.381 1.00 41.40 L c 41.306 1.00 40.06 L 0 42.508 1.00 40.36 L N 41.347 1.00 39.58 L c 41.230 1.00 40.32 L c 40.010 1.00 37.77 L c 41.120 1.00 38.20 L c 41.433 1.00 39.21 L c 42.388 1.00 37.45 L 0 40.429 1.00 39.72 L N 40.389 1.00 40.93 L c 40.082 1.00 43.40 L c 41.092 1.00 45.08 L 0 40.073 1.00 43.33 L c 39.332 1.00 40.49 L c 38.176 1.00 39.58 L 0 39.748 1.00 41.15 L N 38.891 1.00 41.11 L c 39.196 1.00 38.98 L c 38.394 1.00 36.71 L c 37.101 1.00 35.64 L c 38.930 1.00 35.58 L N 38.003 1.00 35.45 L c 36.883 1.00 35.15 L N 39.165 1.00 42.13 L C 40.279 1.00 41.36 L 0 38.151 1.00 44.96 L N 38.298 1.00 47.24 L C 38.489 1.00 49.44 L c 37.394 1.00 53.20 L c 36.076 1.00 57.10 L c 35.082 1.00 59.14 L 0 36.038 1.00 57.31 L 0 39.486 1.00 47.57 L c 40.306 1.00 47.36 L 0 39.586 1.00 49.08 L N 40.626 1.00 50.03 L c 42.040 1.00 52.56 L c 43.000 1.00 54.19 L 0 42.189 1.00 52.78 L N 43.484 1.00 53.25 L c 43.934 1.00 54.26 L c 44.481 1.00 57.58 L 0 43.423 1.00 53.40 L c 42.476 1.00 53.90 L 0 44.439 1.00 53.20 L N 44.486 1.00 54.04 L c 44.891 1.00 54.25 L c 43.926 1.00 55.24 L 0 44.948 1.00 54.82 L c 45.457 1.00 53.61 L c 46.599 1.00 53.73 L 0 44.987 1.00 52.25 L N 45.848 1.00 51.34 L c 45.282 1.00 51.23 L c 46.137 1.00 50.68 L c 45.240 1.00 51.24 L c 45.941 1.00 51.56 L c 44.930 1.00 50.04 L 0 47.154 1.00 51.89 L N 47.389 1.00 51.48 L c 48.241 1.00 53.42 L c 48.538 1.00 58.86 L c 49.224 1.00 61.76 L c 48.569 1.00 63.24 L 0 50.415 1.00 62.32 L 0 256 PCT/US2008/074097 WO 2009/026558 ATOM 5927 c GLU 208 -34.260 36 ATOM 5928 0 GLU 208 -34.530 35 ATOM 5929 N LYS 209 -33.026 36 ATOM 5930 CA LYS 209 -31.877 35 ATOM 5931 CB LYS 209 -31.271 34 ATOM 5932 CG LYS 209 -32.148 33 ATOM 5933 CD LYS 209 -32.621 33 ATOM 5934 CE LYS 209 -33.750 32 ATOM 5935 NZ LYS 209 -33.244 30 ATOM 5936 C LYS 209 -30.825 37 ATOM 5937 0 LYS 209 -30.685 37 ATOM 5938 N THR 210 -30.096 36 ATOM 5939 CA THR 210 -29.125 37 ATOM 5940 CB THR 210 -29.661 38 ATOM 5941 OG1 THR 210 -30.865 39 ATOM 5942 CG2 THR 210 -28.634 39 ATOM 5943 C THR 210 -27.805 37 ATOM 5944 O THR 210 -27.796 36 ATOM 5945 N VAL 211 -26.692 37 ATOM 5946 CA VAL 211 -25.389 37 ATOM 5947 CB VAL 211 -24.565 36 ATOM 5948 CGI VAL 211 -25.186 35 ATOM 5949 CG2 VAL 211 -24.489 37 ATOM 5950 C VAL 211 -24.580 38 ATOM 5951 O VAL 211 -24.732 39 ATOM 5952 N ALA 212 -23.722 38 ATOM 5953 CA ALA 212 -22.915 39 ATOM 5954 CB ALA 212 -23.324 39 ATOM 5955 C ALA 212 -21.431 39 ATOM 5956 O ALA 212 -21.037 37 ATOM 5957 N PRO 213 -20.588 40 ATOM 5958 CD PRO 213 -20.964 41 ATOM 5959 CA PRO 213 -19.137 39 ATOM 5960 CB PRO 213 -18.597 41 ATOM 5961 CG PRO 213 -19.661 42 ATOM 5962 C PRO 213 -18.579 39 ATOM 5963 O PRO 213 -17.587 38 ATOM 5964 N THR 214 -19.236 39 ATOM 5965 CA THR 214 -18.898 38 ATOM 5966 CB THR 214 -19.825 39 ATOM 5967 OG1 THR 214 -19.832 40 ATOM 5968 CG2 THR 214 -19.336 38 ATOM 5969 C THR 214 -19.025 37 ATOM 5970 O THR 214 -19.975 36 ATOM 5971 OXT THR 214 -18.178 36 TER 5972 THR 214 ATOM 5973 CB GLU 1 -30.422 3 ATOM 5974 CG GLU 1 -29.516 3 ATOM 5975 CD GLU 1 -30.286 4 ATOM 5976 OE1 GLU 1 -30.875 3 ATOM 5977 OE2 GLU 1 -30.305 5 ATOM 5978 C GLU 1 -29.301 3 ATOM 5979 0 GLU 1 -28.098 4 ATOM 5980 N GLU 1 -28.667 1 ATOM 5981 CA GLU 1 -29.785 2 ATOM 5982 N VAL 2 -30.249 4 ATOM 5983 CA VAL 2 -29.937 5 ATOM 5984 CB VAL 2 -31.204 6 ATOM 5985 CGI VAL 2 -30.873 7 ATOM 5986 CG2 VAL 2 -31.808 5 ATOM 5987 C VAL 2 -29.313 6 ATOM 5988 O VAL 2 -29.805 7 ATOM 5989 N GLN 3 -28.231 7 ATOM 5990 CA GLN 3 -27.479 8 ATOM 5991 CB GLN 3 -2 6.566 7 ATOM 5992 CG GLN 3 -25.834 8 ATOM 5993 CD GLN 3 -25.334 7 ATOM 5994 OE1 GLN 3 -25.022 7 ATOM 5995 NE2 GLN 3 -25.257 5 ATOM 5996 C GLN 3 -26.663 9 ATOM 5997 0 GLN 3 -26.083 9 ATOM 5998 N LEU 4 -26.622 10 ATOM 5999 CA LEU 4 -25.808 11 ATOM 6000 CB LEU 4 -26.701 12 ATOM 6001 CG LEU 4 -27.484 12 ATOM 6002 CD1 LEU 4 -28.454 13 48.066 1.00 50.33 L C 48.989 1.00 49.28 L O 47.601 1.00 47.90 L N 48.310 1.00 47.26 L C 47.530 1.00 47.11 L C 47.496 1.00 45.45 L c 48.887 1.00 46.72 L c 48.858 1.00 48.50 L c 48.874 1.00 49.58 L N 48.529 1.00 46.93 L c 47.714 1.00 44.32 L 0 49.636 1.00 46.89 L N 50.037 1.00 48.05 L c 51.222 1.00 49.81 L c 50.831 1.00 50.72 L 0 51.643 1.00 50.82 L c 50.470 1.00 47.03 L c 51.170 1.00 45.40 L 0 50.057 1.00 46.63 L N 50.565 1.00 46.45 L c 49.494 1.00 44.37 L c 49.225 1.00 41.67 L c 48.217 1.00 40.70 L c 51.066 1.00 48.37 L c 50.577 1.00 48.59 L 0 52.048 1.00 50.94 L N 52.676 1.00 52.66 L c 54.135 1.00 51.32 L c 52.585 1.00 53.53 L c 52.706 1.00 52.26 L 0 52.383 1.00 55.64 L N 52.338 1.00 56.63 L c 52.293 1.00 59.09 L c 52.069 1.00 57.17 L c 52.577 1.00 57.07 L c 53.554 1.00 63.09 L c 53.511 1.00 63.69 L 0 54.675 1.00 67.26 L N 55.939 1.00 72.25 L c 57.069 1.00 73.76 L c 57.072 1.00 74.88 L 0 58.429 1.00 74.89 L c 55.821 1.00 73.85 L c 56.412 1.00 75.17 L 0 55.130 1.00 74.44 L 0 L 8.715 1.00 67.00 H c 9.599 1.00 72.68 H c 10.699 1.00 76.76 H c 11.574 1.00 78.40 H 0 10.687 1.00 78.19 H 0 6.619 1.00 59.84 H c 6.505 1.00 59.47 H 0 7.662 1.00 63.51 H N 7.395 1.00 63.39 H c 6.086 1.00 56.40 H N 5.366 1.00 53.61 H c 4.751 1.00 53.06 H c 4 . 084 1.00 53.81 H c 3.747 1.00 52.96 H c 6.314 1.00 52.68 H c 7.422 1.00 53.56 H 0 5.887 1.00 49.43 H N 6.805 1.00 48.34 H c 7.64 9 1.00 51.60 H c 8.751 1.00 57.66 H c 9.826 1.00 61.96 H c 10.944 1.00 63.82 H 0 9.496 1.00 62.05 H N 6.121 1.00 44.78 H c 5.056 1.00 45.81 H 0 6.745 1.00 41.09 H N 6.257 1.00 39.82 H c 5.635 1.00 36.60 H c 4.368 1.00 36.08 H c 4 . 027 1.00 34.06 H c 257 PCT/US2008/074097 WO 2009/026558 ATOM 6003 CD2 LEU 4 -2 6 ATOM 6004 C LEU 4 -25 ATOM 6005 O LEU 4 -25 ATOM 6006 N VAL 5 -23 ATOM 6007 CA VAL 5 -22 ATOM 6008 CB VAL 5 -21 ATOM 6009 CGI VAL 5 -21 ATOM 6010 CG2 VAL 5 -22 ATOM 6011 C VAL 5 -21 ATOM 6012 O VAL 5 -21 ATOM 6013 N GLU 6 -22 ATOM 6014 CA GLU 6 -21 ATOM 6015 CB GLU 6 -22 ATOM 6016 CG GLU 6 -23 ATOM 6017 CD GLU 6 -24 ATOM 6018 OE1 GLU 6 -24 ATOM 6019 OE2 GLU 6 -25 ATOM 6020 C GLU 6 -20 ATOM 6021 0 GLU 6 -2 0 ATOM 6022 N SER 7 -19 ATOM 6023 CA SER 7 -18 ATOM 6024 CB SER 7 -17 ATOM 6025 OG SER 7 -16 ATOM 6026 C SER 7 -17 ATOM 6027 O SER 7 -17 ATOM 6028 N GLY 8 -16 ATOM 6029 CA GLY 8 -15 ATOM 6030 C GLY 8 -15 ATOM 6031 0 GLY 8 -15 ATOM 6032 N GLY 9 -16 ATOM 6033 CA GLY 9 -17 ATOM 6034 C GLY 9 -15 ATOM 6035 0 GLY 9 -15 ATOM 6036 N GLY 10 -15 ATOM 6037 CA GLY 10 -14 ATOM 6038 C GLY 10 -15 ATOM 6039 0 GLY 10 -16 ATOM 6040 N LEU 11 -14 ATOM 6041 CA LEU 11 -14 ATOM 6042 CB LEU 11 -13 ATOM 6043 CG LEU 11 -13 ATOM 6044 CDl LEU 11 -14 ATOM 6045 CD2 LEU 11 -12 ATOM 6046 C LEU 11 -13 ATOM 6047 O LEU 11 -12 ATOM 6048 N VAL 12 -13 ATOM 6049 CA VAL 12 -12 ATOM 6050 CB VAL 12 -13 ATOM 6051 CGI VAL 12 -14 ATOM 6052 CG2 VAL 12 -12 ATOM 6053 C VAL 12 -12 ATOM 6054 O VAL 12 -13 ATOM 6055 N LYS 13 -11 ATOM 6056 CA LYS 13 -12 ATOM 6057 CB LYS 13 -10 ATOM 6058 CG LYS 13 -9 ATOM 6059 CD LYS 13 -8 ATOM 6060 CE LYS 13 -8 ATOM 6061 NZ LYS 13 -9 ATOM 6062 C LYS 13 -12 ATOM 6063 0 LYS 13 -12 ATOM 6064 N PRO 14 -13 ATOM 60 65 CD PRO 14 -13 ATOM 6066 CA PRO 14 -13 ATOM 6067 CB PRO 14 -14 ATOM 6068 CG PRO 14 -14 ATOM 6069 C PRO 14 -13 ATOM 6070 O PRO 14 -11 ATOM 6071 N GLY 15 -13 ATOM 6072 CA GLY 15 -12 ATOM 6073 C GLY 15 -12 ATOM 6074 0 GLY 15 -11 ATOM 6075 N GLY 16 -12 ATOM 6076 CA GLY 16 -11 ATOM 6077 C GLY 16 -12 ATOM 6078 0 GLY 16 -13 12 . , 144 3. .226 1. , 00 32 . 76 H C 12 . ,253 7 . ,413 1. .00 39. .72 H C 12 . .613 8 . .444 1. , 00 39. 93 H O 12 . .365 7 . .241 1. .00 39. .98 H N 12 . .906 8 . .293 1. .00 39. .49 H C 11. .827 8 . .851 1. .00 40 . .46 H C 12 . .426 9. .971 1. , 00 37 . .54 H c 10 . ,619 9. , 354 1. .00 38 . .37 H c 14 . , 059 7 . .774 1. .00 40. .34 H c 13. .851 7 . , 004 1. .00 40 . . 18 H 0 15. .278 8 . . 188 1. .00 40 . , 67 H N 16. .411 7 . .744 1. . 00 43 . , 08 H c 17 . . 671 7 . .589 1. . 00 42 . .43 H c 17 . .966 8 . .728 1 . .00 47 . , 10 H c 17 . .139 8 . . 680 1 . .00 45. .96 H c 16. .045 9. .272 1 , . 00 46. ,73 H 0 17 . , 582 8 . . 064 1, . 00 43 . , 63 H 0 16. .668 8 . .689 1, . 00 42 . , 63 H c 16. .352 9. .876 1. . 00 45. , 51 H 0 17 . .215 8 . . 151 1, . 00 41. .61 H N 17 . .544 8 . .967 1, . 00 41. .73 H c 16. .334 9. .090 1, . 00 43. , 65 H c 15 , .958 7 . .832 1, . 00 47 . .20 H 0 18 . .722 8 . .383 1, . 00 40 . , 62 H c 19. .201 7 , .294 1. .00 39. .51 H 0 19. .195 9. . 126 1. .00 39. .23 H N 20. .261 8 . . 640 1, . 00 35. .58 H c 21 , . 589 9, . 309 1. .00 36. .50 H c 22 , .566 9, .069 1. .00 37 . .45 H 0 21, . 642 10 , . 152 1, . 00 36. .88 H N 22 , . 895 10 . .815 1, . 00 39. ,47 H c 23 , .359 11. .717 1. .00 40 . .73 H c 22 , . 579 12 . .053 1. .00 41 , . 05 H 0 24 , . 62 8 12 , . 105 1. .00 40 , . 13 H N 25. . 132 13. .014 1. .00 39. .76 H c 26. .619 13. .266 1. .00 41. .15 H c 27 , .239 12 . .892 1. .00 41 . .81 H 0 27 , . 189 13. .914 1. .00 40 , .63 H N 28 . .62 8 14 . . 137 1. . 00 40. . 05 H c 28 . .926 15. .537 1. .00 39, . 42 H c 30 . .405 15. .850 1 .00 40 , .30 H c 31, . 157 15. .728 1. . 00 39. .60 H c 30 , . 564 17 . .258 1 .00 42 . .60 H c 29. .217 13. .087 1. . 00 39, .22 H c 28 . . 642 12 , . 792 1 . 00 38 , .39 H 0 30 . .356 12 . .521 1 . 00 39, . 30 H N 31. .006 11 .489 1 . 00 41. .06 H c 30 . .525 10 . . 062 1 . 00 43 , .20 H c 30 . .861 9 .809 1 . 00 44 . .60 H c 31. . 172 9 .000 1 .00 45, . 13 H c 32 . .511 11. . 617 1. . 00 40 , . 57 H c 32 . .962 12 . . 179 1 . 00 40. . 30 H 0 33. .283 11 • 111 1 .00 41, .09 H N 34 . .738 11 .137 1 .00 42 . .69 H c 35. .361 11 .253 1 . 00 46, .79 H c 34 . .948 12 .507 1 .00 50 , . 67 H c 35 .953 12 .854 0 .50 53. .26 H c 35. .619 14 . 192 1 . 00 56. .49 H c 35. .477 15. .251 1 .00 58 . .69 H N 35. .268 9 . 883 1 .00 42 . .31 H c 34 .645 8 .823 1 . 00 41, .76 H 0 36 .444 9 .987 1 .00 41. .71 H N 37 .249 11 .210 1 .00 40 . .26 H c 37 .078 8 .822 1 .00 40 . .68 H c 38 . .466 9 .331 1. . 00 40 . .52 H c 38 .266 10. .813 1 .00 41, .11 H c 37 .139 7 .646 1 .00 42 . .52 H c 37 .437 7 .817 1 .00 42 . .90 H 0 36 .839 6 .4 52 1 .00 42 . .59 H N 36 .859 5 .275 1 .00 40 . . 18 H c 35 .524 5 .013 1 .00 40 . .77 H c 35. .320 3. . 948 1 .00 41. .52 H 0 34 . 608 5 .974 1 .00 40 , .21 H N 33 .309 5 .822 1 .00 42 .04 H c 32 .279 5 .0 67 1 .00 43, .65 H c 32 .611 4 .497 1 .00 43 .64 H 0 258 PCT/US2008/074097 WO 2009/026558 ATOM 6079 N SER 17 -11.829 31 ATOM 6080 CA SER 17 -12.407 29 ATOM 6081 CB SER 17 -11.515 29 ATOM 6082 OG SER 17 -11.340 30 ATOM 6083 C SER 17 -12.576 28 ATOM 6084 O SER 17 -11.792 28 ATOM 6085 N LEU 18 -13.592 27 ATOM 6086 CA LEU 18 -13.834 26 ATOM 6087 CB LEU 18 -14.857 26 ATOM 6088 CG LEU 18 -14.385 26 ATOM 6089 CDl LEU 18 -15.602 26 ATOM 6090 CD2 LEU 18 -13.554 25 ATOM 6091 C LEU 18 -14.386 25 ATOM 6092 O LEU 18 -15.068 26 ATOM 6093 N ARG 19 -14 .106 24 ATOM 6094 CA ARG 19 -14.658 23 ATOM 6095 CB ARG 19 -13.538 22 ATOM 6096 CG ARG 19 -14.030 21 ATOM 6097 CD ARG 19 -12.969 21 ATOM 6098 NE ARG 19 -13.459 20 ATOM 6099 CZ ARG 19 -13.334 19 ATOM 6100 NHl ARG 19 -13.807 18 ATOM 6101 NH2 ARG 19 -12.743 18 ATOM 6102 C ARG 19 -15.454 22 ATOM 6103 O ARG 19 -14.884 21 ATOM 6104 N LEU 20 -16.773 22 ATOM 6105 CA LEU 20 -17.617 21 ATOM 6106 CB LEU 20 -19.007 21 ATOM 6107 CG LEU 20 -19.027 23 ATOM 6108 CDl LEU 20 -20.474 23 ATOM 6109 CD2 LEU 20 -18.241 23 ATOM 6110 C LEU 20 -17.731 20 ATOM 6111 O LEU 20 -17.699 20 ATOM 6112 N SER 21 -17.848 18 ATOM 6113 CA SER 21 -18.112 17 ATOM 6114 CB SER 21 -16.935 16 ATOM 6115 OG SER 21 -15.752 17 ATOM 6116 C SER 21 -19.356 17 ATOM 6117 O SER 21 -19.740 17 ATOM 6118 N CYS 22 -19.976 16 ATOM 6119 CA CYS 22 -21.137 15 ATOM 6120 C CYS 22 -20.974 14 ATOM 6121 0 CYS 22 -20.881 13 ATOM 6122 CB CYS 22 -22.413 16 ATOM 6123 SG CYS 22 -24.012 15 ATOM 6124 N ALA 23 -20.901 13 ATOM 6125 CA ALA 23 -20.748 11 ATOM 6126 CB ALA 23 -19.698 10 ATOM 6127 C ALA 23 -22.078 10 ATOM 6128 O ALA 23 -22.754 10 ATOM 6129 N ALA 24 -22.455 10 ATOM 6130 CA ALA 24 -23.727 9 ATOM 6131 CB ALA 24 -24.483 9 ATOM 6132 C ALA 24 -23.512 8 ATOM 6133 O ALA 24 -22.507 7 ATOM 6134 N SER 25 -24.461 7 ATOM 6135 CA SER 25 -24.384 5 ATOM 6136 CB SER 25 -23.532 5 ATOM 6137 OG SER 25 -24.120 5 ATOM 6138 C SER 25 -25.779 5 ATOM 6139 O SER 25 -26.697 6 ATOM 6140 N GLY 26 -25.935 4 ATOM 6141 CA GLY 26 -27.200 3 ATOM 6142 C GLY 26 -28.198 3 ATOM 6143 0 GLY 26 -29.320 3 ATOM 6144 N PHE 27 -27.811 4 ATOM 6145 CA PHE 27 -28.725 4 ATOM 6146 CB PHE 27 -29.741 5 ATOM 6147 CG PHE 27 -29.157 7 ATOM 6148 CDl PHE 27 -28.398 7 ATOM 6149 CD2 PHE 27 -29.386 7 ATOM 6150 CEl PHE 27 -27.878 8 ATOM 6151 CE2 PHE 27 -28.867 9 ATOM 6152 CZ PHE 27 -28.113 9 ATOM 6153 C PHE 27 -28.014 4 ATOM 6154 O PHE 27 -26.808 5 5.076 1.00 44.25 H N 4.261 1.00 45.74 H C 3.050 1.00 46.55 H C 2.267 1.00 53.54 H 0 5.047 1.00 45.37 H c 5.946 1.00 44.90 H 0 4.681 1.00 44.78 H N 5.255 1.00 44.09 H c 6.391 1.00 44.85 H c 7.838 1.00 47.60 H c 8.755 1.00 46.16 H c 8.203 1.00 48.80 H c 4 .183 1.00 43.53 H c 3.2 62 1.00 44.97 H 0 4.315 1.00 41.93 H N 3.407 1.00 41.54 H c 2.617 1.00 42.94 H c 1.573 1.00 46.58 H c 0.511 1.00 51.36 H c -0.627 1.00 56.49 H N -0.746 1.00 59.18 H c -1.821 1.00 59.16 H N 0.213 1.00 59.69 H N 4 . 172 1.00 40.18 H C 4.898 1.00 39.83 H 0 4.002 1.00 37.32 H N 4.647 1.00 35.94 H C 4.928 1.00 33.09 H c 5.656 1.00 35.63 H c 5.917 1.00 34.30 H c 6.976 1.00 32.60 H c 3.7 63 1.00 35.92 H c 2.535 1.00 37.48 H 0 4.396 1.00 35.54 H N 3.685 1.00 37.66 H c 3.826 1.00 38.97 H c 3.290 1.00 45.86 H 0 4.274 1.00 38.28 H c 5.404 1.00 37.83 H 0 3.495 1.00 39.37 H N 3.930 1.00 42.63 H c 3.305 1.00 42.53 H c 2.078 1.00 41.03 H 0 3.431 1.00 46.05 H c 3.610 1.00 55.21 H s 4 . 145 1.00 40.59 H N 3.645 1.00 41.14 H c 4 . 464 1.00 40.28 H c 3.712 1.00 41.05 H c 4.739 1.00 43.31 H 0 2.613 1.00 41.38 H N 2.558 1.00 42.11 H c 1.282 1.00 40.56 H c 2.611 1.00 42.05 H c 2.119 1.00 42.39 H 0 3.207 1.00 40.96 H N 3.243 1.00 40.89 H c 4.430 1.00 41.08 H c 5.651 1.00 44.95 H 0 3.367 1.00 39.60 H c 3.815 1.00 38.57 H 0 2.966 1.00 39.26 H N 3.153 1.00 39.31 H c 2.031 1.00 40.96 H c 2.103 1.00 43.15 H 0 0.994 1.00 39.72 H N -0.117 1.00 39.40 H c 0.240 1.00 39.12 H c 0.282 1.00 37.43 H c 1.369 1.00 34.06 H c -0.760 1.00 34.48 H c 1.421 1.00 33.04 H c -0.716 1.00 34.47 H c 0.376 1.00 34.29 H c -1.422 1.00 38.19 H c -1.449 1.00 38.12 H 0 259 PCT/US2008/074097 WO 2009/026558 ATOM 6155 N THR 28 -28.779 4 ATOM 6156 CA THR 28 -28.236 5 ATOM 6157 CB THR 28 -29.221 4 ATOM 6158 OG1 THR 28 -29.545 3 ATOM 6159 CG2 THR 28 -28.613 4 ATOM 6160 C THR 28 -27.976 6 ATOM 6161 O THR 28 -28.784 7 ATOM 6162 N PHE 29 -26.829 7 ATOM 6163 CA PHE 29 -26.473 8 ATOM 6164 CB PHE 29 -25.055 8 ATOM 6165 CG PHE 29 -24.583 10 ATOM 6166 CDl PHE 29 -25.109 10 ATOM 6167 CD2 PHE 29 -23.562 10 ATOM 6168 CE1 PHE 29 -24.623 12 ATOM 6169 CE2 PHE 29 -23.070 11 ATOM 6170 CZ PHE 29 -23.603 12 ATOM 6171 C PHE 29 -26.566 9 ATOM 6172 O PHE 29 -26.948 10 ATOM 6173 N SER 30 -26.226 8 ATOM 6174 CA SER 30 -26.089 8 ATOM 6175 CB SER 30 -25.270 8 ATOM 6176 OG SER 30 -23.971 7 ATOM 6177 C SER 30 -27.425 9 ATOM 6178 O SER 30 -27.453 9 ATOM 6179 N SER 31 -28.529 8 ATOM 6180 CA SER 31 -29.853 9 ATOM 6181 CB SER 31 -30.753 8 ATOM 6182 OG SER 31 -30.280 7 ATOM 6183 C SER 31 -30.522 10 ATOM 6184 O SER 31 -31.670 10 ATOM 6185 N TYR 32 -29.805 10 ATOM 6186 CA TYR 32 -30.367 11 ATOM 6187 CB TYR 32 -30.301 11 ATOM 6188 CG TYR 32 -31.397 10 ATOM 6189 CDl TYR 32 -31.313 9 ATOM 6190 CEl TYR 32 -32.340 8 ATOM 6191 CD2 TYR 32 -32.533 11 ATOM 6192 CE2 TYR 32 -33.555 10 ATOM 6193 CZ TYR 32 -33.458 8 ATOM 6194 OH TYR 32 -34.487 7 ATOM 6195 C TYR 32 -29.676 13 ATOM 6196 O TYR 32 -28.450 13 ATOM 6197 N SER 33 -30.475 14 ATOM 6198 CA SER 33 -29.953 15 ATOM 6199 CB SER 33 -31.006 16 ATOM 6200 OG SER 33 -31.407 16 ATOM 62 01 C SER 33 -29.604 15 ATOM 6202 O SER 33 -30.146 15 ATOM 6203 N MET 34 -28.702 16 ATOM 6204 CA MET 34 -28.261 17 ATOM 6205 CB MET 34 -26.813 16 ATOM 6206 CG MET 34 -26.657 15 ATOM 6207 SD MET 34 -27.587 14 ATOM 6208 CE MET 34 -26.780 15 ATOM 6209 C MET 34 -28.379 18 ATOM 6210 0 MET 34 -28.388 19 ATOM 6211 N ASN 35 -28.479 19 ATOM 6212 CA ASN 35 -28.740 20 ATOM 6213 CB ASN 35 -30.239 20 ATOM 6214 CG ASN 35 -31.098 20 ATOM 6215 OD1 ASN 35 -31.478 20 ATOM 6216 ND2 ASN 35 -31.410 18 ATOM 6217 C ASN 35 -27.985 20 ATOM 6218 0 ASN 35 -27.755 19 ATOM 6219 N TRP 36 -27.610 22 ATOM 6220 CA TRP 36 -27.153 22 ATOM 6221 CB TRP 36 -25.815 23 ATOM 6222 CG TRP 36 -24.650 22 ATOM 6223 CD2 TRP 36 -23.918 21 ATOM 6224 CE2 TRP 36 -22.939 20 ATOM 6225 CE3 TRP 36 -23.997 21 ATOM 6226 CDl TRP 36 -24.093 22 ATOM 6227 NEl TRP 36 -23.065 21 ATOM 6228 CZ2 TRP 36 -22.046 20 ATOM 6229 CZ3 TRP 36 -23.110 20 ATOM 6230 CH2 TRP 36 -22.148 19 -2.506 1.00 38.67 H N -3.842 1.00 37.98 H C -4.889 1.00 39.03 H C -4.557 1.00 43.37 H 0 -6.272 1.00 39.31 H c -4.094 1.00 37.20 H c -4.715 1.00 37.60 H 0 -3.613 1.00 35.10 H N -3.618 1.00 34.39 H c -3.060 1.00 32.43 H c -2.929 1.00 31.23 H c -1.956 1.00 31.44 H c -3.739 1.00 31.88 H c -1.784 1.00 30.12 H c -3.577 1.00 30.39 H c -2.594 1.00 32.44 H c -5.001 1.00 35.36 H c -5.121 1.00 37.04 H 0 -6.044 1.00 35.18 H N -7.373 1.00 36.29 H c -8.271 1.00 36.47 H c -7.726 1.00 41.17 H 0 -8.041 1.00 35.64 H c -9.116 1.00 33.90 H 0 -7.405 1.00 34.26 H N -7.912 1.00 32.93 H c -7.953 1.00 32.80 H c -8.908 1.00 35.66 H 0 -7.087 1.00 32.29 H c -7.342 1.00 31.47 H 0 -6.099 1.00 30.85 H N -5.261 1.00 29.83 H c -3.783 1.00 28.34 H c -3.380 1.00 28.23 H c -3.680 1.00 28.84 H c -3.340 1.00 28.61 H c -2.727 1.00 27.49 H c -2.383 1.00 27.94 H c -2.690 1.00 30.33 H c -2.339 1.00 32.86 H 0 -5.465 1.00 30.11 H c -5.575 1.00 30.60 H 0 -5.529 1.00 28.01 H N -5.405 1.00 28.98 H c -5.854 1.00 28.82 H c -7.194 1.00 32.46 H 0 -3.940 1.00 29.47 H c -3.058 1.00 28.61 H 0 -3.687 1.00 29.06 H N -2.332 1.00 29.90 H c -2.138 1.00 29.95 H c -2.193 1.00 31.01 H c -0.852 1.00 34.80 H s 0.605 1.00 32.82 H c -2.061 1.00 29.84 H c -2.994 1.00 29.89 H 0 -0.786 1.00 26.73 H N -0.411 1.00 27.72 H c -0.169 1.00 27.88 H c -1.298 1.00 31.61 H c -2.204 1.00 31.06 H 0 -1.244 1.00 27.46 H N 0.863 1.00 29.07 H c 1.729 1.00 28.59 H 0 0.967 1.00 27.79 H N 2.224 1.00 26.46 H c 2.044 1.00 26.13 H c 1.747 1.00 30.50 H c 2.693 1.00 29.81 H c 1.969 1.00 29.00 H c 4.080 1.00 29.79 H c 0.525 1.00 29.38 H c 0.651 1.00 31.64 H N 2.584 1.00 31.48 H c 4.692 1.00 29.03 H c 3.944 1.00 30.42 H c 260 WO 2009/026558 PCT/US2008/074097
ATOM 6231 c TRP 36 -28.209 23.599 2.739 1.00 28.02 H C ATOM 6232 0 TRP 36 -28.731 24.440 1.990 1.00 26.76 H O ATOM 6233 N VAL 37 -28.517 23.467 4.025 1.00 26.57 H N ATOM 6234 CA VAL 37 -29.437 24.355 4.719 1.00 26.25 H C ATOM 6235 CB VAL 37 -30.750 23.618 5.054 1.00 25.90 H C ATOM 6236 CGI VAL 37 -31.734 24.565 5.733 1.00 21.86 H c ATOM 6237 CG2 VAL 37 -31.343 23.019 3.779 1.00 23.23 H c ATOM 6238 C VAL 37 -28.759 24.761 6.023 1.00 28.43 H c ATOM 6239 O VAL 37 -28.183 23.921 6.715 1.00 29.50 H 0 ATOM 62 4 0 N ARG 38 -28.828 26.039 6.368 1.00 27.29 H N ATOM 62 41 CA ARG 38 -28.145 26.503 7.559 1.00 27.16 H c ATOM 6242 CB ARG 38 -27.031 27.481 7.177 1.00 25.84 H c ATOM 6243 CG ARG 38 -27.488 28.872 6.834 1.00 25.35 H c ATOM 6244 CD ARG 38 -26.289 29.696 6.406 1.00 28.59 H c ATOM 6245 NE ARG 38 -26.672 31.009 5.904 1.00 29.47 H N ATOM 6246 CZ ARG 38 -25.815 31.881 5.381 1.00 29.76 H c ATOM 6247 NHl ARG 38 -24.526 31.577 5.291 1.00 29.29 H N ATOM 6248 NH2 ARG 38 -26.247 33.058 4.956 1.00 29.33 H N ATOM 62 4 9 C ARG 38 -29.105 27.149 8.545 1.00 28.31 H C ATOM 6250 O ARG 38 -30.212 27.549 8.177 1.00 27.74 H 0 ATOM 6251 N GLN 39 -28.681 27.234 9.802 1.00 27.51 H N ATOM 6252 CA GLN 39 -29.518 27.796 10.857 1.00 28.91 H C ATOM 6253 CB GLN 39 -30.293 26.674 11.560 1.00 26.80 H c ATOM 6254 CG GLN 39 -31.269 27.149 12.628 1.00 28.63 H c ATOM 6255 CD GLN 39 -32.223 26.054 13.076 1.00 28.81 H c ATOM 6256 OEl GLN 39 -31.833 24.898 13.240 1.00 30.27 H 0 ATOM 6257 NE2 GLN 39 -33.481 26.415 13.274 1.00 28.47 H N ATOM 6258 C GLN 39 -28.644 28.541 11.866 1.00 31.02 H c ATOM 6259 0 GLN 39 -27.842 27.932 12.586 1.00 29.71 H 0 ATOM 6260 N ALA 40 -28.787 29.860 11.900 1.00 33.52 H N ATOM 6261 CA ALA 40 -28.090 30.675 12.886 1.00 37.63 H c ATOM 62 62 CB ALA 40 -28.247 32.156 12.547 1.00 37.07 H c ATOM 62 63 C ALA 40 -28.708 30.371 14.247 1.00 40.34 H c ATOM 6264 O ALA 40 -29.901 30.098 14.347 1.00 39.58 H 0 ATOM 6265 N PRO 41 -27.899 30.402 15.315 1.00 44.34 H N ATOM 6266 CD PRO 41 -26.477 30.793 15.353 1.00 44.86 H c ATOM 6267 CA PRO 41 -28.399 29.989 16.638 1.00 43.86 H c ATOM 6268 CB PRO 41 -27.229 30.292 17.572 1.00 45.74 H c ATOM 6269 CG PRO 41 -26.010 30.221 16.665 1.00 47.13 H c ATOM 6270 C PRO 41 -29.668 30.743 17.032 1.00 43.16 H c ATOM 6271 O PRO 41 -29.700 31.973 16.995 1.00 43.04 H 0 ATOM 6272 N GLY 42 -30.715 29.997 17.383 1.00 42.32 H N ATOM 6273 CA GLY 42 -31.990 30.609 17.720 1.00 40.30 H c ATOM 6274 C GLY 42 -32.770 31.198 16.550 1.00 40.88 H c ATOM 6275 0 GLY 42 -33.703 31.977 16.753 1.00 39.91 H 0 ATOM 6276 N LYS 43 -32.399 30.839 15.324 1.00 40.15 H N ATOM 6277 CA LYS 43 -33.050 31.402 14.135 1.00 39.69 H c ATOM 6278 CB LYS 43 -32.034 32.183 13.297 1.00 44.93 H c ATOM 6279 CG LYS 43 -31.342 33.322 14.031 1.00 49.72 H c ATOM 6280 CD LYS 43 -32.297 34.476 14.299 1.00 55.35 H c ATOM 6281 CE LYS 43 -31.548 35.700 14.832 1.00 59.19 H c ATOM 6282 NZ LYS 43 -30.434 36.120 13.913 1.00 61.48 H N ATOM 6283 C LYS 43 -33.704 30.327 13.258 1.00 36.98 H c ATOM 6284 0 LYS 43 -33.728 29.148 13.611 1.00 34.51 H 0 ATOM 6285 N GLY 44 -34.233 30.748 12.110 1.00 36.40 H N ATOM 6286 CA GLY 44 -34.940 29.831 11.230 1.00 31.67 H c ATOM 6287 C GLY 44 -34.039 29.115 10.240 1.00 30.70 H c ATOM 6288 0 GLY 44 -32.887 29.496 10.049 1.00 31.21 H 0 ATOM 6289 N LEU 45 -34.562 28.069 9.609 1.00 29.44 H N ATOM 6290 CA LEU 45 -33.834 27.377 8.553 1.00 28.81 H c ATOM 6291 CB LEU 45 -34.583 26.103 8.142 1.00 27.99 H c ATOM 6292 CG LEU 45 -34.801 25.086 9.266 1.00 27.14 H c ATOM 6293 CD1 LEU 45 -35.685 23.956 8.765 1.00 26.36 H c ATOM 6294 CD2 LEU 45 -33.454 24.551 9.750 1.00 24.68 H c ATOM 6295 C LEU 45 -33.674 28.302 7.348 1.00 28.72 H c ATOM 6296 O LEU 45 -34.572 29.085 7.033 1.00 27.69 H 0 ATOM 6297 N GLU 46 -32.520 28.219 6.690 1.00 28.43 H N ATOM 6298 CA GLU 46 -32.259 29.005 5.489 1.00 28.83 H c ATOM 6299 CB GLU 46 -31.341 30.193 5.798 1.00 31.44 H c ATOM 6300 CG GLU 46 -31.043 31.069 4.571 1.00 39.18 H c ATOM 6301 CD GLU 46 -30.004 32.169 4.826 1.00 43.02 H c ATOM 6302 OEl GLU 46 -30.027 33.182 4 . 094 1.00 45.99 H 0 ATOM 6303 OE2 GLU 46 -29.163 32.028 5.743 1.00 43.91 H 0 ATOM 6304 C GLU 46 -31.597 28.124 4.438 1.00 28.50 H c ATOM 6305 0 GLU 46 -30.513 27.586 4.664 1.00 28.35 H 0 ATOM 6306 N TRP 47 -32.256 27.974 3.291 1.00 26.22 H N 261 WO 2009/026558 PCT/US2008/074097 ATOM 6307 CA TRP 47 -31.680 27 ATOM 6308 CB TRP 47 -32.691 27 ATOM 6309 CG TRP 47 -32.073 26 ATOM 6310 CD2 TRP 47 -31.798 27 ATOM 6311 CE2 TRP 47 -31.161 26 ATOM 6312 CE3 TRP 47 -32.029 28 ATOM 6313 CDl TRP 47 -31.608 25 ATOM 6314 NEl TRP 47 -31.058 25 ATOM 6315 CZ2 TRP 47 -30.751 26 ATOM 6316 CZ3 TRP 47 -31.623 29 ATOM 6317 CH2 TRP 47 -30.990 28 ATOM 6318 C TRP 47 -30.429 27 ATOM 6319 O TRP 47 -30.433 29 ATOM 6320 N VAL 48 -29.370 27 ATOM 6321 CA VAL 48 -28.082 27 ATOM 6322 CB VAL 48 -26.929 27 ATOM 6323 CGI VAL 48 -25.589 27 ATOM 6324 CG2 VAL 48 -27.130 27 ATOM 6325 C VAL 48 -27.727 27 ATOM 6326 O VAL 48 -27.359 28 ATOM 6327 N SER 49 -27.829 26 ATOM 6328 CA SER 49 -27.422 25 ATOM 6329 CB SER 49 -25.893 25 ATOM 6330 OG SER 49 -25.445 25 ATOM 6331 C SER 49 -27.952 24 ATOM 6332 O SER 49 -28.228 23 ATOM 6333 N SER 50 -28.101 24 ATOM 6334 CA SER 50 -28.581 22 ATOM 6335 CB SER 50 -30.061 22 ATOM 6336 OG SER 50 -30.882 23 ATOM 6337 C SER 50 -27.768 22 ATOM 6338 O SER 50 -27.315 22 ATOM 6339 N ILE 51 -27.595 20 ATOM 6340 CA ILE 51 -26.921 20 ATOM 6341 CB ILE 51 -25.419 20 ATOM 6342 CG2 ILE 51 -25.220 19 ATOM 6343 CGI ILE 51 -24.709 19 ATOM 6344 CDl ILE 51 -23.194 19 ATOM 6345 C ILE 51 -27.552 18 ATOM 6346 0 ILE 51 -27.751 18 ATOM 6347 N SER 52 -27.869 18 ATOM 6348 CA SER 52 -28.633 17 ATOM 6349 CB SER 52 -29.308 17 ATOM 6350 OG SER 52 -28.348 18 ATOM 6351 C SER 52 -27.713 16 ATOM 6352 O SER 52 -26.494 16 ATOM 6353 N SER 53 -28.292 15 ATOM 6354 CA SER 53 -27.523 14 ATOM 6355 CB SER 53 -28.433 12 ATOM 6356 OG SER 53 -29.011 12 ATOM 6357 C SER 53 -26.344 14 ATOM 6358 O SER 53 -25.284 13 ATOM 6359 N SER 54 -26.517 14 ATOM 6360 CA SER 54 -25.437 14 ATOM 6361 CB SER 54 -25.966 14 ATOM 6362 OG SER 54 -26.898 15 ATOM 6363 C SER 54 -24.766 16 ATOM 6364 O SER 54 -23.979 16 ATOM 6365 N SER 55 -25.087 16 ATOM 6366 CA SER 55 -24.520 18 ATOM 6367 CB SER 55 -22.987 18 ATOM 6368 OG SER 55 -22.526 17 ATOM 6369 C SER 55 -24.968 19 ATOM 6370 O SER 55 -24.353 20 ATOM 6371 N SER 56 -26.039 18 ATOM 6372 CA SER 56 -26.501 19 ATOM 6373 CB SER 56 -27.098 18 ATOM 6374 OG SER 56 -28.269 18 ATOM 6375 C SER 56 -27.505 20 ATOM 6376 O SER 56 -27.805 21 ATOM 6377 N TYR 57 -28.028 20 ATOM 6378 CA TYR 57 -28.685 21 ATOM 6379 CB TYR 57 -30.107 21 ATOM 6380 CG TYR 57 -31.053 20 ATOM 6381 CDl TYR 57 -31.126 19 ATOM 6382 CEl TYR 57 -32.050 19 2.174 1.00 23.96 H C 1.020 1.00 25.33 H C -0.243 1.00 25.29 H C -1.431 1.00 24.26 H C -2.342 1.00 24.29 H C -1.812 1.00 25.96 H C -0.478 1.00 24.30 H C -1.737 1.00 26.54 H N -3.610 1.00 23.53 H C -3.073 1.00 25.72 H C -3.956 1.00 24.04 H c 1.684 1.00 23.89 H c 1.520 1.00 23.38 H 0 1.439 1.00 24.56 H N 1.032 1.00 27.13 H c 1.940 1.00 26.57 H c 1.408 1.00 25.87 H c 3.373 1.00 25.68 H c -0.424 1.00 27.12 H c -1.200 1.00 28.60 H 0 -0.789 1.00 25.51 H N -2.113 1.00 27.18 H c -2.204 1.00 27.60 H c -3.514 1.00 30.37 H 0 -2.427 1.00 28.05 H c -1.518 1.00 26.28 H 0 -3.716 1.00 28.27 H N -4.154 1.00 28.54 H c -4.550 1.00 28.85 H c -3.418 1.00 32.42 H 0 -5.345 1.00 28.12 H c -6.169 1.00 28.29 H 0 -5.441 1.00 26.82 H N -6.590 1.00 24.36 H c -6.302 1.00 26.43 H c -5.109 1.00 21.83 H c -7.552 1.00 25.90 H c -7.452 1.00 27.92 H c -6.956 1.00 26.47 H c -6.096 1.00 24.86 H 0 -8.238 1.00 25.97 H N -8.673 1.00 25.28 H c -10.019 1.00 24.40 H c -11.046 1.00 27.24 H 0 -8.782 1.00 26.88 H c -8.650 1.00 28.49 H 0 -9.017 1.00 25.41 H N -8.983 1.00 28.14 H c -9.267 1.00 27.87 H c -10.555 1.00 30.31 H 0 -9.959 1.00 30.57 H c -9.645 1.00 32.17 H 0 -11.135 1.00 28.22 H N -12.123 1.00 28.16 H c -13.520 1.00 27.82 H c -14.023 1.00 29.46 H 0 -12.185 1.00 27.90 H c -13.087 1.00 28.59 H 0 -11.220 1.00 28.14 H N -11.124 1.00 30.31 H c -11.092 1.00 31.88 H c -10.023 1.00 34.17 H 0 -12.244 1.00 30.07 H c -12.457 1.00 29.82 H 0 -12.950 1.00 27.46 H N -14.066 1.00 27.70 H c -15.174 1.00 29.06 H c -14.734 1.00 34.97 H 0 -13.637 1.00 27.78 H c -14.406 1.00 27.41 H 0 -12.413 1.00 27.64 H N -11.742 1.00 27.77 H c -11.294 1.00 27.25 H c -12.400 1.00 29.87 H c -12.798 1.00 28.73 H c -13.735 1.00 30.08 H c 262 WO 2009/026558 PCT/US2008/074097 ATOM 6383 CD2 TYR 57 -31.933 21 ATOM 6384 CE2 TYR 57 -32.861 21 ATOM 6385 CZ TYR 57 -32.917 20 ATOM 6386 OH TYR 57 -33.861 19 ATOM 6387 C TYR 57 -27.881 22 ATOM 6388 O TYR 57 -27.628 21 ATOM 6389 N ILE 58 -27.487 23 ATOM 6390 CA ILE 58 -26.789 24 ATOM 6391 CB ILE 58 -25.270 24 ATOM 6392 CG2 ILE 58 -24.589 24 ATOM 6393 CGI ILE 58 -24.627 22 ATOM 6394 CDl ILE 58 -23.154 22 ATOM 6395 C ILE 58 -27.392 25 ATOM 6396 0 ILE 58 -27.609 26 ATOM 6397 N SER 59 -27.697 25 ATOM 6398 CA SER 59 -28.161 27 ATOM 6399 CB SER 59 -29.680 27 ATOM 6400 OG SER 59 -30.321 26 ATOM 6401 C SER 59 -27.758 27 ATOM 6402 O SER 59 -27.358 26 ATOM 6403 N TYR 60 -27.874 28 ATOM 6404 CA TYR 60 -27.374 29 ATOM 6405 CB TYR 60 -26.039 30 ATOM 6406 CG TYR 60 -24.917 29 ATOM 6407 CDl TYR 60 -24.210 28 ATOM 6408 CEl TYR 60 -23.190 27 ATOM 6409 CD2 TYR 60 -24.567 29 ATOM 6410 CE2 TYR 60 -23.543 28 ATOM 6411 CZ TYR 60 -22.859 27 ATOM 6412 OH TYR 60 -21.854 26 ATOM 6413 C TYR 60 -28.379 30 ATOM 6414 O TYR 60 -29.032 31 ATOM 6415 N ALA 61 -28.499 30 ATOM 6416 CA ALA 61 -29.203 31 ATOM 6417 CB ALA 61 -29.264 31 ATOM 6418 C ALA 61 -28.426 32 ATOM 6419 0 ALA 61 -27.210 32 ATOM 6420 N ASP 62 -29.127 34 ATOM 6421 CA ASP 62 -28.475 35 ATOM 6422 CB ASP 62 -29.500 36 ATOM 6423 CG ASP 62 -29.915 36 ATOM 6424 OD1 ASP 62 -31.131 36 ATOM 6425 OD2 ASP 62 -29.023 37 ATOM 6426 C ASP 62 -27.366 35 ATOM 6427 O ASP 62 -26.320 36 ATOM 6428 N SER 63 -27.606 35 ATOM 6429 CA SER 63 -26.704 35 ATOM 6430 CB SER 63 -27.354 35 ATOM 6431 OG SER 63 -27.781 34 ATOM 6432 C SER 63 -25.333 35 ATOM 6433 O SER 63 -24.396 35 ATOM 6434 N VAL 64 -25.206 34 ATOM 6435 CA VAL 64 -23.923 33 ATOM 6436 CB VAL 64 -24.023 31 ATOM 6437 CGI VAL 64 -24.635 31 ATOM 6438 CG2 VAL 64 -24.844 31 ATOM 6439 C VAL 64 -23.386 33 ATOM 6440 O VAL 64 -22.329 32 ATOM 6441 N LYS 65 -24.117 33 ATOM 6442 CA LYS 65 -23.742 33 ATOM 6443 CB LYS 65 -24.766 34 ATOM 6444 CG LYS 65 -24.604 34 ATOM 6445 CD LYS 65 -25.762 33 ATOM 6446 CE LYS 65 -27.105 34 ATOM 6447 NZ LYS 65 -28.261 33 ATOM 6448 C LYS 65 -22.354 34 ATOM 6449 0 LYS 65 -22.077 35 ATOM 6450 N GLY 66 -21.484 33 ATOM 6451 CA GLY 66 -20.156 34 ATOM 6452 C GLY 66 -19.126 33 ATOM 6453 0 GLY 66 -17.926 34 ATOM 6454 N ARG 67 -19.580 33 ATOM 6455 CA ARG 67 -18.663 33 ATOM 6456 CB ARG 67 -19.063 33 ATOM 6457 CG ARG 67 -19.033 35 ATOM 6458 CD ARG 67 -19.250 36 -12.984 1.00 28.13 H C -13.929 1.00 29.41 H C -14.294 1.00 30.49 H C -15.193 1.00 29.95 H O -10.504 1.00 29.02 H C -9.598 1.00 29.53 H O -10.469 1.00 29.50 H N -9.325 1.00 29.52 H C -9.614 1.00 30.72 H C -8.498 1.00 29.96 H c -9.740 1.00 30.72 H c -10.092 1.00 28.84 H c -9.067 1.00 29.74 H c -10.003 1.00 30.44 H 0 -7.809 1.00 27.57 H N -7.458 1.00 29.06 H c -7.616 1.00 28.15 H c -6.874 1.00 34.72 H 0 -6.044 1.00 28.73 H c -5.213 1.00 29.00 H 0 -5.791 1.00 27.30 H N -4.571 1.00 27.26 H c -4.834 1.00 25.88 H c -5.258 1.00 25.19 H c -4.315 1.00 23.78 H c -4.687 1.00 22.85 H c -6.603 1.00 23.48 H c -6.988 1.00 21.69 H c -6.021 1.00 23.85 H c -6.377 1.00 24.72 H 0 -4.087 1.00 28.79 H c -4.894 1.00 27.21 H 0 -2.770 1.00 28.73 H N -2.180 1.00 30.11 H c -0.658 1.00 28.64 H c -2.544 1.00 31.88 H c -2.702 1.00 2 9.32 H 0 -2.683 1.00 35.01 H N -2.995 1.00 4 0.62 H c -2.997 1.00 47.18 H c -4.390 1.00 55.90 H c -4.693 1.00 59.73 H 0 -5.177 1.00 57.97 H 0 -2.007 1.00 41.05 H c -2.394 1.00 41.21 H 0 -0.731 1.00 40.70 H N 0.337 1.00 41.03 H c 1.695 1.00 41.93 H c 1.795 1.00 42.20 H 0 0.302 1.00 40.04 H c 0.943 1.00 42.70 H 0 -0.434 1.00 37.58 H N -0.516 1.00 35.50 H c -0.010 1.00 34.20 H c 1.399 1.00 32.45 H c -0.987 1.00 32.80 H c -1.941 1.00 36.79 H c -2.203 1.00 35.31 H 0 -2.862 1.00 37.48 H N -4.272 1.00 42.50 H c -5.106 1.00 46.64 H c -6.605 1.00 52.44 H c -7.189 1.00 57.69 H c -6.786 1.00 60.32 H c -7.060 1.00 62.20 H N -4.465 1.00 42.87 H c -3.978 1.00 43.54 H 0 -5.171 1.00 42.33 H N -5.437 1.00 42.49 H c -4.361 1.00 44.27 H c -4.589 1.00 44.84 H 0 -3.189 1.00 41.56 H N -2.108 1.00 39.45 H c -0.830 1.00 40.38 H c -0.968 1.00 39.81 H c 0.366 1.00 39.55 H c 263 WO 2009/026558 PCT/US2008/074097 ATOM 6459 NE ARG 67 -20.572 35 ATOM 6460 CZ ARG 67 -20.786 35 ATOM 6461 NHl ARG 67 -19.760 34 ATOM 64 62 NH2 ARG 67 -22.028 35 ATOM 6463 C ARG 67 -18.616 31 ATOM 6464 O ARG 67 -17.549 31 ATOM 6465 N PHE 68 -19.769 31 ATOM 6466 CA PHE 68 -19.846 29 ATOM 6467 CB PHE 68 -21.092 29 ATOM 64 68 CG PHE 68 -21.064 29 ATOM 6469 CDl PHE 68 -22.001 29 ATOM 6470 CD2 PHE 68 -20.120 30 ATOM 6471 CEl PHE 68 -22.004 29 ATOM 6472 CE2 PHE 68 -20.115 31 ATOM 6473 CZ PHE 68 -21.058 30 ATOM 6474 C PHE 68 -19.895 28 ATOM 6475 O PHE 68 -20.485 29 ATOM 6476 N THR 69 -19.275 27 ATOM 6477 CA THR 69 -19.317 26 ATOM 6478 CB THR 69 -17.954 26 ATOM 6479 OG1 THR 69 -17.583 28 ATOM 6480 CG2 THR 69 -18.026 25 ATOM 6481 C THR 69 -19.680 25 ATOM 6482 O THR 69 -18.985 24 ATOM 6483 N ILE 70 -20.758 24 ATOM 6484 CA ILE 70 -21.203 23 ATOM 6485 CB ILE 70 -22.754 23 ATOM 6486 CG2 ILE 70 -23.308 23 ATOM 6487 CGI ILE 70 -23.219 22 ATOM 6488 CDl ILE 70 -24.719 22 ATOM 6489 C ILE 70 -20.635 22 ATOM 6490 0 ILE 70 -20.373 22 ATOM 6491 N SER 71 -20.406 21 ATOM 6492 CA SER 71 -20.011 20 ATOM 6493 CB SER 71 -18.547 20 ATOM 6494 OG SER 71 -17.673 20 ATOM 6495 C SER 71 -20.195 18 ATOM 6496 O SER 71 -20.456 18 ATOM 6497 N ARG 72 -20.066 17 ATOM 6498 CA ARG 72 -20.285 16 ATOM 6499 CB ARG 72 -21.747 16 ATOM 6500 CG ARG 72 -22.194 16 ATOM 6501 CD ARG 72 -23.691 15 ATOM 6502 NE ARG 72 -24.075 14 ATOM 6503 CZ ARG 72 -25.264 14 ATOM 6504 NHl ARG 72 -26.197 15 ATOM 6505 NH2 ARG 72 -25.525 12 ATOM 650 6 C ARG 72 -19.368 15 ATOM 6507 O ARG 72 -18.870 15 ATOM 6508 N ASP 73 -19.136 14 ATOM 6509 CA ASP 73 -18.327 13 ATOM 6510 CB ASP 73 -16.947 13 ATOM 6511 CG ASP 73 -15.990 12 ATOM 6512 OD1 ASP 73 -16.426 11 ATOM 6513 OD2 ASP 73 -14.791 12 ATOM 6514 C ASP 73 -19.066 12 ATOM 6515 O ASP 73 -18.978 11 ATOM 6516 N ASN 74 -19.797 11 ATOM 6517 CA ASN 74 -20.653 10 ATOM 6518 CB ASN 74 -21.523 10 ATOM 6519 CG ASN 74 -22.648 11 ATOM 6520 OD1 ASN 74 -22.954 11 ATOM 6521 ND2 ASN 74 -23.271 11 ATOM 6522 C ASN 74 -19.865 9 ATOM 6523 0 ASN 74 -20.336 8 ATOM 6524 N ALA 75 -18.667 9 ATOM 6525 CA ALA 75 -17.819 7 ATOM 652 6 CB ALA 75 -16.553 7 ATOM 6527 C ALA 75 -17.450 7 ATOM 6528 O ALA 75 -17.252 6 ATOM 6529 N LYS 76 -17.368 8 ATOM 6530 CA LYS 76 -17.043 8 ATOM 6531 CB LYS 76 -16.034 10 ATOM 6532 CG LYS 76 -14.694 9 ATOM 6533 CD LYS 76 -13.726 10 ATOM 6534 CE LYS 76 -12.383 10 0.933 1.00 39.73 H N 2.064 1.00 39.95 H C 2.760 1.00 36.21 H N 2.498 1.00 37.67 H N -1.849 1.00 38.91 H C -1.566 1.00 38.47 H O -1.951 1.00 37.70 H N -1.714 1.00 34.66 H C -0.889 1.00 33.55 H C 0.530 1.00 34.88 H c 1.453 1.00 34.07 H c 0.937 1.00 34.38 H c 2.747 1.00 33.89 H c 2.238 1.00 34.40 H c 3.143 1.00 35.06 H c -3.029 1.00 34.39 H c -4.006 1.00 33.33 H 0 -3.045 1.00 33.03 H N -4.204 1.00 33.88 H c -4.911 1.00 34.15 H c -5.384 1.00 36.58 H 0 -6.088 1.00 33.48 H c -3.757 1.00 34.59 H c -2.930 1.00 34.69 H 0 -4.315 1.00 32.65 H N -3.957 1.00 31.01 H c -3.936 1.00 30.63 H c -5.351 1.00 29.46 H c -3.329 1.00 29.67 H c -3.004 1.00 27.57 H c -4.987 1.00 31.28 H c -6.122 1.00 33.97 H 0 -4.582 1.00 31.56 H N -5.522 1.00 32.33 H c -5.947 1.00 33.86 H c -4.839 1.00 37.91 H 0 -4.861 1.00 32.41 H c -3.660 1.00 31.10 H 0 -5.648 1.00 31.25 H N -5.140 1.00 32.41 H c -5.343 1.00 30.85 H c -6.802 1.00 29.48 H c -6.912 1.00 28.57 H c -6.497 1.00 28.84 H N -5.989 1.00 27.19 H c -5.828 1.00 26.26 H N -5.641 1.00 26.57 H N -5.860 1.00 34.09 H C -6.944 1.00 33.62 H 0 -5.243 1.00 38.28 H N -5.849 1.00 39.48 H C -5.179 1.00 41.60 H c -5.843 1.00 44.95 H c -6.225 1.00 45.18 H 0 -5.974 1.00 46.94 H 0 -5.624 1.00 39.78 H c -4.545 1.00 40.60 H 0 -6.639 1.00 38.88 H N -6.486 1.00 39.67 H c -7.732 1.00 37.88 H c -7.821 1.00 38.36 H c -6.848 1.00 38.42 H 0 -8.989 1.00 35.16 H N -6.212 1.00 41.22 H c -5.499 1.00 42.03 H 0 -6.780 1.00 41.81 H N -6.554 1.00 44.00 H c -7.410 1.00 42.83 H c -5.074 1.00 45.21 H c -4.550 1.00 45.78 H 0 -4.402 1.00 46.01 H N -2.982 1.00 47.14 H c -2.696 1.00 49.80 H c -3.389 1.00 52.73 H c -3.012 1.00 56.34 H c -3.724 1.00 58.48 H c 264 WO 2009/026558 PCT/US2008/074097 ATOM 6535 NZ LYS 76 -11.483 11 ATOM 6536 C LYS 76 -18.271 9 ATOM 6537 0 LYS 76 -18.141 9 ATOM 6538 N ASN 77 -19.460 9 ATOM 6539 CA ASN 77 -20.689 9 ATOM 6540 CB ASN 77 -21.023 8 ATOM 6541 CG ASN 77 -21.302 6 ATOM 6542 OD1 ASN 77 -22.410 6 ATOM 6543 ND2 ASN 77 -20.292 6 ATOM 6544 C ASN 77 -20.545 10 ATOM 6545 0 ASN 77 -20.883 10 ATOM 6546 N SER 78 -20.039 11 ATOM 6547 CA SER 78 -19.787 12 ATOM 6548 CB SER 78 -18.291 13 ATOM 6549 OG SER 78 -17.830 11 ATOM 6550 C SER 78 -20.310 14 ATOM 6551 O SER 78 -20.320 14 ATOM 6552 N LEU 79 -20.733 15 ATOM 6553 CA LEU 79 -21.212 16 ATOM 6554 CB LEU 79 -22.642 16 ATOM 6555 CG LEU 79 -23.219 18 ATOM 6556 CDl LEU 79 -23.487 18 ATOM 6557 CD2 LEU 79 -24.504 18 ATOM 6558 C LEU 79 -20.263 17 ATOM 6559 O LEU 79 -19.834 17 ATOM 6560 N TYR 80 -19.931 18 ATOM 6561 CA TYR 80 -19.001 19 ATOM 6562 CB TYR 80 -17.698 19 ATOM 6563 CG TYR 80 -17.067 18 ATOM 6564 CDl TYR 80 -17.045 17 ATOM 6565 CEl TYR 80 -16.486 16 ATOM 6566 CD2 TYR 80 -16.507 17 ATOM 6567 CE2 TYR 80 -15.945 16 ATOM 65 68 CZ TYR 80 -15.938 15 ATOM 6569 OH TYR 80 -15.387 14 ATOM 6570 C TYR 80 -19.574 20 ATOM 6571 O TYR 80 -20.414 21 ATOM 6572 N LEU 81 -19.118 21 ATOM 6573 CA LEU 81 -19.394 23 ATOM 6574 CB LEU 81 -20.476 23 ATOM 6575 CG LEU 81 -20.966 25 ATOM 6576 CDl LEU 81 -21.629 25 ATOM 6577 CD2 LEU 81 -21.955 25 ATOM 6578 C LEU 81 -18.106 23 ATOM 6579 O LEU 81 -17.618 23 ATOM 6580 N GLN 82 -17.558 24 ATOM 6581 CA GLN 82 -16.424 25 ATOM 6582 CB GLN 82 -15.592 25 ATOM 6583 CG GLN 82 -14.362 26 ATOM 6584 CD GLN 82 -13.374 25 ATOM 6585 OE1 GLN 82 -12.986 24 ATOM 6586 NE2 GLN 82 -12.968 26 ATOM 6587 C GLN 82 -16.940 26 ATOM 6588 0 GLN 82 -17.640 27 ATOM 6589 N MET 83 -16.600 27 ATOM 6590 CA MET 83 -17.043 28 ATOM 6591 CB MET 83 -17.682 28 ATOM 6592 CG MET 83 -18.815 27 ATOM 6593 SD MET 83 -19.506 27 ATOM 6594 CE MET 83 -18.162 26 ATOM 6595 C MET 83 -15.868 29 ATOM 6596 0 MET 83 -14.917 29 ATOM 6597 N ASN 84 -15.942 30 ATOM 6598 CA ASN 84 -14.899 31 ATOM 6599 CB ASN 84 -14.353 31 ATOM 6600 CG ASN 84 -13.545 30 ATOM 6601 OD1 ASN 84 -13.083 29 ATOM 6602 ND2 ASN 84 -13.368 30 ATOM 6603 C ASN 84 -15.443 33 ATOM 6604 0 ASN 84 -16.657 33 ATOM 6605 N SER 85 -14.532 33 ATOM 6606 CA SER 85 -14.898 35 ATOM 6607 CB SER 85 -15.383 36 ATOM 6608 OG SER 85 -14.432 36 ATOM 6609 C SER 85 -15.981 35 ATOM 6610 O SER 85 -16.959 36 -3.476 1.00 60.20 H N -2.090 1.00 47.47 H C -0.875 1.00 47.19 H O -2.690 1.00 46.65 H N -1.933 1.00 44.74 H C -1.052 1.00 45.89 H C -1.860 1.00 47.96 H c -2.352 1.00 49.54 H 0 -2.000 1.00 50.93 H N -1.050 1.00 42.51 H c 0.134 1.00 42.35 H 0 -1.621 1.00 39.28 H N -0.836 1.00 38.34 H c -0.565 1.00 40.48 H c 0.169 1.00 46.08 H 0 -1.456 1.00 37.03 H c -2.678 1.00 37.05 H 0 -0.580 1.00 33.76 H N -0.945 1.00 33.07 H c -0.412 1.00 30.60 H c -0.350 1.00 29.82 H c -1.763 1.00 28.74 H c 0.470 1.00 26.94 H c -0.294 1.00 33.73 H c 0.844 1.00 35.43 H 0 -1.003 1.00 31.34 H N -0.479 1.00 30.56 H c -1.274 1.00 32.57 H c -1.386 1.00 35.32 H c -2.599 1.00 36.45 H c -2.711 1.00 38.72 H c -0.275 1.00 36.23 H c -0.374 1.00 37.75 H c -1.598 1.00 40.42 H c -1.721 1.00 42.98 H 0 -0.508 1.00 31.38 H c -1.336 1.00 31.59 H 0 0.413 1.00 32.68 H N 0.341 1.00 33.13 H c 1.350 1.00 30.32 H c 1.180 1.00 31.03 H c -0.186 1.00 30.17 H c 2.279 1.00 29.51 H c 0.633 1.00 35.97 H c 1.770 1.00 35.94 H 0 -0.400 1.00 35.80 H N -0.235 1.00 37.59 H c -1.521 1.00 38.62 H c -1.448 1.00 42.10 H c -0.368 1.00 43.68 H c -0.292 1.00 43.76 H 0 0.473 1.00 43.92 H N 0.099 1.00 38.25 H c -0.698 1.00 39.65 H 0 1.289 1.00 40.33 H N 1.733 1.00 42.26 H c 3.120 1.00 42.53 H c 3.240 1.00 46.08 H c 4.929 1.00 4 9.67 H s 5.786 1.00 50.01 H c 1.785 1.00 43.58 H c 2.545 1.00 45.85 H 0 0.979 1.00 42.66 H N 0.945 1.00 42.04 H c -0.472 1.00 42.61 H c -0.917 1.00 45.11 H c -0.098 1.00 4 6.92 H 0 -2.224 1.00 47.46 H N 1.416 1.00 42.87 H c 1.478 1.00 41.82 H 0 1.752 1.00 42.16 H N 2.153 1.00 41.46 H c 0.938 1.00 43.66 H c -0.110 1.00 47.73 H 0 3.217 1.00 40.30 H c 3.135 1.00 39.19 H 0 265 WO 2009/026558 PCT/US2008/074097 ATOM 6611 N LEU 86 -15.798 34.409 4.217 1.00 39.13 H N ATOM 6612 CA LEU 86 -16.785 34.255 5.281 1.00 39.06 H C ATOM 6613 CB LEU 86 -16.347 33.159 6.245 1.00 37.15 H C ATOM 6614 CG LEU 86 -16.565 31.763 5.669 1.00 38.36 H c ATOM 6615 CDl LEU 86 -15.834 30.724 6.492 1.00 37.27 H c ATOM 6616 CD2 LEU 86 -18.054 31.485 5.628 1.00 37.79 H c ATOM 6617 C LEU 86 -17.039 35.540 6.051 1.00 39.98 H c ATOM 6618 O LEU 86 -16.138 36.359 6.235 1.00 41.95 H 0 ATOM 6619 N ARG 87 -18.280 35.714 6.489 1.00 40.79 H N ATOM 6620 CA ARG 87 -18.662 36.863 7.296 1.00 43.46 H c ATOM 6621 CB ARG 87 -19.635 37.754 6.532 1.00 45.67 H c ATOM 6622 CG ARG 87 -19.140 38.192 5.182 1.00 49.88 H c ATOM 6623 CD ARG 87 -20.293 38.703 4.351 1.00 53.41 H c ATOM 6624 NE ARG 87 -19.920 38.894 2.955 1.00 57.94 H N ATOM 6625 CZ ARG 87 -20.781 39.233 2.001 1.00 59.50 H c ATOM 6626 NHl ARG 87 -20.366 39.389 0.750 1.00 59.64 H N ATOM 6627 NH2 ARG 87 -22.062 39.410 2.303 1.00 58.79 H N ATOM 6628 C ARG 87 -19.329 36.387 8.577 1.00 43.92 H C ATOM 6629 O ARG 87 -19.737 35.227 8.681 1.00 42.74 H 0 ATOM 6630 N ALA 88 -19.444 37.291 9.544 1.00 44.62 H N ATOM 6631 CA ALA 88 -20.030 36.960 10.838 1.00 45.48 H C ATOM 6632 CB ALA 88 -20.133 38.222 11.699 1.00 44.63 H c ATOM 6633 C ALA 88 -21.413 36.335 10.649 1.00 44.68 H c ATOM 6634 O ALA 88 -21.762 35.364 11.320 1.00 43.24 H 0 ATOM 6635 N GLU 89 -22.180 36.900 9.718 1.00 45.01 H N ATOM 6636 CA GLU 89 -23.546 36.460 9.441 1.00 44.88 H c ATOM 6637 CB GLU 89 -24.219 37.419 8.453 1.00 49.04 H c ATOM 6638 CG GLU 89 -24.223 38.878 8.894 1.00 58.20 H c ATOM 6639 CD GLU 89 -22.918 39.596 8.569 1.00 62.22 H c ATOM 6640 OEl GLU 89 -22.376 40.289 9.461 1.00 64.59 H 0 ATOM 6641 OE2 GLU 89 -22.441 39.466 7.419 1.00 64.36 H 0 ATOM 6642 C GLU 89 -23.625 35.041 8.883 1.00 41.48 H c ATOM 6643 0 GLU 89 -24.703 34.461 8.822 1.00 40.85 H 0 ATOM 6644 N ASP 90 -22.491 34.487 8.465 1.00 38.97 H N ATOM 6645 CA ASP 90 -22.451 33.104 8.003 1.00 36.93 H c ATOM 6646 CB ASP 90 -21.268 32.884 7.058 1.00 38.32 H c ATOM 6647 CG ASP 90 -21.391 33.687 5.772 1.00 41.49 H c ATOM 6648 ODl ASP 90 -22.526 33.850 5.265 1.00 41.50 H 0 ATOM 6649 OD2 ASP 90 -20.348 34.160 5.272 1.00 42.86 H 0 ATOM 6650 C ASP 90 -22.357 32.120 9.162 1.00 36.53 H c ATOM 6651 O ASP 90 -22.304 30.907 8.951 1.00 37.19 H 0 ATOM 6652 N THR 91 -22.334 32.643 10.385 1.00 34.31 H N ATOM 6653 CA THR 91 -22.252 31.797 11.572 1.00 34.08 H c ATOM 6654 CB THR 91 -22.036 32.656 12.849 1.00 34.84 H c ATOM 6655 OG1 THR 91 -20.738 33.263 12.799 1.00 36.83 H 0 ATOM 6656 CG2 THR 91 -22.160 31.804 14.109 1.00 31.37 H c ATOM 6657 C THR 91 -23.553 31.019 11.710 1.00 32.40 H c ATOM 6658 O THR 91 -24.628 31.613 11.763 1.00 32.80 H 0 ATOM 6659 N ALA 92 -23.465 29.695 11.774 1.00 29.43 H N ATOM 6660 CA ALA 92 -24.674 28.884 11.827 1.00 29.39 H c ATOM 6661 CB ALA 92 -25.551 29.177 10.601 1.00 31.93 H c ATOM 6662 C ALA 92 -24.334 27.409 11.867 1.00 28.87 H c ATOM 6663 O ALA 92 -23.197 27.025 11.599 1.00 28.15 H 0 ATOM 6664 N VAL 93 -25.321 26.581 12.202 1.00 28.51 H N ATOM 6665 CA VAL 93 -25.210 25.145 11.954 1.00 28.45 H c ATOM 6666 CB VAL 93 -26.178 24.339 12.851 1.00 30.44 H c ATOM 6667 CGI VAL 93 -26.090 22.866 12.503 1.00 29.75 H c ATOM 6668 CG2 VAL 93 -25.836 24.558 14.344 1.00 31.02 H c ATOM 6669 C VAL 93 -25.562 24.877 10.485 1.00 30.00 H c ATOM 6670 O VAL 93 -26.553 25.403 9.969 1.00 30.05 H 0 ATOM 6671 N TYR 94 -24.741 24.077 9.812 1.00 29.21 H N ATOM 6672 CA TYR 94 -24.997 23.711 8.424 1.00 29.79 H c ATOM 6673 CB TYR 94 -23.742 23.945 7.570 1.00 29.58 H c ATOM 6674 CG TYR 94 -23.442 25.410 7.332 1.00 32.16 H c ATOM 6675 CDl TYR 94 -23.617 25.981 6.074 1.00 31.93 H c ATOM 6676 CEl TYR 94 -23.410 27.336 5.865 1.00 30.72 H c ATOM 6677 CD2 TYR 94 -23.041 26.237 8.379 1.00 31.28 H c ATOM 6678 CE2 TYR 94 -22.831 27.592 8.182 1.00 30.20 H c ATOM 6679 CZ TYR 94 -23.022 28.137 6.922 1.00 32.69 H c ATOM 6680 OH TYR 94 -22.863 29.495 6.727 1.00 32.53 H 0 ATOM 6681 C TYR 94 -25.424 22.249 8.320 1.00 29.99 H c ATOM 6682 O TYR 94 -24.688 21.352 8.750 1.00 30.54 H 0 ATOM 6683 N PHE 95 -26.610 22.019 7.754 1.00 29.58 H N ATOM 6684 CA PHE 95 -27.123 20.666 7.512 1.00 29.84 H c ATOM 6685 CB PHE 95 -28.601 20.557 7.905 1.00 27.29 H c ATOM 6686 CG PHE 95 -28.900 20.937 9.334 1.00 30.50 H c 266 WO 2009/026558 PCT/US2008/074097 ATOM 6687 CDl PHE 95 -28.783 20 ATOM 6688 CD2 PHE 95 -29.336 22 ATOM 6689 CEl PHE 95 -29.098 20 ATOM 6690 CE2 PHE 95 -29.652 22 ATOM 6691 CZ PHE 95 -29.531 21 ATOM 6692 C PHE 95 -27.016 20 ATOM 6693 O PHE 95 -27.203 21 ATOM 6694 N CYS 96 -26.734 19 ATOM 6695 CA CYS 96 -27.051 18 ATOM 6696 C CYS 96 -28.344 17 ATOM 6697 0 CYS 96 -28.718 17 ATOM 6698 CB CYS 96 -25.898 17 ATOM 6699 SG CYS 96 -25.132 16 ATOM 6700 N ALA 97 -29.028 17 ATOM 6701 CA ALA 97 -30.273 16 ATOM 6702 CB ALA 97 -31.450 17 ATOM 6703 C ALA 97 -30.457 16 ATOM 6704 0 ALA 97 -30.050 17 ATOM 6705 N ARG 98 -31.067 15 ATOM 6706 CA ARG 98 -31.226 14 ATOM 6707 CB ARG 98 -30.979 13 ATOM 6708 CG ARG 98 -32.090 12 ATOM 6709 CD ARG 98 -31.942 11 ATOM 6710 NE ARG 98 -33.217 10 ATOM 6711 CZ ARG 98 -33.400 9 ATOM 6712 NHl ARG 98 -32.384 8 ATOM 6713 NH2 ARG 98 -34.605 8 ATOM 6714 C ARG 98 -32.635 15 ATOM 6715 O ARG 98 -33.546 15 ATOM 6716 N ASP 99 -32.803 15 ATOM 6717 CA ASP 99 -34.121 14 ATOM 6718 CB ASP 99 -34.795 16 ATOM 6719 CG ASP 99 -34.086 17 ATOM 6720 OD1 ASP 99 -32.927 17 ATOM 6721 OD2 ASP 99 -34.699 17 ATOM 6722 C ASP 99 -33.963 14 ATOM 6723 O ASP 99 -33.051 14 ATOM 6724 N TYR 100 -34.832 13 ATOM 6725 CA TYR 100 -34.683 12 ATOM 6726 CB TYR 100 -35.791 11 ATOM 6727 CG TYR 100 -35.608 10 ATOM 6728 CDl TYR 100 -34.740 9 ATOM 6729 CEl TYR 100 -34.511 8 ATOM 6730 CD2 TYR 100 -36.252 10 ATOM 6731 CE2 TYR 100 -36.032 9 ATOM 6732 CZ TYR 100 -35.157 8 ATOM 6733 OH TYR 100 -34.924 7 ATOM 6734 C TYR 100 -34.708 13 ATOM 6735 O TYR 100 -35.485 14 ATOM 6736 N ASP 101 -33.850 13 ATOM 6737 CA ASP 101 -33.715 13 ATOM 6738 CB ASP 101 -32.296 13 ATOM 6739 CG ASP 101 -32.013 14 ATOM 6740 OD1 ASP 101 -32.949 15 ATOM 6741 OD2 ASP 101 -30.846 14 ATOM 6742 C ASP 101 -34.751 13 ATOM 6743 O ASP 101 -34.602 12 ATOM 67 4 4 N PHE 102 -35.808 14 ATOM 67 4 5 CA PHE 102 -36.838 14 ATOM 6746 CB PHE 102 -38.225 14 ATOM 6747 CG PHE 102 -38.652 13 ATOM 6748 CDl PHE 102 -39.240 12 ATOM 67 4 9 CD2 PHE 102 -38.482 13 ATOM 6750 CEl PHE 102 -39.654 11 ATOM 6751 CE2 PHE 102 -38.894 13 ATOM 6752 CZ PHE 102 -39.481 11 ATOM 6753 C PHE 102 -36.578 14 ATOM 6754 O PHE 102 -37.447 15 ATOM 6755 N TRP 103 -35.384 15 ATOM 6756 CA TRP 103 -34.952 16 ATOM 6757 CB TRP 103 -34.858 15 ATOM 6758 CG TRP 103 -33.937 14 ATOM 6759 CD2 TRP 103 -32.526 14 ATOM 6760 CE2 TRP 103 -32.080 12 ATOM 6761 CE3 TRP 103 -31.598 14 ATOM 67 62 CDl TRP 103 -34.276 12 10.357 1.00 30.20 H C 9.651 1.00 30.58 H C 11.671 1.00 27.42 H C 10.960 1.00 29.43 H C 11.968 1.00 27.23 H C 6.023 1.00 31.72 H C 5.185 1.00 30.65 H O 5.694 1.00 32.57 H N 4.366 1.00 35.64 H C 4.388 1.00 34.02 H C 5.414 1.00 33.53 H 0 3.784 1.00 41.97 H c 4 . 858 1.00 55.63 H s 3.249 1.00 30.78 H N 3.134 1.00 30.15 H c 3.582 1.00 28.28 H c 1.690 1.00 29.71 H c 0.768 1.00 31.75 H 0 1.492 1.00 27.73 H N 0.155 1.00 28.67 H c 0.164 1.00 28.08 H c 0.851 1.00 29.78 H c 0.677 1.00 27.61 H c 0.910 1.00 30.98 H N 0.859 1.00 31.84 H c 0.587 1.00 32.85 H N 1.064 1.00 29.18 H N -0.344 1.00 28.25 H C 0.447 1.00 27.82 H 0 -1.663 1.00 28.56 H N -2.262 1.00 27.74 H C -2.466 1.00 28.14 H c -3.497 1.00 34.77 H c -3.252 1.00 34.38 H 0 -4.556 1.00 36.63 H 0 -3.586 1.00 27.51 H c -4.364 1.00 27.91 H 0 -3.838 1.00 25.59 H N -5.036 1.00 25.30 H c -5.123 1.00 26.94 H c -6.296 1.00 28.57 H c -6.214 1.00 28.82 H c -7.310 1.00 28.92 H c -7.505 1.00 28.98 H c -8.607 1.00 31.42 H c -8.504 1.00 32.55 H c -9.604 1.00 33.58 H 0 -6.274 1.00 25.64 H c -6.355 1.00 23.00 H 0 -7.239 1.00 26.57 H N -8.410 1.00 28.69 H c -8.978 1.00 28.46 H c -10.074 1.00 31.11 H c -10.483 1.00 30.58 H 0 -10.525 1.00 32.28 H 0 -9.458 1.00 28.47 H c -10.112 1.00 27.60 H 0 -9.593 1.00 28.19 H N -10.604 1.00 28.93 H c -10.036 1.00 28.62 H c -8.889 1.00 28.28 H c -9.134 1.00 27.61 H c -7.573 1.00 28.22 H c -8.086 1.00 29.20 H c -6.508 1.00 29.50 H c -6.767 1.00 28.70 H c -11.859 1.00 28.33 H c -12.725 1.00 29.51 H 0 -11.939 1.00 25.45 H N -13.123 1.00 25.17 H c -14.323 1.00 25.43 H c -14.091 1.00 26.29 H c -14.361 1.00 27.47 H c -13.970 1.00 27.34 H c -14.898 1.00 26.51 H c -13.565 1.00 2 6.52 H c 267 WO 2009/026558 PCT/US2008/074097
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ocNrHoonor-r-cocNoocNCNoo 00 00 00 00 00 00 00 00 00 00 00 00 00 OOOOOOOOOOOOO OOOOOOOOOOOOO (^ror^Hra^roΦn^ornHHHtησ^fηΦr,^(Nco^(N(N^J^LΛ^coσ'rϊ,l^coH'T'J,coco(NCOHn^(N'τσ^σ^σ^σ^L/^'τ,7,σ^cT'(T'LnH^Φ^Φr^H^)α^α^ΦH'τ^'TLnLn^Hco co(7i(NC\i'THi7iLi,)^o^'TH'T(N^hroLn'TCO(7i^co'Th'TH^^oo'TH^h(N^Hhinr''Ta''T'ThWHroh^oo(7iHcorooco'TCOOLr)^hrii^^M^n,)o^Li,io ^oo^'T^tri'T'TCor'co^HLna3(7ih'TO^Ln(r)^(NH^<T«T<T<Tr)Lnii,)^h^cooo'T^Ln^coHco(N(riHH(N'T(Nr\ico'TLr)OHH^(Nco^'Tt,i'j,^rontrimHHh n'TLn'TrO'jtNfMn'TOjMtNronHHotri^h^inh^inmcocoh^^hcoaihcoaiHLn'T'TromtNfMtN^ojHOHooHHfviHMOHoooj^wntNHHH'Tin'TLn'T i—I i—I i—I i—I i—I i—I i—I t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H I I I! I I ! I I I I I t ! I I I I I I t-H 1 I I I 1 I I I I I I I It I I t I I I I I 1 I I I I I I I I I I ot-i^Lnno^nouooi-HLncoocoocNLOi-HCNOCNLna>a>LnnOi-H^^^i-H^no^cNLna>i-icononoa>^^nonocNCNOocN'2,:T«=j,r'-,:Tr'-'2'2ooooor'-o'2r'-«=j,'2oooo<T>Lnooi-HLn 'j^H^h'j^rNCOOMn^ho^hroo^'T'joocotohtDHn^HOin^hhtNHamnMHtO'jo^o'TCOHro^'j^^cotNHMntDmininro'THtD^o^Hoo ornLn(N(^^o(N(Norar^LnHr^^^rnLnH(NLn^oorn^ra^r^o^(NrarnoLn(Nr^^a>^^(N'^Lno(N(Nr'H^r'r'':T<T>H(N':T(N*5'(Nno<T>(N'^'^LOr'HLnono(NcoLn 00 ............................................................................ cNCN^nor--r--coa>oocoa>r--r--Lnr--r--r--r--^^LnLnr--r--^^r--r--coa>Oi-Hi-HCNi-ii-icNCNcocor--^Ln^^nor--couor--^^Lnr--^co<T>oa'ii-HOi-HLn'2«=j,oocNi-HCNooocNoocNi-H fN i-H i-H i-H i-H i-H i-H t-H i-H CN CN i-H i-H i-H ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η i-H CN CN (NJ (NJ (NJ CN CN CN t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H (\j t-H (NJ (NJ (NJ ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η ι-Η r-'TtNCOiO'TOCN^iOir) ^Tr'Lor'r't-Hoco'^Ln HhOvltOCOHrOfN^O^ Γ'ι-ΗίΤι^Ο^ΟτΤΓΟΓΟΓ'^Ο (Ti^^otTiOLfirotNdih 'τΦΓΟ'ΓΗ'τιηΜ^ιπο
οοιη^οιησιη(Ν(ΝΗ>τ r'^Tt-HocoLO^Drot—ir' ^Dr^rOCOTt-HOLO^DLOCO
CO<T>OH(\JlOO><Ti^O<T>^0 ΠιΠΗίΝΟΗ^ΙΝιη^Φ ^OLO^r't-Hoomr't-H
(NCDhO^'TCOO^’^CD rOt-Ht-HLOLOOT^Dt-HTt-H <Ti<TiLn(N,=J,r'(N>—icomH (7ir'CO'T'TOLOH(N(7' (NCOCMCO'T^f'ICO^^ ΟΟΟΓ'ΟΟΓ'Γ'Οι-ΗΤ
inotNin^MDhC'icoinai ^^LncohuiH^HtNco o^DromcNr'r't-H'sT'sr'^D
moo&amp;iniDiDT-'&amp;T-co OOOOOOCNOOOOOOOOOOOOOO I I I I I I I I I I I <T>COOOt-HCNOt-Hi-HCNCN rorO'T^T'T'T'T'T'T'T'T i I I I I I I i i i i ojoO'toO'to^o^^co 'Τ'Τ'Τ'Τ'Τ'ΤΟΟ'ΤΟΟΟΟΟΟ i i i i i i i i i i i
σιΦΓ'^Γ'Γ'θΗσισ>σι OOOOOOOOOOOOTTOOOOOO I I I ! I I i t I I I
ijio^uico^aiohhh OOTOOOOOOOOOOTOOOOOO inLii'T'jinro^'T^^ 00 00 00 00 00 00 00 00 00 00 I I I I I I J t l ]
^^r^^Ln'^LnuD'T'rotN 00 00 00 00 00 00 00 00 00 00 00 I I I I I I I i I I I
no no no no no no lO lO lO lO lO iO iO iO iO iO iO iO iO iO iO iO iO r> τ τ τ τ τ τ τ τ τ τ τ CO CO CO CO CO CO CO CO <T> <T> <T> <T> <T> o o o o O O O o O O O t-H t-H t-H t-H t-H t-H t-H t-H CN CN o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o ο ο ο ο ο ο ο ο ο ο ο o o o o o o o o o o o o O t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H Cn Cn Cn Cn Cn Cn cc cc cc cc cc cc < < < < < cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc cc Cn Cn Cn 2 2 2 2 2 < < < < < ω ω ω ω ω ω ω ω ω ω ω 2 2 2 2 2 2 2 2 2 2 CC CC CC CC CC CC ω ω ω ω ω ω >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H >H in in in in in in in CO 2 2 2 2 2 2 2 2 2 2 2 2 in in in in in in in in < < in in in in in in < < < < < Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh Eh < < < < < < < < < < < < < 2 2 2 2 2 2 2 2 2 2 2 < < < < < < < < > > t-H (N no CN t-H t-H CN CN t-H t-H CN CN t-H CN t-H CN t-H CN t-H CN ω ESI EN 2 < CO CJ < CQ < CQ CJ Q ω a ω CN 2 < CO CJ a ω a ω CN 2 < 2 CJ a a < 2 < 2 CJ a Q ω ω ΕΝ < 2 CJ a a < 2 CJ CJ CJ CJ o 2 CJ CJ o CJ o 2 CJ CJ CJ o 2 CJ CJ CJ CJ CJ CJ CJ CJ O CJ o 2 CJ CJ CJ CJ CJ CJ CJ CJ O o o 2 CJ CJ CJ o o CJ o 2 CJ CJ CJ O 2 CJ CJ CJ CJ CJ CJ CJ CJ CJ o 2 CJ CJ CJ o o CJ o 2 CJ no ln U0 r> CO <T> o t-H CN no ln i£> r> CO o t-H CN no ln iO Γ" CO <T> O t-H CN no ln iO Γ" CO <T> O t-H CN no ln i£> Γ" CO o t-H CN no ln i£> Γ" CO <J\ o t-H CN no lO UO r> CO <j\ o t-H CN no ln i£> Γ" uo uo uo U0 uo uo i£> Γ" Γ" Γ" Γ" f~ r~ r> Γ" Γ" r~ CO CO CO CO CO CO CO CO CO CO <Ts <T> <T> <T> <T> <T> <T> <T> <T> <T> O O O o o o o o o o t-H t-H t-H t-H t-H t-H t-H t-H t-H t-H CN CN CN CN CN CN CN CN CN CN no no no no no no no no t- r> t- r> Γ" r> t- r> r> r> r> r> r> r> r> r> r> Γ" Γ" Γ" Γ" r> r> Γ" r> Γ" r> r> Γ" r> r> r> Γ" r> Γ" r> CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO uo uo uo uo uo uo i£> iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO iO (N 2 CJ ___,~^~~~~222222222222:22:222oooooooooooooooooooo 2 < > 6838 ____________________oooooooooooooooooooooooooooooooooooooooooooooooooooooooo <<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<< WO 2009/026558 PCT/US2008/074097 ATOM 6839 CGI VAL 112 -31.585 ATOM 6840 CG2 VAL 112 -33.688 ATOM 6841 C VAL 112 -32.400 ATOM 6842 O VAL 112 -31.889 ATOM 6843 N TRP 113 -32.112 ATOM 6844 CA TRP 113 -31.161 ATOM 6845 CB TRP 113 -31.843 ATOM 6846 CG TRP 113 -32.931 ATOM 6847 CD2 TRP 113 -33.006 ATOM 6848 CE2 TRP 113 -34.217 ATOM 6849 CE3 TRP 113 -32.167 ATOM 6850 CD1 TRP 113 -34.069 ATOM 6851 NEl TRP 113 -34.847 ATOM 6852 CZ2 TRP 113 -34.611 ATOM 6853 CZ3 TRP 113 -32.558 ATOM 6854 CH2 TRP 113 -33.771 ATOM 6855 C TRP 113 -29.996 ATOM 68 56 O TRP 113 -30.136 ATOM 6857 N GLY 114 -28.855 ATOM 6858 CA GLY 114 -27.776 ATOM 6859 C GLY 114 -27.980 ATOM 6860 0 GLY 114 -28.984 ATOM 6861 N GLN 115 -27.036 ATOM 6862 CA GLN 115 -27.189 ATOM 6863 CB GLN 115 -26.590 ATOM 6864 CG GLN 115 -27.488 ATOM 68 65 CD GLN 115 -28.955 ATOM 6866 OE1 GLN 115 -29.269 ATOM 6867 NE2 GLN 115 -29.853 ATOM 6868 C GLN 115 -26.573 ATOM 6869 0 GLN 115 -26.820 ATOM 6870 N GLY 116 -25.782 ATOM 6871 CA GLY 116 -25.283 ATOM 6872 C GLY 116 -23.874 ATOM 6873 0 GLY 116 -23.407 ATOM 6874 N THR 117 -23.188 ATOM 6875 CA THR 117 -21.862 ATOM 6876 CB THR 117 -20.776 ATOM 6877 OGl THR 117 -19.482 ATOM 6878 CG2 THR 117 -20.912 ATOM 6879 C THR 117 -21.849 ATOM 6880 O THR 117 -22.412 ATOM 6881 N MET 118 -21.227 ATOM 6882 CA MET 118 -21.275 ATOM 6883 CB MET 118 -21.189 ATOM 6884 CG MET 118 -21.254 ATOM 6885 SD MET 118 -22.818 ATOM 6886 CE MET 118 -22.441 ATOM 6887 C MET 118 -20.147 ATOM 6888 0 MET 118 -19.013 ATOM 6889 N VAL 119 -20.474 ATOM 6890 CA VAL 119 -19.506 ATOM 6891 CB VAL 119 -19.783 ATOM 6892 CGI VAL 119 -19.007 ATOM 6893 CG2 VAL 119 -19.376 ATOM 6894 C VAL 119 -19.643 ATOM 6895 O VAL 119 -20.724 ATOM 6896 N THR 120 -18.553 ATOM 6897 CA THR 120 -18.554 ATOM 6898 CB THR 120 -18.134 ATOM 6899 OGl THR 120 -19.037 ATOM 6900 CG2 THR 120 -18.154 ATOM 6901 C THR 120 -17.578 ATOM 6902 O THR 120 -16.442 ATOM 6903 N VAL 121 -18.028 ATOM 6904 CA VAL 121 -17.166 ATOM 6905 CB VAL 121 -17.718 ATOM 6906 CGI VAL 121 -16.839 ATOM 6907 CG2 VAL 121 -17.774 ATOM 6908 C VAL 121 -17.063 ATOM 6909 O VAL 121 -18.029 ATOM 6910 N SER 122 -15.884 ATOM 6911 CA SER 122 -15.694 ATOM 6912 CB SER 122 -15.947 ATOM 6913 OG SER 122 -15.882 ATOM 6914 C SER 122 -14.284 5.718 1.00 30.53 H C 4.599 1.00 31.40 H C 5.343 1.00 32.58 H C 4.370 1.00 33.04 H O 6.602 1.00 32.15 H N 6.953 1.00 31.65 H C 7.816 1.00 29.50 H C 7.128 1.00 28.47 H c 6.977 1.00 25.65 H c 6.315 1.00 26.45 H c 7.341 1.00 24.52 H c 6.562 1.00 26.10 H c 6.074 1.00 28.26 H N 6.008 1.00 26.31 H c 7.037 1.00 24.40 H c 6.377 1.00 25.50 H c 7.746 1.00 33.12 H c 8.371 1.00 31.88 H 0 7.723 1.00 32.68 H N 8.639 1.00 35.69 H c 9.974 1.00 37.38 H c 10.170 1.00 38.62 H 0 10.894 1.00 38.12 H N 12.218 1.00 40.72 H c 13.285 1.00 43.53 H c 13.619 1.00 51.75 H c 13.857 1.00 56.93 H c 14.778 1.00 58.91 H 0 13.018 1.00 58.11 H N 12.303 1.00 39.58 H c 13.254 1.00 38.68 H 0 11.298 1.00 37.78 H N 11.220 1.00 38.42 H c 11.752 1.00 39.35 H c 12.568 1.00 39.93 H 0 11.267 1.00 39.58 H N 11.750 1.00 39.22 H c 10.720 1.00 39.77 H c 11.284 1.00 41.61 H 0 9.445 1.00 38.56 H c 11.985 1.00 38.56 H c 11.194 1.00 39.43 H 0 13.079 1.00 38.05 H N 13.498 1.00 36.74 H c 15.024 1.00 38.21 H c 15.561 1.00 41.58 H c 15.157 1.00 50.65 H s 15.524 1.00 47.35 H c 12.871 1.00 34.48 H c 12.768 1.00 34.26 H 0 12.449 1.00 34.68 H N 11.833 1.00 33.91 H c 10.311 1.00 33.34 H c 9.793 1.00 33.26 H c 9.531 1.00 31.55 H c 12.520 1.00 34.59 H c 12.517 1.00 37.76 H 0 13.117 1.00 34.91 H N 13.762 1.00 35.35 H c 15.256 1.00 35.88 H c 15.960 1.00 37.94 H 0 15.902 1.00 34.25 H c 13.038 1.00 35.16 H c 12.768 1.00 35.56 H 0 12.721 1.00 36.37 H N 12.088 1.00 37.55 H c 10.703 1.00 38.08 H c 10.089 1.00 36.30 H c 9.784 1.00 36.74 H c 12.985 1.00 38.28 H c 13.156 1.00 39.94 H 0 13.563 1.00 38.45 H N 14.550 1.00 39.93 H c 15.962 1.00 40.21 H c 16.929 1.00 42.15 H 0 14.473 1.00 39.50 H c 269 WO 2009/026558 PCT/US2008/074097 ATOM 6915 0 SER 122 -13.320 35 ATOM 6916 N SER 123 -14.165 37 ATOM 6917 CA SER 123 -12.849 38 ATOM 6918 CB SER 123 -12.993 39 ATOM 6919 OG SER 123 -13.875 40 ATOM 6920 C SER 123 -12.105 37 ATOM 6921 O SER 123 -10.893 37 ATOM 6922 N ALA 124 -12.837 37 ATOM 6923 CA ALA 124 -12.262 36 ATOM 6924 CB ALA 124 -13.326 36 ATOM 6925 C ALA 124 -11.675 35 ATOM 6926 O ALA 124 -12.274 34 ATOM 6927 N SER 125 -10.503 35 ATOM 6928 CA SER 125 -9.862 33 ATOM 6929 CB SER 125 -8.355 34 ATOM 6930 OG SER 125 -7.752 34 ATOM 6931 C SER 125 -10.466 33 ATOM 6932 O SER 125 -11.093 33 ATOM 6933 N THR 126 -10.271 31 ATOM 6934 CA THR 126 -10.785 30 ATOM 6935 CB THR 126 -10.669 29 ATOM 6936 OG1 THR 126 -11.284 28 ATOM 6937 CG2 THR 126 -9.217 29 ATOM 6938 C THR 126 -10.049 31 ATOM 6939 O THR 126 -8.841 31 ATOM 6940 N LYS 127 -10.794 31 ATOM 6941 CA LYS 127 -10.262 31 ATOM 6942 CB LYS 127 -10.599 32 ATOM 6943 CG LYS 127 -10.108 33 ATOM 6944 CD LYS 127 -10.581 34 ATOM 6945 CE LYS 127 -10.208 34 ATOM 6946 NZ LYS 127 -10.600 33 ATOM 6947 C LYS 127 -10.862 30 ATOM 6948 0 LYS 127 -12.080 30 ATOM 6949 N GLY 128 -10.005 29 ATOM 6950 CA GLY 128 -10.476 28 ATOM 6951 C GLY 128 -11.064 29 ATOM 6952 0 GLY 128 -10.832 30 ATOM 6953 N PRO 129 -11.856 28 ATOM 6954 CD PRO 129 -12.255 27 ATOM 6955 CA PRO 129 -12.553 29 ATOM 6956 CB PRO 129 -13.695 28 ATOM 6957 CG PRO 129 -13.119 27 ATOM 6958 C PRO 129 -11.663 29 ATOM 6959 O PRO 129 -10.742 28 ATOM 6960 N SER 130 -11.954 30 ATOM 6961 CA SER 130 -11.478 30 ATOM 6962 CB SER 130 -11.275 31 ATOM 6963 OG SER 130 -10.239 32 ATOM 6964 C SER 130 -12.522 29 ATOM 6965 O SER 130 -13.708 30 ATOM 6966 N VAL 131 -12.091 28 ATOM 6967 CA VAL 131 -13.026 28 ATOM 6968 CB VAL 131 -12.840 26 ATOM 6969 CGI VAL 131 -13.882 25 ATOM 6970 CG2 VAL 131 -12.938 26 ATOM 6971 C VAL 131 -12.860 28 ATOM 6972 O VAL 131 -11.760 28 ATOM 6973 N PHE 132 -13.955 28 ATOM 6974 CA PHE 132 -13.953 29 ATOM 6975 CB PHE 132 -14.266 30 ATOM 6976 CG PHE 132 -13.327 31 ATOM 6977 CDl PHE 132 -12.103 31 ATOM 6978 CD2 PHE 132 -13.651 32 ATOM 6979 CEl PHE 132 -11.214 32 ATOM 6980 CE2 PHE 132 -12.769 32 ATOM 6981 CZ PHE 132 -11.548 33 ATOM 6982 C PHE 132 -14.963 28 ATOM 6983 O PHE 132 -16.041 28 ATOM 6984 N PRO 133 -14.617 27 ATOM 6985 CD PRO 133 -13.324 28 ATOM 6986 CA PRO 133 -15.511 27 ATOM 6987 CB PRO 133 -14.593 26 ATOM 6988 CG PRO 133 -13.541 27 ATOM 6989 C PRO 133 -16.645 27 ATOM 6990 O PRO 133 -16.426 29 14.199 1.00 37.65 H O 14.726 1.00 41.58 H N 14.807 1.00 44.16 H C 14.777 1.00 44.85 H C 15.794 1.00 49.05 H 0 16.079 1.00 44.60 H c 16.184 1.00 45.68 H 0 17.031 1.00 43.93 H N 18.301 1.00 42.24 H c 19.390 1.00 40.10 H c 18.214 1.00 42.14 H c 17.620 1.00 43.33 H 0 18.820 1.00 42.38 H N 18.876 1.00 40.59 H c 19.109 1.00 42.02 H c 18.072 1.00 45.10 H 0 20.010 1.00 38.95 H c 20.907 1.00 37.48 H 0 19.977 1.00 37.66 H N 21.042 1.00 39.23 H c 20.674 1.00 38.28 H c 21.697 1.00 41.97 H 0 20.533 1.00 37.08 H c 22.370 1.00 41.01 H c 22.392 1.00 41.24 H 0 23.471 1.00 40.95 H N 24.806 1.00 38.98 H c 25.231 1.00 38.46 H c 26.625 1.00 39.85 H c 27.043 1.00 39.69 H c 28.494 1.00 40.59 H c 29.429 1.00 41.49 H N 25.809 1.00 37.64 H c 25.916 1.00 37.85 H 0 26.536 1.00 36.50 H N 27.566 1.00 33.05 H c 28.750 1.00 32.53 H c 28.923 1.00 32.58 H 0 29.578 1.00 32.14 H N 29.361 1.00 32.62 H c 30.728 1.00 32.53 H c 30.978 1.00 31.17 H c 30.561 1.00 30.16 H c 31.967 1.00 33.22 H c 32.161 1.00 31.90 H 0 32.804 1.00 32.62 H N 34.185 1.00 35.02 H c 34.687 1.00 34.24 H c 33.964 1.00 41.41 H 0 35.050 1.00 35.50 H c 34.958 1.00 37.01 H 0 35.884 1.00 34.84 H N 36.716 1.00 34.36 H c 36.526 1.00 34.23 H c 37.333 1.00 33.85 H c 35.046 1.00 34.73 H c 38.198 1.00 35.71 H c 38.750 1.00 35.77 H 0 38.834 1.00 34.57 H N 40.261 1.00 33.58 H c 40.489 1.00 32.57 H c 39.782 1.00 34.21 H c 40.344 1.00 35.59 H c 38.538 1.00 33.19 H c 39.674 1.00 37.01 H c 37.862 1.00 35.41 H c 38.430 1.00 36.28 H c 41.022 1.00 34.57 H c 40.512 1.00 32.06 H 0 42.258 1.00 34.29 H N 42.918 1.00 34.35 H c 43.108 1.00 35.13 H c 44.220 1.00 33.32 H c 44.336 1.00 34.24 H c 43.662 1.00 35.55 H c 44.068 1.00 36.64 H 0 270 WO 2009/026558 PCT/US2008/074097 ATOM 6991 N LEU 134 -17.852 27 ATOM 6992 CA LEU 134 -18.977 28 ATOM 6993 CB LEU 134 -20.209 28 ATOM 6994 CG LEU 134 -19.960 28 ATOM 6995 CDl LEU 134 -21.140 28 ATOM 6996 CD2 LEU 134 -19.697 30 ATOM 6997 C LEU 134 -19.259 27 ATOM 6998 O LEU 134 -19.999 26 ATOM 6999 N ALA 135 -18.645 27 ATOM 7000 CA ALA 135 -18.596 26 ATOM 7001 CB ALA 135 -17.561 27 ATOM 7002 C ALA 135 -19.957 26 ATOM 7003 O ALA 135 -20.712 27 ATOM 7004 N PRO 136 -20.283 25 ATOM 7005 CD PRO 136 -19.446 24 ATOM 7006 CA PRO 136 -21.531 25 ATOM 7007 CB PRO 136 -21.528 23 ATOM 7008 CG PRO 136 -20.085 23 ATOM 7009 C PRO 136 -21.586 26 ATOM 7010 O PRO 136 -20.570 26 ATOM 7011 N SER 137 -22.782 26 ATOM 7012 CA SER 137 -22.993 27 ATOM 7013 CB SER 137 -24.411 28 ATOM 7014 OG SER 137 -24.664 29 ATOM 7015 C SER 137 -22.774 26 ATOM 7016 O SER 137 -22.866 25 ATOM 7017 N SER 138 -22.492 27 ATOM 7018 CA SER 138 -22.171 27 ATOM 7019 CB SER 138 -21.280 28 ATOM 7020 OG SER 138 -20.112 28 ATOM 7021 C SER 138 -23.414 26 ATOM 7022 O SER 138 -23.688 27 ATOM 7023 N LYS 139 -24.161 25 ATOM 7024 CA LYS 139 -25.298 25 ATOM 7025 CB LYS 139 -26.616 25 ATOM 7026 CG LYS 139 -26.910 27 ATOM 7027 CD LYS 139 -26.118 28 ATOM 7028 CE LYS 139 -26.243 29 ATOM 7029 NZ LYS 139 -25.510 30 ATOM 7030 C LYS 139 -25.349 23 ATOM 7031 0 LYS 139 -26.414 23 ATOM 7032 N GLY 143 -30.107 19 ATOM 7033 CA GLY 143 -29.319 19 ATOM 7034 C GLY 143 -29.957 18 ATOM 7035 0 GLY 143 -30.100 17 ATOM 7036 N GLY 144 -30.342 19 ATOM 7037 CA GLY 144 -30.925 18 ATOM 7038 C GLY 144 -29.972 18 ATOM 7039 0 GLY 144 -29.023 17 ATOM 7040 N THR 145 -30.216 19 ATOM 7041 CA THR 145 -29.334 19 ATOM 7042 CB THR 145 -30.109 19 ATOM 7043 OG1 THR 145 -31.019 20 ATOM 7044 CG2 THR 145 -30.877 18 ATOM 7045 C THR 145 -28.562 20 ATOM 7046 O THR 145 -28.979 21 ATOM 7047 N ALA 146 -27.428 20 ATOM 7048 CA ALA 146 -26.691 21 ATOM 7049 CB ALA 146 -25.407 22 ATOM 7050 C ALA 146 -26.374 22 ATOM 7051 O ALA 146 -26.227 21 ATOM 7052 N ALA 147 -26.278 23 ATOM 7053 CA ALA 147 -25.943 23 ATOM 7054 CB ALA 147 -26.894 24 ATOM 7055 C ALA 147 -24.500 23 ATOM 7056 O ALA 147 -24.055 24 ATOM 7057 N LEU 148 -23.765 23 ATOM 7058 CA LEU 148 -22.421 23 ATOM 7059 CB LEU 148 -21.402 23 ATOM 7060 CG LEU 148 -21.395 21 ATOM 7061 CDl LEU 148 -20.408 21 ATOM 7062 CD2 LEU 148 -21. Oil 20 ATOM 7063 C LEU 148 -22.221 23 ATOM 7064 O LEU 148 -22.934 22 ATOM 7065 N GLY 149 -21.267 24 ATOM 7066 CA GLY 149 -21.040 24 43.674 1.00 35.32 H N 44.366 1.00 36.08 H C 43.450 1.00 34.28 H C 42.142 1.00 34.73 H c 41.185 1.00 31.18 H c 42.475 1.00 33.05 H c 45.618 1.00 36.52 H c 45.585 1.00 34.85 H 0 46.720 1.00 37.22 H N 47.917 1.00 40.97 H c 48.891 1.00 38.81 H c 48.594 1.00 44.00 H c 48.626 1.00 40.78 H 0 49.148 1.00 48.76 H N 49.152 1.00 49.46 H c 49.890 1.00 54.13 H c 50.232 1.00 52.72 H c 50.205 1.00 51.83 H c 51.132 1.00 59.78 H c 51.794 1.00 59.54 H 0 51.432 1.00 67.10 H N 52.560 1.00 74.14 H c 52.507 1.00 75.09 H c 53.617 1.00 78.01 H 0 53.892 1.00 77.67 H c 53.977 1.00 78.44 H 0 54.931 1.00 82.40 H N 56.248 1.00 86.84 H c 57. Oil 1.00 87.07 H c 56.271 1.00 87.61 H 0 57.087 1.00 89.30 H c 58.085 1.00 89.91 H 0 56.678 1.00 91.76 H N 57.457 1.00 93.44 H c 56.899 1.00 93.81 H c 57.291 1.00 94.61 H c 56.442 1.00 95.03 H c 56.976 1.00 95.42 H c 56.125 1.00 95.24 H N 57.464 1.00 94.08 H c 57.638 1.00 95.08 H 0 59.281 1.00 59.11 H N 58.062 1.00 61.11 H c 56.968 1.00 60.28 H c 57.106 1.00 60.72 H 0 55.877 1.00 58.29 H N 54.746 1.00 54.60 H c 53.562 1.00 52.81 H c 53.550 1.00 53.00 H 0 52.565 1.00 49.01 H N 51.403 1.00 46.11 H c 50.080 1.00 46.35 H c 49.929 1.00 48.50 H 0 50.056 1.00 44.98 H c 51.343 1.00 44.27 H c 51.912 1.00 42.47 H 0 50.651 1.00 41.79 H N 50.374 1.00 40.00 H c 51.187 1.00 40.43 H c 48.888 1.00 39.46 H c 48.212 1.00 38.93 H 0 48.380 1.00 37.34 H N 46.986 1.00 35.51 H c 46.374 1.00 34.09 H c 46.874 1.00 35.59 H c 47.620 1.00 35.64 H 0 45.942 1.00 34.79 H N 45.658 1.00 34.42 H c 46.425 1.00 35.26 H c 46.088 1.00 38.02 H c 44.961 1.00 38.18 H c 47.323 1.00 39.69 H c 44.159 1.00 33.02 H c 43.498 1.00 32.43 H 0 43.612 1.00 32.54 H N 42.187 1.00 35.20 H c 271 WO 2009/026558 PCT/US2008/074097 ATOM 7067 c GLY 149 -19.729 24 ATOM 7068 0 GLY 149 -18.812 25 ATOM 7069 N CYS 150 -19.626 25 ATOM 7070 CA CYS 150 -18.464 25 ATOM 7071 C CYS 150 -18.825 26 ATOM 7072 0 CYS 150 -19.729 26 ATOM 7073 CB CYS 150 -17.360 24 ATOM 7074 SG CYS 150 -17.554 23 ATOM 7075 N LEU 151 -18.141 27 ATOM 7076 CA LEU 151 -18.431 29 ATOM 7077 CB LEU 151 -18.334 30 ATOM 7078 CG LEU 151 -18.258 31 ATOM 7079 CDl LEU 151 -19.607 31 ATOM 7080 CD2 LEU 151 -17.863 32 ATOM 7081 C LEU 151 -17.415 29 ATOM 7082 O LEU 151 -16.204 29 ATOM 7083 N VAL 152 -17.909 29 ATOM 7084 CA VAL 152 -17.053 28 ATOM 7085 CB VAL 152 -17.542 27 ATOM 7086 CGI VAL 152 -16.662 27 ATOM 7087 CG2 VAL 152 -17.540 26 ATOM 7088 C VAL 152 -17.090 30 ATOM 7089 O VAL 152 -18.059 30 ATOM 7090 N LYS 153 -16.025 30 ATOM 7091 CA LYS 153 -16.020 32 ATOM 7092 CB LYS 153 -15.435 33 ATOM 7093 CG LYS 153 -16.456 33 ATOM 7094 CD LYS 153 -15.778 34 ATOM 7095 CE LYS 153 -15.056 35 ATOM 7096 NZ LYS 153 -14.280 36 ATOM 7097 C LYS 153 -15.250 32 ATOM 7098 0 LYS 153 -14.178 32 ATOM 7099 N ASP 154 -15.803 33 ATOM 7100 CA ASP 154 -15.069 34 ATOM 7101 CB ASP 154 -13.929 34 ATOM 7102 CG ASP 154 -14.421 36 ATOM 7103 OD1 ASP 154 -15.540 36 ATOM 7104 OD2 ASP 154 -13.675 36 ATOM 7105 C ASP 154 -14.473 33 ATOM 7106 O ASP 154 -13.271 33 ATOM 7107 N TYR 155 -15.286 32 ATOM 7108 CA TYR 155 -14.769 31 ATOM 7109 CB TYR 155 -15.004 29 ATOM 7110 CG TYR 155 -16.462 29 ATOM 7111 CDl TYR 155 -17.179 29 ATOM 7112 CEl TYR 155 -18.510 28 ATOM 7113 CD2 TYR 155 -17.123 29 ATOM 7114 CE2 TYR 155 -18.457 29 ATOM 7115 CZ TYR 155 -19.144 28 ATOM 7116 OH TYR 155 -20.475 28 ATOM 7117 C TYR 155 -15.398 31 ATOM 7118 O TYR 155 -16.382 32 ATOM 7119 N PHE 156 -14.814 31 ATOM 7120 CA PHE 156 -15.321 31 ATOM 7121 CB PHE 156 -15.072 32 ATOM 7122 CG PHE 156 -15.588 33 ATOM 7123 CDl PHE 156 -14.798 32 ATOM 7124 CD2 PHE 156 -16.870 33 ATOM 7125 CEl PHE 156 -15.280 33 ATOM 7126 CE2 PHE 156 -17.358 33 ATOM 7127 CZ PHE 156 -16.561 33 ATOM 7128 C PHE 156 -14.646 30 ATOM 7129 O PHE 156 -13.452 30 ATOM 7130 N PRO 157 -15.410 29 ATOM 7131 CD PRO 157 -14.843 29 ATOM 7132 CA PRO 157 -16.873 29 ATOM 7133 CB PRO 157 -17.141 29 ATOM 7134 CG PRO 157 -16.070 28 ATOM 7135 C PRO 157 -17.533 28 ATOM 7136 O PRO 157 -16.863 28 ATOM 7137 N GLU 158 -18.845 28 ATOM 7138 CA GLU 158 -19.543 27 ATOM 7139 CB GLU 158 -21.058 27 ATOM 7140 CG GLU 158 -21.620 28 ATOM 7141 CD GLU 158 -22.272 28 ATOM 7142 OE1 GLU 158 -21.641 27 41.742 1.00 35.35 H C 42.537 1.00 34.93 H O 40.451 1.00 36.17 H N 39.974 1.00 38.63 H C 38.841 1.00 36.98 H C 38.048 1.00 37.67 H 0 39.601 1.00 42.69 H c 38.089 1.00 55.77 H s 38.818 1.00 35.05 H N 37.898 1.00 33.32 H c 38.640 1.00 31.86 H c 37.803 1.00 34.10 H c 37.141 1.00 31.52 H c 38.701 1.00 32.35 H c 36.764 1.00 35.15 H c 37.002 1.00 34.70 H 0 35.531 1.00 35.15 H N 34.365 1.00 33.97 H C 33.519 1.00 34.25 H C 32.298 1.00 33.15 H C 34.373 1.00 33.07 H c 33.536 1.00 35.52 H c 32.816 1.00 35.70 H 0 33.644 1.00 35.56 H N 33.194 1.00 36.98 H c 34.288 1.00 37.29 H c 35.205 1.00 44.06 H c 36.286 1.00 45.54 H c 35.687 1.00 48.07 H c 36.708 1.00 48.70 H N 31.896 1.00 35.32 H c 31.674 1.00 33.48 H 0 31.061 1.00 35.67 H N 29.951 1.00 38.13 H c 30.488 1.00 38.72 H c 31.326 1.00 42.66 H c 31.078 1.00 42.06 H 0 32.241 1.00 47.57 H 0 28.945 1.00 37.85 H c 28.676 1.00 39.38 H 0 28.377 1.00 36.72 H N 27.326 1.00 35.87 H c 27.690 1.00 35.27 H c 27.807 1.00 37.64 H c 26.693 1.00 36.63 H c 26.793 1.00 38.10 H c 29.032 1.00 36.52 H c 29.140 1.00 36.48 H c 28.017 1.00 37.43 H c 28.105 1.00 38.45 H 0 25.966 1.00 36.12 H c 25.881 1.00 35.25 H 0 24.908 1.00 36.85 H N 23.554 1.00 38.37 H c 23.088 1.00 38.82 H c 21.705 1.00 42.82 H c 20.588 1.00 43.82 H c 21.516 1.00 43.40 H c 19.308 1.00 44.30 H c 20.235 1.00 43.81 H c 19.134 1.00 41.90 H c 22.593 1.00 39.91 H c 22.710 1.00 40.67 H 0 21.635 1.00 40.59 H N 20.491 1.00 41.29 H c 21.549 1.00 40.24 H c 20.065 1.00 41.39 H c 19.661 1.00 42.40 H c 22.402 1.00 38.74 H c 23.163 1.00 36.64 H 0 22.258 1.00 39.77 H N 22.849 1.00 41.74 H c 22.739 1.00 40.97 H c 23.634 1.00 42.42 H c 24.893 1.00 45.45 H c 25.594 1.00 47.64 H 0 272 WO 2009/026558 PCT/US2008/074097 ATOM 7143 OE2 GLU 158 -23.423 28 ATOM 7144 C GLU 158 -19.135 26 ATOM 7145 0 GLU 158 -18.668 26 ATOM 7146 N PRO 159 -19.324 25 ATOM 7147 CD PRO 159 -19.151 23 ATOM 7148 CA PRO 159 -19.854 24 ATOM 7149 CB PRO 159 -20.732 23 ATOM 7150 CG PRO 159 -19.907 22 ATOM 7151 C PRO 159 -18.755 24 ATOM 7152 O PRO 159 -17.610 24 ATOM 7153 N VAL 160 -19.112 24 ATOM 7154 CA VAL 160 -18.333 23 ATOM 7155 CB VAL 160 -17.819 24 ATOM 7156 CGI VAL 160 -17.135 25 ATOM 7157 CG2 VAL 160 -18.960 24 ATOM 7158 C VAL 160 -19.223 22 ATOM 7159 O VAL 160 -20.436 22 ATOM 7160 N THR 161 -18.621 21 ATOM 7161 CA THR 161 -19.341 20 ATOM 7162 CB THR 161 -19.128 19 ATOM 7163 OG1 THR 161 -17.767 18 ATOM 7164 CG2 THR 161 -19.424 19 ATOM 7165 C THR 161 -18.838 20 ATOM 7166 O THR 161 -17.665 20 ATOM 7167 N VAL 162 -19.733 20 ATOM 7168 CA VAL 162 -19.364 20 ATOM 7169 CB VAL 162 -19.983 21 ATOM 7170 CGI VAL 162 -19.557 21 ATOM 7171 CG2 VAL 162 -19.553 22 ATOM 7172 C VAL 162 -19.853 18 ATOM 7173 O VAL 162 -21.023 18 ATOM 7174 N SER 163 -18.955 17 ATOM 7175 CA SER 163 -19.347 16 ATOM 7176 CB SER 163 -18.732 15 ATOM 7177 OG SER 163 -17.328 15 ATOM 7178 C SER 163 -18.854 16 ATOM 7179 O SER 163 -18.027 17 ATOM 7180 N TRP 164 -19.366 16 ATOM 7181 CA TRP 164 -18.936 16 ATOM 7182 CB TRP 164 -20.109 16 ATOM 7183 CG TRP 164 -20.453 17 ATOM 7184 CD2 TRP 164 -19.970 18 ATOM 7185 CE2 TRP 164 -20.531 20 ATOM 7186 CE3 TRP 164 -19.117 18 ATOM 7187 CDl TRP 164 -21.268 18 ATOM 7188 NEl TRP 164 -21.319 19 ATOM 7189 CZ2 TRP 164 -20.265 21 ATOM 7190 CZ3 TRP 164 -18.853 20 ATOM 7191 CH2 TRP 164 -19.427 21 ATOM 7192 C TRP 164 -18.365 14 ATOM 7193 O TRP 164 -18.923 13 ATOM 7194 N ASN 165 -17.247 14 ATOM 7195 CA ASN 165 -16.524 13 ATOM 7196 CB ASN 165 -17.216 12 ATOM 7197 CG ASN 165 -17.097 13 ATOM 7198 OD1 ASN 165 -16.354 14 ATOM 7199 ND2 ASN 165 -17.823 13 ATOM 7200 C ASN 165 -16.426 12 ATOM 7201 0 ASN 165 -16.682 11 ATOM 7202 N SER 166 -16.071 13 ATOM 7203 CA SER 166 -15.795 12 ATOM 7204 CB SER 166 -14.620 11 ATOM 7205 OG SER 166 -13.465 12 ATOM 7206 C SER 166 -17.003 11 ATOM 7207 O SER 166 -16.854 10 ATOM 7208 N GLY 167 -18.199 11 ATOM 7209 CA GLY 167 -19.403 11 ATOM 7210 C GLY 167 -20.035 10 ATOM 7211 0 GLY 167 -21.137 9 ATOM 7212 N ALA 168 -19.340 10 ATOM 7213 CA ALA 168 -19.868 9 ATOM 7214 CB ALA 168 -18.762 8 ATOM 7215 C ALA 168 -21.030 9 ATOM 7216 0 ALA 168 -21.869 9 ATOM 7217 N LEU 169 -21.073 11 ATOM 7218 CA LEU 169 -22.129 12 25.182 1.00 45.92 H O 22.117 1.00 41.79 H C 20.981 1.00 43.21 H O 22.746 1.00 43.12 H N 21.993 1.00 40.80 H C 24.090 1.00 42.75 H C 23.861 1.00 41.21 H c 22.852 1.00 42.04 H c 25.116 1.00 43.47 H c 24.748 1.00 43.74 H 0 26.399 1.00 44.59 H N 27.381 1.00 45.26 H c 28.546 1.00 44.95 H c 28.015 1.00 45.98 H c 29.455 1.00 47.14 H c 27.980 1.00 45.46 H c 28.090 1.00 45.76 H 0 28.358 1.00 44.80 H N 29.095 1.00 45.47 H c 28.470 1.00 47.53 H c 28.658 1.00 50.04 H 0 26.973 1.00 47.52 H c 30.536 1.00 44.68 H c 30.800 1.00 44.39 H 0 31.468 1.00 43.69 H N 32.874 1.00 42.46 H c 33.710 1.00 41.02 H c 35.159 1.00 39.15 H c 33.154 1.00 39.60 H c 33.439 1.00 42.98 H c 33.302 1.00 44.77 H 0 34.067 1.00 41.43 H N 34.767 1.00 41.82 H c 34.095 1.00 43.74 H c 34.281 1.00 47.54 H 0 36.199 1.00 40.92 H c 36.505 1.00 40.33 H 0 37.081 1.00 39.41 H N 38.469 1.00 39.92 H c 39.367 1.00 38.97 H c 39.251 1.00 36.68 H c 40.083 1.00 35.35 H c 39.599 1.00 35.70 H c 41.189 1.00 35.83 H c 38.320 1.00 36.06 H c 38.524 1.00 34.61 H N 40.185 1.00 36.66 H c 41.770 1.00 38.04 H c 41.266 1.00 37.96 H c 38.899 1.00 41.57 H c 38.579 1.00 41.54 H 0 39.623 1.00 43.99 H N 40.015 1.00 45.28 H c 41.211 1.00 44.38 H c 42.477 1.00 44.74 H c 42.515 1.00 48.85 H 0 43.520 1.00 43.07 H N 38.848 1.00 48.10 H c 38.998 1.00 48.86 H 0 37.679 1.00 50.62 H N 36.507 1.00 54.00 H c 36.787 1.00 54.39 H c 37.171 1.00 56.87 H 0 36.065 1.00 55.66 H c 35.505 1.00 56.97 H 0 36.317 1.00 56.98 H N 35.835 1.00 56.82 H c 36.853 1.00 57.13 H c 36.640 1.00 57.48 H 0 37.962 1.00 55.72 H N 39.024 1.00 56.14 H c 40.018 1.00 54.67 H c 39.746 1.00 56.76 H c 40.359 1.00 57.75 H 0 39.676 1.00 55.50 H N 40.325 1.00 53.11 H c 273 WO 2009/026558 PCT/US2008/074097 ATOM 7219 CB LEU 169 -21.519 13 ATOM 7220 CG LEU 169 -22.471 14 ATOM 7221 CD1 LEU 169 -23.459 13 ATOM 7222 CD2 LEU 169 -21.660 15 ATOM 7223 C LEU 169 -22.989 12 ATOM 7224 O LEU 169 -22.540 13 ATOM 7225 N THR 170 -24.230 12 ATOM 7226 CA THR 170 -25.126 12 ATOM 7227 CB THR 170 -25.414 11 ATOM 7228 OG1 THR 170 -25.938 10 ATOM 7229 CG2 THR 170 -24.135 11 ATOM 7230 C THR 170 -26.447 13 ATOM 7231 O THR 170 -27.083 14 ATOM 7232 N SER 171 -26.854 12 ATOM 7233 CA SER 171 -28.080 13 ATOM 7234 CB SER 171 -28.477 11 ATOM 7235 OG SER 171 -29.732 12 ATOM 7236 C SER 171 -27.898 14 ATOM 7237 O SER 171 -26.913 14 ATOM 7238 N GLY 172 -28.848 15 ATOM 7239 CA GLY 172 -28.794 16 ATOM 7240 C GLY 172 -27.951 17 ATOM 7241 0 GLY 172 -27.815 18 ATOM 7242 N VAL 173 -27.381 17 ATOM 7243 CA VAL 173 -26.556 18 ATOM 7244 CB VAL 173 -25.533 17 ATOM 7245 CGI VAL 173 -24.782 18 ATOM 7246 CG2 VAL 173 -24.556 16 ATOM 7247 C VAL 173 -27.414 18 ATOM 7248 O VAL 173 -28.250 18 ATOM 7249 N HIS 174 -27.202 20 ATOM 7250 CA HIS 174 -27.856 21 ATOM 7251 CB HIS 174 -29.001 21 ATOM 7252 CG HIS 174 -29.858 22 ATOM 7253 CD2 HIS 174 -29.788 22 ATOM 7254 ND1 HIS 174 -30.944 23 ATOM 7255 CEl HIS 174 -31.506 23 ATOM 7256 NE2 HIS 174 -30.823 23 ATOM 7257 C HIS 174 -26.850 22 ATOM 7258 0 HIS 174 -26.371 23 ATOM 7259 N THR 175 -26.534 21 ATOM 7260 CA THR 175 -25.664 22 ATOM 7261 CB THR 175 -24.692 22 ATOM 7262 OGl THR 175 -23.814 21 ATOM 72 63 CG2 THR 175 -23.868 23 ATOM 7264 C THR 175 -26.504 23 ATOM 7265 O THR 175 -27.269 23 ATOM 7266 N PHE 176 -26.370 25 ATOM 7267 CA PHE 176 -27.245 26 ATOM 7268 CB PHE 176 -27.366 27 ATOM 7269 CG PHE 176 -28.218 27 ATOM 7270 CD1 PHE 176 -27.803 26 ATOM 7271 CD2 PHE 176 -29.437 27 ATOM 7272 CEl PHE 176 -28.597 25 ATOM 7273 CE2 PHE 176 -30.233 27 ATOM 7274 CZ PHE 176 -29.812 26 ATOM 7275 C PHE 176 -26.734 26 ATOM 7276 O PHE 176 -25.530 26 ATOM 7277 N PRO 177 -27.652 27 ATOM 7278 CD PRO 177 -29.113 26 ATOM 7279 CA PRO 177 -27.251 27 ATOM 7280 CB PRO 177 -28.583 27 ATOM 7281 CG PRO 177 -29.548 26 ATOM 7282 C PRO 177 -26.419 28 ATOM 7283 O PRO 177 -26.689 29 ATOM 7284 N ALA 178 -25.410 29 ATOM 7285 CA ALA 178 -2 4.4 68 30 ATOM 7286 CB ALA 178 -23.295 29 ATOM 7287 C ALA 178 -25.129 31 ATOM 7288 O ALA 178 -26.116 31 ATOM 7289 N VAL 179 -24.583 32 ATOM 7290 CA VAL 179 -24.940 33 ATOM 7291 CB VAL 179 -24.935 34 ATOM 7292 CGI VAL 179 -23.532 34 ATOM 7293 CG2 VAL 179 -25.460 36 ATOM 7294 C VAL 179 -23.904 34 41.263 1.00 52.46 H C 41.979 1.00 52.36 H C 42.831 1.00 50.70 H C 42.847 1.00 50.44 H C 39.273 1.00 52.77 H C 38.588 1.00 52.53 H O 39.147 1.00 52.69 H N 38.110 1.00 52.29 H C 37.077 1.00 52.97 H C 37.744 1.00 52.52 H 0 36.339 1.00 51.54 H c 38.702 1.00 52.12 H c 38.182 1.00 52.03 H 0 39.798 1.00 51.23 H N 40.469 1.00 50.24 H c 41.490 1.00 51.95 H c 42.075 1.00 55.96 H 0 41.164 1.00 48.92 H c 41.879 1.00 48.18 H 0 40.946 1.00 46.35 H N 41.589 1.00 44.63 H c 40.839 1.00 43.58 H c 41.276 1.00 43.02 H 0 39.711 1.00 41.66 H N 38.907 1.00 40.61 H c 38.052 1.00 40.49 H c 37.122 1.00 36.94 H c 38.959 1.00 38.36 H c 37.974 1.00 39.99 H c 37.240 1.00 39.43 H 0 38.008 1.00 39.34 H N 37.065 1.00 39.73 H c 37.751 1.00 41.08 H c 36.800 1.00 45.12 H c 35.455 1.00 46.87 H c 37.210 1.00 47.42 H N 36.159 1.00 46.85 H c 35.082 1.00 47.87 H N 36.485 1.00 38.58 H C 37.176 1.00 37.51 H p 35.208 1.00 38.03 H N 34.507 1.00 36.61 H C 33.585 1.00 37.00 H c 34.390 1.00 36.64 H 0 32.749 1.00 36.37 H c 33.694 1.00 36.47 H c 32.822 1.00 38.71 H 0 33.994 1.00 34.80 H N 33.416 1.00 33.49 H c 34.350 1.00 29.26 H c 35.554 1.00 29.36 H c 36.543 1.00 28.93 H c 35.701 1.00 26.76 H c 37.666 1.00 30.31 H c 36.814 1.00 28.16 H c 37.798 1.00 29.02 H c 32.068 1.00 34.89 H c 31.822 1.00 35.66 H 0 31.175 1.00 35.42 H N 31.270 1.00 34.38 H c 29.881 1.00 35.34 H c 29.182 1.00 34.43 H c 29.830 1.00 35.56 H c 30.082 1.00 35.62 H c 30.986 1.00 37.58 H 0 29.237 1.00 34.61 H N 29.379 1.00 34.64 H c 28.424 1.00 32.42 H c 29.121 1.00 34.20 H c 28.394 1.00 35.25 H 0 29.734 1.00 33.24 H N 29.372 1.00 34.36 H c 30.613 1.00 35.45 H c 31.198 1.00 34.78 H c 30.246 1.00 33.91 H c 28.359 1.00 35.86 H c 274 WO 2009/026558 PCT/US2008/074097 ATOM 7295 0 VAL 179 -22.734 33 ATOM 7296 N LEU 180 -24.336 35 ATOM 7297 CA LEU 180 -23.402 35 ATOM 7298 CB LEU 180 -23.998 35 ATOM 7299 CG LEU 180 -23.180 36 ATOM 7300 CDl LEU 180 -21.808 35 ATOM 7301 CD2 LEU 180 -23.925 36 ATOM 7302 C LEU 180 -23.112 37 ATOM 7303 O LEU 180 -24.023 38 ATOM 7304 N GLN 181 -21.845 37 ATOM 7305 CA GLN 181 -21.494 38 ATOM 7306 CB GLN 181 -20.189 38 ATOM 7307 CG GLN 181 -20.135 37 ATOM 7308 CD GLN 181 -18.767 37 ATOM 7309 OE1 GLN 181 -18.275 38 ATOM 7310 NE2 GLN 181 -18.140 36 ATOM 7311 C GLN 181 -21.339 39 ATOM 7312 0 GLN 181 -21.008 39 ATOM 7313 N SER 182 -21.569 41 ATOM 7314 CA SER 182 -21.284 42 ATOM 7315 CB SER 182 -21.346 43 ATOM 7316 OG SER 182 -22.606 43 ATOM 7317 C SER 182 -19.910 42 ATOM 7318 O SER 182 -19.711 42 ATOM 7319 N SER 183 -18.964 41 ATOM 7320 CA SER 183 -17.606 41 ATOM 7321 CB SER 183 -16.691 40 ATOM 7322 OG SER 183 -16.966 39 ATOM 7323 C SER 183 -17.558 40 ATOM 7324 O SER 183 -16.549 40 ATOM 7325 N GLY 184 -18.634 39 ATOM 7326 CA GLY 184 -18.630 38 ATOM 7327 C GLY 184 -18.155 37 ATOM 7328 0 GLY 184 -18.108 36 ATOM 7329 N LEU 185 -17.797 37 ATOM 7330 CA LEU 185 -17.391 35 ATOM 7331 CB LEU 185 -16.222 36 ATOM 7332 CG LEU 185 -14.954 36 ATOM 7333 CDl LEU 185 -13.943 37 ATOM 7334 CD2 LEU 185 -14.363 35 ATOM 7335 C LEU 185 -18.566 35 ATOM 7336 O LEU 185 -19.534 35 ATOM 7337 N TYR 186 -18.479 33 ATOM 7338 CA TYR 186 -19.544 33 ATOM 7339 CB TYR 186 -19.905 31 ATOM 7340 CG TYR 186 -20.484 32 ATOM 7341 CDl TYR 186 -21.859 32 ATOM 7342 CEl TYR 186 -22.393 32 ATOM 7343 CD2 TYR 186 -19.658 32 ATOM 7344 CE2 TYR 186 -20.178 32 ATOM 7345 CZ TYR 186 -21.545 32 ATOM 7346 OH TYR 186 -22.060 32 ATOM 7347 C TYR 186 -19.137 32 ATOM 7348 O TYR 186 -17.962 32 ATOM 7349 N SER 187 -20.118 32 ATOM 7350 CA SER 187 -19.939 32 ATOM 7351 CB SER 187 -19.760 33 ATOM 7352 OG SER 187 -18.614 34 ATOM 7353 C SER 187 -21.157 31 ATOM 7354 O SER 187 -22.288 31 ATOM 7355 N LEU 188 -20.932 30 ATOM 7356 CA LEU 188 -22.041 29 ATOM 7357 CB LEU 188 -22.372 28 ATOM 7358 CG LEU 188 -21.331 27 ATOM 7359 CDl LEU 188 -21.234 26 ATOM 7360 CD2 LEU 188 -21.747 26 ATOM 7361 C LEU 188 -21.753 29 ATOM 7362 O LEU 188 -20.650 29 ATOM 7363 N SER 189 -22.758 28 ATOM 7364 CA SER 189 -22.580 27 ATOM 7365 CB SER 189 -23.270 28 ATOM 7366 OG SER 189 -22.656 29 ATOM 7367 C SER 189 -23.159 26 ATOM 7368 O SER 189 -24.163 26 ATOM 7369 N SER 190 -22.502 25 ATOM 7370 CA SER 190 -23.029 24 28.413 1.00 34.73 H O 27.416 1.00 39.05 H N 26.476 1.00 41.77 H C 25.065 1.00 41.69 H C 23.982 1.00 43.45 H c 23.862 1.00 43.12 H c 22.655 1.00 42.68 H c 26.939 1.00 42.76 H c 27.071 1.00 44.73 H 0 27.202 1.00 44.83 H N 27.750 1.00 47.27 H c 28.534 1.00 48.86 H c 29.554 1.00 52.26 H c 30.198 1.00 53.89 H c 30.794 1.00 56.33 H 0 30.075 1.00 51.83 H N 26.648 1.00 47.64 H c 25.508 1.00 45.43 H 0 27.005 1.00 48.50 H N 26.117 1.00 50.22 H c 26.897 1.00 50.75 H c 27.526 1.00 55.71 H 0 25.468 1.00 49.58 H c 24.327 1.00 50.47 H 0 26.198 1.00 47.76 H N 25.693 1.00 46.55 H c 26.803 1.00 46.41 H c 27.074 1.00 47.06 H 0 24.533 1.00 45.50 H c 23.830 1.00 47.15 H 0 24.354 1.00 43.61 H N 23.354 1.00 41.62 H c 23.873 1.00 41.63 H c 23.127 1.00 42.12 H 0 25.154 1.00 41.06 H N 25.782 1.00 39.48 H c 26.740 1.00 40.59 H c 26.134 1.00 41.75 H c 27.238 1.00 41.08 H c 25.088 1.00 40.63 H c 26.541 1.00 37.17 H c 26.870 1.00 36.34 H 0 26.811 1.00 35.21 H N 27.520 1.00 35.82 H c 26.790 1.00 35.22 H c 25.400 1.00 38.74 H c 25.201 1.00 39.50 H c 23.930 1.00 41.29 H c 24.286 1.00 37.63 H c 23.018 1.00 40.69 H c 22.840 1.00 43.16 H c 21.565 1.00 45.56 H 0 28.956 1.00 35.42 H c 29.233 1.00 36.05 H 0 29.854 1.00 33.07 H N 31.166 1.00 33.69 H c 32.249 1.00 30.64 H c 31.992 1.00 31.70 H 0 31.508 1.00 33.84 H c 31.153 1.00 33.92 H 0 32.198 1.00 33.13 H N 32.762 1.00 32.13 H c 31.880 1.00 30.17 H c 31.701 1.00 32.49 H c 32.963 1.00 30.00 H c 30.518 1.00 29.79 H c 34.183 1.00 33.34 H c 34.700 1.00 33.47 H 0 34.814 1.00 32.89 H N 36.125 1.00 32.77 H c 37.201 1.00 31.98 H c 37.313 1.00 33.26 H 0 36.123 1.00 33.45 H c 35.458 1.00 32.42 H 0 36.856 1.00 34.16 H N 37.108 1.00 34.97 H c 275 WO 2009/026558 PCT/US2008/074097 ATOM 7371 CB SER 190 -22.098 23 ATOM 7372 OG SER 190 -22.601 21 ATOM 7373 C SER 190 -23.130 24 ATOM 7374 O SER 190 -22.185 24 ATOM 7375 N VAL 191 -24.281 23 ATOM 7376 CA VAL 191 -24.522 23 ATOM 7377 CB VAL 191 -25.583 24 ATOM 7378 CGI VAL 191 -25.902 24 ATOM 7379 CG2 VAL 191 -25.066 25 ATOM 7380 C VAL 191 -24.998 21 ATOM 7381 O VAL 191 -25.663 21 ATOM 7382 N VAL 192 -24.647 21 ATOM 7383 CA VAL 192 -25.145 20 ATOM 7384 CB VAL 192 -24.027 19 ATOM 7385 CGI VAL 192 -22.875 19 ATOM 7386 CG2 VAL 192 -24.579 17 ATOM 7387 C VAL 192 -25.700 20 ATOM 7388 O VAL 192 -25.123 20 ATOM 7389 N THR 193 -26.838 19 ATOM 7390 CA THR 193 -27.465 19 ATOM 7391 CB THR 193 -29.000 19 ATOM 7392 OG1 THR 193 -29.342 20 ATOM 7393 CG2 THR 193 -29.675 19 ATOM 7394 C THR 193 -27.102 18 ATOM 7395 O THR 193 -27.343 17 ATOM 7396 N VAL 194 -26.508 18 ATOM 7397 CA VAL 194 -25.998 17 ATOM 7398 CB VAL 194 -24.452 17 ATOM 7399 CGI VAL 194 -23.986 17 ATOM 7400 CG2 VAL 194 -23.841 18 ATOM 7401 C VAL 194 -26.402 17 ATOM 7402 O VAL 194 -26.782 18 ATOM 7403 N PRO 195 -26.315 16 ATOM 7404 CD PRO 195 -26.009 14 ATOM 7405 CA PRO 195 -26.603 15 ATOM 7406 CB PRO 195 -26.475 14 ATOM 7407 CG PRO 195 -26.632 13 ATOM 7408 C PRO 195 -25.585 16 ATOM 7409 O PRO 195 -24.381 16 ATOM 7410 N SER 196 -26.054 17 ATOM 7411 CA SER 196 -25.130 18 ATOM 7412 CB SER 196 -25.879 19 ATOM 7413 OG SER 196 -26.802 19 ATOM 7414 C SER 196 -24.354 17 ATOM 7415 O SER 196 -23.330 18 ATOM 7416 N SER 197 -24.838 16 ATOM 7417 CA SER 197 -24.154 15 ATOM 7418 CB SER 197 -25.098 14 ATOM 7419 OG SER 197 -25.329 13 ATOM 7420 C SER 197 -22.912 15 ATOM 7421 O SER 197 -21.974 14 ATOM 7422 N SER 198 -22.909 14 ATOM 7423 CA SER 198 -21.781 14 ATOM 7424 CB SER 198 -22.231 14 ATOM 7425 OG SER 198 -22.374 15 ATOM 7426 C SER 198 -20.659 15 ATOM 7427 O SER 198 -19.515 15 ATOM 7428 N LEU 199 -20.989 16 ATOM 7429 CA LEU 199 -19.986 17 ATOM 7430 CB LEU 199 -20.591 19 ATOM 7431 CG LEU 199 -21.688 19 ATOM 7432 CD1 LEU 199 -22.169 21 ATOM 7433 CD2 LEU 199 -21.159 19 ATOM 7434 C LEU 199 -18.859 17 ATOM 7435 O LEU 199 -19.092 17 ATOM 7436 N GLY 200 -17.635 17 ATOM 7437 CA GLY 200 -16.505 17 ATOM 7438 C GLY 200 -16.023 15 ATOM 7439 0 GLY 200 -14.974 15 ATOM 7440 N THR 201 -16.771 14 ATOM 7441 CA THR 201 -16.241 13 ATOM 7442 CB THR 201 -17.079 12 ATOM 7443 OG1 THR 201 -18.284 12 ATOM 7444 CG2 THR 201 -17.430 12 ATOM 7445 C THR 201 -16.217 13 ATOM 7446 O THR 201 -15.265 12 36.521 1.00 35.56 H C 36.764 1.00 36.81 H O 38.617 1.00 36.41 H C 39.350 1.00 35.33 H O 39.075 1.00 36.33 H N 40.495 1.00 38.43 H C 41.013 1.00 39.52 H C 42.471 1.00 41.66 H c 40.876 1.00 41.62 H c 40.761 1.00 39.28 H c 39.927 1.00 40.77 H 0 41.924 1.00 39.29 H N 42.316 1.00 38.27 H c 42.249 1.00 37.49 H c 43.149 1.00 39.66 H c 42.650 1.00 38.15 H c 43.724 1.00 37.59 H c 44.587 1.00 35.77 H 0 43.944 1.00 39.03 H N 45.264 1.00 40.19 H c 45.142 1.00 42.63 H c 44.618 1.00 45.54 H 0 46.504 1.00 41.23 H c 45.967 1.00 38.72 H c 45.438 1.00 38.35 H 0 47.150 1.00 38.96 H N 47.862 1.00 40.70 H c 47.801 1.00 38.53 H c 46.362 1.00 39.05 H c 48.566 1.00 34.97 H c 49.333 1.00 42.41 H c 49.876 1.00 42.66 H 0 50.003 1.00 44.22 H N 49.463 1.00 45.72 H c 51.439 1.00 46.23 H c 51.786 1.00 47.19 H c 50.476 1.00 47.45 H c 52.191 1.00 47.52 H c 52.005 1.00 48.34 H 0 53.031 1.00 47.83 H N 53.787 1.00 52.32 H c 54.514 1.00 52.90 H c 55.450 1.00 57.28 H 0 54.789 1.00 53.77 H c 55.317 1.00 54.68 H 0 55.045 1.00 55.89 H N 55.957 1.00 58.39 H c 56.397 1.00 57.25 H c 55.345 1.00 56.57 H 0 55.292 1.00 59.35 H c 55.970 1.00 59.77 H 0 53.963 1.00 60.41 H N 53.213 1.00 60.89 H c 51.818 1.00 59.87 H c 50.967 1.00 60.91 H 0 53.080 1.00 61.53 H c 52.807 1.00 62.27 H 0 53.264 1.00 62.42 H N 53.170 1.00 63.79 H c 53.518 1.00 60.27 H c 52.607 1.00 58.84 H c 53.158 1.00 56.44 H c 51.190 1.00 56.85 H c 54.142 1.00 66.35 H c 55.337 1.00 68.30 H 0 53.634 1.00 67.32 H N 54.519 1.00 69.17 H c 54.633 1.00 68.88 H c 55.224 1.00 70.04 H 0 54.083 1.00 67.65 H N 53.930 1.00 67.09 H c 54.702 1.00 67.94 H c 53.981 1.00 69.01 H 0 56.094 1.00 67.66 H c 52.456 1.00 65.62 H c 51.984 1.00 66.99 H 0 276 WO 2009/026558 PCT/US2008/074097 ATOM 7447 N GLN 202 -17.265 13 ATOM 7448 CA GLN 202 -17.288 13 ATOM 7449 CB GLN 202 -18.726 13 ATOM 7450 CG GLN 202 -18.853 13 ATOM 7451 CD GLN 202 -18.191 11 ATOM 7452 OE1 GLN 202 -18.749 10 ATOM 7453 NE2 GLN 202 -16.994 12 ATOM 7454 C GLN 202 -16.617 14 ATOM 7455 0 GLN 202 -16.892 15 ATOM 7456 N THR 203 -15.725 14 ATOM 7457 CA THR 203 -15.092 15 ATOM 7458 CB THR 203 -13.615 14 ATOM 7459 OG1 THR 203 -13.537 13 ATOM 7460 CG2 THR 203 -12.826 14 ATOM 7461 C THR 203 -15.838 15 ATOM 7462 O THR 203 -16.299 14 ATOM 7463 N TYR 204 -15.962 16 ATOM 7464 CA TYR 204 -16.675 17 ATOM 7465 CB TYR 204 -17.884 18 ATOM 7466 CG TYR 204 -18.919 17 ATOM 7467 CDl TYR 204 -19.065 17 ATOM 7468 CEl TYR 204 -19.994 16 ATOM 7469 CD2 TYR 204 -19.731 16 ATOM 7470 CE2 TYR 204 -20.659 15 ATOM 7471 CZ TYR 204 -20.785 15 ATOM 7472 OH TYR 204 -21.706 15 ATOM 7473 C TYR 204 -15.762 17 ATOM 7474 O TYR 204 -15.124 18 ATOM 7475 N ILE 205 -15.694 17 ATOM 7476 CA ILE 205 -14.812 17 ATOM 7477 CB ILE 205 -13.640 16 ATOM 7478 CG2 ILE 205 -12.732 17 ATOM 7479 CGI ILE 205 -12.850 16 ATOM 7480 CDl ILE 205 -11.695 15 ATOM 7481 C ILE 205 -15.601 18 ATOM 7482 0 ILE 205 -16.240 17 ATOM 7483 N CYS 206 -15.563 19 ATOM 7484 CA CYS 206 -16.252 19 ATOM 7485 C CYS 206 -15.242 19 ATOM 7486 0 CYS 206 -14.135 20 ATOM 7487 CB CYS 206 -16.974 20 ATOM 7488 SG CYS 206 -16.108 22 ATOM 7489 N ASN 207 -15.613 18 ATOM 7490 CA ASN 207 -14.714 18 ATOM 7491 CB ASN 207 -14.680 17 ATOM 7492 CG ASN 207 -14.565 16 ATOM 7493 OD1 ASN 207 -15.521 15 ATOM 7494 ND2 ASN 207 -13.392 16 ATOM 7495 C ASN 207 -15.198 19 ATOM 7496 0 ASN 207 -16.219 19 ATOM 7497 N VAL 208 -14.456 20 ATOM 7498 CA VAL 208 -14.853 21 ATOM 7499 CB VAL 208 -14.612 22 ATOM 7500 CGI VAL 208 -14.979 23 ATOM 7501 CG2 VAL 208 -15.432 23 ATOM 7502 C VAL 208 -14.069 21 ATOM 7503 O VAL 208 -12.839 21 ATOM 7504 N ASN 209 -14.782 20 ATOM 7505 CA ASN 209 -14.136 20 ATOM 7506 CB ASN 209 -14.500 19 ATOM 7507 CG ASN 209 -13.650 18 ATOM 7508 OD1 ASN 209 -12.994 19 ATOM 7509 ND2 ASN 209 -13.657 17 ATOM 7510 C ASN 209 -14.556 21 ATOM 7511 0 ASN 209 -15.745 21 ATOM 7512 N HIS 210 -13.573 22 ATOM 7513 CA HIS 210 -13.823 23 ATOM 7514 CB HIS 210 -13.448 24 ATOM 7515 CG HIS 210 -13.788 25 ATOM 7516 CD2 HIS 210 -14.971 26 ATOM 7517 NDl HIS 210 -12.845 26 ATOM 7518 CEl HIS 210 -13.432 27 ATOM 7519 NE2 HIS 210 -14.722 27 ATOM 7520 C HIS 210 -12.987 22 ATOM 7521 0 HIS 210 -11.847 23 ATOM 7522 N LYS 211 -13.558 22
51.731 1.00 63.03 H N 50.286 1.00 60.90 H C 49.795 1.00 61.55 H C 48.289 1.00 64.43 H c 47.677 1.00 66.51 H c 47.694 1.00 67.79 H 0 47.129 1.00 66.84 H N 49.607 1.00 58.78 H c 49.936 1.00 58.19 H 0 48.666 1.00 55.82 H N 47.934 1.00 53.36 H c 47.617 1.00 54.58 H c 46.810 1.00 55.09 H 0 48.903 1.00 54.39 H c 46.631 1.00 49.49 H c 45.965 1.00 47.29 H 0 46.278 1.00 45.01 H N 45.068 1.00 42.84 H c 45.427 1.00 40.12 H c 46.224 1.00 38.49 H c 47.590 1.00 38.48 H c 48.330 1.00 38.92 H c 45.615 1.00 38.50 H c 46.343 1.00 38.51 H c 47.699 1.00 38.77 H c 48.425 1.00 41.78 H 0 44.097 1.00 41.23 H c 44.436 1.00 40.31 H 0 42.885 1.00 41.27 H N 41.868 1.00 41.45 H c 41.577 1.00 42.17 H c 40.499 1.00 40.04 H c 42.865 1.00 41.38 H c 42.693 1.00 41.84 H c 40.591 1.00 41.22 H c 40.083 1.00 41.08 H 0 40.067 1.00 40.41 H N 38.819 1.00 42.57 H c 37.667 1.00 42.00 H c 37.752 1.00 41.39 H 0 38.895 1.00 45.38 H c 38.247 1.00 54.25 H s 36.609 1.00 40.73 H N 35.482 1.00 40.35 H c 35.124 1.00 39.81 H c 36.350 1.00 42.88 H c 36.725 1.00 42.86 H 0 36.981 1.00 40.06 H N 34.281 1.00 39.79 H c 33.677 1.00 39.54 H 0 33.941 1.00 38.89 H N 32.875 1.00 39.31 H c 33.288 1.00 39.03 H c 32.147 1.00 36.52 H c 34.533 1.00 36.09 H c 31.604 1.00 41.22 H c 31.611 1.00 43.41 H 0 30.511 1.00 43.06 H N 29.234 1.00 44.34 H c 28.756 1.00 47.58 H c 27.578 1.00 54.59 H c 26.913 1.00 57.77 H 0 27.316 1.00 55.14 H N 28.196 1.00 4 3.67 H c 27.942 1.00 44.34 H 0 27.612 1.00 42.73 H N 26.548 1.00 42.37 H c 27.019 1.00 41.38 H c 26.040 1.00 40.95 H c 25.494 1.00 40.98 H c 25.529 1.00 42.03 H N 24.712 1.00 40.17 H c 24.673 1.00 41.17 H N 25.331 1.00 43.48 H C 25.185 1.00 43.46 H 0 24.455 1.00 44.53 H N 277 WO 2009/026558 PCT/US2008/074097 ATOM 7523 CA LYS 211 -12.811 21 ATOM 7524 CB LYS 211 -13.644 20 ATOM 7525 CG LYS 211 -13.903 19 ATOM 7526 CD LYS 211 -14.558 18 ATOM 7527 CE LYS 211 -14.674 16 ATOM 7528 NZ LYS 211 -15.144 15 ATOM 7529 C LYS 211 -12.313 22 ATOM 7530 0 LYS 211 -11.200 22 ATOM 7531 N PRO 212 -13.113 23 ATOM 7532 CD PRO 212 -14.467 23 ATOM 7533 CA PRO 212 -12.628 24 ATOM 7534 CB PRO 212 -13.702 25 ATOM 7535 CG PRO 212 -14.939 24 ATOM 7536 C PRO 212 -11.229 25 ATOM 7537 O PRO 212 -10.457 25 ATOM 7538 N SER 213 -10.903 25 ATOM 7539 CA SER 213 -9.593 25 ATOM 7540 CB SER 213 -9.751 26 ATOM 7541 OG SER 213 -10.185 26 ATOM 7542 C SER 213 -8.690 24 ATOM 7543 O SER 213 -7.572 24 ATOM 7544 N ASN 214 -9.172 23 ATOM 7545 CA ASN 214 -8.372 22 ATOM 7546 CB ASN 214 -7.097 22 ATOM 7547 CG ASN 214 -7.388 21 ATOM 7548 OD1 ASN 214 -7.140 22 ATOM 7549 ND2 ASN 214 -7.919 20 ATOM 7550 C ASN 214 -7.999 22 ATOM 7551 0 ASN 214 -6.891 22 ATOM 7552 N THR 215 -8.935 22 ATOM 7553 CA THR 215 -8.716 23 ATOM 7554 CB THR 215 -9.062 24 ATOM 7555 OG1 THR 215 -8.385 25 ATOM 7556 CG2 THR 215 -8.635 24 ATOM 7557 C THR 215 -9.599 22 ATOM 7558 O THR 215 -10.815 22 ATOM 7559 N LYS 216 -8.985 21 ATOM 7560 CA LYS 216 -9.725 20 ATOM 7561 CB LYS 216 -9.439 19 ATOM 7562 CG LYS 216 -10.062 18 ATOM 7563 CD LYS 216 -9.851 16 ATOM 7564 CE LYS 216 -10.309 16 ATOM 7565 NZ LYS 216 -9.548 16 ATOM 7566 C LYS 216 -9.311 21 ATOM 7567 0 LYS 216 -8.132 21 ATOM 7568 N VAL 217 -10.282 21 ATOM 7569 CA VAL 217 -9.998 22 ATOM 7570 CB VAL 217 -10.428 23 ATOM 7571 CGI VAL 217 -10.096 24 ATOM 7572 CG2 VAL 217 -9.743 24 ATOM 7573 C VAL 217 -10.734 21 ATOM 7574 O VAL 217 -11.927 20 ATOM 7575 N ASP 218 -10.021 20 ATOM 7576 CA ASP 218 -10.647 20 ATOM 7577 CB ASP 218 -9.980 18 ATOM 7578 CG ASP 218 -10.346 17 ATOM 7579 OD1 ASP 218 -11.245 17 ATOM 7580 OD2 ASP 218 -9.732 16 ATOM 7581 C ASP 218 -10.534 21 ATOM 7582 O ASP 218 -9.450 21 ATOM 7583 N LYS 219 -11.658 21 ATOM 7584 CA LYS 219 -11.679 22 ATOM 7585 CB LYS 219 -12.358 23 ATOM 7586 CG LYS 219 -12.481 24 ATOM 7587 CD LYS 219 -11.136 24 ATOM 7588 CE LYS 219 -10.569 25 ATOM 7589 NZ LYS 219 -9.622 26 ATOM 7590 C LYS 219 -12.416 21 ATOM 7591 0 LYS 219 -13.581 21 ATOM 7592 N LYS 220 -11.728 21 ATOM 7593 CA LYS 220 -12.356 20 ATOM 7594 CB LYS 220 -11.294 20 ATOM 7595 CG LYS 220 -11.843 19 ATOM 7596 CD LYS 220 -10.696 18 ATOM 7597 CE LYS 220 -11.185 17 ATOM 7598 NZ LYS 220 -11.920 18
23.328 1.00 45.35 H C 22.623 1.00 48.43 H C 23.508 1.00 54.24 H C 22.751 1.00 59.93 H C 23.638 1.00 63.06 H C 22.888 1.00 64.57 H N 22.317 1.00 41.93 H C 21.816 1.00 43.23 H O 22.020 1.00 40.22 H N 22.506 1.00 38.83 H C 21.052 1.00 41.43 H C 21.083 1.00 39.54 H c 21.540 1.00 37.50 H c 21.373 1.00 44.16 H c 20.464 1.00 46.27 H 0 22.661 1.00 44.31 H N 23.077 1.00 43.30 H c 24.139 1.00 43.36 H c 25.375 1.00 42.70 H 0 23.630 1.00 43.68 H c 24.062 1.00 44.07 H 0 23.630 1.00 43.44 H N 24.110 1.00 46.08 H c 23.272 1.00 48.48 H c 21.832 1.00 52.65 H c 20.895 1.00 52.37 H 0 21.652 1.00 52.33 H N 25.584 1.00 46.19 H c 25.996 1.00 45.93 H 0 26.372 1.00 45.35 H N 27.794 1.00 44.99 H c 28.198 1.00 44.21 H c 27.329 1.00 44.83 H 0 29.632 1.00 43.77 H c 28.608 1.00 45.50 H c 28.414 1.00 45.25 H 0 29.511 1.00 44.26 H N 30.577 1.00 45.60 H c 30.595 1.00 47.96 H c 29.460 1.00 52.62 H c 29.685 1.00 55.74 H c 28.487 1.00 58.57 H c 27.249 1.00 60.46 H N 31.913 1.00 44 . 05 H c 32.144 1.00 43.16 H 0 32.790 1.00 43.83 H N 34.134 1.00 42.88 H c 34.297 1.00 42.10 H c 35.702 1.00 40.43 H c 33.250 1.00 41.13 H c 35.178 1.00 44.48 H c 35.034 1.00 44.28 H 0 36.224 1.00 45.43 H N 37.368 1.00 46.54 H c 37.663 1.00 49.28 H c 36.657 1.00 54.06 H c 35.822 1.00 56.26 H 0 36.701 1.00 59.11 H 0 38.593 1.00 45.42 H c 38.925 1.00 45.41 H 0 39.265 1.00 43.94 H N 40.444 1.00 43.70 H c 40.119 1.00 43.41 H c 41.302 1.00 45.72 H c 41.689 1.00 46.20 H c 40.560 1.00 45.39 H c 41.087 1.00 48.37 H N 41.578 1.00 44.16 H c 41.442 1.00 44.32 H 0 42.697 1.00 44.00 H N 43.875 1.00 45.01 H c 44.794 1.00 48.33 H c 46.009 1.00 51.01 H c 46.869 1.00 57.34 H c 47.990 1.00 60.75 H c 49.066 1.00 62.49 H N 278 WO 2009/026558 PCT/US2008/074097
ATOM 7599 c LYS 220 -13.092 21 ATOM 7600 0 LYS 220 -12.560 22 ATOM 7601 N VAL 221 -14.324 21 ATOM 7602 CA VAL 221 -15.142 22 ATOM 7603 CB VAL 221 -16.521 22 ATOM 7604 CGI VAL 221 -17.341 23 ATOM 7605 CG2 VAL 221 -16.330 22 ATOM 7606 C VAL 221 -15.336 22 ATOM 7607 O VAL 221 -15.936 21 ATOM 7608 N GLU 222 -14.814 22 ATOM 7609 CA GLU 222 -14.822 22 ATOM 7610 CB GLU 222 -13.394 22 ATOM 7611 CG GLU 222 -12.501 21 ATOM 7612 CD GLU 222 -11.109 21 ATOM 7613 OE1 GLU 222 -10.566 20 ATOM 7614 OE2 GLU 222 -10.556 22 ATOM 7615 C GLU 222 -15.609 23 ATOM 7616 0 GLU 222 -15.745 24 ATOM 7617 N PRO 223 -16.124 23 ATOM 7618 CD PRO 223 -16.157 21 ATOM 7619 CA PRO 223 -16.809 24 ATOM 7620 CB PRO 223 -17.228 23 ATOM 7 621 CG PRO 223 -17.264 21 ATOM 7622 C PRO 223 -15.892 25 ATOM 7623 O PRO 223 -14.674 25 ATOM 7624 N LYS 224 -16.481 26 ATOM 7625 CA LYS 224 -15.710 27 ATOM 7 62 6 CB LYS 224 -16.608 28 ATOM 7627 CG LYS 224 -17.358 29 ATOM 7628 CD LYS 224 -18.487 30 ATOM 7629 CE LYS 224 -19.142 30 ATOM 7630 NZ LYS 224 -20.308 31 ATOM 7631 C LYS 224 -15.090 27 ATOM 7632 0 LYS 224 -13.862 27 ATOM 7633 OXT LYS 224 -15.848 27 TER 7634 LYS 224 ATOM 8057 NA NA 1 -48.879 -0 TER 8058 NA 1 END
44.601 1.00 43.21 H C 44.779 1.00 40.91 H 0 45.007 1.00 42.53 H N 45.666 1.00 43.36 H C 44.975 1.00 40.89 H c 45.641 1.00 37.25 H c 43.489 1.00 37.55 H c 47.126 1.00 45.76 H c 47.428 1.00 45.44 H 0 48.025 1.00 49.29 H N 49.455 1.00 53.13 H c 50.004 1.00 54.80 H c 49.408 1.00 59.95 H c 50.028 1.00 63.23 H c 50.289 1.00 65.91 H 0 50.256 1.00 63.80 H 0 50.234 1.00 53.98 H c 49.798 1.00 52.85 H 0 51.412 1.00 55.55 H N 51.886 1.00 55.58 H c 52.339 1.00 57.83 H c 53.492 1.00 57.45 H c 52.896 1.00 56.88 H c 52.807 1.00 61.01 H c 52.821 1.00 61.88 H 0 53.189 1.00 64.76 H N 53.598 1.00 68.89 H c 53.602 1.00 71.49 H c 52.302 1.00 74.50 H c 52.518 1.00 76.86 H c 51.212 1.00 77.87 H c 51.451 1.00 78.94 H N 54.988 1.00 69.98 H c 55.125 1.00 70.34 H 0 55.928 1.00 70.58 H 0 H -21.279 1.00 64.24 ION N ION 279 WO 2009/026558 PCT/US2008/074097
Table 35.2 ATOM 1 CB THR 61 10.449 -40.746 -18.654 1.00 36.37 A C ATOM 2 OG1 THR 61 10.788 -42.078 -18.244 1.00 39.29 A O ATOM 3 CG2 THR 61 11.631 -39.827 -18.376 1.00 36.88 A C ATOM 4 C THR 61 9.503 -39.926 -16.424 1.00 32.74 A c ATOM 5 O THR 61 10.188 -38.932 -16.133 1.00 32.55 A 0 ATOM 6 N THR 61 8.558 -39.083 -18.582 1.00 33.91 A N ATOM 7 CA THR 61 9.165 -40.263 -17.892 1.00 34.36 A c ATOM 8 N ALA 62 9.017 -40.768 -15.509 1.00 30.00 A N ATOM 9 CA ALA 62 8.977 -40.452 -14.074 1.00 26.49 A C ATOM 10 CB ALA 62 8.158 -41.501 -13.337 1.00 24.81 A c ATOM 11 C ALA 62 10.345 -40.330 -13.425 1.00 24.06 A c ATOM 12 O ALA 62 11.301 -40.970 -13.849 1.00 26.36 A 0 ATOM 13 N THR 63 10.427 -39.513 -12.381 1.00 21.77 A N ATOM 14 CA THR 63 11.687 -39.264 -11.691 1.00 18.83 A c ATOM 15 CB THR 63 12.049 -37.757 -11.731 1.00 17.84 A c ATOM 16 OG1 THR 63 11.064 -37.000 -11.029 1.00 19.65 A 0 ATOM 17 CG2 THR 63 12.086 -37.256 -13.151 1.00 17.35 A c ATOM 18 C THR 63 11.667 -39.741 -10.234 1.00 17.55 A c ATOM 19 O THR 63 10.611 -39.991 -9.663 1.00 17.43 A 0 ATOM 20 N PHE 64 12.851 -39.886 -9.649 1.00 18.91 A N ATOM 21 CA PHE 64 12.987 -40.230 -8.239 1.00 18.70 A c ATOM 22 CB PHE 64 13.904 -41.433 -8.066 1.00 18.53 A c ATOM 23 CG PHE 64 14.182 -41.779 -6.631 1.00 19.76 A c ATOM 24 CDl PHE 64 13.146 -42.007 -5.745 1.00 21.07 A c ATOM 25 CD2 PHE 64 15.479 -41.893 -6.169 1.00 20.97 A c ATOM 26 CEl PHE 64 13.405 -42.353 -4.418 1.00 22.93 A c ATOM 27 CE2 PHE 64 15.745 -42.237 -4.847 1.00 20.76 A c ATOM 28 CZ PHE 64 14.712 -42.465 -3.972 1.00 20.85 A c ATOM 29 C PHE 64 13.562 -39.062 -7.457 1.00 19.32 A c ATOM 30 O PHE 64 14.475 -38.380 -7.932 1.00 19.55 A 0 ATOM 31 N HIS 65 13.028 -38.846 -6.2 56 1.00 19.72 A N ATOM 32 CA HIS 65 13.445 -37.744 -5.395 1.00 18.95 A c ATOM 33 CB HIS 65 12.394 -36.638 -5.417 1.00 17.76 A c ATOM 34 CG HIS 65 12.152 -36.074 -6.780 1.00 19.55 A c ATOM 35 CD2 HIS 65 11.341 -36.481 -7.783 1.00 20.70 A c ATOM 36 NDl HIS 65 12.813 -34.962 -7.253 1.00 20.16 A N ATOM 37 CEl HIS 65 12.420 -34.709 -8.488 1.00 17.64 A c ATOM 38 NE2 HIS 65 11.527 -35.616 -8.834 1.00 17.20 A N ATOM 39 C HIS 65 13.682 -38.196 -3.959 1.00 19.09 A C ATOM 40 0 HIS 65 13.039 -39.123 -3.468 1.00 18.05 A 0 ATOM 41 N ARG 66 14.608 -37.519 -3.289 1.00 19.61 A N ATOM 42 CA ARG 66 15.107 -37.964 -2.000 1.00 20.80 A C ATOM 43 CB ARG 66 16.306 -38.873 -2.238 1.00 20.79 A c ATOM 44 CG ARG 66 16.797 -39.615 -1.039 1.00 23.33 A c ATOM 45 CD ARG 66 18.313 -39.719 -1.112 1.00 25.65 A c ATOM 46 NE ARG 66 18.769 -41.038 -1.533 1.00 25.62 A N ATOM 47 CZ ARG 66 20.031 -41.338 -1.827 1.00 24.86 A c ATOM 48 NHl ARG 66 20.346 -42.573 -2.195 1.00 24.37 A N ATOM 49 NH2 ARG 66 20.974 -40.408 -1.760 1.00 23.60 A N ATOM 50 C ARG 66 15.496 -36.737 -1.172 1.00 22.22 A C ATOM 51 O ARG 66 15.836 -35.695 -1.727 1.00 21.06 A 0 ATOM 52 N CYS 67 15.429 -36.852 0.152 1.00 24.84 A N ATOM 53 CA CYS 67 15.637 -35.694 1.022 1.00 2 6.62 A C ATOM 54 CB CYS 67 15.124 -35.966 2.437 1.00 26.30 A c ATOM 55 SG CYS 67 15.480 -34.603 3.602 1.00 2 9.02 A s ATOM 56 C CYS 67 17.105 -35.321 1. 107 1.00 28.15 A c ATOM 57 O CYS 67 17.951 -36.170 1.412 1.00 29.15 A 0 ATOM 58 N ALA 68 17.404 -34.045 0.863 1.00 28.74 A N ATOM 59 CA ALA 68 18.786 -33.593 0.787 1.00 28.43 A c ATOM 60 CB ALA 68 18.856 -32.228 0.139 1.00 27.23 A c ATOM 61 C ALA 68 19.438 -33.564 2.162 1.00 28.95 A c ATOM 62 O ALA 68 20.660 -33.551 2.270 1.00 30.22 A 0 ATOM 63 N LYS 69 18.623 -33.565 3.212 1.00 29.94 A N ATOM 64 CA LYS 69 19.131 -33.726 4.570 1.00 31.16 A c ATOM 65 CB LYS 69 18.197 -33.047 5.575 1.00 33.82 A c ATOM 66 CG LYS 69 17.843 -31.621 5.209 1.00 36.96 A c ATOM 67 CD LYS 69 18.947 -30.629 5.550 1.00 38.61 A c ATOM 68 CE LYS 69 18.481 -29.195 5.237 1.00 41.46 A c ATOM 69 NZ LYS 69 19.397 -28.113 5.730 1.00 40.68 A N ATOM 70 C LYS 69 19.233 -35.212 4.887 1.00 29.96 A c ATOM 71 0 LYS 69 18.252 -35.845 5.273 1.00 30.13 A 0 ATOM 72 N ASP 70 20.427 -35.764 4.731 1.00 28.75 A N ATOM 73 CA ASP 70 20.580 -37.202 4.782 1.00 27.72 A c ATOM 74 CB ASP 70 22.052 -37.571 4.623 1.00 30.38 A c 280 WO 2009/026558 PCT/US2008/074097
ATOM 75 CG ASP 70 22.243 -38.864 3.847 1.00 33.51 A C ATOM 76 OD1 ASP 70 21.800 -38.932 2.675 1.00 34.66 A O ATOM 77 OD2 ASP 70 22.834 -39.813 4 . 406 1.00 33.99 A 0 ATOM 78 C ASP 70 20.008 -37.850 6.045 1.00 25.79 A c ATOM 79 O ASP 70 19.346 -38.878 5.970 1.00 25.05 A 0 ATOM 80 N PRO 71 20.258 -37.265 7.225 1.00 24.83 A N ATOM 81 CD PRO 71 21.116 -36.107 7.526 1.00 24.43 A c ATOM 82 CA PRO 71 19.729 -37.890 8.445 1.00 24.69 A c ATOM 83 CB PRO 71 20.456 -37.157 9.572 1.00 24.48 A c ATOM 84 CG PRO 71 20.847 -35.854 8.980 1.00 24.31 A c ATOM 85 C PRO 71 18.207 -37.806 8.587 1.00 24.67 A c ATOM 86 O PRO 71 17.603 -38.557 9.353 1.00 25.53 A 0 ATOM 87 N TRP 72 17.589 -36.892 7.848 1.00 22.88 A N ATOM 88 CA TRP 72 16.145 -36.742 7.892 1.00 21.03 A c ATOM 89 CB TRP 72 15.749 -35.337 7.462 1.00 21.00 A c ATOM 90 CG TRP 72 16.168 -34.308 8.454 1.00 20.77 A c ATOM 91 CD2 TRP 72 15.958 -32.894 8.366 1.00 18.78 A c ATOM 92 CE2 TRP 72 16.470 -32.326 9.551 1.00 18.39 A c ATOM 93 CE3 TRP 72 15.390 -32.056 7.406 1.00 16.68 A c ATOM 94 CDl TRP 72 16.785 -34.531 9.650 1.00 19.91 A c ATOM 95 NEl TRP 72 16.967 -33.345 10.316 1.00 19.30 A N ATOM 96 CZ2 TRP 72 16.425 -30.956 9.796 1.00 15.74 A c ATOM 97 CZ3 TRP 72 15.348 -30.701 7.654 1.00 14 . 03 A c ATOM 98 CH2 TRP 72 15.861 -30.165 8.838 1.00 14.11 A c ATOM 99 C TRP 72 15.486 -37.762 6.993 1.00 21.80 A c ATOM 100 O TRP 72 14.281 -38.007 7.090 1.00 24.16 A 0 ATOM 101 N ARG 73 16.288 -38.362 6.120 1.00 21.43 A N ATOM 102 CA ARG 73 15.820 -39.451 5.266 1.00 18.71 A c ATOM 103 CB ARG 73 16.942 -39.936 4.341 1.00 15.20 A c ATOM 104 CG ARG 73 17.321 -38.950 3.272 1.00 13.51 A c ATOM 105 CD ARG 73 18.419 -39.521 2.401 1.00 15.16 A c ATOM 106 NE ARG 73 18.059 -40.830 1.856 1.00 15.36 A N ATOM 107 CZ ARG 73 18.930 -41.794 1.576 1.00 13.61 A c ATOM 108 NH1 ARG 73 20.222 -41.601 1.793 1.00 10.92 A N ATOM 109 NH2 ARG 73 18.507 -42.950 1.079 1.00 11.59 A N ATOM 110 C ARG 73 15.297 -40.629 6.081 1.00 17.55 A C ATOM 111 O ARG 73 15.826 -40.952 7.147 1.00 16.42 A 0 ATOM 112 N LEU 74 14.245 -41.248 5.556 1.00 17.09 A N ATOM 113 CA LEU 74 13.646 -42.438 6.131 1.00 17.51 A C ATOM 114 CB LEU 74 12.264 -42.115 6.721 1.00 16.82 A c ATOM 115 CG LEU 74 12.207 -41.101 7.868 1.00 17.36 A c ATOM 116 CDl LEU 74 10.767 -40.742 8.206 1.00 15.71 A c ATOM 117 CD2 LEU 74 12.914 -41.689 9.069 1.00 14.95 A c ATOM 118 C LEU 74 13.493 -43.437 4.994 1.00 18.74 A c ATOM 119 O LEU 74 12.401 -43.611 4 . 451 1.00 20.09 A 0 ATOM 120 N PRO 75 14.594 -44.102 4.610 1.00 19.33 A N ATOM 121 CD PRO 75 15.932 -43.950 5.198 1.00 17.44 A c ATOM 122 CA PRO 75 14.608 -44.997 3.446 1.00 18.25 A c ATOM 123 CB PRO 75 16.091 -45.274 3.226 1.00 16.29 A c ATOM 124 CG PRO 75 16.714 -45.036 4.531 1.00 15.69 A c ATOM 125 C PRO 75 13.802 -46.280 3.619 1.00 18.01 A c ATOM 126 O PRO 75 13.625 -46.766 4.729 1.00 19.35 A 0 ATOM 127 N GLY 76 13.319 -46.828 2.510 1.00 17.66 A N ATOM 128 CA GLY 76 12.610 -48.092 2.568 1.00 16.82 A c ATOM 129 C GLY 76 11.119 -47.864 2.556 1.00 16.73 A c ATOM 130 0 GLY 76 10.328 -48.792 2.431 1.00 16.37 A 0 ATOM 131 N THR 77 10.732 -46.610 2.702 1.00 16.94 A N ATOM 132 CA THR 77 9.352 -46.241 2.510 1.00 18.46 A c ATOM 133 CB THR 77 8.753 -45.699 3.799 1.00 20.12 A c ATOM 134 OG1 THR 77 8.988 -46.643 4.850 1.00 22.67 A 0 ATOM 135 CG2 THR 77 7.250 -45.499 3.642 1.00 20.19 A c ATOM 136 C THR 77 9.301 -45.189 1.427 1.00 17.73 A c ATOM 137 O THR 77 10.106 -44.259 1.415 1.00 17.66 A 0 ATOM 138 N TYR 78 8.362 -45.354 0.501 1.00 18.93 A N ATOM 139 CA TYR 78 8.281 -44.474 -0.656 1.00 19.73 A c ATOM 140 CB TYR 78 8.854 -45.173 -1.892 1.00 18.09 A c ATOM 141 CG TYR 78 10.285 -45.575 -1.679 1.00 19.07 A c ATOM 142 CDl TYR 78 10.601 -46.777 -1.050 1.00 19.20 A c ATOM 143 CEl TYR 78 11.909 -47.114 -0.777 1.00 18.84 A c ATOM 144 CD2 TYR 78 11.323 -44.727 -2.035 1.00 18.89 A c ATOM 145 CE2 TYR 78 12.633 -45.061 -1.771 1.00 18.34 A c ATOM 146 CZ TYR 78 12.917 -46.252 -1.137 1.00 18 . 13 A c ATOM 147 OH TYR 78 14.215 -46.565 -0.835 1.00 20.00 A 0 ATOM 148 C TYR 78 6.861 -44.025 -0.917 1.00 20.34 A c ATOM 149 O TYR 78 5.894 -44.735 -0.617 1.00 21.95 A 0 ATOM 150 N VAL 79 6.750 -42.826 -1.472 1.00 20.31 A N 281 WO 2009/026558 PCT/US2008/074097 ATOM 151 CA VAL 79 5.460 -42 ATOM 152 CB VAL 79 5.336 -40 ATOM 153 CGI VAL 79 3.957 -40 ATOM 154 CG2 VAL 79 5.620 -40 ATOM 155 C VAL 79 5.344 -42 ATOM 156 O VAL 79 5.816 -41 ATOM 157 N VAL 80 4.716 -43 ATOM 158 CA VAL 80 4.508 -43 ATOM 159 CB VAL 80 4 . 142 -44 ATOM 160 CGI VAL 80 4.083 -44 ATOM 161 CG2 VAL 80 5.150 -45 ATOM 162 C VAL 80 3.386 -42 ATOM 163 O VAL 80 2.241 -42 ATOM 164 N VAL 81 3.733 -41 ATOM 165 CA VAL 81 2.808 -40 ATOM 166 CB VAL 81 3.451 -38 ATOM 167 CGI VAL 81 2.536 -37 ATOM 168 CG2 VAL 81 3.718 -38 ATOM 169 C VAL 81 2.398 -40 ATOM 170 O VAL 81 3.212 -40 ATOM 171 N LEU 82 1.123 -40 ATOM 172 CA LEU 82 0.622 -40 ATOM 173 CB LEU 82 -0.593 -41 ATOM 174 CG LEU 82 -0.289 -42 ATOM 175 CDl LEU 82 -1.516 -43 ATOM 176 CD2 LEU 82 0.889 -43 ATOM 177 C LEU 82 0.261 -39 ATOM 178 O LEU 82 0.098 -38 ATOM 179 N LYS 83 0.162 -39 ATOM 180 CA LYS 83 -0.317 -38 ATOM 181 CB LYS 83 -0.422 -38 ATOM 182 CG LYS 83 0.905 -38 ATOM 183 CD LYS 83 0.707 -39 ATOM 184 CE LYS 83 1.989 -39 ATOM 185 NZ LYS 83 1.749 -39 ATOM 186 C LYS 83 -1.682 -37 ATOM 187 0 LYS 83 -2.568 -38 ATOM 188 N GLU 84 -1.855 -36 ATOM 189 CA GLU 84 -3.128 -36 ATOM 190 CB GLU 84 -3.069 -34 ATOM 191 CG GLU 84 -2.933 -33 ATOM 192 CD GLU 84 -3.066 -32 ATOM 193 OE1 GLU 84 -3.370 -31 ATOM 194 OE2 GLU 84 -2.872 -31 ATOM 195 C GLU 84 -4.181 -36 ATOM 196 0 GLU 84 -3.880 -36 ATOM 197 N GLU 85 -5.413 -36 ATOM 198 CA GLU 85 -6.483 -36 ATOM 199 CB GLU 85 -6.446 -36 ATOM 200 CG GLU 85 -6.820 -34 ATOM 201 CD GLU 85 -6.879 -33 ATOM 202 OE1 GLU 85 -7.821 -33 ATOM 203 OE2 GLU 85 -5.985 -34 ATOM 204 C GLU 85 -6.407 -38 ATOM 205 0 GLU 85 -7.152 -38 ATOM 206 N THR 86 -5.503 -39 ATOM 207 CA THR 86 -5.578 -40 ATOM 208 CB THR 86 -4.213 -41 ATOM 209 OG1 THR 86 -3.301 -40 ATOM 210 CG2 THR 86 -4.379 -42 ATOM 211 C THR 86 -6.599 -40 ATOM 212 O THR 86 -6.593 -40 ATOM 213 N HIS 87 -7.482 -41 ATOM 214 CA HIS 87 -8.564 -42 ATOM 215 CB HIS 87 -9.823 -42 ATOM 216 CG HIS 87 -10.446 -41 ATOM 217 CD2 HIS 87 -11.072 -40 ATOM 218 NDl HIS 87 -10.461 -40 ATOM 219 CEl HIS 87 -11.070 -39 ATOM 220 NE2 HIS 87 -11.451 -39 ATOM 221 C HIS 87 -8.239 -43 ATOM 222 0 HIS 87 -7.406 -44 ATOM 223 N LEU 88 -8.925 -43 ATOM 224 CA LEU 88 -8.567 -44 ATOM 225 CB LEU 88 -9.537 -43 ATOM 226 CG LEU 88 -9.207 -44 -1.791 1.00 19.33 A C -1.171 1.00 19.66 A C -1.436 1.00 20.37 A C 0.319 1.00 17.38 A c -3.302 1.00 18.08 A c -3.900 1.00 18.83 A 0 -3.919 1.00 18.93 A N -5.359 1.00 18.97 A c -5.872 1.00 18.62 A c -7.391 1.00 16.15 A c -5.356 1.00 16.43 A c -5.727 1.00 19.40 A c -5.327 1.00 19.75 A 0 -6.492 1.00 20.81 A N -6.889 1.00 22.10 A c -6.730 1.00 22.25 A c -7.304 1.00 19.18 A c -5.264 1.00 22.64 A c -8.341 1.00 24.17 A c -9.259 1.00 24.19 A 0 -8.546 1.00 26.03 A N -9.885 1.00 27.03 A c -9.828 1.00 27.37 A c -8.959 1.00 28.39 A c -8.828 1.00 28.17 A c -9.574 1.00 27.31 A c -10.448 1.00 27.34 A c -9.701 1.00 24.96 A 0 -11.768 1.00 30.55 A N -12.414 1.00 33.51 A c -13.915 1.00 31.93 A c -14.576 1.00 34.59 A c -15.898 1.00 37.08 A c -16.705 1.00 38.83 A c -18.052 1.00 40.48 A N -11.852 1.00 36.22 A c -11.750 1.00 36.20 A 0 -11.475 1.00 38.84 A N -10.919 1.00 40.89 A c -10.428 1.00 42.22 A c -11.512 1.00 46.22 A c -10.964 1.00 49.28 A c -9.759 1.00 50.03 A 0 -11.734 1.00 51.27 A 0 -11.996 1.00 41.56 A c -13.190 1.00 40.94 A 0 -11.558 1.00 42.71 A N -12.443 1.00 43.97 A c -13.759 1.00 47.49 A c -13.615 1.00 53.47 A c -14.955 1.00 57.25 A c -15.160 1.00 58.40 A 0 -15.804 1.00 58.66 A 0 -12.724 1.00 41.83 A c -13.549 1.00 42.95 A 0 -12.042 1.00 39.72 A N -11.973 1.00 36.25 A c -11.608 1.00 34.62 A c -12.701 1.00 30.95 A 0 -11.295 1.00 33.47 A c -10.902 1.00 35.99 A c -9.817 1.00 36.01 A 0 -11.213 1.00 35.71 A N -10.312 1.00 36.27 A c -11.112 1.00 38.72 A c -11.715 1.00 41.65 A c -11.143 1.00 41.88 A c -13.074 1.00 43.71 A N -13.314 1.00 43.53 A c -12.159 1.00 43.79 A N -9.393 1.00 35.80 A C -9.705 1.00 36.51 A 0 -8.258 1.00 34.46 A N -7.168 1.00 32.12 A C -6.004 1.00 28.85 A c -4.817 1.00 26.89 A c 282 WO 2009/026558 PCT/US2008/074097 ATOM 227 CDl LEU 88 -7.810 -44 ATOM 228 CD2 LEU 88 -10.249 -44 ATOM 229 C LEU 88 -8.511 -45 ATOM 230 O LEU 88 -7.850 -46 ATOM 231 N SER 89 -9.184 -46 ATOM 232 CA SER 89 -9.173 -47 ATOM 233 CB SER 89 -10.412 -47 ATOM 234 OG SER 89 -10.215 -47 ATOM 235 C SER 89 -7.938 -47 ATOM 236 O SER 89 -7.371 -48 ATOM 237 N GLN 90 -7.533 -46 ATOM 238 CA GLN 90 -6.260 -46 ATOM 239 CB GLN 90 -6.130 -45 ATOM 240 CG GLN 90 -7.054 -45 ATOM 241 CD GLN 90 -7.386 -44 ATOM 242 OE1 GLN 90 -6.964 -43 ATOM 243 NE2 GLN 90 -8.148 -44 ATOM 244 C GLN 90 -5.081 -46 ATOM 245 0 GLN 90 -4 . 123 -47 ATOM 246 N SER 91 -5.176 -45 ATOM 247 CA SER 91 -4.234 -46 ATOM 248 CB SER 91 -4.673 -45 ATOM 249 OG SER 91 -4.020 -43 ATOM 250 C SER 91 -4.116 -47 ATOM 251 O SER 91 -3.053 -48 ATOM 252 N GLU 92 -5.219 -48 ATOM 253 CA GLU 92 -5.238 -49 ATOM 254 CB GLU 92 -6.652 -49 ATOM 255 CG GLU 92 -7.297 -48 ATOM 256 CD GLU 92 -8.720 -49 ATOM 257 OE1 GLU 92 -9.229 -50 ATOM 258 OE2 GLU 92 -9.326 -48 ATOM 259 C GLU 92 -4.738 -50 ATOM 260 0 GLU 92 -4.051 -51 ATOM 261 N ARG 93 -5.087 -50 ATOM 2 62 CA ARG 93 -4.744 -51 ATOM 263 CB ARG 93 -5.381 -50 ATOM 264 CG ARG 93 -5.574 -52 ATOM 265 CD ARG 93 -6.296 -51 ATOM 266 NE ARG 93 -7.724 -51 ATOM 2 67 CZ ARG 93 -8.288 -50 ATOM 268 NH1 ARG 93 -9.594 -49 ATOM 269 NH2 ARG 93 -7.548 -49 ATOM 270 C ARG 93 -3.229 -51 ATOM 271 O ARG 93 -2.613 -52 ATOM 272 N THR 94 -2.640 -50 ATOM 273 CA THR 94 -1.197 -49 ATOM 274 CB THR 94 -0.822 -48 ATOM 275 OG1 THR 94 -1.140 -47 ATOM 276 CG2 THR 94 0.657 -48 ATOM 277 C THR 94 -0.407 -50 ATOM 278 O THR 94 0.637 -51 ATOM 279 N ALA 95 -0.898 -50 ATOM 280 CA ALA 95 -0.282 -50 ATOM 281 CB ALA 95 -1.066 -50 ATOM 282 C ALA 95 -0.241 -52 ATOM 283 0 ALA 95 0.753 -52 ATOM 284 N ARG 96 -1.318 -52 ATOM 285 CA ARG 96 -1.386 -54 ATOM 286 CB ARG 96 -2.785 -54 ATOM 287 CG ARG 96 -3.808 -54 ATOM 288 CD ARG 96 -5.163 -55 ATOM 289 NE ARG 96 -6.184 -54 ATOM 290 CZ ARG 96 -6.973 -53 ATOM 291 NH1 ARG 96 -7.874 -52 ATOM 292 NH2 ARG 96 -6.865 -54 ATOM 293 C ARG 96 -0.336 -54 ATOM 294 O ARG 96 0.303 -55 ATOM 295 N ARG 97 -0.163 -54 ATOM 296 CA ARG 97 0.755 -54 ATOM 297 CB ARG 97 0.576 -53 ATOM 298 CG ARG 97 1.419 -53 ATOM 299 CD ARG 97 1.054 -52 ATOM 300 NE ARG 97 0.580 -53 ATOM 301 CZ ARG 97 -0.693 -53 ATOM 302 NH1 ARG 97 -1.037 -54
-4.298 1.00 25.11 A C -3.744 1.00 24.99 A C -7.549 1.00 31.90 A C -6.866 1.00 32.53 A 0 -8.628 1.00 31.60 A N -9.012 1.00 32.76 A c -9.813 1.00 32.88 A c -11.183 1.00 37.17 A 0 -9.875 1.00 32.28 A c -9.852 1.00 32.59 A 0 -10.641 1.00 33.53 A N -11.384 1.00 35.45 A c -12.337 1.00 38.30 A c -13.538 1.00 41.60 A c -14.107 1.00 44.93 A c -13.553 1.00 46.74 A 0 -15.214 1.00 46.21 A N -10.399 1.00 33.56 A c -10.636 1.00 33.85 A 0 -9.289 1.00 32.27 A N -8.168 1.00 31.90 A c -7.010 1.00 32.61 A c -7.044 1.00 35.88 A 0 -7.667 1.00 30.46 A c -7.740 1.00 29.82 A 0 -7.159 1.00 30.78 A N -6.616 1.00 2 9.62 A c -6.200 1.00 30.03 A c -5.173 1.00 31.12 A c -4.847 1.00 33.15 A c -5.540 1.00 33.55 A 0 -3.908 1.00 32.58 A 0 -7.632 1.00 28.84 A c -7.275 1.00 27.60 A 0 -8.899 1.00 28.96 A N -9.911 1.00 29.05 A c -11.259 1.00 31.00 A c -12.218 1.00 34.57 A c -13.519 1.00 39.82 A c -13.341 1.00 44.62 A N -13.651 1.00 45.59 A c -13.456 1.00 44.61 A N -14.155 1.00 45.28 A N -10.020 1.00 27.72 A C -10.149 1.00 26.82 A 0 -9.932 1.00 27.00 A N -10.068 1.00 26.48 A C -10.250 1.00 25.41 A c -11.585 1.00 24.63 A 0 -9.995 1.00 25.11 A c -8.894 1.00 26.50 A c -9.081 1.00 26.28 A 0 -7.684 1.00 26.80 A N -6.508 1.00 26.79 A c -5.265 1.00 25.54 A c -6.662 1.00 27.87 A c -6.322 1.00 28.83 A 0 -7.180 1.00 28.88 A N -7.327 1.00 28.84 A c -7.793 1.00 29.30 A c -6.680 1.00 29.85 A c -7.206 1.00 31.96 A c -6.887 1.00 36.30 A N -7.789 1.00 37.39 A c -7.410 1.00 37.42 A N -9.072 1.00 37.61 A N -8.320 1.00 28.39 A C -8.113 1.00 28.76 A 0 -9.391 1.00 27.77 A N -10.459 1.00 28.70 A C -11.628 1.00 30.62 A c -12.834 1.00 34.83 A c -14.005 1.00 39.80 A c -15.155 1.00 43.80 A N -15.537 1.00 45.70 A c -16.595 1.00 47.10 A N 283 WO 2009/026558 PCT/US2008/074097 ATOM 303 NH2 ARG 97 -1.627 -53 ATOM 304 C ARG 97 2.202 -54 ATOM 305 O ARG 97 2.983 -55 ATOM 306 N LEU 98 2.545 -53 ATOM 307 CA LEU 98 3.852 -53 ATOM 308 CB LEU 98 3.863 -51 ATOM 309 CG LEU 98 4.960 -51 ATOM 310 CDl LEU 98 6.330 -51 ATOM 311 CD2 LEU 98 4.798 -50 ATOM 312 C LEU 98 4 . 115 -54 ATOM 313 O LEU 98 5.145 -55 ATOM 314 N GLN 99 3.147 -54 ATOM 315 CA GLN 99 3.208 -55 ATOM 316 CB GLN 99 1.848 -55 ATOM 317 CG GLN 99 1.895 -56 ATOM 318 CD GLN 99 1.583 -55 ATOM 319 OE1 GLN 99 1.373 -55 ATOM 320 NE2 GLN 99 1.551 -54 ATOM 321 C GLN 99 3.569 -57 ATOM 322 0 GLN 99 4.434 -57 ATOM 323 N ALA 100 2.886 -57 ATOM 324 CA ALA 100 3.071 -58 ATOM 325 CB ALA 100 2.023 -58 ATOM 326 C ALA 100 4.464 -58 ATOM 327 0 ALA 100 5.216 -59 ATOM 328 N GLN 101 4.803 -57 ATOM 329 CA GLN 101 6.090 -57 ATOM 330 CB GLN 101 6.204 -56 ATOM 331 CG GLN 101 5.063 -55 ATOM 332 CD GLN 101 5.207 -54 ATOM 333 OE1 GLN 101 4.281 -54 ATOM 334 NE2 GLN 101 6.364 -54 ATOM 335 C GLN 101 7.217 -57 ATOM 336 0 GLN 101 8.253 -58 ATOM 337 N ALA 102 6.997 -57 ATOM 338 CA ALA 102 7.975 -57 ATOM 339 CB ALA 102 7.632 -56 ATOM 340 C ALA 102 8.047 -58 ATOM 341 0 ALA 102 9.107 -58 ATOM 342 N ALA 103 6.918 -59 ATOM 343 CA ALA 103 6.904 -60 ATOM 344 CB ALA 103 5.488 -61 ATOM 345 C ALA 103 7.587 -61 ATOM 346 0 ALA 103 8.338 -62 ATOM 347 N ARG 104 7.329 -61 ATOM 348 CA ARG 104 7.976 -62 ATOM 349 CB ARG 104 7.556 -61 ATOM 350 CG ARG 104 6.248 -62 ATOM 351 CD ARG 104 5.898 -61 ATOM 352 NE ARG 104 4.707 -61 ATOM 353 CZ ARG 104 4.716 -59 ATOM 354 NH1 ARG 104 3.572 -59 ATOM 355 NH2 ARG 104 5.861 -59 ATOM 356 C ARG 104 9.481 -62 ATOM 357 O ARG 104 10.200 -62 ATOM 358 N ARG 105 9.963 -60 ATOM 359 CA ARG 105 11.384 -60 ATOM 360 CB ARG 105 11.786 -59 ATOM 361 CG ARG 105 11.942 -58 ATOM 362 CD ARG 105 12.558 -57 ATOM 363 NE ARG 105 14.002 -57 ATOM 364 CZ ARG 105 14.688 -56 ATOM 365 NH1 ARG 105 16.004 -56 ATOM 366 NH2 ARG 105 14.057 -55 ATOM 367 C ARG 105 11.775 -61 ATOM 368 O ARG 105 12.947 -61 ATOM 369 N GLY 106 10.793 -61 ATOM 370 CA GLY 106 11.090 -62 ATOM 371 C GLY 106 11.029 -61 ATOM 372 0 GLY 106 11.455 -61 ATOM 373 N TYR 107 10.497 -60 ATOM 374 CA TYR 107 10.483 -58 ATOM 375 CB TYR 107 10.780 -57 ATOM 376 CG TYR 107 12.237 -57 ATOM 377 CDl TYR 107 13.070 -56 ATOM 378 CEl TYR 107 14.406 -56 -14.865 1.00 45.89 A N -9.964 1.00 27.88 A C -10.248 1.00 28.38 A O -9.223 1.00 27.13 A N -8.585 1.00 23.63 A C -7.705 1.00 23.28 A c -6.656 1.00 24.24 A c -7.301 1.00 25.92 A c -5.996 1.00 23.55 A c -7.732 1.00 22.69 A c -7.849 1.00 23.28 A 0 -6.874 1.00 22.76 A N -5.931 1.00 21.72 A c -5.261 1.00 23.87 A c -3.838 1.00 28.10 A c -2.857 1.00 28.27 A c -1.669 1.00 29.74 A 0 -3.351 1.00 29.27 A N -6.644 1.00 20.42 A c -6.196 1.00 18.61 A 0 -7.759 1.00 19.89 A N -8.567 1.00 19.33 A c -9.668 1.00 17.45 A c -9.180 1.00 18.79 A c -8.959 1.00 21.98 A 0 -9.950 1.00 16.83 A N -10.617 1.00 14.81 A c -11.339 1.00 14.22 A c -12.293 1.00 17.42 A c -13.146 1.00 20.01 A c -13.870 1.00 24.17 A 0 -13.070 1.00 20.43 A N -9.607 1.00 15.13 A c -9.893 1.00 14.83 A 0 -8.417 1.00 14.58 A N -7.348 1.00 13.30 A c -6.279 1.00 11.40 A c -6.749 1.00 13.44 A c -6.339 1.00 12.59 A 0 -6.698 1.00 15.23 A N -6.142 1.00 17.52 A c -5.894 1.00 13.93 A c -7.124 1.00 20.68 A c -6.731 1.00 20.64 A 0 -8.407 1.00 23.25 A N -9.411 1.00 26.07 A c -10.806 1.00 28.33 A c -11.215 1.00 33.77 A c -12.629 1.00 39.49 A c -12.687 1.00 46.45 A N -12.988 1.00 48.94 A c -13.016 1.00 50.90 A N -13.265 1.00 49.24 A N -9.257 1.00 27.46 A C -9.467 1.00 29.34 A 0 -8.874 1.00 28.17 A N -8.636 1.00 27.57 A C -8.778 1.00 29.99 A c -10.220 1.00 34.08 A c -10.326 1.00 38.94 A c -10.107 1.00 43.02 A N -9.635 1.00 46.10 A c -9.470 1.00 48.21 A N -9.319 1.00 46.61 A N -7.260 1.00 26.22 A C -6.917 1.00 25.88 A 0 -6.473 1.00 26.12 A N -5.174 1.00 25.74 A C -4.000 1.00 2 5.62 A c -2.892 1.00 25.64 A 0 -4.237 1.00 25.48 A N -3.222 1.00 25.01 A c -3.846 1.00 24.93 A c -4.137 1.00 26.36 A c -3.183 1.00 25.53 A c -3.448 1.00 26.30 A c 284 WO 2009/026558 PCT/US2008/074097 ATOM 379 CD2 TYR 107 12.781 -57 ATOM 380 CE2 TYR 107 14.117 -57 ATOM 381 CZ TYR 107 14.927 -56 ATOM 382 OH TYR 107 16.248 -56 ATOM 383 C TYR 107 9.173 -58 ATOM 384 O TYR 107 8.110 -58 ATOM 385 N LEU 108 9.266 -59 ATOM 386 CA LEU 108 8.158 -58 ATOM 387 CB LEU 108 8.537 -59 ATOM 388 CG LEU 108 7.498 -58 ATOM 389 CDl LEU 108 6.261 -59 ATOM 390 CD2 LEU 108 8.078 -59 ATOM 391 C LEU 108 7.891 -57 ATOM 392 O LEU 108 8.830 -56 ATOM 393 N THR 109 6.625 -56 ATOM 394 CA THR 109 6.268 -55 ATOM 395 CB THR 109 6.087 -54 ATOM 396 OG1 THR 109 4.895 -55 ATOM 397 CG2 THR 109 7.274 -55 ATOM 398 C THR 109 4.956 -55 ATOM 399 O THR 109 4 .152 -56 ATOM 400 N LYS 110 4.741 -54 ATOM 401 CA LYS 110 3.512 -53 ATOM 402 CB LYS 110 3.736 -53 ATOM 403 CG LYS 110 2.505 -53 ATOM 404 CD LYS 110 2.449 -54 ATOM 405 CE LYS 110 1.013 -54 ATOM 406 NZ LYS 110 0.944 -56 ATOM 407 C LYS 110 3.001 -52 ATOM 408 0 LYS 110 3.728 -51 ATOM 409 N ILE 111 1.741 -52 ATOM 410 CA ILE 111 1.085 -50 ATOM 411 CB ILE 111 -0.029 -51 ATOM 412 CG2 ILE 111 -0.751 -49 ATOM 413 CGI ILE 111 0.559 -51 ATOM 414 CDl ILE 111 1.519 -50 ATOM 415 C ILE 111 0.498 -50 ATOM 416 0 ILE 111 -0.408 -51 ATOM 417 N LEU 112 1.016 -49 ATOM 418 CA LEU 112 0.667 -48 ATOM 419 CB LEU 112 1.845 -47 ATOM 420 CG LEU 112 3.124 -48 ATOM 421 CDl LEU 112 4.303 -47 ATOM 422 CD2 LEU 112 2.935 -49 ATOM 423 C LEU 112 -0.565 -47 ATOM 424 O LEU 112 -1.298 -47 ATOM 425 N HIS 113 -0.800 -47 ATOM 426 CA HIS 113 -1.900 -46 ATOM 427 CB HIS 113 -1.589 -45 ATOM 428 CG HIS 113 -2.658 -44 ATOM 429 CD2 HIS 113 -2.829 -42 ATOM 430 NDl HIS 113 -3.716 -43 ATOM 431 CEl HIS 113 -4.492 -42 ATOM 432 NE2 HIS 113 -3.977 -42 ATOM 433 C HIS 113 -2.114 -46 ATOM 434 0 HIS 113 -1.163 -45 ATOM 435 N VAL 114 -3.366 -45 ATOM 436 CA VAL 114 -3.662 -45 ATOM 437 CB VAL 114 -4.528 -46 ATOM 438 CGI VAL 114 -4.729 -45 ATOM 439 CG2 VAL 114 -3.865 -47 ATOM 440 C VAL 114 -4.414 -44 ATOM 441 O VAL 114 -5.416 -43 ATOM 442 N PHE 115 -3.932 -43 ATOM 443 CA PHE 115 -4.532 -41 ATOM 444 CB PHE 115 -3.513 -40 ATOM 445 CG PHE 115 -2.287 -40 ATOM 446 CDl PHE 115 -1.182 -41 ATOM 447 CD2 PHE 115 -2.247 -39 ATOM 448 CEl PHE 115 -0.068 -41 ATOM 449 CE2 PHE 115 -1.130 -39 ATOM 450 CZ PHE 115 -0.043 -40 ATOM 451 C PHE 115 -5.813 -41 ATOM 452 O PHE 115 -5.856 -41 ATOM 453 N HIS 116 -6.844 -41 ATOM 454 CA HIS 116 -8.118 -40 -5.369 1.00 26.57 A C -5.647 1.00 27.76 A C -4.684 1.00 28.67 A C -4.975 1.00 29.04 A 0 -2.471 1.00 24.19 A c -3.054 1.00 25.14 A 0 -1.159 1.00 24.06 A N -0.275 1.00 23.48 A c 1. 142 1.00 22.61 A c 2.234 1.00 24.41 A c 1.881 1.00 27.40 A c 3.562 1.00 25.45 A c -0.343 1.00 22.40 A c -0.309 1.00 23.50 A 0 -0.464 1.00 21.22 A N -0.403 1.00 19.07 A c -1.794 1.00 19.59 A c -2.398 1.00 19.90 A 0 -2.694 1.00 20.38 A c 0.309 1.00 17.86 A c 0.351 1.00 17.14 A 0 0.849 1.00 18.44 A N 1.552 1.00 19.57 A c 3.054 1.00 20.21 A c 3.861 1.00 22.66 A c 5.061 1.00 24.45 A c 5.367 1.00 26.17 A c 6.235 1.00 28.22 A N 1.219 1.00 19.90 A c 1.344 1.00 20.91 A 0 0.809 1.00 19.04 A N 0.623 1.00 18.90 A c -0.406 1.00 17.72 A c -0.525 1.00 18.36 A c -1.750 1.00 19.16 A c -2.347 1.00 17.38 A c 1.927 1.00 18.80 A c 2.512 1.00 17.44 A 0 2.373 1.00 19.52 A N 3.687 1.00 19.22 A c 4.273 1.00 19.32 A c 4 . 439 1.00 22.22 A c 4.746 1.00 22.17 A c 5.534 1.00 20.39 A c 3.622 1.00 18.62 A c 4.599 1.00 18.34 A 0 2.460 1.00 18.84 A N 2.299 1.00 19.02 A c 3.057 1.00 20.19 A c 2.949 1.00 22.51 A c 2.066 1.00 22.37 A c 3.830 1.00 21.62 A N 3.494 1.00 21.55 A c 2.428 1.00 21.95 A N 0.829 1.00 18.98 A C 0.059 1.00 19.75 A 0 0.434 1.00 19.49 A N -0.910 1.00 20.33 A C -1.678 1.00 19.03 A c -3.119 1.00 16.98 A c -1.635 1.00 18.60 A c -0.793 1.00 21.30 A c -0.098 1.00 22.35 A 0 -1.468 1.00 22.44 A N -1.351 1.00 25.41 A c -1.757 1.00 26.99 A c -0.890 1.00 27.32 A c -1.209 1.00 26.01 A c 0.259 1.00 26.96 A c -0.403 1.00 24.13 A c 1.070 1.00 25.59 A c 0.736 1.00 24.86 A c -2.171 1.00 26.85 A c -3.371 1.00 27.95 A 0 -1.503 1.00 26.78 A N -2.124 1.00 27.32 A c 285 WO 2009/026558 PCT/US2008/074097 ATOM 455 CB HIS 116 -9.299 -40 ATOM 456 CG HIS 116 -9.464 -42 ATOM 457 CD2 HIS 116 -10.571 -43 ATOM 458 NDl HIS 116 -8.406 -43 ATOM 459 CEl HIS 116 -8.852 -44 ATOM 460 NE2 HIS 116 -10.162 -44 ATOM 461 C HIS 116 -8.144 -39 ATOM 4 62 0 HIS 116 -9.172 -38 ATOM 463 N GLY 117 -7.022 -38 ATOM 464 CA GLY 117 -7.061 -37 ATOM 465 C GLY 117 -7.039 -36 ATOM 466 0 GLY 117 -7.454 -36 ATOM 467 N LEU 118 -6.568 -34 ATOM 468 CA LEU 118 -6.261 -34 ATOM 469 CB LEU 118 -6.188 -32 ATOM 470 CG LEU 118 -7.442 -31 ATOM 471 CDl LEU 118 -7.061 -30 ATOM 472 CD2 LEU 118 -8.421 -31 ATOM 473 C LEU 118 -4.906 -34 ATOM 474 O LEU 118 -4.345 -33 ATOM 475 N LEU 119 -4.382 -35 ATOM 476 CA LEU 119 -3.057 -36 ATOM 477 CB LEU 119 -2.093 -35 ATOM 478 CG LEU 119 -0.605 -35 ATOM 479 CDl LEU 119 0.070 -34 ATOM 480 CD2 LEU 119 0.025 -36 ATOM 481 C LEU 119 -3.090 -37 ATOM 482 O LEU 119 -2.874 -38 ATOM 483 N PRO 120 -3.369 -38 ATOM 484 CD PRO 120 -3.629 -37 ATOM 485 CA PRO 120 -3.499 -39 ATOM 486 CB PRO 120 -4.078 -39 ATOM 487 CG PRO 120 -3.675 -38 ATOM 488 C PRO 120 -2.178 -40 ATOM 489 O PRO 120 -1.167 -39 ATOM 490 N GLY 121 -2.196 -41 ATOM 491 CA GLY 121 -0.998 -42 ATOM 492 C GLY 121 -1.206 -43 ATOM 493 0 GLY 121 -2.343 -43 ATOM 494 N PHE 122 -0.108 -43 ATOM 495 CA PHE 122 -0.166 -44 ATOM 496 CB PHE 122 -0.560 -45 ATOM 497 CG PHE 122 0.355 -46 ATOM 498 CDl PHE 122 1.428 -47 ATOM 499 CD2 PHE 122 0.128 -46 ATOM 500 CEl PHE 122 2.252 -47 ATOM 501 CE2 PHE 122 0.952 -46 ATOM 502 CZ PHE 122 2.015 -47 ATOM 503 C PHE 122 1.196 -44 ATOM 504 O PHE 122 2.181 -44 ATOM 505 N LEU 123 1.237 -45 ATOM 506 CA LEU 123 2.466 -45 ATOM 507 CB LEU 123 2.257 -44 ATOM 508 CG LEU 123 3.295 -44 ATOM 509 CDl LEU 123 4.386 -43 ATOM 510 CD2 LEU 123 2.585 -44 ATOM 511 C LEU 123 2.882 -46 ATOM 512 O LEU 123 2.122 -47 ATOM 513 N VAL 124 4 . 094 -46 ATOM 514 CA VAL 124 4.541 -48 ATOM 515 CB VAL 124 4.718 -48 ATOM 516 CGI VAL 124 5.646 -47 ATOM 517 CG2 VAL 124 5.263 -50 ATOM 518 C VAL 124 5.838 -48 ATOM 519 O VAL 124 6.769 -47 ATOM 520 N LYS 125 5.860 -49 ATOM 521 CA LYS 125 7.057 -50 ATOM 522 CB LYS 125 6.696 -50 ATOM 523 CG LYS 125 7.812 -51 ATOM 52 4 CD LYS 125 7.383 -51 ATOM 525 CE LYS 125 8.566 -52 ATOM 526 NZ LYS 125 8.220 -52 ATOM 527 C LYS 125 7.673 -51 ATOM 528 O LYS 125 7.025 -52 ATOM 529 N MET 126 8.926 -51 ATOM 530 CA MET 126 9.587 -52 -1.192 1.00 24.94 A C -0.886 1.00 24.70 A C -0.597 1.00 24.63 A C -0.821 1.00 25.06 A N -0.506 1.00 23.26 A C -0.365 1.00 22.78 A N -2.418 1.00 28.43 A C -2.819 1.00 29.04 A O -2.215 1.00 29.51 A N -2.127 1.00 32.31 A C -3.416 1.00 32.25 A C -4.489 1.00 32.39 A 0 -3.286 1.00 30.44 A N -4.427 1.00 29.49 A c -3.991 1.00 27.76 A c -3.399 1.00 26.47 A c -2.612 1.00 26.36 A c -4.511 1.00 25.77 A c -4.966 1.00 29.07 A c -5.848 1.00 29.41 A 0 -4.407 1.00 29.30 A N -4.747 1.00 29.49 A c -3.624 1.00 28.72 A c -3.870 1.00 30.16 A c -4.268 1.00 29.01 A c -2.602 1.00 29.14 A c -4.935 1.00 29.79 A c -3.988 1.00 30.11 A 0 -6.164 1.00 29.03 A N -7.367 1.00 28.57 A c -6.422 1.00 28.72 A c -7.831 1.00 27.70 A c -8.455 1.00 28.64 A c -6.312 1.00 27.90 A c -6.890 1.00 28.70 A 0 -5.561 1.00 27.12 A N -5.392 1.00 25.12 A c -4.315 1.00 24.57 A c -4.009 1.00 25.06 A 0 -3.746 1.00 23.56 A N -2.611 1.00 22.66 A c -3.064 1.00 23.01 A c -4.109 1.00 25.01 A c -3.747 1.00 24.64 A c -5.457 1.00 25.34 A c -4.707 1.00 23.88 A c -6.421 1.00 25.50 A c -6.043 1.00 24.61 A c -1.945 1.00 22.06 A c -2.520 1.00 22.52 A 0 -0.722 1.00 22.50 A N 0.064 1.00 23.34 A c 1.424 1.00 22.27 A c 2.522 1.00 20.76 A c 2.536 1.00 18.72 A c 3.841 1.00 19.62 A c 0.279 1.00 23.45 A c 0.828 1.00 23.19 A 0 -0.152 1.00 23.78 A N -0.136 1.00 23.86 A c -1.580 1.00 21.15 A c -2.357 1.00 19.01 A c -1.550 1.00 21.68 A c 0.657 1.00 24.98 A c 0.596 1.00 23.20 A 0 1.418 1.00 26.11 A N 2.098 1.00 27.32 A c 3.498 1.00 25.97 A c 4 . 183 1.00 23.58 A c 5.549 1.00 25.85 A c 6.316 1.00 28.11 A c 7.731 1.00 32.00 A N 1.289 1.00 29.44 A c 1.057 1.00 30.59 A 0 0.873 1.00 29.55 A N -0.066 1.00 27.34 A c 286 WO 2009/026558 PCT/US2008/074097 ATOM 531 CB MET 126 8.929 -51 ATOM 532 CG MET 126 9.170 -50 ATOM 533 SD MET 126 8.824 -50 ATOM 534 CE MET 126 9.694 -48 ATOM 535 C MET 126 11.054 -51 ATOM 536 0 MET 126 11.407 -50 ATOM 537 N SER 127 11.900 -52 ATOM 538 CA SER 127 13.272 -52 ATOM 539 CB SER 127 13.991 -53 ATOM 540 OG SER 127 15.272 -53 ATOM 541 C SER 127 13.336 -51 ATOM 542 O SER 127 12.560 -51 ATOM 543 N GLY 128 14.279 -50 ATOM 544 CA GLY 128 14.572 -49 ATOM 545 C GLY 128 15.125 -49 ATOM 546 0 GLY 128 15.369 -49 ATOM 547 N ASP 129 15.321 -51 ATOM 548 CA ASP 129 15.845 -51 ATOM 549 CB ASP 129 16.282 -53 ATOM 550 CG ASP 129 17.578 -53 ATOM 551 OD1 ASP 129 18.089 -52 ATOM 552 OD2 ASP 129 18.086 -54 ATOM 553 C ASP 129 14.833 -51 ATOM 554 O ASP 129 15.178 -52 ATOM 555 N LEU 130 13.580 -51 ATOM 556 CA LEU 130 12.493 -51 ATOM 557 CB LEU 130 11.257 -52 ATOM 558 CG LEU 130 11.441 -53 ATOM 559 CDl LEU 130 10.365 -53 ATOM 560 CD2 LEU 130 11.390 -54 ATOM 561 C LEU 130 12.139 -50 ATOM 562 O LEU 130 11.138 -50 ATOM 563 N LEU 131 12.954 -49 ATOM 564 CA LEU 131 12.666 -48 ATOM 565 CB LEU 131 13.665 -47 ATOM 566 CG LEU 131 13.505 -46 ATOM 567 CDl LEU 131 14.687 -45 ATOM 568 CD2 LEU 131 12.188 -46 ATOM 569 C LEU 131 12.662 -48 ATOM 570 O LEU 131 11.704 -47 ATOM 571 N GLU 132 13.726 -48 ATOM 572 CA GLU 132 13.782 -48 ATOM 573 CB GLU 132 15.045 -49 ATOM 574 CG GLU 132 16.295 -48 ATOM 575 CD GLU 132 17.528 -49 ATOM 576 OE1 GLU 132 17.661 -50 ATOM 577 OE2 GLU 132 18.359 -48 ATOM 578 C GLU 132 12.547 -49 ATOM 579 O GLU 132 12.005 -48 ATOM 580 N LEU 133 12.106 -50 ATOM 581 CA LEU 133 10.930 -50 ATOM 582 CB LEU 133 10.769 -52 ATOM 583 CG LEU 133 9.429 -52 ATOM 584 CDl LEU 133 9.241 -53 ATOM 585 CD2 LEU 133 9.397 -54 ATOM 586 C LEU 133 9.660 -50 ATOM 587 O LEU 133 8.901 -50 ATOM 588 N ALA 134 9.435 -49 ATOM 589 CA ALA 134 8.198 -48 ATOM 590 CB ALA 134 8.147 -48 ATOM 591 C ALA 134 8.032 -47 ATOM 592 O ALA 134 6.917 -47 ATOM 593 N LEU 135 9.141 -46 ATOM 594 CA LEU 135 9.103 -45 ATOM 595 CB LEU 135 10.491 -45 ATOM 596 CG LEU 135 10.969 -44 ATOM 597 CDl LEU 135 12.446 -44 ATOM 598 CD2 LEU 135 10.227 -43 ATOM 599 C LEU 135 8.579 -46 ATOM 600 O LEU 135 7.968 -45 ATOM 601 N LYS 136 8.802 -47 ATOM 602 CA LYS 136 8.217 -47 ATOM 603 CB LYS 136 8.974 -48 ATOM 604 CG LYS 136 10.417 -48 ATOM 605 CD LYS 136 11.128 -49 ATOM 606 CE LYS 136 12.629 -49 -1.435 1.00 25.09 A C -2.052 1.00 24.16 A C -3.795 1.00 24.67 A S -4.214 1.00 24.23 A c -0.208 1.00 27.55 A c 0.069 1.00 28.53 A 0 -0.658 1.00 26.25 A N -1.035 1.00 24.19 A c -1.590 1.00 23.41 A c -2.093 1.00 19.90 A 0 -2.081 1.00 23.63 A c -3.036 1.00 23.04 A 0 -1.907 1.00 23.89 A N -2.958 1.00 25.02 A c -4.221 1.00 25.07 A c -5.221 1.00 25.81 A 0 -4.182 1.00 24.43 A N -5.327 1.00 23.02 A c -4.923 1.00 25.00 A c -4.157 1.00 26.85 A c -3.878 1.00 29.00 A 0 -3.840 1.00 27.23 A 0 -6.433 1.00 22.97 A c -7.556 1.00 24.66 A 0 -6.114 1.00 23.97 A N -7.077 1.00 23.49 A c -6.393 1.00 22.01 A c -5.597 1.00 21.51 A c -4.524 1.00 19.81 A c -6.543 1.00 20.88 A c -7.700 1.00 23.13 A c -8.410 1.00 23.93 A 0 -7.429 1.00 23.29 A N -7.915 1.00 24.47 A c -7.331 1.00 23.09 A c -5.843 1.00 22.95 A c -5.418 1.00 22.36 A c -5.568 1.00 20.28 A c -9.437 1.00 25.34 A c -10.025 1.00 25.04 A 0 -10.077 1.00 27.24 A N -11.534 1.00 28.71 A c -12.034 1.00 30.19 A c -12.008 1.00 32.76 A c -12.454 1.00 34.92 A c -12.069 1.00 34.12 A 0 -13.191 1.00 36.98 A 0 -12.112 1.00 29.50 A c -13.128 1.00 30.00 A 0 -11.451 1.00 29.35 A N -11.879 1.00 28.02 A c -11.036 1.00 28.47 A c -11.156 1.00 2 6.56 A c -12.578 1.00 26.64 A c -10.206 1.00 25.35 A c -11.769 1.00 27.30 A c -12.733 1.00 27.98 A 0 -10.592 1.00 25.72 A N -10.314 1.00 24.04 A c -8.847 1.00 24.07 A c -11.195 1.00 21.33 A c -11.603 1.00 21.21 A 0 -11.487 1.00 18.76 A N -12.323 1.00 17.09 A c -12.414 1.00 17.50 A c -11.139 1.00 18.25 A c -11.239 1.00 18.59 A c -10.937 1.00 19.48 A c -13.713 1.00 17.06 A c -14.352 1.00 16.31 A 0 -14.178 1.00 18.88 A N -15.438 1.00 18.70 A c -15.967 1.00 19.33 A c -16.319 1.00 21.05 A c -16.527 1.00 25.15 A c -16.488 1.00 29.77 A c 287 WO 2009/026558 PCT/US2008/074097 ATOM 607 NZ LYS 136 13.174 -49 ATOM 608 C LYS 136 6.718 -48 ATOM 609 0 LYS 136 6.0 62 -48 ATOM 610 N LEU 137 6.175 -48 ATOM 611 CA LEU 137 4.736 -48 ATOM 612 CB LEU 137 4.378 -48 ATOM 613 CG LEU 137 4.790 -50 ATOM 614 CDl LEU 137 4.652 -49 ATOM 615 CD2 LEU 137 3.936 -51 ATOM 616 C LEU 137 3.903 -47 ATOM 617 O LEU 137 4.313 -46 ATOM 618 N PRO 138 2.713 -47 ATOM 619 CD PRO 138 1.982 -48 ATOM 620 CA PRO 138 1.918 -46 ATOM 621 CB PRO 138 0.8 62 -47 ATOM 622 CG PRO 138 0.653 -48 ATOM 623 C PRO 138 1.306 -45 ATOM 624 O PRO 138 0.952 -46 ATOM 62 5 N HIS 139 1.195 -44 ATOM 62 6 CA HIS 139 0.543 -43 ATOM 627 CB HIS 139 -0.625 -43 ATOM 62 8 CG HIS 139 -1.698 -44 ATOM 62 9 CD2 HIS 139 -2.450 -43 ATOM 630 NDl HIS 139 -2.103 -45 ATOM 631 CEl HIS 139 -3.058 -46 ATOM 632 NE2 HIS 139 -3.286 -44 ATOM 633 C HIS 139 1. 476 -42 ATOM 634 0 HIS 139 1. 107 -41 ATOM 635 N VAL 140 2.677 -43 ATOM 636 CA VAL 140 3.650 -42 ATOM 637 CB VAL 140 4.872 -43 ATOM 638 CGI VAL 140 5.852 -42 ATOM 639 CG2 VAL 140 4.427 -44 ATOM 640 C VAL 140 4 . 138 -41 ATOM 641 O VAL 140 4.483 -41 ATOM 642 N ASP 141 4 .158 -40 ATOM 643 CA ASP 141 4.647 -39 ATOM 644 CB ASP 141 3.736 -37 ATOM 645 CG ASP 141 3.853 -36 ATOM 646 OD1 ASP 141 4.819 -36 ATOM 647 OD2 ASP 141 2.971 -35 ATOM 648 C ASP 141 6.057 -38 ATOM 649 O ASP 141 6.989 -38 ATOM 650 N TYR 142 6.194 -39 ATOM 651 CA TYR 142 7.488 -39 ATOM 652 CB TYR 142 8.044 -37 ATOM 653 CG TYR 142 7.128 -37 ATOM 654 CDl TYR 142 7.309 -36 ATOM 655 CEl TYR 142 6.496 -36 ATOM 656 CD2 TYR 142 6.103 -36 ATOM 657 CE2 TYR 142 5.285 -35 ATOM 658 CZ TYR 142 5.486 -35 ATOM 659 OH TYR 142 4.676 -34 ATOM 660 C TYR 142 7.333 -40 ATOM 661 O TYR 142 6.219 -40 ATOM 662 N ILE 143 8.447 -40 ATOM 663 CA ILE 143 8.388 -41 ATOM 664 CB ILE 143 8.795 -42 ATOM 665 CG2 ILE 143 8.693 -43 ATOM 666 CGI ILE 143 7.907 -43 ATOM 667 CDl ILE 143 8.575 -44 ATOM 668 C ILE 143 9.348 -40 ATOM 669 0 ILE 143 10.498 -40 ATOM 670 N GLU 144 8.876 -40 ATOM 671 CA GLU 144 9.733 -39 ATOM 672 CB GLU 144 9.167 -38 ATOM 673 CG GLU 144 10.120 -37 ATOM 674 CD GLU 144 9.478 -36 ATOM 675 OE1 GLU 144 8.950 -35 ATOM 676 OE2 GLU 144 9.503 -35 ATOM 677 C GLU 144 9.880 -40 ATOM 678 0 GLU 144 8.907 -40 ATOM 679 N GLU 145 11.100 -40 ATOM 680 CA GLU 145 11.344 -41 ATOM 681 CB GLU 145 12.780 -41 ATOM 682 CG GLU 145 13.257 -42 -17.824 1.00 33.49 A N -15.366 1.00 18.94 A C -16.403 1.00 19.33 A O -14.160 1.00 19.09 A N -13.999 1.00 18.90 A C -12.526 1.00 16.30 A C -11.878 1.00 15.79 A c -10.379 1.00 14.21 A c -12.414 1.00 16.03 A c -14.522 1.00 20.04 A c -14.450 1.00 19.08 A 0 -15.057 1.00 21.62 A N -14.964 1.00 23.18 A c -15.721 1.00 23.00 A c -16.471 1.00 22.04 A c -15.607 1.00 21.35 A c -14.705 1.00 22.95 A c -13.608 1.00 23.32 A 0 -15.080 1.00 23.11 A N -14.258 1.00 23.62 A c -13.473 1.00 27.86 A c -14.334 1.00 31.12 A c -15.320 1.00 30.94 A c -14.227 1.00 32.87 A N -15.108 1.00 32.29 A c -15.784 1.00 32.01 A N -13.278 1.00 22.78 A C -12.658 1.00 23.61 A 0 -13.124 1.00 22.21 A N -12.189 1.00 19.92 A C -12.021 1.00 18.16 A c -11.029 1.00 16.60 A c -11.555 1.00 16.58 A c -12.677 1.00 19.89 A c -13.841 1.00 18.54 A 0 -11.765 1.00 21.38 A N -12.065 1.00 21.70 A c -11.401 1.00 23.53 A c -12.018 1.00 24.88 A c -12.776 1.00 26.94 A 0 -11.741 1.00 27.24 A 0 -11.508 1.00 19.63 A c -12.190 1.00 18.59 A 0 -10.256 1.00 18.63 A N -9.609 1.00 19.45 A c -9.335 1.00 18.30 A c -8.527 1.00 19.04 A c -7.157 1.00 18.23 A c -6.421 1.00 17.86 A c -9.141 1.00 18.51 A c -8.413 1.00 18.75 A c -7.054 1.00 19.08 A c -6.331 1.00 18.33 A 0 -8.302 1.00 19.33 A c -7.843 1.00 19.86 A 0 -7.709 1.00 18.21 A N -6.421 1.00 18.63 A c -6.568 1.00 19.75 A c -5.224 1.00 19.43 A c -7.620 1.00 18.58 A c -8.370 1.00 15.29 A c -5.471 1.00 18.03 A c -5.819 1.00 20.14 A 0 -4.284 1.00 18.26 A N -3.292 1.00 19.45 A c -2.908 1.00 18.29 A c -2.068 1.00 19.87 A c -1.543 1.00 21.24 A c -2.362 1.00 22.48 A 0 -0.307 1.00 19.26 A 0 -2.041 1.00 19.63 A c -1.536 1.00 20.55 A 0 -1.539 1.00 20.79 A N -0.384 1.00 22.29 A c -0.408 1.00 24.00 A c 0.904 1.00 25.67 A c 288 WO 2009/026558 PCT/US2008/074097 ATOM 683 CD GLU 145 14.657 -41 ATOM 684 OE1 GLU 145 14.909 -40 ATOM 685 OE2 GLU 145 15.501 -42 ATOM 686 C GLU 145 11.071 -40 ATOM 687 O GLU 145 11.501 -39 ATOM 688 N ASP 146 10.361 -41 ATOM 689 CA ASP 146 9.805 -40 ATOM 690 CB ASP 146 8.946 -41 ATOM 691 CG ASP 146 8.061 -41 ATOM 692 OD1 ASP 146 7.680 -39 ATOM 693 OD2 ASP 146 7.735 -41 ATOM 694 C ASP 146 10.901 -40 ATOM 695 O ASP 146 11.944 -40 ATOM 696 N SER 147 10.653 -39 ATOM 697 CA SER 147 11.635 -38 ATOM 698 CB SER 147 12.306 -37 ATOM 699 OG SER 147 11.393 -36 ATOM 700 C SER 147 10.917 -37 ATOM 701 O SER 147 9.683 -37 ATOM 702 N SER 148 11.682 -37 ATOM 703 CA SER 148 11.097 -36 ATOM 704 CB SER 148 12.030 -36 ATOM 705 OG SER 148 11.817 -38 ATOM 706 C SER 148 10.740 -35 ATOM 707 O SER 148 11.243 -34 ATOM 708 N VAL 149 9.817 -34 ATOM 709 CA VAL 149 9.528 -33 ATOM 710 CB VAL 149 8.123 -32 ATOM 711 CGI VAL 149 8.098 -32 ATOM 712 CG2 VAL 149 7.022 -33 ATOM 713 C VAL 149 9.565 -33 ATOM 714 O VAL 149 9.483 -34 ATOM 715 N PHE 150 9.687 -31 ATOM 716 CA PHE 150 9.958 -31 ATOM 717 CB PHE 150 11.455 -31 ATOM 718 CG PHE 150 12.340 -32 ATOM 719 CDl PHE 150 12.825 -32 ATOM 720 CD2 PHE 150 12.699 -33 ATOM 721 CEl PHE 150 13.651 -33 ATOM 722 CE2 PHE 150 13.528 -34 ATOM 723 CZ PHE 150 14.007 -34 ATOM 724 C PHE 150 9.161 -30 ATOM 725 O PHE 150 9.022 -29 ATOM 726 N ALA 151 8.652 -30 ATOM 727 CA ALA 151 7.941 -2 9 ATOM 728 CB ALA 151 7.546 -29 ATOM 729 C ALA 151 8.807 -28 ATOM 730 0 ALA 151 9.987 -28 ATOM 731 N GLN 152 8.224 -26 ATOM 732 CA GLN 152 8.999 -2 5 ATOM 733 CB GLN 152 8.816 -25 ATOM 734 CG GLN 152 9.251 -2 5 ATOM 735 CD GLN 152 10.729 -26 ATOM 736 OE1 GLN 152 11.555 -25 ATOM 737 NE2 GLN 152 11.073 -27 ATOM 738 C GLN 152 8.690 -24 ATOM 739 0 GLN 152 8.769 -23 ATOM 740 OXT GLN 152 8.403 -25 TER 741 GLN 152 ATOM 742 CB SER 153 -2.118 -5 ATOM 743 OG SER 153 -3.502 -5 ATOM 744 C SER 153 -1.938 -7 ATOM 745 O SER 153 -2.486 -9 ATOM 746 N SER 153 -0.031 -6 ATOM 747 CA SER 153 -1.516 -7 ATOM 748 N ILE 154 -1.691 -7 ATOM 749 CA ILE 154 -1.789 -8 ATOM 750 CB ILE 154 -2.590 -7 ATOM 751 CG2 ILE 154 -2.566 -8 ATOM 752 CGI ILE 154 -4.033 -7 ATOM 753 CDl ILE 154 -4.702 -8 ATOM 754 C ILE 154 -0.387 -8 ATOM 755 0 ILE 154 0.459 -7 ATOM 756 N PRO 155 -0.124 -9 ATOM 757 CD PRO 155 -1.077 -10 ATOM 758 CA PRO 155 1 .190 -10 1.229 1.00 27.32 A C 1.121 1.00 29.46 A O 1.578 1.00 25.95 A 0 0.934 1.00 22.03 A c 1.141 1.00 21.79 A 0 1.826 1.00 21.77 A N 3.010 1.00 21.81 A c 3.792 1.00 23.57 A c 4.831 1.00 26.04 A c 4.626 1.00 25.09 A 0 5.851 1.00 26.40 A 0 3.902 1.00 20.29 A c 4.066 1.00 20.15 A 0 4 . 472 1.00 20.99 A N 5.32 0 1.00 21.78 A c 4.553 1.00 21.45 A c 3.622 1.00 21.30 A 0 6.539 1.00 22.03 A c 6.594 1.00 22.28 A 0 7.495 1.00 20.88 A N 8.695 1.00 18.56 A c 9.875 1.00 17.76 A c 10.343 1.00 23.02 A 0 8.591 1.00 17.96 A c 7.705 1.00 18.68 A 0 9.464 1.00 17.56 A N 9.732 1.00 14.60 A c 9.188 1.00 10.11 A c 7.681 1.00 7.29 A c 9.768 1.00 4.64 A c 11.243 1.00 14.75 A c 12.034 1.00 13.75 A 0 11.635 1.00 14.76 A N 13.020 1.00 14.98 A c 13.209 1.00 13.78 A c 12.706 1.00 13.73 A c 11.399 1.00 13.23 A c 13.544 1.00 12.73 A c 10.940 1.00 13.20 A c 13.093 1.00 12.62 A c 11.789 1.00 13.49 A c 13.493 1.00 15.59 A c 12.769 1.00 15.48 A 0 14.721 1.00 16.70 A N 15.405 1.00 17.59 A c 16.800 1.00 14.66 A c 15.499 1.00 20.08 A c 15.863 1.00 21.40 A 0 15.185 1.00 21.45 A N 15.123 1.00 22.94 A c 13.751 1.00 22.61 A c 12.600 1.00 24.12 A c 12.639 1.00 24.23 A c 12.900 1.00 25.38 A 0 12.384 1.00 25.68 A N 16.212 1.00 24.95 A c 15.892 1.00 25.70 A 0 17.372 1.00 25.96 A 0 A 31.558 1.00 64.33 B c 31.243 1.00 65.73 B 0 30.526 1.00 60.48 B c 30.714 1.00 61.28 B 0 31.819 1.00 62.19 B N 31.716 1.00 62.27 B c 29.312 1.00 56.98 B N 28.096 1.00 53.64 B C 26.997 1.00 54.07 B c 25.696 1.00 53.46 B c 27.459 1.00 54.70 B c 27.999 1.00 55.43 B c 27.576 1.00 50.51 B c 27.493 1.00 51.05 B 0 27.215 1.00 46.28 B N 27.297 1.00 44.83 B c 26.719 1.00 42.26 B c 289 WO 2009/026558 PCT/US2008/074097 ATOM 759 CB PRO 155 1.044 -11 ATOM 760 CG PRO 155 -0.419 -12 ATOM 761 C PRO 155 1.624 -9 ATOM 762 O PRO 155 0.810 -9 ATOM 763 N TRP 156 2.883 -9 ATOM 764 CA TRP 156 3.404 -8 ATOM 765 CB TRP 156 4.931 -8 ATOM 766 CG TRP 156 5.560 -9 ATOM 767 CD2 TRP 156 5.935 -9 ATOM 768 CE2 TRP 156 6.429 -10 ATOM 769 CE3 TRP 156 5.893 -8 ATOM 770 CDl TRP 156 5.845 -10 ATOM 771 NEl TRP 156 6.367 -11 ATOM 772 CZ2 TRP 156 6.878 -11 ATOM 773 CZ3 TRP 156 6.337 -9 ATOM 774 CH2 TRP 156 6.821 -10 ATOM 775 C TRP 156 2.945 -8 ATOM 776 O TRP 156 2.745 -7 ATOM 777 N ASN 157 2.790 -9 ATOM 778 CA ASN 157 2.496 -10 ATOM 779 CB ASN 157 2.841 -11 ATOM 780 CG ASN 157 2.297 -12 ATOM 781 OD1 ASN 157 2.678 -12 ATOM 782 ND2 ASN 157 1.406 -13 ATOM 783 C ASN 157 1.042 -10 ATOM 784 0 ASN 157 0.759 -9 ATOM 785 N LEU 158 0.118 -10 ATOM 786 CA LEU 158 -1.275 -10 ATOM 787 CB LEU 158 -2.159 -10 ATOM 788 CG LEU 158 -2.299 -12 ATOM 789 CDl LEU 158 -3.369 -12 ATOM 790 CD2 LEU 158 -2.656 -12 ATOM 791 C LEU 158 -1.380 -8 ATOM 792 O LEU 158 -2.015 -7 ATOM 793 N GLU 159 -0.734 -7 ATOM 794 CA GLU 159 -0.599 -6 ATOM 795 CB GLU 159 0.373 -5 ATOM 796 CG GLU 159 0.570 -4 ATOM 797 CD GLU 159 1.497 -4 ATOM 798 OE1 GLU 159 1.838 -5 ATOM 799 OE2 GLU 159 1.884 -2 ATOM 800 C GLU 159 -0.081 -5 ATOM 801 O GLU 159 -0.657 -5 ATOM 802 N ARG 160 0.993 -6 ATOM 803 CA ARG 160 1.690 -6 ATOM 804 CB ARG 160 2.871 -7 ATOM 805 CG ARG 160 3.727 -6 ATOM 806 CD ARG 160 4 .297 -5 ATOM 807 NE ARG 160 4.594 -5 ATOM 808 CZ ARG 160 5.820 -5 ATOM 809 NH1 ARG 160 5.986 -4 ATOM 810 NH2 ARG 160 6.879 -5 ATOM 811 C ARG 160 0.789 -6 ATOM 812 O ARG 160 0.748 -5 ATOM 813 N ILE 161 0.071 -7 ATOM 814 CA ILE 161 -0.735 -7 ATOM 815 CB ILE 161 -1.083 -9 ATOM 816 CG2 ILE 161 0.167 -9 ATOM 817 CGI ILE 161 -2.096 -9 ATOM 818 CDl ILE 161 -2.663 -10 ATOM 819 C ILE 161 -2.037 -6 ATOM 820 0 ILE 161 -2.845 -6 ATOM 821 N THR 162 -2.228 -5 ATOM 822 CA THR 162 -3.346 -5 ATOM 823 CB THR 162 -3.960 -5 ATOM 824 OG1 THR 162 -4.768 -6 ATOM 825 CG2 THR 162 -4.795 -3 ATOM 826 C THR 162 -2.896 -3 ATOM 827 O THR 162 -2.007 -3 ATOM 828 N PRO 163 -3.507 -2 ATOM 829 CD PRO 163 -4.456 -3 ATOM 830 CA PRO 163 -3.231 -1 ATOM 831 CB PRO 163 -3.865 -1 ATOM 832 CG PRO 163 -4.953 -2 ATOM 833 C PRO 163 -3.824 -0 ATOM 834 O PRO 163 -4.773 -1 26.515 1.00 43.54 B C 26.469 1.00 43.77 B C 25.468 1.00 38.35 B c 24.581 1.00 37.59 B 0 25.464 1.00 35.05 B N 24.434 1.00 31.77 B c 24.492 1.00 30.82 B c 23.877 1.00 29.15 B c 22.504 1.00 28.01 B c 22.365 1.00 28.46 B c 21.383 1.00 26.98 B c 24.498 1.00 28.63 B c 23.592 1.00 27.53 B N 21.145 1.00 27.62 B c 20.183 1.00 27.01 B c 20.068 1.00 27.44 B c 23.034 1.00 30.37 B c 22.188 1.00 29.94 B 0 22.792 1.00 30.00 B N 21.461 1.00 30.04 B c 21.387 1.00 30.90 B c 22.566 1.00 32.76 B c 23.720 1.00 32.26 B 0 22.282 1.00 32.40 B N 21.050 1.00 29.16 B c 19.905 1.00 28.18 B 0 21.979 1.00 28.71 B N 21.720 1.00 29.10 B c 22.869 1.00 26.66 B c 23.001 1.00 23.99 B c 24. Oil 1.00 22.11 B c 21.661 1.00 22.63 B c 21.595 1.00 30.36 B c 20.690 1.00 27.77 B 0 22.531 1.00 34.34 B N 22.499 1.00 38.03 B c 23.596 1.00 42.36 B c 23.754 1.00 49.60 B c 24.917 1.00 54.93 B c 25.690 1.00 56.11 B 0 25.053 1.00 57.72 B 0 21.133 1.00 37.92 B c 20.497 1.00 38.35 B 0 20.685 1.00 37.80 B N 19.451 1.00 37.18 B c 19.217 1.00 38.09 B c 18. Oil 1.00 40.19 B c 18.181 1.00 43.31 B c 19.590 1.00 47.57 B N 20.106 1.00 48.38 B c 21.409 1.00 48.57 B N 19.321 1.00 47.72 B N 18.220 1.00 36.61 B C 17.457 1.00 35.07 B 0 18.034 1.00 37.09 B N 16.832 1.00 36.70 B C 16.649 1.00 34.95 B c 16.787 1.00 34.16 B c 17.698 1.00 31.99 B c 17.425 1.00 31.11 B c 16.842 1.00 37.39 B c 15.922 1.00 36.70 B 0 17.893 1.00 38.96 B N 17.977 1.00 39.63 B c 19.366 1.00 37.84 B c 19.511 1.00 36.55 B 0 19.588 1.00 37.94 B c 17.696 1.00 42.17 B c 18.373 1.00 43.46 B 0 16.695 1.00 44.52 B N 15.722 1.00 44.90 B c 16.428 1.00 46.29 B c 15.062 1.00 45.47 B c 14.977 1.00 45.09 B c 17.508 1.00 48.53 B c 18.198 1.00 47.74 B 0 290 > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > > H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H O O O O O () () O O O O () O () O () () O () () () () () () () () () () () O () () () O O () O O O O O () () () () () () () O O O O O O o O o o o o o o o o o o o o o o o o o o o o 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 >x >x vx vx vx vx vx VX VX VX VX CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO h-1 o o o o o o O O O O VX vx VX vx VX VX vx vx VX VX CO CO CO CO CO CO CO CO CO CO -j -j -J -J -J -j -J -J -j -j Ch Ολ Ολ Ολ Ολ Ch Ολ Ολ Ολ Ολ U1 U1 U1 U1 U1 U1 CO CO U1 CO U) U) U) U) U) O VX CO g Ch Oi U) ho 1-1 o VX CO G Ch Ui ,£» U) ho M o vx CO -J Ch U1 .£> U) ho 1-1 o VX CO -J Ολ Ui .£> U) ho 1-1 o vx CO -J σ\ U1 .£> U) ho M o VX CO G ΟΛ Ui U) ho o vx CO G Ch U1 U) ho o vx CO G Ch U1 o o o z O o o o Π Π o Z o O o o O o o O Π o o Z O o o n n O Z O O o n o n o O Z O o n n η o z O o o o n O O z O o o o o z o O O z o O o Z O O O o o o z C) Cd > Π Π C) Cd > Z [S3 PI a PI Π C) Cd > C) f,) Cd > PI PI a C) Cd > C) f,) Cd > π π o Cd > o Cd > > > o Cd > a 1-1 ho ho 1-1 1-1 ho ho ho ho g g g g g g g g g g g g < < < < < < < o O o o o o O O O < < < < < < < r r r r r r r r CO CO CO CO CO CO O O o O o O O O »T1 »T1 »T1 »n »T1 »n »T1 PI PI PI PI PI PI PI PI PI PI PI PI k; K K K K k; k; K K K K K > > > > > > > r r r r r r r r r > > > > > > > PI PI PI PI PI PI PI PI PI PI PI PI PI PI G G G G G G G G P0 P0 P0 P0 P0 P0 P0 <j <j <j <j <j <j <j <j <j <j <j <j po po po PO po po Pd Pd po PO Pd Pd f f f f f f f a a a a a a a a a f f f f f f f G G G G G G G G po PO PO po PO PO K K K K K K K K o o o o o o o M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO -j -j G G G G G G G G G G G G G G G G G G G G Oi Oi Ui Ui .£> .£> ,£» .£> ,£» ,£» ,£» .£> U) U) U) U) U) U) U) U) U) U) U) U) ho ho ho ho ho ho ho o o o o o o o VX VX VX VX VX vx VX VX CO CO CO CO CO CO G G G G Ch Ch Ολ ΟΛ f 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 i 1 1 1 1 1 t 1 1 1 1 1 1 1 i 1 1 i 1 1 1 1 1 1 1 1 1 1 } 1 1 1 1 1 1 1 1 1 1 1 1 1 UJ UJ N) UJ U) Ui Ui o CO o vx CO -J -J -J CO CO CO Ch -J CO o o o Ui .£> U) U) ho ho U) U) ho ho U) Ολ Ui VX CO CO G Ch Ch G Ολ G G Ολ CO U) .£> ho ho U) ho CO CO ho U) ho U) ujhjuiuJcouj^<T><T>^^ujco<T>hoooGcouiuihOhJ<T><T>ujhj^^<T>HJ^co<T><T><T>ujhouJG<T>ujJ^<T>uj<T>GUJ^uiuihoho^<T>HJG<T><T>ujhOGo^Gouj'Xh-iGh-i<T>coo'>h-iho N)^^H^CX)(^CX)(Ji(Ji(TiK)(Ti(TiUJN)HV£)Hv£)(TiK)H£ihOOCOlJiOJCON)UICX)'Jcn^OO(TiHUiUiCnvriCO^DOO(TiHCD-JO^HXil£i(^HCOCX)(Ti^-J-JvriU)vri^CO'JOJOJ'J(^Cn (ΓιΜ^Ν)^θσΐιβ.ΙιΟφω^Ο)Ην]ίίίί^03^^μυ1£.φφ(?ι^υι^θυΗυΐΗμφ(Τι^α)ν10ν1ΜθΟΦ(Για)1£>υυ^Ηυ(?ι^φιχιμα)θυισιθυιθυΐώι£>θα)ΦΚ)Η(Γι I I I I I I I I I I I I I I I I ! 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(^χ1Οϋΐυΐι£>ν0υΐΛ00ΜθΝ)Ηωθ(Γ\θν0ι£>00·^ωθ'ΰωυωΜ(ΓιΗ(^α)ι£>οσΐΝ)ι£>υιωΗΝ)υ^Ν)νΐυι^ν0Η(»υιΚ)ΟΗυ(Γι^Μω00Μν0ι£>υι-^^(^θΗ00υια)10(Γ>ω (»O^NJUJVD(r\(r\UiUiVD^W^H(^^^|guJVDO^^J^COHUJN)V£><r\i£»K)UiCD(^N)OUJUJV£>i£»'JCOOUJ'JUiUiWi£»'^'JUi(riK)OUiUiV£>HV£>(^<r\CD-J(^Oi£»OCOvDUJ'Ji£»UJ ooozooooooozooooooooooozoooooozoooooooozoooooozooooooozooooozooozooozooooooz WO 2009/026558 PCT/US2008/074097 WO 2009/026558 PCT/US2008/074097 ATOM 911 CDl LEU 185 -2.960 -30 ATOM 912 CD2 LEU 185 -1.813 -32 ATOM 913 C LEU 185 -0.340 -30 ATOM 914 O LEU 185 0.518 -2 9 ATOM 915 N ASP 186 -0.244 -31 ATOM 916 CA ASP 186 0.716 -31 ATOM 917 CB ASP 186 0.299 -30 ATOM 918 CG ASP 186 1.439 -29 ATOM 919 OD1 ASP 186 2.197 -28 ATOM 920 OD2 ASP 186 1.575 -2 9 ATOM 921 C ASP 186 0.797 -32 ATOM 922 O ASP 186 0.362 -33 ATOM 923 N THR 187 1.365 -32 ATOM 924 CA THR 187 1.426 -33 ATOM 925 CB THR 187 2.265 -32 ATOM 92 6 OG1 THR 187 1.568 -31 ATOM 927 CG2 THR 187 3.625 -32 ATOM 928 C THR 187 0.021 -33 ATOM 929 O THR 187 -0.934 -32 ATOM 930 N SER 188 -0.101 -34 ATOM 931 CA SER 188 -1.387 -34 ATOM 932 CB SER 188 -1.352 -35 ATOM 933 OG SER 188 -0.424 -35 ATOM 934 C SER 188 -1.703 -33 ATOM 935 O SER 188 -0.801 -32 ATOM 936 N ILE 189 -2.991 -32 ATOM 937 CA ILE 189 -3.458 -31 ATOM 938 CB ILE 189 -4.547 -31 ATOM 939 CG2 ILE 189 -5.002 -29 ATOM 940 CGI ILE 189 -4.000 -30 ATOM 941 CDl ILE 189 -2.550 -30 ATOM 942 C ILE 189 -4.033 -32 ATOM 943 0 ILE 189 -4.439 -33 ATOM 944 N GLN 190 -4.063 -31 ATOM 945 CA GLN 190 -4.861 -31 ATOM 946 CB GLN 190 -4.083 -31 ATOM 947 CG GLN 190 -4.502 -31 ATOM 948 CD GLN 190 -5.107 -30 ATOM 949 OE1 GLN 190 -6.187 -30 ATOM 950 NE2 GLN 190 -4.410 -30 ATOM 951 C GLN 190 -6.135 -30 ATOM 952 0 GLN 190 -6.184 -29 ATOM 953 N SER 191 -7.162 -31 ATOM 954 CA SER 191 -8.255 -30 ATOM 955 CB SER 191 -9.034 -31 ATOM 956 OG SER 191 -9.937 -32 ATOM 957 C SER 191 -9.231 -29 ATOM 958 O SER 191 -10.183 -29 ATOM 959 N ASP 192 -9.010 -30 ATOM 960 CA ASP 192 -9.853 -29 ATOM 961 CB ASP 192 -10.593 -30 ATOM 962 CG ASP 192 -9.655 -31 ATOM 963 OD1 ASP 192 -8.434 -31 ATOM 964 OD2 ASP 192 -10.142 -32 ATOM 965 C ASP 192 -9.078 -28 ATOM 966 O ASP 192 -9.563 -28 ATOM 967 N HIS 193 -7.872 -28 ATOM 968 CA HIS 193 -7.174 -27 ATOM 969 CB HIS 193 -5.859 -27 ATOM 970 CG HIS 193 -5.066 -25 ATOM 971 CD2 HIS 193 -3.978 -26 ATOM 972 NDl HIS 193 -5.379 -24 ATOM 973 CEl HIS 193 -4.517 -23 ATOM 974 NE2 HIS 193 -3.658 -24 ATOM 975 C HIS 193 -8.089 -2 6 ATOM 976 0 HIS 193 -8.669 -25 ATOM 977 N ARG 194 -8.214 -25 ATOM 978 CA ARG 194 -9.264 -24 ATOM 979 CB ARG 194 -9.101 -23 ATOM 980 CG ARG 194 -8.795 -22 ATOM 981 CD ARG 194 -9.657 -21 ATOM 982 NE ARG 194 -8.938 -21 ATOM 983 CZ ARG 194 -7.921 -20 ATOM 984 NHl ARG 194 -7.334 -19 ATOM 985 NH2 ARG 194 -7.479 -19 ATOM 986 C ARG 194 -9.235 -23
9.644 1.00 34.74 B C 8.788 1.00 33.81 B C 13.284 1.00 32.10 B c 13.016 1.00 33.06 B 0 14.312 1.00 32.16 B N 15.365 1.00 33.03 B c 16.118 1.00 35.89 B c 16.876 1.00 40.10 B c 16.272 1.00 41.27 B 0 18.082 1.00 44.20 B 0 16.315 1.00 32.10 B c 15.981 1.00 33.15 B 0 17.494 1.00 30.56 B N 18.525 1.00 29.30 B c 19.706 1.00 29.76 B c 20.387 1.00 28.42 B 0 19.235 1.00 28.84 B c 19.042 1.00 29.16 B c 18.496 1.00 30.34 B 0 20.109 1.00 29.21 B N 20.756 1.00 28.11 B c 21.637 1.00 25.78 B c 22.688 1.00 23.67 B 0 21.594 1.00 29.15 B c 22.020 1.00 29.20 B 0 21.815 1.00 31.00 B N 22.560 1.00 31.96 B c 21.767 1.00 32.72 B c 22.512 1.00 34.17 B c 20.393 1.00 34.80 B c 20.422 1.00 34.94 B c 23.915 1.00 31.62 B c 24.105 1.00 32.27 B 0 24.860 1.00 32.36 B N 26.064 1.00 33.98 B c 27.305 1.00 32.89 B c 28.548 1.00 36.37 B c 29.599 1.00 39.51 B c 29.403 1.00 42.37 B 0 30.726 1.00 40.58 B N 25.936 1.00 34.78 B c 26.356 1.00 35.39 B 0 25.353 1.00 35.46 B N 24.721 1.00 36.57 B c 23.787 1.00 36.91 B c 24.540 1.00 37.76 B 0 25.718 1.00 37.07 B c 25.333 1.00 36.92 B 0 26.995 1.00 37.93 B N 28.032 1.00 38.96 B c 28.784 1.00 43.84 B c 29.420 1.00 47.60 B c 29.155 1.00 50.20 B 0 30.182 1.00 48.68 B 0 29.001 1.00 36.46 B c 30.078 1.00 35.83 B 0 28.611 1.00 34.81 B N 29.319 1.00 34.03 B c 28.619 1.00 33.96 B c 29.308 1.00 33.51 B c 30.108 1.00 33.22 B c 29.215 1.00 33.43 B N 29.930 1.00 33.67 B c 30.483 1.00 33.30 B N 29.309 1.00 33.86 B C 28.274 1.00 34.18 B 0 30.461 1.00 32.52 B N 30.662 1.00 31.10 B C 32.026 1.00 29.16 B c 31.959 1.00 28.99 B c 32.934 1.00 26.01 B c 34.132 1.00 23.97 B N 34.126 1.00 23.47 B c 35.262 1.00 23.18 B N 32.984 1.00 23.23 B N 29.552 1.00 31.87 B C 292 WO 2009/026558 PCT/US2008/074097 ATOM 987 0 ARG 194 -10.245 -22.835 29.249 1.00 32.31 B O ATOM 988 N GLU 195 -8.073 -23.327 28.930 1.00 31.93 B N ATOM 989 CA GLU 195 -7.834 -22.250 27.981 1.00 31.02 B C ATOM 990 CB GLU 195 -6.324 -22.075 27.807 1.00 31.22 B C ATOM 991 CG GLU 195 -5.917 -21.036 26.791 1.00 32.56 B c ATOM 992 CD GLU 195 -5.879 -19.625 27.358 1.00 33.36 B c ATOM 993 OE1 GLU 195 -6.529 -19.363 28.404 1.00 31.05 B 0 ATOM 994 OE2 GLU 195 -5.191 -18.782 26.736 1.00 32.52 B 0 ATOM 995 C GLU 195 -8.506 -22.462 26.617 1.00 30.14 B c ATOM 996 0 GLU 195 -8.857 -21.496 25.939 1.00 29.15 B 0 ATOM 997 N ILE 196 -8.690 -23.720 26.221 1.00 29.91 B N ATOM 998 CA ILE 196 -9.100 -24.037 24.855 1.00 29.25 B c ATOM 999 CB ILE 196 -7.951 -24.687 24.064 1.00 27.84 B c ATOM 1000 CG2 ILE 196 -6.854 -23.670 23.801 1.00 26.24 B c ATOM 1001 CGI ILE 196 -7.436 -25.909 24.834 1.00 26.53 B c ATOM 1002 CD1 ILE 196 -6.554 -26.819 24.033 1.00 24.05 B c ATOM 1003 C ILE 196 -10.274 -24.999 24.811 1.00 30.60 B c ATOM 1004 0 ILE 196 -10.948 -25.135 23.788 1.00 30.51 B 0 ATOM 1005 N GLU 197 -10.512 -25.686 25.916 1.00 32.24 B N ATOM 1006 CA GLU 197 -11.490 -26.759 25.910 1.00 34.74 B c ATOM 1007 CB GLU 197 -11.610 -27.350 27.309 1.00 35.54 B c ATOM 1008 CG GLU 197 -12.153 -26.413 28.324 1.00 38.11 B c ATOM 1009 CD GLU 197 -13.648 -26.430 28.324 1.00 41.53 B c ATOM 1010 OE1 GLU 197 -14.254 -25.395 28.669 1.00 45.11 B 0 ATOM 1011 OE2 GLU 197 -14.219 -27.484 27.971 1.00 43.30 B 0 ATOM 1012 C GLU 197 -12.855 -26.287 25.413 1.00 34.89 B c ATOM 1013 0 GLU 197 -13.359 -25.251 25.844 1.00 34.37 B 0 ATOM 1014 N GLY 198 -13.446 -27.046 24.497 1.00 34.64 B N ATOM 1015 CA GLY 198 -14.707 -26.631 23.918 1.00 34.42 B c ATOM 1016 C GLY 198 -14.534 -25.954 22.570 1.00 35.86 B c ATOM 1017 0 GLY 198 -15.436 -26.002 21.732 1.00 36.41 B 0 ATOM 1018 N ARG 199 -13.383 -25.318 22.354 1.00 36.46 B N ATOM 1019 CA ARG 199 -13.081 -24.694 21.066 1.00 37.77 B c ATOM 1020 CB ARG 199 -12.258 -23.416 21.257 1.00 39.47 B c ATOM 1021 CG ARG 199 -12.909 -22.372 22.129 1.00 41.61 B c ATOM 1022 CD ARG 199 -11.888 -21.766 23.062 1.00 43.31 B c ATOM 1023 NE ARG 199 -12.472 -20.711 23.877 1.00 45.69 B N ATOM 1024 CZ ARG 199 -12.610 -19.453 23.475 1.00 48.05 B c ATOM 1025 NHl ARG 199 -13.153 -18.552 24.283 1.00 49.22 B N ATOM 1026 NH2 ARG 199 -12.208 -19.095 22.262 1.00 48.95 B N ATOM 1027 C ARG 199 -12.275 -25.673 20.242 1.00 37.48 B C ATOM 1028 O ARG 199 -12.100 -25.507 19.042 1.00 37.33 B 0 ATOM 1029 N VAL 200 -11.768 -26.692 20.916 1.00 38.28 B N ATOM 1030 CA VAL 200 -10.894 -27.662 20.286 1.00 39.41 B C ATOM 1031 CB VAL 200 -9.503 -27.665 20.976 1.00 40.93 B c ATOM 1032 CGI VAL 200 -8.662 -28.836 20.488 1.00 40.39 B c ATOM 1033 CG2 VAL 200 -8.791 -26.346 20.688 1.00 40.81 B c ATOM 1034 C VAL 200 -11.516 -29.051 20.361 1.00 39.27 B c ATOM 1035 O VAL 200 -11.652 -29.628 21.443 1.00 39.35 B 0 ATOM 1036 N MET 201 -11.904 -29.565 19.199 1.00 39.35 B N ATOM 1037 CA MET 201 -12.387 -30.930 19.063 1.00 38.47 B c ATOM 1038 CB MET 201 -13.537 -30.968 18.057 1.00 39.97 B c ATOM 1039 CG MET 201 -14.150 -32.335 17.862 1.00 43.51 B c ATOM 1040 SD MET 201 -13.407 -33.296 16.515 1.00 49.43 B s ATOM 1041 CE MET 201 -13.750 -34.985 17.094 1.00 46.63 B c ATOM 1042 C MET 201 -11.233 -31.801 18.575 1.00 37.52 B c ATOM 1043 0 MET 201 -10.835 -31.727 17.414 1.00 37.13 B 0 ATOM 1044 N VAL 202 -10.680 -32.612 19.467 1.00 36.78 B N ATOM 1045 CA VAL 202 -9.624 -33.533 19.076 1.00 35.76 B c ATOM 1046 CB VAL 202 -8.927 -34.157 20.303 1.00 34.80 B c ATOM 1047 CGI VAL 202 -8.212 -35.428 19.905 1.00 33.07 B c ATOM 1048 CG2 VAL 202 -7.934 -33.173 20.888 1.00 33.22 B c ATOM 1049 C VAL 202 -10.226 -34.641 18.230 1.00 36.18 B c ATOM 1050 O VAL 202 -11.025 -35.447 18.716 1.00 35.82 B 0 ATOM 1051 N THR 203 -9.848 -34.668 16.956 1.00 36.30 B N ATOM 1052 CA THR 203 -10.380 -35.662 16.041 1.00 35.62 B c ATOM 1053 CB THR 203 -10.067 -35.316 14.568 1.00 34.74 B c ATOM 1054 OG1 THR 203 -8.719 -35.682 14.257 1.00 34.72 B 0 ATOM 1055 CG2 THR 203 -10.240 -33.821 14.334 1.00 33.32 B c ATOM 1056 C THR 203 -9.745 -36.993 16.389 1.00 36.32 B c ATOM 1057 O THR 203 -9.147 -37.151 17.447 1.00 37.09 B 0 ATOM 1058 N ASP 204 -9.881 -37.956 15.497 1.00 37.59 B N ATOM 1059 CA ASP 204 -9.461 -39.315 15.786 1.00 38.74 B c ATOM 1060 CB ASP 204 -10.615 -40.264 15.511 1.00 42.30 B c ATOM 1061 CG ASP 204 -11.162 -40.090 14.112 1.00 47.00 B c ATOM 1062 OD1 ASP 204 -10.783 -40.892 13.228 1.00 50.09 B 0 293 WO 2009/026558 PCT/US2008/074097 ATOM 1063 OD2 ASP 204 -11.953 -39 ATOM 1064 C ASP 204 -8.293 -39 ATOM 1065 O ASP 204 -7.862 -40 ATOM 1066 N PHE 205 -7.790 -38 ATOM 1067 CA PHE 205 -6.668 -38 ATOM 1068 CB PHE 205 -6.603 -37 ATOM 1069 CG PHE 205 -5.544 -38 ATOM 1070 CDl PHE 205 -4 .288 -37 ATOM 1071 CD2 PHE 205 -5.798 -38 ATOM 1072 CEl PHE 205 -3.303 -37 ATOM 1073 CE2 PHE 205 -4.813 -39 ATOM 1074 CZ PHE 205 -3.568 -38 ATOM 1075 C PHE 205 -5.314 -39 ATOM 1076 O PHE 205 -4.991 -38 ATOM 1077 N GLU 206 -4.515 -39 ATOM 1078 CA GLU 206 -3.160 -40 ATOM 1079 CB GLU 206 -3.156 -40 ATOM 1080 CG GLU 206 -1.784 -40 ATOM 1081 CD GLU 206 -1.797 -41 ATOM 1082 OE1 GLU 206 -1.549 -41 ATOM 1083 OE2 GLU 206 -2.063 -42 ATOM 1084 C GLU 206 -2.250 -40 ATOM 1085 0 GLU 206 -2.529 -41 ATOM 1086 N ASN 207 -1.163 -40 ATOM 1087 CA ASN 207 -0.115 -40 ATOM 1088 CB ASN 207 -0.283 -40 ATOM 1089 CG ASN 207 0.661 -41 ATOM 1090 OD1 ASN 207 0.231 -42 ATOM 1091 ND2 ASN 207 1.956 -41 ATOM 1092 C ASN 207 1.249 -40 ATOM 1093 0 ASN 207 1.760 -39 ATOM 1094 N VAL 208 1.835 -41 ATOM 1095 CA VAL 208 3.126 -40 ATOM 1096 CB VAL 208 2.987 -40 ATOM 1097 CGI VAL 208 2.211 -38 ATOM 1098 CG2 VAL 208 2.278 -41 ATOM 1099 C VAL 208 4 .127 -41 ATOM 1100 O VAL 208 3.752 -42 ATOM 1101 N PRO 209 5.418 -41 ATOM 1102 CD PRO 209 5.845 -40 ATOM 1103 CA PRO 209 6.562 -42 ATOM 1104 CB PRO 209 7.692 -41 ATOM 1105 CG PRO 209 7.339 -40 ATOM 1106 C PRO 209 6.872 -42 ATOM 1107 O PRO 209 6.671 -41 ATOM 1108 N GLU 210 7.378 -43 ATOM 1109 CA GLU 210 7.634 -44 ATOM 1110 CB GLU 210 8.115 -45 ATOM 1111 CG GLU 210 7.149 -46 ATOM 1112 CD GLU 210 7.807 -48 ATOM 1113 OE1 GLU 210 8.749 -48 ATOM 1114 OE2 GLU 210 7.390 -48 ATOM 1115 C GLU 210 8.682 -43 ATOM 1116 0 GLU 210 9.615 -42 ATOM 1117 N GLU 211 8.532 -43 ATOM 1118 CA GLU 211 9.508 -42 ATOM 1119 CB GLU 211 9.122 -42 ATOM 1120 CG GLU 211 7.641 -42 ATOM 1121 CD GLU 211 6.791 -41 ATOM 1122 OE1 GLU 211 7.332 -40 ATOM 1123 OE2 GLU 211 5.589 -41 ATOM 1124 C GLU 211 10.872 -43 ATOM 1125 0 GLU 211 10.981 -44 ATOM 1126 N ASP 212 11.907 -42 ATOM 1127 CA ASP 212 13.257 -42 ATOM 1128 CB ASP 212 13.335 -43 ATOM 1129 CG ASP 212 14.753 -43 ATOM 1130 OD1 ASP 212 15.701 -43 ATOM 1131 OD2 ASP 212 14.911 -44 ATOM 1132 C ASP 212 13.595 -43 ATOM 1133 O ASP 212 14.004 -43 ATOM 1134 N LYS 222 5.879 -33 ATOM 1135 CA LYS 222 4.625 -34 ATOM 1136 CB LYS 222 3.455 -33 ATOM 1137 CG LYS 222 3.481 -33 ATOM 1138 CD LYS 222 2.205 -33 13.891 1.00 48.97 B O 14.886 1.00 37.76 B C 14.846 1.00 38.21 B O 14.151 1.00 35.84 B N 13.249 1.00 33.48 B C 12.190 1.00 31.69 B C 11.166 1.00 31.35 B c 11.317 1.00 31.19 B c 10.051 1.00 32.23 B c 10.371 1.00 31.97 B c 9.102 1.00 32.26 B c 9.264 1.00 30.67 B c 13.959 1.00 32.69 B c 14.842 1.00 32.36 B 0 13.563 1.00 31.16 B N 14.060 1.00 30.22 B c 15.456 1.00 30.05 B c 16.058 1.00 32.36 B c 17.292 1.00 35.04 B c 18.397 1.00 38.43 B 0 17.160 1.00 34.75 B 0 13.142 1.00 28.87 B c 12.825 1.00 27.95 B 0 12.712 1.00 29.34 B N 11.966 1.00 29.09 B c 10.462 1.00 29.34 B c 9.62 0 1.00 28.97 B c 8.961 1.00 27.55 B 0 9.643 1.00 30.27 B N 12.415 1.00 28.09 B c 11.878 1.00 29.19 B 0 13.397 1.00 26.80 B N 13.925 1.00 25.13 B c 15.371 1.00 23.53 B c 15.388 1.00 22.53 B c 16.219 1.00 21.79 B c 13.892 1.00 26.28 B c 13.992 1.00 26.48 B 0 13.722 1.00 28.18 B N 13.351 1.00 29.06 B c 13.827 1.00 30.05 B c 13.190 1.00 28.79 B c 13.468 1.00 26.64 B c 15.280 1.00 33.78 B c 16.166 1.00 34.02 B 0 15.529 1.00 38.83 B N 16.899 1.00 44.60 B c 16.947 1.00 46.99 B c 16.350 1.00 52.51 B c 16.052 1.00 56.68 B c 16.791 1.00 58.71 B 0 15.077 1.00 58.58 B 0 17.531 1.00 46.80 B c 16.867 1.00 4 5.67 B 0 18.823 1.00 50.25 B N 19.545 1.00 53.81 B c 21.020 1.00 54.42 B c 21.242 1.00 56.19 B c 20.950 1.00 56.76 B c 21.041 1.00 58.23 B 0 20.631 1.00 55.21 B 0 19.410 1.00 55.25 B c 19.400 1.00 55.73 B 0 19.296 1.00 57.47 B N 19.497 1.00 59.60 B c 20.870 1.00 61.46 B c 21.348 1.00 63.54 B c 20.613 1.00 65.22 B 0 22.468 1.00 65.41 B 0 18.407 1.00 61.25 B c 17.310 1.00 62.44 B 0 27.994 1.00 46.08 B N 27.575 1.00 46.76 B c 28.341 1.00 47.87 B c 29.823 1.00 50.38 B c 30.501 1.00 52.96 B c 294 WO 2009/026558 PCT/US2008/074097 ATOM 1139 CE LYS 222 2.195 -33 ATOM 1140 NZ LYS 222 1.005 -33 ATOM 1141 C LYS 222 4.382 -34 ATOM 1142 0 LYS 222 4 . 825 -33 ATOM 1143 N CYS 223 3.64 6 -35 ATOM 1144 CA CYS 223 3.327 -35 ATOM 1145 C CYS 223 2.291 -33 ATOM 1146 0 CYS 223 2.093 -33 ATOM 1147 CB CYS 223 2.774 -36 ATOM 1148 SG CYS 223 3.674 -37 ATOM 1149 N ASP 224 1.613 -33 ATOM 1150 CA ASP 224 0.589 -32 ATOM 1151 CB ASP 224 -0.267 -32 ATOM 1152 CG ASP 224 -0.850 -33 ATOM 1153 OD1 ASP 224 -0.148 -34 ATOM 1154 OD2 ASP 224 -2.017 -33 ATOM 1155 C ASP 224 1.280 -31 ATOM 1156 O ASP 224 0.778 -30 ATOM 1157 N SER 225 2.442 -30 ATOM 1158 CA SER 225 3.169 -29 ATOM 1159 CB SER 225 4.651 -30 ATOM 1160 OG SER 225 5.418 -28 ATOM 1161 C SER 225 3.004 -28 ATOM 1162 O SER 225 2.371 -27 ATOM 1163 N HIS 226 3.576 -29 ATOM 1164 CA HIS 226 3.721 -28 ATOM 1165 CB HIS 226 4.530 -28 ATOM 1166 CG HIS 226 4.905 -28 ATOM 1167 CD2 HIS 226 5.842 -27 ATOM 1168 NDl HIS 226 4.308 -28 ATOM 1169 CEl HIS 226 4.864 -27 ATOM 1170 NE2 HIS 226 5.799 -26 ATOM 1171 C HIS 226 2.382 -27 ATOM 1172 0 HIS 226 2.193 -26 ATOM 1173 N GLY 227 1.460 -28 ATOM 1174 CA GLY 227 0.196 -28 ATOM 1175 C GLY 227 -0.772 -27 ATOM 1176 0 GLY 227 -1.589 -26 ATOM 1177 N THR 228 -0.684 -28 ATOM 1178 CA THR 228 -1.561 -27 ATOM 1179 CB THR 228 -1.394 -28 ATOM 1180 OG1 THR 228 -1.516 -29 ATOM 1181 CG2 THR 228 -2.456 -27 ATOM 1182 C THR 228 -1.233 -25 ATOM 1183 O THR 228 -2.121 -25 ATOM 1184 N HIS 229 0.050 -25 ATOM 1185 CA HIS 229 0.446 -24 ATOM 1186 CB HIS 229 1.964 -24 ATOM 1187 CG HIS 229 2.448 -22 ATOM 1188 CD2 HIS 229 2.598 -22 ATOM 1189 NDl HIS 229 2.896 -21 ATOM 1190 CEl HIS 229 3.305 -20 ATOM 1191 NE2 HIS 229 3.136 -20 ATOM 1192 C HIS 229 -0.080 -23 ATOM 1193 0 HIS 229 -0.646 -22 ATOM 1194 N LEU 230 0.096 -24 ATOM 1195 CA LEU 230 -0.314 -23 ATOM 1196 CB LEU 230 0.134 -24 ATOM 1197 CG LEU 230 1.647 -24 ATOM 1198 CDl LEU 230 1.993 -25 ATOM 1199 CD2 LEU 230 2.204 -23 ATOM 1200 C LEU 230 -1.821 -23 ATOM 1201 O LEU 230 -2.296 -22 ATOM 1202 N ALA 231 -2.569 -24 ATOM 1203 CA ALA 231 -4.026 -24 ATOM 1204 CB ALA 231 -4.618 -25 ATOM 1205 C ALA 231 -4.473 -22 ATOM 1206 0 ALA 231 -5.335 -22 ATOM 1207 N GLY 232 -3.868 -22 ATOM 1208 CA GLY 232 -4.181 -21 ATOM 1209 C GLY 232 -3.799 -20 ATOM 1210 0 GLY 232 -4.573 -19 ATOM 1211 N VAL 233 -2.609 -20 ATOM 1212 CA VAL 233 -2.169 -19 ATOM 1213 CB VAL 233 -0.805 -19 ATOM 1214 CGI VAL 233 -0.390 -17 31.954 1.00 55.83 B C 32.731 1.00 59.69 B N 26.079 1.00 45.41 B C 25.445 1.00 45.49 B O 25.540 1.00 43.53 B N 24.125 1.00 41.93 B C 23.784 1.00 40.12 B C 22.619 1.00 39.88 B 0 23.779 1.00 43.01 B c 24.630 1.00 45.72 B s 24.809 1.00 38.82 B N 24.646 1.00 36.21 B c 25.907 1.00 38.96 B c 26.351 1.00 41.36 B c 26.266 1.00 44.99 B 0 26.792 1.00 42.87 B 0 24.421 1.00 34.07 B c 23.706 1.00 32.46 B 0 25.053 1.00 31.41 B N 25.120 1.00 28.08 B c 25.351 1.00 26.55 B c 25.088 1.00 27.45 B 0 23.906 1.00 26.58 B c 23.991 1.00 25.91 B 0 22.778 1.00 25.93 B N 21.651 1.00 25.28 B c 20.541 1.00 25.17 B c 19.419 1.00 25.61 B c 19.339 1.00 25.96 B c 18.177 1.00 25.61 B N 17.380 1.00 26.84 B c 18.060 1.00 26.81 B N 21.095 1.00 24.30 B C 20.867 1.00 24.47 B 0 20.883 1.00 23.30 B N 20.251 1.00 22.28 B C 21.184 1.00 23.20 B c 20.754 1.00 23.88 B 0 22.471 1.00 23.01 B N 23.447 1.00 22.63 B c 24.842 1.00 23.38 B c 24.748 1.00 23.12 B 0 25.782 1.00 21.83 B c 23.542 1.00 22.38 B c 23.614 1.00 23.83 B 0 23.534 1.00 22.67 B N 23.574 1.00 22.18 B c 23.632 1.00 22.78 B c 24.041 1.00 23.95 B c 25.264 1.00 23.15 B c 23.132 1.00 23.61 B N 23.778 1.00 23.68 B c 25.074 1.00 23.94 B N 22.321 1.00 21.39 B C 22.381 1.00 20.56 B 0 21.184 1.00 20.66 B N 19.919 1.00 21.11 B C 18.764 1.00 21.06 B c 18.592 1.00 22.74 B c 17.359 1.00 21.39 B c 18.478 1.00 23.15 B c 19.858 1.00 21.39 B c 19.304 1.00 21.76 B 0 20.431 1.00 21.33 B N 20.417 1.00 21.00 B c 21.138 1.00 18.46 B c 21.090 1.00 22.12 B c 20.572 1.00 21.92 B 0 22.240 1.00 22.96 B N 22.965 1.00 24.03 B c 22.207 1.00 24.50 B c 22.132 1.00 25.89 B 0 21.628 1.00 25.98 B N 20.908 1.00 26.71 B c 20.252 1.00 25.92 B c 19.531 1.00 25.35 B c 295 WO 2009/026558 PCT/US2008/074097 ATOM 1215 CG2 VAL 233 0.215 -19 ATOM 1216 C VAL 233 -3.171 -18 ATOM 1217 O VAL 233 -3.284 -17 ATOM 1218 N VAL 234 -3.906 -19 ATOM 1219 CA VAL 234 -4.922 -19 ATOM 1220 CB VAL 234 -5.133 -20 ATOM 1221 CGI VAL 234 -6.540 -20 ATOM 1222 CG2 VAL 234 -4.135 -20 ATOM 1223 C VAL 234 -6.281 -19 ATOM 1224 O VAL 234 -6.833 -18 ATOM 1225 N SER 235 -6.819 -19 ATOM 1226 CA SER 235 -8.194 -19 ATOM 1227 CB SER 235 -9.046 -20 ATOM 1228 OG SER 235 -8.946 -21 ATOM 1229 C SER 235 -8.354 -19 ATOM 1230 O SER 235 -9.471 -19 ATOM 1231 N GLY 236 -7.243 -19 ATOM 1232 CA GLY 236 -7.295 -19 ATOM 1233 C GLY 236 -8.147 -18 ATOM 1234 0 GLY 236 -8.256 -17 ATOM 1235 N ARG 237 -8.749 -18 ATOM 1236 CA ARG 237 -9.678 -17 ATOM 1237 CB ARG 237 -10.412 -18 ATOM 1238 CG ARG 237 -11.558 -19 ATOM 1239 CD ARG 237 -11.972 -20 ATOM 1240 NE ARG 237 -13.193 -2 0 ATOM 1241 CZ ARG 237 -13.224 -22 ATOM 1242 NH1 ARG 237 -14.395 -22 ATOM 1243 NH2 ARG 237 -12.093 -22 ATOM 1244 C ARG 237 -9.021 -16 ATOM 1245 O ARG 237 -9.582 -15 ATOM 1246 N ASP 238 -7.838 -16 ATOM 1247 CA ASP 238 -7.118 -15 ATOM 1248 CB ASP 238 -6.617 -15 ATOM 1249 CG ASP 238 -7.733 -16 ATOM 1250 OD1 ASP 238 -8.918 -15 ATOM 1251 OD2 ASP 238 -7.429 -16 ATOM 1252 C ASP 238 -5.935 -15 ATOM 1253 O ASP 238 -5.566 -13 ATOM 1254 N ALA 239 -5.342 -15 ATOM 1255 CA ALA 239 -4.086 -15 ATOM 1256 CB ALA 239 -3.024 -16 ATOM 1257 C ALA 239 -4.251 -15 ATOM 1258 0 ALA 239 -3.298 -15 ATOM 1259 N GLY 240 -5.462 -16 ATOM 1260 CA GLY 240 -5.670 -16 ATOM 1261 C GLY 240 -5.746 -15 ATOM 1262 0 GLY 240 -5.981 -14 ATOM 1263 N VAL 241 -5.539 -15 ATOM 1264 CA VAL 241 -5.801 -14 ATOM 1265 CB VAL 241 -4.887 -14 ATOM 1266 CGI VAL 241 -5.211 -13 ATOM 1267 CG2 VAL 241 -3.441 -14 ATOM 1268 C VAL 241 -7.261 -14 ATOM 1269 O VAL 241 -8.006 -13 ATOM 1270 N ALA 242 -7.670 -15 ATOM 1271 CA ALA 242 -9.018 -15 ATOM 1272 CB ALA 242 -8.964 -16 ATOM 1273 C ALA 242 -9.921 -16 ATOM 1274 0 ALA 242 -10.393 -17 ATOM 1275 N LYS 243 -10.159 -15 ATOM 1276 CA LYS 243 -11.157 -16 ATOM 1277 CB LYS 243 -11.445 -15 ATOM 1278 CG LYS 243 -10.347 -14 ATOM 1279 CD LYS 243 -9.612 -14 ATOM 1280 CE LYS 243 -8.704 -13 ATOM 1281 NZ LYS 243 -8.473 -13 ATOM 1282 C LYS 243 -12.415 -16 ATOM 1283 0 LYS 243 -12.645 -16 ATOM 1284 N GLY 244 -13.220 -17 ATOM 1285 CA GLY 244 -14.451 -17 ATOM 1286 C GLY 244 -14.296 -18 ATOM 1287 0 GLY 244 -15.258 -19 ATOM 1288 N ALA 245 -13.100 -18 ATOM 1289 CA ALA 245 -12.768 -19 ATOM 1290 CB ALA 245 -11.446 -19 21.294 1.00 25.45 B C 19.823 1.00 28.02 B C 19.424 1.00 29.94 B 0 19.349 1.00 29.13 B N 18.320 1.00 28.46 B c 17.455 1.00 29.28 B c 16.905 1.00 29.41 B c 16.310 1.00 30.36 B c 18.854 1.00 26.66 B c 18.425 1.00 26.52 B 0 19.781 1.00 25.95 B N 20.222 1.00 2 6.62 B c 19.740 1.00 27.81 B c 20.639 1.00 30.51 B 0 21.735 1.00 26.18 B c 22.230 1.00 25.76 B 0 22.464 1.00 26.66 B N 23.917 1.00 26.34 B c 24.488 1.00 27.10 B c 23.899 1.00 26.56 B 0 25.646 1.00 27.20 B N 26.258 1.00 28.66 B c 27.422 1.00 31.42 B c 26.990 1.00 36.85 B c 28.086 1.00 41.17 B c 27.729 1.00 46.01 B N 27.114 1.00 48.46 B c 26.833 1.00 49.07 B N 26.784 1.00 48.35 B N 26.748 1.00 27.85 B C 26.603 1.00 26.35 B 0 27.334 1.00 28.76 B N 27.861 1.00 30.27 B C 29.280 1.00 33.62 B c 30.216 1.00 37.65 B c 29.852 1.00 39.82 B 0 31.316 1.00 37.81 B 0 26.978 1.00 29.53 B c 26.902 1.00 29.35 B 0 26.311 1.00 30.01 B N 25.601 1.00 29.41 B c 26.132 1.00 27.71 B c 24.098 1.00 29.33 B c 23.342 1.00 29.65 B 0 23.663 1.00 30.49 B N 22.258 1.00 29.73 B c 21.434 1.00 29.50 B c 21.967 1.00 28.77 B 0 20.129 1.00 29.66 B N 19.165 1.00 29.00 B c 17.934 1.00 27.73 B c 16.912 1.00 27.00 B c 18.359 1.00 27.06 B c 18.703 1.00 29.65 B c 18.869 1.00 30.73 B 0 18.130 1.00 29.93 B N 17.580 1.00 29.53 B c 16.220 1.00 28.85 B c 18.515 1.00 28.85 B c 18.176 1.00 28.12 B 0 19.696 1.00 29.26 B N 20.582 1.00 29.82 B c 21.697 1.00 28.15 B c 21.869 1.00 26.26 B c 23.175 1.00 26.89 B c 23.508 1.00 26.93 B c 24.973 1.00 26.14 B N 19.747 1.00 31.25 B c 18.750 1.00 33.02 B 0 20.123 1.00 31.12 B N 19.385 1.00 31.63 B c 18.025 1.00 31.24 B c 17.487 1.00 31.27 B 0 17.456 1.00 31.32 B N 16.366 1.00 32.05 B c 15.757 1.00 31.24 B c 296 WO 2009/026558 PCT/US2008/074097 ATOM 1291 c ALA 245 -12.683 -2 0 ATOM 1292 0 ALA 245 -12.548 -21 ATOM 1293 N SER 246 -12.764 -21 ATOM 1294 CA SER 246 -12.791 -23 ATOM 1295 CB SER 246 -14.207 -23 ATOM 1296 OG SER 246 -15.062 -23 ATOM 1297 C SER 246 -11.821 -24 ATOM 1298 O SER 246 -11.525 -24 ATOM 1299 N MET 247 -11.334 -25 ATOM 1300 CA MET 247 -10.205 -25 ATOM 1301 CB MET 247 -9.026 -25 ATOM 1302 CG MET 247 -8.439 -24 ATOM 1303 SD MET 247 -7.185 -2 3 ATOM 1304 CE MET 247 -5.832 -24 ATOM 1305 C MET 247 -10.499 -27 ATOM 1306 0 MET 247 -11.242 -28 ATOM 1307 N ARG 248 -9.909 -28 ATOM 1308 CA ARG 248 -9.950 -29 ATOM 1309 CB ARG 248 -10.815 -29 ATOM 1310 CG ARG 248 -11.884 -28 ATOM 1311 CD ARG 248 -12.886 -29 ATOM 1312 NE ARG 248 -13.589 -30 ATOM 1313 CZ ARG 248 -14.713 -30 ATOM 1314 NHl ARG 248 -15.285 -31 ATOM 1315 NH2 ARG 248 -15.268 -29 ATOM 1316 C ARG 248 -8.526 -30 ATOM 1317 O ARG 248 -7.850 -29 ATOM 1318 N SER 249 -8.083 -30 ATOM 1319 CA SER 249 -6.694 -31 ATOM 1320 CB SER 249 -6.250 -31 ATOM 1321 OG SER 249 -5.681 -32 ATOM 1322 C SER 249 -6.420 -32 ATOM 1323 O SER 249 -7.102 -33 ATOM 1324 N LEU 250 -5.415 -32 ATOM 1325 CA LEU 250 -4.862 -34 ATOM 1326 CB LEU 250 -4.708 -34 ATOM 1327 CG LEU 250 -5.964 -34 ATOM 1328 CDl LEU 250 -6.634 -32 ATOM 1329 CD2 LEU 250 -5.574 -34 ATOM 1330 C LEU 250 -3.493 -34 ATOM 1331 O LEU 250 -2.813 -33 ATOM 1332 N ARG 251 -3.091 -35 ATOM 1333 CA ARG 251 -1.769 -35 ATOM 1334 CB ARG 251 -1.859 -36 ATOM 1335 CG ARG 251 -0.487 -37 ATOM 1336 CD ARG 251 -0.542 -37 ATOM 1337 NE ARG 251 0.709 -37 ATOM 1338 CZ ARG 251 1.351 -39 ATOM 1339 NHl ARG 251 0.863 -40 ATOM 1340 NH2 ARG 251 2.477 -38 ATOM 1341 C ARG 251 -0.812 -36 ATOM 1342 O ARG 251 -0.951 -37 ATOM 1343 N VAL 252 0.174 -35 ATOM 1344 CA VAL 252 1. 136 -35 ATOM 1345 CB VAL 252 1.134 -35 ATOM 1346 CGI VAL 252 -0.182 -35 ATOM 1347 CG2 VAL 252 1.350 -33 ATOM 1348 C VAL 252 2.546 -36 ATOM 1349 O VAL 252 3.447 -36 ATOM 1350 N LEU 253 2.720 -35 ATOM 1351 CA LEU 253 4.006 -35 ATOM 1352 CB LEU 253 4.361 -33 ATOM 1353 CG LEU 253 4.361 -32 ATOM 1354 CDl LEU 253 4.645 -31 ATOM 1355 CD2 LEU 253 5.408 -33 ATOM 1356 C LEU 253 3.950 -36 ATOM 1357 O LEU 253 3.063 -36 ATOM 1358 N ASN 254 4.907 -37 ATOM 1359 CA ASN 254 4.999 -37 ATOM 1360 CB ASN 254 5.988 -39 ATOM 1361 CG ASN 254 7.439 -38 ATOM 1362 OD1 ASN 254 7.727 -37 ATOM 1363 ND2 ASN 254 8.358 -39 ATOM 1364 C ASN 254 5.414 -37 ATOM 1365 0 ASN 254 5.418 -35 ATOM 1366 N CYS 255 5.756 -37
16.956 1.00 32.80 B C 18.170 1.00 33.98 B O 16.111 1.00 33.54 B N 16.625 1.00 34.92 B C 16.536 1.00 36.59 B C 17.353 1.00 39.79 B 0 15.951 1.00 34.43 B c 14.768 1.00 34.27 B 0 16.719 1.00 34.89 B N 16.292 1.00 35.66 B c 17.237 1.00 38.44 B c 17.103 1.00 41.75 B c 18.326 1.00 45.85 B s 17.796 1.00 44.65 B c 16.194 1.00 35.05 B c 16.995 1.00 34.54 B 0 15.190 1.00 34.28 B N 15.083 1.00 33.81 B c 13.897 1.00 35.62 B c 13.551 1.00 38.31 B c 12.566 1.00 40.68 B c 13.149 1.00 44.00 B N 13.849 1.00 45.66 B c 14.351 1.00 46.06 B N 14.041 1.00 46.30 B N 14.905 1.00 32.41 B C 13.928 1.00 32.44 B 0 15.857 1.00 29.90 B N 15.930 1.00 27.61 B C 17.393 1.00 27.24 B c 17.811 1.00 27.75 B 0 15.330 1.00 26.69 B c 15.649 1.00 27.35 B 0 14 . 462 1.00 25.20 B N 14.044 1.00 24.40 B c 12.521 1.00 25.99 B c 11.643 1.00 25.42 B c 11.736 1.00 25.61 B c 10.205 1.00 25.09 B c 14.691 1.00 23.33 B c 15.010 1.00 23.67 B 0 14.891 1.00 22.89 B N 15.438 1.00 22.61 B c 16.630 1.00 21.26 B c 17.209 1.00 23.82 B c 18.419 1.00 26.20 B c 19.182 1.00 26.31 B N 19.585 1.00 25.27 B c 19.299 1.00 24.93 B N 20.275 1.00 25.73 B N 14.406 1.00 23.38 B C 13.993 1.00 23.07 B 0 14.002 1.00 23.27 B N 12.999 1.00 24.29 B C 11.791 1.00 24.61 B c 11.053 1.00 24.12 B c 12.261 1.00 25.97 B c 13.570 1.00 24.19 B c 12.959 1.00 25.34 B 0 14.744 1.00 24.84 B N 15.430 1.00 24.76 B c 15.776 1.00 23.72 B c 14.625 1.00 22.29 B c 15.154 1.00 21.59 B c 13.607 1.00 22.92 B c 16.714 1.00 26.34 B c 17.551 1.00 26.64 B 0 16.870 1.00 27.39 B N 18.066 1.00 27.84 B c 17.832 1.00 28.42 B c 17.836 1.00 28.34 B c 17.881 1.00 28.47 B 0 17.788 1.00 28.22 B N 19.306 1.00 28.27 B c 19.295 1.00 28.25 B 0 20.376 1.00 28.16 B N 297 WO 2009/026558 PCT/US2008/074097 ATOM 1367 CA CYS 255 6.024 -37 ATOM 1368 C CYS 255 7.325 -36 ATOM 1369 0 CYS 255 7.62 6 -35 ATOM 1370 CB CYS 255 6.045 -38 ATOM 1371 SG CYS 255 4.407 -38 ATOM 1372 N GLN 256 8.111 -36 ATOM 1373 CA GLN 256 9.348 -35 ATOM 1374 CB GLN 256 10.503 -36 ATOM 1375 CG GLN 256 10.613 -37 ATOM 1376 CD GLN 256 11.095 -39 ATOM 1377 OE1 GLN 256 11.508 -39 ATOM 1378 NE2 GLN 256 11.045 -40 ATOM 1379 C GLN 256 9.337 -34 ATOM 1380 0 GLN 256 10.385 -34 ATOM 1381 N GLY 257 8.139 -34 ATOM 1382 CA GLY 257 8.004 -33 ATOM 1383 C GLY 257 8.241 -33 ATOM 1384 0 GLY 257 8.408 -33 ATOM 1385 N LYS 258 8.248 -35 ATOM 1386 CA LYS 258 8.682 -35 ATOM 1387 CB LYS 258 9.762 -36 ATOM 1388 CG LYS 258 10.399 -37 ATOM 1389 CD LYS 258 11.905 -37 ATOM 1390 CE LYS 258 12.624 -38 ATOM 1391 NZ LYS 258 14.066 -38 ATOM 1392 C LYS 258 7.536 -36 ATOM 1393 0 LYS 258 6.699 -37 ATOM 1394 N GLY 259 7.504 -36 ATOM 1395 CA GLY 259 6.571 -36 ATOM 1396 C GLY 259 7.238 -37 ATOM 1397 0 GLY 259 8.467 -37 ATOM 1398 N THR 260 6.435 -37 ATOM 1399 CA THR 260 6.966 -37 ATOM 1400 CB THR 260 6.869 -39 ATOM 1401 OG1 THR 260 5.496 -39 ATOM 1402 CG2 THR 260 7.622 -40 ATOM 1403 C THR 260 6.203 -37 ATOM 1404 O THR 260 5.080 -36 ATOM 1405 N VAL 261 6.811 -37 ATOM 1406 CA VAL 261 6.173 -36 ATOM 1407 CB VAL 261 7.091 -36 ATOM 1408 CGI VAL 261 6.402 -35 ATOM 1409 CG2 VAL 261 8.388 -35 ATOM 1410 C VAL 261 4.872 -36 ATOM 1411 O VAL 261 3.850 -36 ATOM 1412 N SER 2 62 4.911 -38 ATOM 1413 CA SER 2 62 3.757 -39 ATOM 1414 CB SER 2 62 4 . 165 -40 ATOM 1415 OG SER 2 62 4.955 -40 ATOM 1416 C SER 2 62 2.605 -38 ATOM 1417 O SER 2 62 1.457 -38 ATOM 1418 N GLY 263 2.916 -39 ATOM 1419 CA GLY 263 1.909 -38 ATOM 1420 C GLY 263 1.256 -37 ATOM 1421 0 GLY 263 0.063 -37 ATOM 1422 N THR 264 2.039 -36 ATOM 1423 CA THR 264 1.527 -35 ATOM 1424 CB THR 264 2.644 -34 ATOM 1425 OG1 THR 264 3.532 -34 ATOM 1426 CG2 THR 264 2.074 -32 ATOM 1427 C THR 264 0.585 -35 ATOM 1428 O THR 264 -0.547 -34 ATOM 1429 N LEU 265 1.058 -35 ATOM 1430 CA LEU 265 0.233 -35 ATOM 1431 CB LEU 265 0.904 -36 ATOM 1432 CG LEU 265 2.200 -36 ATOM 1433 CDl LEU 265 2.879 -37 ATOM 1434 CD2 LEU 265 1.898 -35 ATOM 1435 C LEU 265 -1.135 -36 ATOM 1436 O LEU 265 -2.159 -35 ATOM 1437 N ILE 266 -1.136 -37 ATOM 1438 CA ILE 266 -2.355 -38 ATOM 1439 CB ILE 266 -2.002 -39 ATOM 1440 CG2 ILE 266 -3.251 -40 ATOM 1441 CGI ILE 266 -1.151 -40 ATOM 1442 CDl ILE 266 -0.945 -41 21.655 1.00 28.63 B C 21.675 1.00 26.69 B C 22.645 1.00 27.25 B 0 22.781 1.00 32.30 B c 23.137 1.00 43.56 B s 20.617 1.00 24.58 B N 20.520 1.00 21.14 B c 20.406 1.00 21.92 B c 21.623 1.00 24.98 B c 21.295 1.00 28.39 B c 20.165 1.00 30.69 B 0 22.283 1.00 30.25 B N 19.357 1.00 20.02 B c 18.843 1.00 19.29 B 0 18.950 1.00 19.22 B N 17.957 1.00 19.26 B c 16.542 1.00 19.45 B c 15.619 1.00 18.96 B 0 16.370 1.00 20.81 B N 15.123 1.00 21.90 B c 15.415 1.00 21.99 B c 14.179 1.00 27.25 B c 14.196 1.00 30.54 B c 13.536 1.00 34.07 B c 13.269 1.00 37.21 B N 14.353 1.00 21.86 B c 14.923 1.00 23.60 B 0 13.050 1.00 22.07 B N 12.178 1.00 22.34 B c 10.862 1.00 22.86 B c 10.747 1.00 23.37 B 0 9.866 1.00 21.84 B N 8.548 1.00 21.86 B c 8.253 1.00 20.56 B c 8.248 1.00 19.54 B 0 9.309 1.00 19.92 B c 7.475 1.00 22.65 B c 7.704 1.00 24.48 B 0 6.306 1.00 22.69 B N 5.247 1.00 21.49 B c 4 .018 1.00 20.59 B c 2.919 1.00 19.43 B c 4 .408 1.00 19.44 B c 4.860 1.00 21.94 B c 4.624 1.00 22.12 B 0 4.830 1.00 22.53 B N 4 . 428 1.00 22.26 B c 4.284 1.00 22.47 B c 5.390 1.00 25.99 B 0 5.414 1.00 21.68 B c 5.009 1.00 22.09 B 0 6.702 1.00 21.45 B N 7.724 1.00 21.21 B c 7.567 1.00 22.43 B c 7.845 1.00 21.36 B 0 7.103 1.00 22.11 B N 6.887 1.00 21.72 B c 6.597 1.00 21.29 B c 7.715 1.00 20.27 B 0 6.348 1.00 21.16 B c 5.701 1.00 23.10 B c 5.796 1.00 25.02 B 0 4.584 1.00 23.29 B N 3.388 1.00 21.86 B c 2.412 1.00 20.38 B c 1.805 1.00 20.98 B c 1.015 1.00 20.52 B c 0.919 1.00 19.35 B c 3.745 1.00 21.27 B c 3.361 1.00 23.43 B 0 4 . 485 1.00 19.76 B N 4.838 1.00 18.31 B c 5.543 1.00 16.80 B c 5.957 1.00 13.78 B c 4.603 1.00 14 . 04 B c 5.071 1.00 14.81 B c 298 WO 2009/026558 PCT/US2008/074097 ATOM 1443 c ILE 266 -3.219 -37 ATOM 1444 0 ILE 266 -4.454 -37 ATOM 1445 N GLY 267 -2.560 -36 ATOM 1446 CA GLY 2 67 -3.283 -35 ATOM 1447 C GLY 2 67 -4.098 -34 ATOM 1448 0 GLY 2 67 -5.301 -34 ATOM 1449 N LEU 268 -3.444 -34 ATOM 1450 CA LEU 268 -4.124 -33 ATOM 1451 CB LEU 268 -3.108 -32 ATOM 1452 CG LEU 268 -1.978 -31 ATOM 1453 CDl LEU 268 -1.029 -31 ATOM 1454 CD2 LEU 268 -2.550 -30 ATOM 1455 C LEU 268 -5.214 -33 ATOM 1456 O LEU 268 -6.269 -33 ATOM 1457 N GLU 269 -4.983 -35 ATOM 1458 CA GLU 269 -6.009 -35 ATOM 1459 CB GLU 269 -5.553 -37 ATOM 1460 CG GLU 269 -6.368 -38 ATOM 1461 CD GLU 269 -6.354 -39 ATOM 1462 OE1 GLU 269 -5.320 -40 ATOM 1463 OE2 GLU 269 -7.382 -40 ATOM 1464 C GLU 269 -7.250 -35 ATOM 1465 O GLU 269 -8.365 -35 ATOM 1466 N PHE 270 -7.032 -36 ATOM 1467 CA PHE 270 -8.100 -36 ATOM 1468 CB PHE 270 -7.495 -36 ATOM 1469 CG PHE 270 -8.467 -36 ATOM 1470 CDl PHE 270 -8.923 -38 ATOM 1471 CD2 PHE 270 -8.884 -35 ATOM 1472 CEl PHE 270 -9.774 -38 ATOM 1473 CE2 PHE 270 -9.728 -35 ATOM 1474 CZ PHE 270 -10.176 -36 ATOM 1475 C PHE 270 -8.860 -35 ATOM 1476 O PHE 270 -10.089 -35 ATOM 1477 N ILE 271 -8.125 -34 ATOM 1478 CA ILE 271 -8.743 -32 ATOM 1479 CB ILE 271 -7.686 -31 ATOM 1480 CG2 ILE 271 -8.346 -30 ATOM 1481 CGI ILE 271 -6.715 -31 ATOM 1482 CDl ILE 271 -5.899 -30 ATOM 1483 C ILE 271 -9.697 -32 ATOM 1484 0 ILE 271 -10.801 -31 ATOM 1485 N ARG 272 -9.276 -32 ATOM 1486 CA ARG 272 -10.058 -32 ATOM 1487 CB ARG 272 -9.167 -32 ATOM 1488 CG ARG 272 -9.870 -32 ATOM 1489 CD ARG 272 -10.647 -31 ATOM 1490 NE ARG 272 -10.958 -30 ATOM 1491 CZ ARG 272 -11.694 -30 ATOM 1492 NH1 ARG 272 -11.920 -29 ATOM 1493 NH2 ARG 272 -12.217 -29 ATOM 1494 C ARG 272 -11.332 -33 ATOM 1495 O ARG 272 -12.411 -32 ATOM 1496 N LYS 273 -11.213 -34 ATOM 1497 CA LYS 273 -12.380 -35 ATOM 1498 CB LYS 273 -11.971 -36 ATOM 1499 CG LYS 273 -13.115 -37 ATOM 1500 CD LYS 273 -13.108 -37 ATOM 1501 CE LYS 273 -14.534 -37 ATOM 1502 NZ LYS 273 -14.605 -37 ATOM 1503 C LYS 273 -13.424 -34 ATOM 1504 0 LYS 273 -14.622 -34 ATOM 1505 N SER 274 -12.970 -34 ATOM 1506 CA SER 274 -13.879 -34 ATOM 1507 CB SER 274 -13.089 -33 ATOM 1508 OG SER 274 -12.088 -34 ATOM 1509 C SER 274 -14.713 -32 ATOM 1510 O SER 274 -15.902 -32 ATOM 1511 N GLN 275 -14.068 -32 ATOM 1512 CA GLN 275 -14.668 -30 ATOM 1513 CB GLN 275 -13.566 -29 ATOM 1514 CG GLN 275 -14.035 -28 ATOM 1515 CD GLN 275 -13.215 -2 8 ATOM 1516 OE1 GLN 275 -12.708 -29 ATOM 1517 NE2 GLN 275 -13.057 -26 ATOM 1518 C GLN 275 -15.632 -31 5.746 1.00 20.40 B C 5.703 1.00 20.07 B O 6.560 1.00 21.94 B N 7.393 1.00 21.97 B C 6.520 1.00 22.46 B C 6.717 1.00 23.67 B 0 5.538 1.00 21.50 B N 4.639 1.00 21.24 B c 3.697 1.00 21.08 B c 4.354 1.00 20.19 B c 3.291 1.00 20.01 B c 5.130 1.00 19.67 B c 3.841 1.00 22.54 B c 3.558 1.00 24.32 B 0 3.488 1.00 21.86 B N 2.778 1.00 21.18 B c 2.519 1.00 22.31 B c 1.431 1.00 24.62 B c 1.562 1.00 25.91 B c 1.966 1.00 27.02 B 0 1.257 1.00 27.61 B 0 3.650 1.00 20.82 B c 3.209 1.00 21.02 B 0 4.906 1.00 19.63 B N 5.881 1.00 17.51 B c 7.220 1.00 16.07 B c 8.342 1.00 15.79 B c 8.844 1.00 16.82 B c 8.940 1.00 16.62 B c 9.933 1.00 17.22 B c 10.023 1.00 17.59 B c 10.523 1.00 18.31 B c 5.997 1.00 16.78 B c 6.065 1.00 17.12 B 0 6.008 1.00 15.76 B N 6.185 1.00 16.00 B c 6.253 1.00 16.26 B c 6.509 1.00 15.52 B c 7.390 1.00 16.87 B c 7.767 1.00 16.57 B c 5.039 1.00 16.31 B c 5.247 1.00 18.27 B 0 3.825 1.00 15.58 B N 2.657 1.00 14.76 B c 1.425 1.00 13.53 B c 0.112 1.00 14.31 B c -0.054 1.00 14.45 B c -1.464 1.00 18.03 B N -1.939 1.00 17.53 B c -3.237 1.00 18.77 B N -1.117 1.00 17.11 B N 2.569 1.00 14.98 B C 2.240 1.00 13.74 B 0 2.898 1.00 16.77 B N 2.914 1.00 19.15 B C 3.234 1.00 19.12 B c 3.711 1.00 21.09 B c 5.246 1.00 28.83 B c 5.868 1.00 32.67 B c 7.263 1.00 30.13 B N 3.924 1.00 20.09 B c 3.639 1.00 20.19 B 0 5.104 1.00 20.81 B N 6.166 1.00 21.13 B c 7.385 1.00 20.17 B c 7.707 1.00 21.58 B 0 5.648 1.00 20.96 B c 5.927 1.00 22.15 B 0 4 . 867 1.00 20.71 B N 4 . 471 1.00 20.82 B c 4.085 1.00 19.43 B c 3.568 1.00 18.84 B c 2.389 1.00 19.76 B c 1.681 1.00 22.34 B 0 2.163 1.00 18.84 B N 3.320 1.00 21.36 B c 299 WO 2009/026558 PCT/US2008/074097 ATOM 1519 0 GLN 275 -16.578 -30 ATOM 1520 N LEU 276 -15.393 -32 ATOM 1521 CA LEU 276 -16.293 -32 ATOM 1522 CB LEU 276 -15.569 -33 ATOM 1523 CG LEU 276 -14.412 -32 ATOM 1524 CDl LEU 276 -13.352 -33 ATOM 1525 CD2 LEU 276 -14.946 -31 ATOM 1526 C LEU 276 -17.540 -33 ATOM 1527 O LEU 276 -18.622 -33 ATOM 1528 N VAL 277 -17.378 -33 ATOM 1529 CA VAL 277 -18.449 -34 ATOM 1530 CB VAL 277 -17.867 -35 ATOM 1531 CGI VAL 277 -18.977 -36 ATOM 1532 CG2 VAL 277 -16.941 -36 ATOM 1533 C VAL 277 -19.370 -33 ATOM 1534 O VAL 277 -20.541 -34 ATOM 1535 N GLN 278 -18.826 -32 ATOM 1536 CA GLN 278 -19.583 -31 ATOM 1537 CB GLN 278 -19.440 -32 ATOM 1538 CG GLN 278 -20.458 -33 ATOM 1539 CD GLN 278 -21.228 -32 ATOM 1540 OE1 GLN 278 -20.635 -32 ATOM 1541 NE2 GLN 278 -22.562 -32 ATOM 1542 C GLN 278 -19.108 -30 ATOM 1543 0 GLN 278 -18.602 -29 ATOM 1544 N PRO 279 -19.272 -29 ATOM 1545 CD PRO 279 -20.021 -30 ATOM 1546 CA PRO 279 -18.773 -28 ATOM 1547 CB PRO 279 -19.302 -28 ATOM 1548 CG PRO 279 -20.342 -29 ATOM 1549 C PRO 279 -19.239 -27 ATOM 1550 O PRO 279 -20.374 -27 ATOM 1551 N VAL 280 -18.336 -26 ATOM 1552 CA VAL 280 -18.598 -25 ATOM 1553 CB VAL 280 -17.728 -25 ATOM 1554 CGI VAL 280 -18.175 -27 ATOM 1555 CG2 VAL 280 -16.267 -25 ATOM 1556 C VAL 280 -18.283 -24 ATOM 1557 O VAL 280 -18.635 -23 ATOM 1558 N GLY 281 -17.613 -23 ATOM 1559 CA GLY 281 -17.163 -22 ATOM 1560 C GLY 281 -15.768 -22 ATOM 1561 0 GLY 281 -15.317 -23 ATOM 1562 N PRO 282 -15.059 -21 ATOM 1563 CD PRO 282 -15.556 -19 ATOM 1564 CA PRO 282 -13.654 -21 ATOM 1565 CB PRO 282 -13.274 -19 ATOM 1566 CG PRO 282 -14.564 -18 ATOM 1567 C PRO 282 -12.796 -21 ATOM 1568 O PRO 282 -13.047 -21 ATOM 1569 N LEU 283 -11.792 -22 ATOM 1570 CA LEU 283 -10.926 -23 ATOM 1571 CB LEU 283 -10.884 -24 ATOM 1572 CG LEU 283 -12.166 -25 ATOM 1573 CDl LEU 283 -11.845 -27 ATOM 1574 CD2 LEU 283 -12.784 -25 ATOM 1575 C LEU 283 -9.512 -22 ATOM 1576 O LEU 283 -8.999 -22 ATOM 1577 N VAL 284 -8.881 -22 ATOM 1578 CA VAL 284 -7.471 -22 ATOM 1579 CB VAL 284 -7.271 -21 ATOM 1580 CGI VAL 284 -5.794 -21 ATOM 1581 CG2 VAL 284 -7.825 -20 ATOM 1582 C VAL 284 -6.679 -23 ATOM 1583 O VAL 284 -6.957 -24 ATOM 1584 N VAL 285 -5.696 -2 4 ATOM 1585 CA VAL 285 -4.803 -25 ATOM 1586 CB VAL 285 -4.470 -26 ATOM 1587 CGI VAL 285 -3.716 -27 ATOM 1588 CG2 VAL 285 -5.747 -26 ATOM 1589 C VAL 285 -3.506 -24 ATOM 1590 O VAL 285 -2.849 -23 ATOM 1591 N LEU 286 -3.161 -25 ATOM 1592 CA LEU 286 -1.912 -24 ATOM 1593 CB LEU 286 -2.150 -24 ATOM 1594 CG LEU 286 -0.864 -23 3.144 1.00 21.85 B O 2.542 1.00 21.35 B N 1.458 1.00 21.46 B C 0.468 1.00 20.85 B C -0.222 1.00 21.54 B c -0.648 1.00 21.26 B c -1.410 1.00 18.00 B c 1.994 1.00 22.78 B c 1.406 1.00 23.18 B 0 3.119 1.00 23.69 B N 3.719 1.00 23.85 B c 4.570 1.00 21.82 B c 5.132 1.00 21.54 B c 3.735 1.00 22.34 B c 4.596 1.00 25.25 B c 4 . 804 1.00 25.41 B 0 5.115 1.00 26.20 B N 5.960 1.00 26.06 B c 7.414 1.00 28.61 B c 7.843 1.00 35.11 B c 9.047 1.00 39.20 B c 10.033 1.00 40.40 B 0 8.980 1.00 41.21 B N 5.791 1.00 25.07 B c 6.729 1.00 25.51 B 0 4.586 1.00 24.43 B N 3.449 1.00 22.73 B c 4.320 1.00 23.37 B c 2.922 1.00 21.77 B c 2.644 1.00 22.09 B c 5.362 1.00 22.65 B c 5.820 1.00 23.20 B 0 5.742 1.00 23.67 B N 6.768 1.00 22.67 B c 8.019 1.00 22.17 B c 8.729 1.00 20.68 B c 7.607 1.00 23.06 B c 6.220 1.00 22.17 B c 5.088 1.00 20.16 B 0 7.032 1.00 23.75 B N 6.570 1.00 24.31 B c 5.984 1.00 24.09 B c 5.636 1.00 24.64 B 0 5.865 1.00 24.04 B N 6.123 1.00 24.55 B c 5.451 1.00 24.01 B c 5.493 1.00 24.10 B c 5.411 1.00 23.06 B c 6.409 1.00 24.43 B c 7.617 1.00 24.10 B 0 5.863 1.00 24.32 B N 6.651 1.00 23.30 B c 6.057 1.00 22.99 B c 6.083 1.00 23.79 B c 5.708 1.00 24.80 B c 7.465 1.00 25.21 B c 6.687 1.00 22.69 B c 5.679 1.00 23.60 B 0 7.851 1.00 22.49 B N 7.973 1.00 21.61 B c 8.918 1.00 21.87 B c 9.247 1.00 20.77 B c 8.268 1.00 20.07 B c 8.496 1.00 20.93 B c 9.573 1.00 20.79 B 0 7.718 1.00 21.45 B N 8.175 1.00 21.67 B c 7.049 1.00 23.02 B c 7.613 1.00 22.15 B c 6.363 1.00 24.14 B c 8.687 1.00 20.61 B c 7.986 1.00 18.40 B 0 9.924 1.00 20.05 B N 10.535 1.00 20.46 B c 11.973 1.00 21.88 B c 12.738 1.00 22.20 B c 300 WO 2009/026558 PCT/US2008/074097 ATOM 1595 CDl LEU 286 -0.189 -22 ATOM 1596 CD2 LEU 286 -1.201 -23 ATOM 1597 C LEU 286 -0.892 -25 ATOM 1598 O LEU 286 -1.162 -2 6 ATOM 1599 N LEU 287 0.286 -25 ATOM 1600 CA LEU 287 1.346 -26 ATOM 1601 CB LEU 287 1.646 -26 ATOM 1602 CG LEU 287 0.453 -27 ATOM 1603 CDl LEU 287 0.647 -27 ATOM 1604 CD2 LEU 287 0.292 -28 ATOM 1605 C LEU 287 2.616 -26 ATOM 1606 O LEU 287 3.545 -25 ATOM 1607 N PRO 288 2.657 -26 ATOM 1608 CD PRO 288 1.636 -26 ATOM 1609 CA PRO 288 3.741 -25 ATOM 1610 CB PRO 288 3.0 62 -25 ATOM 1611 CG PRO 288 2.020 -26 ATOM 1612 C PRO 288 4.925 -26 ATOM 1613 O PRO 288 5.436 -27 ATOM 1614 N LEU 289 5.341 -27 ATOM 1615 CA LEU 289 6.372 -28 ATOM 1616 CB LEU 289 5.741 -29 ATOM 1617 CG LEU 289 4.678 -29 ATOM 1618 CDl LEU 289 5.301 -30 ATOM 1619 CD2 LEU 289 3.525 -30 ATOM 1620 C LEU 289 7.200 -27 ATOM 1621 O LEU 289 6.795 -2 6 ATOM 1622 N ALA 290 8.371 -28 ATOM 1623 CA ALA 290 9.266 -28 ATOM 1624 CB ALA 290 10.198 -27 ATOM 1625 C ALA 290 10.080 -29 ATOM 162 6 0 ALA 290 10.594 -30 ATOM 1627 N GLY 291 10.181 -29 ATOM 1628 CA GLY 291 11.138 -30 ATOM 1629 C GLY 291 11.980 -30 ATOM 1630 0 GLY 291 11.786 -29 ATOM 1631 N GLY 292 12.919 -31 ATOM 1632 CA GLY 292 13.737 -30 ATOM 1633 C GLY 292 12.862 -30 ATOM 1634 0 GLY 292 11.752 -31 ATOM 1635 N TYR 293 13.340 -29 ATOM 1636 CA TYR 293 12.499 -29 ATOM 1637 CB TYR 293 13.293 -28 ATOM 1638 CG TYR 293 12.489 -28 ATOM 1639 CDl TYR 293 11.931 -27 ATOM 1640 CEl TYR 293 11.215 -26 ATOM 1641 CD2 TYR 293 12.304 -29 ATOM 1642 CE2 TYR 293 11.589 -29 ATOM 1643 CZ TYR 293 11.051 -27 ATOM 1644 OH TYR 293 10.373 -27 ATOM 1645 C TYR 293 11.897 -30 ATOM 1646 O TYR 293 12.579 -31 ATOM 1647 N SER 294 10.607 -30 ATOM 1648 CA SER 294 9.865 -31 ATOM 1649 CB SER 294 8.982 -32 ATOM 1650 OG SER 294 8.273 -33 ATOM 1651 C SER 294 9.012 -31 ATOM 1652 O SER 294 8.284 -30 ATOM 1653 N ARG 295 9.110 -32 ATOM 1654 CA ARG 295 8.328 -32 ATOM 1655 CB ARG 295 8.908 -32 ATOM 1656 CG ARG 295 7.854 -33 ATOM 1657 CD ARG 295 8.040 -32 ATOM 1658 NE ARG 295 8.627 -33 ATOM 1659 CZ ARG 295 8.278 -33 ATOM 1660 NHl ARG 295 7.331 -33 ATOM 1661 NH2 ARG 295 8.889 -34 ATOM 1662 C ARG 295 6.903 -32 ATOM 1663 O ARG 295 5.956 -31 ATOM 1664 N VAL 296 6.754 -33 ATOM 1665 CA VAL 296 5.425 -34 ATOM 1666 CB VAL 296 5.459 -35 ATOM 1667 CGI VAL 296 6.315 -35 ATOM 1668 CG2 VAL 296 4.061 -36 ATOM 1669 C VAL 296 4.710 -33 ATOM 1670 O VAL 296 3.544 -33 12.136 1.00 20.76 B C 14.196 1.00 21.62 B C 10.532 1.00 20.34 B c 11.035 1.00 19.43 B 0 9.978 1.00 21.20 B N 9.881 1.00 21.06 B c 8.406 1.00 20.12 B c 7.608 1.00 17.86 B c 6.144 1.00 16.35 B c 7.864 1.00 17.11 B c 10.612 1.00 20.61 B c 10.001 1.00 20.04 B 0 11.941 1.00 20.31 B N 12.681 1.00 19.79 B c 12.823 1.00 19.59 B c 14 . 187 1.00 19.77 B c 14.126 1.00 19.23 B c 12.786 1.00 18.73 B c 13.829 1.00 17.76 B 0 11.565 1.00 17.09 B N 11.355 1.00 16.76 B c 11.230 1.00 15.59 B c 10.138 1.00 16.71 B c 8.897 1.00 17.39 B c 10.662 1.00 14.29 B c 10.120 1.00 16.66 B c 9.267 1.00 15.85 B 0 10.046 1.00 17.02 B N 8.910 1.00 17.79 B c 9.127 1.00 16.37 B c 8.714 1.00 19.12 B c 9.682 1.00 18.31 B 0 7.452 1.00 20.09 B N 7.050 1.00 20.48 B c 5.915 1.00 20.72 B c 5.500 1.00 21.90 B 0 5.412 1.00 20.93 B N 4.299 1.00 20.49 B c 3.088 1.00 20.99 B c 3.027 1.00 22.41 B 0 2.116 1.00 22.10 B N 0.969 1.00 21.97 B c -0.106 1.00 22.23 B c -1.344 1.00 22.52 B c -1.554 1.00 23.24 B c -2.706 1.00 23.07 B c -2.318 1.00 22.54 B c -3.470 1.00 23.87 B c -3.662 1.00 24.37 B c -4.829 1.00 24.90 B 0 0.373 1.00 21.19 B c 0.186 1.00 21.55 B 0 0.078 1.00 20.40 B N -0.397 1.00 19.74 B c 0.724 1.00 18.39 B c 0.313 1.00 19.04 B 0 -1.619 1.00 19.99 B c -1.625 1.00 19.62 B 0 -2.658 1.00 20.06 B N -3.859 1.00 18.83 B c -5.033 1.00 16.98 B c -5.999 1.00 18.85 B c -7.377 1.00 20.56 B c -8.290 1.00 22.09 B N -9.567 1.00 22.80 B c -10.103 1.00 20.61 B N -10.316 1.00 24.02 B N -3.608 1.00 18.54 B C -3.908 1.00 17.83 B 0 -3.053 1.00 19.37 B N -2.812 1.00 19.78 B C -2.372 1.00 18.32 B c -1.154 1.00 16.29 B c -2.074 1.00 16.25 B c -1.749 1.00 20.69 B c -1.917 1.00 23.04 B 0 301 WO 2009/026558 PCT/US2008/074097 ATOM 1671 N LEU 297 5.405 -33 ATOM 1672 CA LEU 297 4.784 -32 ATOM 1673 CB LEU 297 5.766 -32 ATOM 1674 CG LEU 297 5.115 -31 ATOM 1675 CDl LEU 297 3.837 -32 ATOM 167 6 CD2 LEU 297 6.048 -31 ATOM 1677 C LEU 297 4.330 -30 ATOM 1678 O LEU 297 3.187 -30 ATOM 1679 N ASN 298 5.237 -30 ATOM 1680 CA ASN 298 4.924 -28 ATOM 1681 CB ASN 298 6.132 -28 ATOM 1682 CG ASN 298 7.070 -27 ATOM 1683 OD1 ASN 298 7.070 -27 ATOM 1684 ND2 ASN 298 7.878 -2 6 ATOM 1685 C ASN 298 3.712 -29 ATOM 1686 0 ASN 298 2.981 -28 ATOM 1687 N ALA 299 3.512 -30 ATOM 1688 CA ALA 299 2.475 -30 ATOM 1689 CB ALA 299 2.808 -31 ATOM 1690 C ALA 299 1.113 -30 ATOM 1691 0 ALA 299 0.110 -29 ATOM 1692 N ALA 300 1.090 -31 ATOM 1693 CA ALA 300 -0.084 -31 ATOM 1694 CB ALA 300 0.283 -32 ATOM 1695 C ALA 300 -0.622 -30 ATOM 1696 0 ALA 300 -1.786 -29 ATOM 1697 N CYS 301 0.249 -29 ATOM 1698 CA CYS 301 -0.120 -28 ATOM 1699 CB CYS 301 1.070 -27 ATOM 1700 SG CYS 301 1.582 -28 ATOM 1701 C CYS 301 -0.618 -27 ATOM 1702 O CYS 301 -1.618 -26 ATOM 1703 N GLN 302 0.077 -27 ATOM 1704 CA GLN 302 -0.368 -26 ATOM 1705 CB GLN 302 0.572 -26 ATOM 1706 CG GLN 302 0.020 -26 ATOM 1707 CD GLN 302 0.813 -26 ATOM 1708 OE1 GLN 302 0.632 -25 ATOM 1709 NE2 GLN 302 1.708 -27 ATOM 1710 C GLN 302 -1.784 -26 ATOM 1711 0 GLN 302 -2.604 -25 ATOM 1712 N ARG 303 -2.075 -28 ATOM 1713 CA ARG 303 -3.357 -28 ATOM 1714 CB ARG 303 -3.414 -30 ATOM 1715 CG ARG 303 -2.200 -30 ATOM 1716 CD ARG 303 -2.556 -31 ATOM 1717 NE ARG 303 -1.353 -31 ATOM 1718 CZ ARG 303 -1.188 -33 ATOM 1719 NHl ARG 303 -0.048 -33 ATOM 1720 NH2 ARG 303 -2.158 -34 ATOM 1721 C ARG 303 -4.448 -28 ATOM 1722 O ARG 303 -5.502 -27 ATOM 1723 N LEU 304 -4.184 -28 ATOM 1724 CA LEU 304 -5.166 -27 ATOM 1725 CB LEU 304 -4.613 -28 ATOM 1726 CG LEU 304 -5.650 -28 ATOM 1727 CDl LEU 304 -6.880 -29 ATOM 1728 CD2 LEU 304 -5.056 -29 ATOM 1729 C LEU 304 -5.498 -26 ATOM 1730 O LEU 304 -6.647 -26 ATOM 1731 N ALA 305 -4.474 -25 ATOM 1732 CA ALA 305 -4.595 -24 ATOM 1733 CB ALA 305 -3.223 -23 ATOM 1734 C ALA 305 -5.452 -23 ATOM 1735 0 ALA 305 -6.277 -22 ATOM 1736 N ARG 306 -5.238 -24 ATOM 1737 CA ARG 306 -6.015 -24 ATOM 1738 CB ARG 306 -5.258 -24 ATOM 1739 CG ARG 306 -3.873 -24 ATOM 1740 CD ARG 306 -2.949 -24 ATOM 1741 NE ARG 306 -2.167 -24 ATOM 1742 CZ ARG 306 -1.806 -24 ATOM 1743 NHl ARG 306 -1.094 -24 ATOM 1744 NH2 ARG 306 -2.157 -26 ATOM 1745 C ARG 306 -7.400 -24 ATOM 1746 O ARG 306 -8.291 -24 -0.664 1.00 20.71 B N 0.408 1.00 20.16 B C 1.561 1.00 19.83 B C 2.748 1.00 19.79 B c 3.088 1.00 19.32 B c 3.942 1.00 17.12 B c -0.133 1.00 19.04 B c 0.051 1.00 18.61 B 0 -0.814 1.00 19.03 B N -1.438 1.00 19.13 B c -2.233 1.00 19.01 B c -1.397 1.00 20.79 B c -0.161 1.00 19.14 B 0 -2.072 1.00 21.14 B N -2.358 1.00 19.17 B c -2.502 1.00 20.60 B 0 -2.991 1.00 20.42 B N -4.010 1.00 19.62 B c -4.892 1.00 18.75 B c -3.350 1.00 20.32 B c -3.740 1.00 18.83 B 0 -2.347 1.00 19.46 B N -1.521 1.00 19.11 B c -0.286 1.00 16.69 B c -1.140 1.00 20.79 B c -1.387 1.00 21.71 B 0 -0.551 1.00 22.30 B N -0.080 1.00 22.76 B c 0.582 1.00 23.52 B c 2.077 1.00 26.02 B s -1.200 1.00 22.64 B c -1.052 1.00 24.93 B 0 -2.323 1.00 23.10 B N -3.442 1.00 24.66 B c -4.615 1.00 26.73 B c -5.874 1.00 32.13 B c -7.091 1.00 36.06 B c -8.176 1.00 37.94 B 0 -6.921 1.00 39.51 B N -3.881 1.00 24.41 B c -4 .146 1.00 25.13 B 0 -3.960 1.00 23.65 B N -4.490 1.00 21.86 B c -4.570 1.00 21.24 B c -5.168 1.00 22.97 B c -6.363 1.00 23.46 B c -7.067 1.00 25.29 B N -7.632 1.00 26.86 B c -8.251 1.00 26.86 B N -7.578 1.00 27.68 B N -3.561 1.00 21.46 B C -3.994 1.00 22.14 B 0 -2.273 1.00 20.16 B N -1.250 1.00 18.95 B C 0.113 1.00 17.05 B c 1.225 1.00 17.78 B c 0.750 1.00 18.88 B c 2.460 1.00 17.39 B c -1.262 1.00 17.86 B c -1.060 1.00 16.37 B 0 -1.503 1.00 18.14 B N -1.499 1.00 18.65 B c -1.606 1.00 18.26 B c -2.664 1.00 19.54 B c -2.537 1.00 19.94 B 0 -3.803 1.00 20.90 B N -4.996 1.00 23.22 B c -6.217 1.00 26.07 B c -6.332 1.00 32.51 B c -7.079 1.00 40.27 B c -8.100 1.00 46.05 B N -9.261 1.00 48.83 B c -10.133 1.00 50.33 B N -9.552 1.00 49.46 B N -4.923 1.00 21.55 B C -5.710 1.00 22.43 B 0 302 WO 2009/026558 PCT/US2008/074097 ATOM 1747 N ALA 307 -7.581 -25 ATOM 1748 CA ALA 307 -8.861 -26 ATOM 1749 CB ALA 307 -8.662 -27 ATOM 1750 C ALA 307 -9.737 -25 ATOM 1751 0 ALA 307 -10.925 -2 5 ATOM 1752 N GLY 308 -9.131 -24 ATOM 1753 CA GLY 308 -9.883 -23 ATOM 1754 C GLY 308 -9.464 -23 ATOM 1755 0 GLY 308 -9.854 -22 ATOM 1756 N VAL 309 -8.679 -24 ATOM 1757 CA VAL 309 -8.288 -23 ATOM 1758 CB VAL 309 -8.113 -25 ATOM 1759 CGI VAL 309 -7.427 -25 ATOM 1760 CG2 VAL 309 -9.465 -25 ATOM 1761 C VAL 309 -7.039 -23 ATOM 1762 O VAL 309 -6.136 -22 ATOM 1763 N VAL 310 -7.020 -22 ATOM 1764 CA VAL 310 -5.918 -21 ATOM 1765 CB VAL 310 -6.408 -20 ATOM 1766 CGI VAL 310 -5.227 -19 ATOM 1767 CG2 VAL 310 -7.334 -19 ATOM 1768 C VAL 310 -4.854 -22 ATOM 1769 O VAL 310 -5.146 -22 ATOM 1770 N LEU 311 -3.612 -22 ATOM 1771 CA LEU 311 -2.539 -22 ATOM 1772 CB LEU 311 -1.847 -23 ATOM 1773 CG LEU 311 -2.719 -25 ATOM 1774 CDl LEU 311 -3.169 -25 ATOM 1775 CD2 LEU 311 -1.929 -26 ATOM 1776 C LEU 311 -1.523 -21 ATOM 1777 O LEU 311 -0.989 -20 ATOM 1778 N VAL 312 -1.287 -21 ATOM 1779 CA VAL 312 -0.284 -21 ATOM 1780 CB VAL 312 -0.954 -20 ATOM 1781 CGI VAL 312 0.103 -19 ATOM 1782 CG2 VAL 312 -1.998 -19 ATOM 1783 C VAL 312 0.774 -22 ATOM 1784 O VAL 312 0.442 -23 ATOM 1785 N THR 313 2.043 -21 ATOM 1786 CA THR 313 3.130 -22 ATOM 1787 CB THR 313 3.775 -23 ATOM 1788 OG1 THR 313 4 . 473 -24 ATOM 1789 CG2 THR 313 4.772 -22 ATOM 1790 C THR 313 4.265 -21 ATOM 1791 O THR 313 4.567 -20 ATOM 1792 N ALA 314 4 . 893 -22 ATOM 1793 CA ALA 314 6.148 -22 ATOM 1794 CB ALA 314 6.611 -23 ATOM 1795 C ALA 314 7.231 -21 ATOM 1796 0 ALA 314 7.228 -22 ATOM 1797 N ALA 315 8.152 -21 ATOM 1798 CA ALA 315 9.267 -2 0 ATOM 1799 CB ALA 315 9.764 -19 ATOM 1800 C ALA 315 10.398 -21 ATOM 1801 0 ALA 315 11.223 -22 ATOM 1802 N GLY 316 10.416 -22 ATOM 1803 CA GLY 316 11.460 -23 ATOM 1804 C GLY 316 12.487 -22 ATOM 1805 0 GLY 316 12.662 -21 ATOM 1806 N ASN 317 13.173 -23 ATOM 1807 CA ASN 317 14.084 -22 ATOM 1808 CB ASN 317 13.729 -23 ATOM 1809 CG ASN 317 12.270 -22 ATOM 1810 OD1 ASN 317 11.632 -21 ATOM 1811 ND2 ASN 317 11.721 -23 ATOM 1812 C ASN 317 15.535 -22 ATOM 1813 0 ASN 317 16.302 -23 ATOM 1814 N PHE 318 15.899 -22 ATOM 1815 CA PHE 318 17.167 -23 ATOM 1816 CB PHE 318 16.905 -24 ATOM 1817 CG PHE 318 16.091 -25 ATOM 1818 CDl PHE 318 16.578 -26 ATOM 1819 CD2 PHE 318 14.847 -25 ATOM 1820 CEl PHE 318 15.839 -27 ATOM 1821 CE2 PHE 318 14.104 -26 ATOM 1822 CZ PHE 318 14.601 -27 -3.974 1.00 19.75 B N -3.807 1.00 18.30 B C -3.143 1.00 18.38 B C -2.946 1.00 18.11 B c -2.752 1.00 18.26 B 0 -2.427 1.00 18.07 B N -1.670 1.00 17.27 B c -0.224 1.00 17.47 B c 0.371 1.00 18.26 B 0 0.358 1.00 17.85 B N 1.762 1.00 17.40 B c 2.426 1.00 15.52 B c 3.750 1.00 16.49 B c 2.660 1.00 14 . 46 B c 2.012 1.00 17.87 B c 1. 179 1.00 19.05 B 0 3.159 1.00 17.38 B N 3.550 1.00 18.63 B c 4 . 464 1.00 19.64 B c 5.018 1.00 18.09 B c 3.702 1.00 18.46 B c 4.318 1.00 19.53 B c 5.327 1.00 19.08 B 0 3.857 1.00 20.49 B N 4.601 1.00 20.59 B c 3.729 1.00 21.10 B c 3.374 1.00 20.77 B c 1.924 1.00 19.01 B c 3.595 1.00 19.85 B c 5.170 1.00 19.52 B c 4.465 1.00 18.71 B 0 6.469 1.00 19.75 B N 7.165 1.00 20.13 B c 8.283 1.00 21.70 B c 9.048 1.00 20.27 B c 7.660 1.00 18.86 B c 7.784 1.00 18.09 B c 8.528 1.00 15.74 B 0 7.4 63 1.00 17.81 B N 8.001 1.00 17.87 B c 6.924 1.00 16.57 B c 7.568 1.00 15.42 B 0 6.088 1.00 13.87 B c 8.670 1.00 17.42 B c 8.306 1.00 19.31 B 0 9.645 1.00 15.83 B N 10.220 1.00 14.33 B c 11.316 1.00 12.97 B c 9.147 1.00 13.75 B c 8.139 1.00 12.56 B 0 9.366 1.00 14.84 B N 8.455 1.00 15.19 B c 8.563 1.00 12.98 B c 8.793 1.00 16.33 B c 7.933 1.00 16.84 B 0 10.049 1.00 15.86 B N 10.522 1.00 15.85 B c 11.352 1.00 17.04 B c 11.191 1.00 15.26 B 0 12.230 1.00 18.37 B N 13.205 1.00 20.16 B c 14.600 1.00 17.67 B c 14.894 1.00 17.51 B c 14.385 1.00 15.76 B 0 15.709 1.00 19.11 B N 12.897 1.00 20.80 B c 13.779 1.00 20.23 B 0 11.635 1.00 21.80 B N 11.126 1.00 24.16 B c 9.979 1.00 24.38 B c 10.383 1.00 25.06 B c 11.319 1.00 23.42 B c 9.816 1.00 24.55 B c 11.681 1.00 23.94 B c 10.175 1.00 22.84 B c 11.108 1.00 22.93 B c 303 WO 2009/026558 PCT/US2008/074097 ATOM 1823 c PHE 318 18.106 -22.038 10.666 1.00 25.02 B C ATOM 1824 0 PHE 318 19.162 -22.312 10.109 1.00 26.36 B O ATOM 1825 N ARG 319 17.716 -20.789 10.893 1.00 25.77 B N ATOM 1826 CA ARG 319 18.570 -19.654 10.571 1.00 26.61 B C ATOM 1827 CB ARG 319 19.788 -19.643 11.508 1.00 28.47 B C ATOM 1828 CG ARG 319 20.420 -18.273 11.749 1.00 32.16 B c ATOM 1829 CD ARG 319 21.502 -18.345 12.822 1.00 36.07 B c ATOM 1830 NE ARG 319 21.972 -17.023 13.247 1.00 42.52 B N ATOM 1831 CZ ARG 319 23.231 -16.735 13.597 1.00 45.72 B c ATOM 1832 NHl ARG 319 24.169 -17.674 13.579 1.00 44.82 B N ATOM 1833 NH2 ARG 319 23.560 -15.499 13.966 1.00 45.86 B N ATOM 1834 C ARG 319 19.019 -19.766 9.115 1.00 26.48 B C ATOM 1835 O ARG 319 20.203 -19.627 8.808 1.00 26.94 B 0 ATOM 1836 N ASP 320 18.066 -20.022 8.221 1.00 25.91 B N ATOM 1837 CA ASP 320 18.377 -20.386 6.839 1.00 25.38 B C ATOM 1838 CB ASP 320 18.482 -21.907 6.716 1.00 27.38 B c ATOM 1839 CG ASP 320 19.283 -22.347 5.492 1.00 31.81 B c ATOM 1840 OD1 ASP 320 19.625 -21.483 4.646 1.00 30.34 B 0 ATOM 1841 OD2 ASP 320 19.572 -23.567 5.381 1.00 34.03 B 0 ATOM 1842 C ASP 320 17.310 -19.879 5.882 1.00 23.72 B c ATOM 1843 O ASP 320 16.259 -19.420 6.311 1.00 24.64 B 0 ATOM 1844 N ASP 321 17.578 -19.959 4.584 1.00 21.64 B N ATOM 1845 CA ASP 321 16.545 -19.676 3.604 1.00 20.23 B c ATOM 1846 CB ASP 321 17.118 -19.655 2.187 1.00 20.01 B c ATOM 1847 CG ASP 321 16.160 -19.032 1.177 1.00 23.00 B c ATOM 1848 OD1 ASP 321 15.034 -18.631 1.557 1.00 25.85 B 0 ATOM 1849 OD2 ASP 321 16.529 -18.936 -0.009 1.00 24.40 B 0 ATOM 1850 C ASP 321 15.500 -20.768 3.715 1.00 20.33 B c ATOM 1851 O ASP 321 15.785 -21.937 3.470 1.00 20.93 B 0 ATOM 1852 N ALA 322 14.289 -20.376 4.092 1.00 20.81 B N ATOM 1853 CA ALA 322 13.189 -21.311 4.245 1.00 20.82 B c ATOM 1854 CB ALA 322 12.027 -20.619 4.903 1.00 20.87 B c ATOM 1855 C ALA 322 12.773 -21.879 2.896 1.00 22.07 B c ATOM 1856 0 ALA 322 11.925 -22.770 2.814 1.00 24.23 B 0 ATOM 1857 N CYS 323 13.380 -21.362 1.836 1.00 21.62 B N ATOM 1858 CA CYS 323 13.189 -21.906 0.505 1.00 21.78 B c ATOM 1859 C CYS 323 13.745 -23.327 0.420 1.00 20.87 B c ATOM 1860 0 CYS 323 13.523 -24.041 -0.562 1.00 20.76 B 0 ATOM 1861 CB CYS 323 13.883 -21.013 -0.517 1.00 23.38 B c ATOM 1862 SG CYS 323 12.973 -19.497 -0.993 1.00 34.53 B s ATOM 1863 N LEU 324 14.473 -23.729 1.457 1.00 19.41 B N ATOM 1864 CA LEU 324 15.129 -25.034 1.485 1.00 17.45 B c ATOM 1865 CB LEU 324 16.580 -24.895 1.928 1.00 14.89 B c ATOM 1866 CG LEU 324 17.426 -23.921 1.129 1.00 14.62 B c ATOM 1867 CDl LEU 324 18.812 -23.877 1.719 1.00 12.16 B c ATOM 1868 CD2 LEU 324 17.470 -24.357 -0.324 1.00 16.39 B c ATOM 1869 C LEU 324 14.436 -26.000 2.426 1.00 17.67 B c ATOM 1870 O LEU 324 14.998 -27.046 2.769 1.00 17.60 B 0 ATOM 1871 N TYR 325 13.231 -25.643 2.862 1.00 16.35 B N ATOM 1872 CA TYR 325 12.460 -26.512 3.744 1.00 15.57 B c ATOM 1873 CB TYR 325 12.534 -26.011 5.178 1.00 14 .14 B c ATOM 1874 CG TYR 325 13.949 -25.807 5.651 1.00 14.56 B c ATOM 1875 CDl TYR 325 14.620 -26.806 6.355 1.00 12.52 B c ATOM 1876 CEl TYR 325 15.915 -26.636 6.755 1.00 11.36 B c ATOM 1877 CD2 TYR 325 14.626 -24.631 5.363 1.00 10.83 B c ATOM 1878 CE2 TYR 325 15.916 -24.455 5.753 1.00 12.48 B c ATOM 1879 CZ TYR 32 5 16.563 -25.459 6.449 1.00 13.44 B c ATOM 1880 OH TYR 325 17.869 -25.275 6.839 1.00 14.00 B 0 ATOM 1881 C TYR 325 11.017 -26.553 3.303 1.00 16.17 B c ATOM 1882 O TYR 325 10.554 -25.661 2.593 1.00 19.07 B 0 ATOM 1883 N SER 326 10.307 -27.594 3.718 1.00 15.32 B N ATOM 1884 CA SER 326 8.884 -27.706 3.436 1.00 14.45 B c ATOM 1885 CB SER 326 8.643 -28.777 2.365 1.00 13.51 B c ATOM 1886 OG SER 326 9.232 -28.396 1.136 1.00 9.68 B 0 ATOM 1887 C SER 326 8.098 -28.036 4.702 1.00 14.43 B c ATOM 1888 O SER 326 8.596 -28.721 5.593 1.00 13.96 B 0 ATOM 1889 N PRO 327 6.846 -27.557 4.791 1.00 16.56 B N ATOM 1890 CD PRO 327 5.970 -27.849 5.938 1.00 16.61 B c ATOM 1891 CA PRO 327 6.131 -26.829 3.729 1.00 17.34 B c ATOM 1892 CB PRO 327 4.669 -26.884 4.171 1.00 15.73 B c ATOM 1893 CG PRO 327 4.735 -27.040 5.641 1.00 16.44 B c ATOM 1894 C PRO 327 6.582 -25.397 3.456 1.00 18.31 B c ATOM 1895 O PRO 327 6.117 -24.779 2.501 1.00 18.41 B 0 ATOM 1896 N ALA 328 7.478 -24.872 4.286 1.00 20.01 B N ATOM 1897 CA ALA 328 7.811 -23.450 4.231 1.00 22.14 B c ATOM 1898 CB ALA 328 9.031 -23.170 5.107 1.00 21.67 B c 304 WO 2009/026558 PCT/US2008/074097 ATOM 1899 c ALA 328 8.056 -22 ATOM 1900 0 ALA 328 7.640 -21 ATOM 1901 N SER 329 8.711 -23 ATOM 1902 CA SER 329 9.159 -23 ATOM 1903 CB SER 329 10.296 -2 4 ATOM 1904 OG SER 329 9.830 -2 5 ATOM 1905 C SER 329 8.054 -23 ATOM 1906 O SER 329 8.228 -22 ATOM 1907 N ALA 330 6.92 6 -23 ATOM 1908 CA ALA 330 5.835 -24 ATOM 1909 CB ALA 330 4.822 -25 ATOM 1910 C ALA 330 5.160 -22 ATOM 1911 0 ALA 330 4.727 -22 ATOM 1912 N PRO 331 5.065 -22 ATOM 1913 CD PRO 331 5.431 -23 ATOM 1914 CA PRO 331 4.718 -20 ATOM 1915 CB PRO 331 4.844 -20 ATOM 1916 CG PRO 331 5.727 -22 ATOM 1917 C PRO 331 3.326 -20 ATOM 1918 O PRO 331 3.115 -19 ATOM 1919 N GLU 332 2.384 -21 ATOM 1920 CA GLU 332 0.983 -21 ATOM 1921 CB GLU 332 0.121 -22 ATOM 1922 CG GLU 332 0.851 -23 ATOM 1923 CD GLU 332 1.701 -23 ATOM 1924 OE1 GLU 332 1.169 -22 ATOM 1925 OE2 GLU 332 2.904 -23 ATOM 1926 C GLU 332 0.637 -21 ATOM 1927 0 GLU 332 -0.452 -20 ATOM 1928 N VAL 333 1.575 -21 ATOM 1929 CA VAL 333 1.422 -21 ATOM 1930 CB VAL 333 2.269 -22 ATOM 1931 CGI VAL 333 2.247 -22 ATOM 1932 CG2 VAL 333 1.727 -24 ATOM 1933 C VAL 333 1.848 -20 ATOM 1934 O VAL 333 2.781 -19 ATOM 1935 N ILE 334 1. 156 -19 ATOM 1936 CA ILE 334 1.588 -18 ATOM 1937 CB ILE 334 0.413 -17 ATOM 1938 CG2 ILE 334 0.908 -16 ATOM 1939 CGI ILE 334 -0.617 -17 ATOM 1940 CDl ILE 334 -1.908 -16 ATOM 1941 C ILE 334 2.62 6 -18 ATOM 1942 0 ILE 334 2.337 -19 ATOM 1943 N THR 335 3.844 -18 ATOM 1944 CA THR 335 5.010 -18 ATOM 1945 CB THR 335 6.141 -19 ATOM 1946 OG1 THR 335 5.600 -20 ATOM 1947 CG2 THR 335 7.219 -20 ATOM 1948 C THR 335 5.463 -17 ATOM 1949 O THR 335 5.772 -16 ATOM 1950 N VAL 336 5.486 -18 ATOM 1951 CA VAL 336 5.552 -17 ATOM 1952 CB VAL 336 4.355 -17 ATOM 1953 CGI VAL 336 4.359 -16 ATOM 1954 CG2 VAL 336 3.069 -17 ATOM 1955 C VAL 336 6.824 -17 ATOM 1956 O VAL 336 7.119 -18 ATOM 1957 N GLY 337 7.553 -16 ATOM 1958 CA GLY 337 8.746 -16 ATOM 1959 C GLY 337 8.500 -15 ATOM 1960 0 GLY 337 7.451 -14 ATOM 1961 N ALA 338 9.463 -15 ATOM 1962 CA ALA 338 9.243 -14 ATOM 1963 CB ALA 338 9.544 -15 ATOM 1964 C ALA 338 10.081 -13 ATOM 1965 0 ALA 338 11.271 -13 ATOM 1966 N THR 339 9.452 -12 ATOM 1967 CA THR 339 10.165 -11 ATOM 1968 CB THR 339 9.680 -10 ATOM 1969 OG1 THR 339 8.410 -9 ATOM 1970 CG2 THR 339 9.535 -10 ATOM 1971 C THR 339 9.912 -11 ATOM 1972 O THR 339 9.127 -12 ATOM 1973 N ASN 340 10.576 -10 ATOM 1974 CA ASN 340 10.390 -10 2.799 1.00 23.20 B C 2.438 1.00 23.95 B O 1.986 1.00 22.51 B N 0.662 1.00 22.34 B C 0.199 1.00 21.26 B C -0.021 1.00 18.71 B 0 -0.399 1.00 23.40 B c -1.476 1.00 23.51 B 0 -0.100 1.00 25.31 B N -1.064 1.00 26.56 B c -0.590 1.00 27.06 B c -1.250 1.00 27.53 B c -0.284 1.00 29.15 B 0 -2.503 1.00 28.24 B N -3.682 1.00 28.39 B c -2.866 1.00 29.18 B c -4.391 1.00 28.66 B c -4.711 1.00 28.90 B c -2.416 1.00 29.39 B c -2.078 1.00 29.76 B 0 -2.420 1.00 28.61 B N -2.211 1.00 28.81 B c -2.970 1.00 31.96 B c -3.296 1.00 36.23 B c -4.566 1.00 39.36 B c -5.630 1.00 41.08 B 0 -4.503 1.00 40.19 B 0 -0.722 1.00 27.73 B c -0.318 1.00 26.94 B 0 0.091 1.00 26.86 B N 1.541 1.00 25.32 B c 2.227 1.00 23.61 B c 3.732 1.00 23.08 B c 1.873 1.00 23.25 B c 2.101 1.00 24.40 B c 1.596 1.00 24.78 B 0 3.145 1.00 23.38 B N 3.878 1.00 22.82 B c 4.582 1.00 23.36 B c 5.373 1.00 21.37 B c 3.546 1.00 22.38 B c 4 . 149 1.00 19.76 B c 4.910 1.00 21.94 B c 5.863 1.00 20.41 B 0 4.694 1.00 21.71 B N 5.419 1.00 22.66 B c 4 . 426 1.00 24.07 B c 3 . 315 1.00 24.80 B 0 5.100 1.00 23.59 B c 6.394 1.00 22.37 B c 5.988 1.00 21.19 B 0 7.682 1.00 22.56 B N 8.731 1.00 22.60 B c 9.692 1.00 22.03 B c 10.689 1.00 19.46 B c 8.897 1.00 21.19 B c 9.566 1.00 22.61 B c 10.160 1.00 22.75 B 0 9.623 1.00 23.52 B N 10.454 1.00 24.53 B c 11.784 1.00 25.08 B c 11.996 1.00 26.14 B 0 12.691 1.00 25.21 B N 14.036 1.00 25.87 B c 15.047 1.00 25.68 B c 14.340 1.00 27.22 B c 14.033 1.00 28.69 B 0 14.943 1.00 27.73 B N 15.529 1.00 27.88 B c 14.944 1.00 28.43 B c 15.515 1.00 30.24 B 0 13.438 1.00 27.60 B c 17.038 1.00 28.11 B c 17.545 1.00 29.32 B 0 17.754 1.00 28.25 B N 19.197 1.00 28.64 B c 305 WO 2009/026558 PCT/US2008/074097 ATOM 1975 CB ASN 340 11.683 -10 ATOM 1976 CG ASN 340 12.780 -9 ATOM 1977 OD1 ASN 340 12.778 -8 ATOM 1978 ND2 ASN 340 13.718 -9 ATOM 1979 C ASN 340 9.947 -9 ATOM 1980 0 ASN 340 9.662 -8 ATOM 1981 N ALA 341 9.886 -8 ATOM 1982 CA ALA 341 9.383 -7 ATOM 1983 CB ALA 341 9.352 -7 ATOM 1984 C ALA 341 10.193 -6 ATOM 1985 0 ALA 341 9.686 -5 ATOM 1986 N GLN 342 11.449 -6 ATOM 1987 CA GLN 342 12.237 -5 ATOM 1988 CB GLN 342 13.682 -5 ATOM 1989 CG GLN 342 14.069 -6 ATOM 1990 CD GLN 342 13.394 -6 ATOM 1991 OE1 GLN 342 13.198 -7 ATOM 1992 NE2 GLN 342 13.024 -5 ATOM 1993 C GLN 342 12.239 -5 ATOM 1994 0 GLN 342 13.174 -5 ATOM 1995 N ASP 343 11.189 -6 ATOM 1996 CA ASP 343 10.986 -6 ATOM 1997 CB ASP 343 10.524 -4 ATOM 1998 CG ASP 343 9.011 -4 ATOM 1999 OD1 ASP 343 8.245 -5 ATOM 2000 OD2 ASP 343 8.587 -3 ATOM 2001 C ASP 343 12.244 -6 ATOM 2002 O ASP 343 12.546 -6 ATOM 2003 N GLN 344 12.976 -7 ATOM 2004 CA GLN 344 14.134 -8 ATOM 2005 CB GLN 344 15.408 -7 ATOM 2006 CG GLN 344 15.384 -8 ATOM 2007 CD GLN 344 16.394 -7 ATOM 2008 OE1 GLN 344 16.657 -7 ATOM 2009 NE2 GLN 344 16.968 -6 ATOM 2010 C GLN 344 13.963 -9 ATOM 2011 0 GLN 344 13.247 -10 ATOM 2012 N PRO 345 14.614 -10 ATOM 2013 CD PRO 345 15.492 -9 ATOM 2014 CA PRO 345 14.416 -11 ATOM 2015 CB PRO 345 15.331 -11 ATOM 2016 CG PRO 345 15.514 -10 ATOM 2017 C PRO 345 14.759 -12 ATOM 2018 O PRO 345 15.782 -12 ATOM 2019 N VAL 346 13.910 -13 ATOM 2020 CA VAL 346 14.149 -14 ATOM 2021 CB VAL 346 12.915 -15 ATOM 2022 CGI VAL 346 13.244 -16 ATOM 2023 CG2 VAL 346 11.740 -14 ATOM 2024 C VAL 346 15.333 -15 ATOM 2025 O VAL 346 15.385 -16 ATOM 2026 N THR 347 16.285 -15 ATOM 2027 CA THR 347 17.388 -16 ATOM 2028 CB THR 347 18.718 -15 ATOM 2029 OG1 THR 347 18.567 -14 ATOM 2030 CG2 THR 347 19.129 -14 ATOM 2031 C THR 347 17.084 -17 ATOM 2032 O THR 347 16.755 -17 ATOM 2033 N LEU 348 17.188 -18 ATOM 2034 CA LEU 348 16.839 -19 ATOM 2035 CB LEU 348 15.727 -20 ATOM 2036 CG LEU 348 14.364 -19 ATOM 2037 CDl LEU 348 13.468 -20 ATOM 2038 CD2 LEU 348 13.725 -19 ATOM 2039 C LEU 348 18.076 -20 ATOM 2040 O LEU 348 18.481 -21 ATOM 2041 N GLY 349 18.680 -20 ATOM 2042 CA GLY 349 19.985 -21 ATOM 2043 C GLY 349 20.931 -20 ATOM 2044 0 GLY 349 20.898 -19 ATOM 2045 N THR 350 21.761 -21 ATOM 2046 CA THR 350 22.649 -20 ATOM 2047 CB THR 350 23.967 -21 ATOM 2048 OG1 THR 350 23.689 -22 ATOM 2049 CG2 THR 350 24.679 -21 ATOM 2050 C THR 350 21.976 -20 19.937 1.00 26.79 B C 19.842 1.00 24.82 B C 18.954 1.00 23.33 B 0 20.768 1.00 21.41 B N 19.614 1.00 30.56 B c 18.776 1.00 30.36 B 0 20.917 1.00 32.81 B N 21.435 1.00 34.72 B c 22.943 1.00 33.86 B c 20.959 1.00 37.05 B c 20.932 1.00 37.22 B 0 20.582 1.00 39.17 B N 20.037 1.00 41.65 B c 20.558 1.00 43.43 B c 21.353 1.00 47.47 B c 22.709 1.00 49.49 B c 23.289 1.00 48.68 B 0 23.223 1.00 50.00 B N 18.518 1.00 43.22 B c 17.869 1.00 43.77 B 0 17.956 1.00 43.93 B N 16.509 1.00 43.53 B c 16.050 1.00 43.99 B c 16.209 1.00 44 . 42 B c 16.276 1.00 42.52 B 0 16.260 1.00 44.78 B 0 15.737 1.00 42.39 B c 14.657 1.00 42.07 B 0 16.302 1.00 41.78 B N 15.629 1.00 41.56 B c 16.396 1.00 44.09 B c 17.839 1.00 48.25 B c 18.687 1.00 50.65 B c 19.840 1.00 51.73 B 0 18.118 1.00 51.25 B N 15.540 1.00 38.96 B c 16.341 1.00 38.19 B 0 14.556 1.00 37.58 B N 13.555 1.00 36.39 B c 14.298 1.00 37.16 B c 13.101 1.00 35.35 B c 12.446 1.00 35.43 B c 15.510 1.00 37.13 B c 16.162 1.00 39.08 B 0 15.811 1.00 36.05 B N 16.957 1.00 34.82 B c 17.287 1.00 33.18 B c 18.428 1.00 33.07 B c 17.664 1.00 31.64 B c 16.745 1.00 35.10 B c 15.770 1.00 34.39 B 0 17.669 1.00 35.85 B N 17.671 1.00 37.77 B c 18.074 1.00 36.41 B c 19.358 1.00 35.69 B 0 17.050 1.00 33.79 B c 18.661 1.00 39.16 B c 19.819 1.00 39.34 B 0 18.196 1.00 40.40 B N 19.014 1.00 42.15 B c 18.334 1.00 42.90 B c 18.207 1.00 44.13 B c 17.284 1.00 44.95 B c 19.584 1.00 44.34 B c 19.221 1.00 42.53 B c 18.333 1.00 44 . 15 B 0 20.396 1.00 41.43 B N 20.581 1.00 40.94 B c 19.636 1.00 40.49 B c 19.536 1.00 40.57 B 0 18.934 1.00 40.43 B N 17.923 1.00 40.06 B c 17.796 1.00 41.33 B c 17.311 1.00 42.85 B 0 19.142 1.00 39.97 B c 16.557 1.00 38.80 B c 306 WO 2009/026558 PCT/US2008/074097 ATOM 2051 0 THR 350 22.599 -20 ATOM 2052 N LEU 351 20.702 -20 ATOM 2053 CA LEU 351 19.916 -20 ATOM 2054 CB LEU 351 19.330 -22 ATOM 2055 CG LEU 351 20.325 -23 ATOM 2056 CDl LEU 351 20.033 -2 4 ATOM 2057 CD2 LEU 351 20.247 -22 ATOM 2058 C LEU 351 18.825 -19 ATOM 2059 O LEU 351 18.970 -18 ATOM 2060 N GLY 352 17.747 -19 ATOM 2061 CA GLY 352 16.666 -18 ATOM 2062 C GLY 352 15.731 -18 ATOM 2063 0 GLY 352 15.681 -19 ATOM 2064 N THR 353 14.991 -17 ATOM 2065 CA THR 353 13.991 -17 ATOM 2066 CB THR 353 13.177 -16 ATOM 2067 OG1 THR 353 12.050 -16 ATOM 2068 CG2 THR 353 14.054 -15 ATOM 2069 C THR 353 14.657 -17 ATOM 2070 O THR 353 15.659 -17 ATOM 2071 N ASN 354 14.099 -18 ATOM 2072 CA ASN 354 14.513 -18 ATOM 2073 CB ASN 354 13.905 -19 ATOM 2074 CG ASN 354 14.733 -21 ATOM 2075 OD1 ASN 354 15.835 -21 ATOM 2076 ND2 ASN 354 14.211 -22 ATOM 2077 C ASN 354 14.057 -17 ATOM 2078 0 ASN 354 13.425 -16 ATOM 2079 N PHE 355 14.380 -17 ATOM 2080 CA PHE 355 14.126 -15 ATOM 2081 CB PHE 355 15.174 -14 ATOM 2082 CG PHE 355 16.550 -15 ATOM 2083 CDl PHE 355 17.080 -15 ATOM 2084 CD2 PHE 355 17.281 -15 ATOM 2085 CEl PHE 355 18.305 -16 ATOM 2086 CE2 PHE 355 18.504 -16 ATOM 2087 CZ PHE 355 19.016 -16 ATOM 2088 C PHE 355 14.188 -16 ATOM 2089 O PHE 355 14.063 -17 ATOM 2090 N GLY 356 14.384 -15 ATOM 2091 CA GLY 356 14.478 -15 ATOM 2092 C GLY 356 13.145 -14 ATOM 2093 0 GLY 356 12.172 -14 ATOM 2094 N ARG 357 13.103 -15 ATOM 2095 CA ARG 357 11.921 -14 ATOM 2096 CB ARG 357 12.312 -14 ATOM 2097 CG ARG 357 12.919 -15 ATOM 2098 CD ARG 357 12.688 -15 ATOM 2099 NE ARG 357 13.524 -14 ATOM 2100 CZ ARG 357 14.766 -15 ATOM 2101 NHl ARG 357 15.456 -14 ATOM 2102 NH2 ARG 357 15.322 -16 ATOM 2103 C ARG 357 10.802 -15 ATOM 2104 O ARG 357 9.708 -15 ATOM 2105 N CYS 358 11.064 -16 ATOM 2106 CA CYS 358 9.998 -17 ATOM 2107 C CYS 358 9.170 -17 ATOM 2108 0 CYS 358 8.119 -18 ATOM 2109 CB CYS 358 10.570 -19 ATOM 2110 SG CYS 358 10.992 -19 ATOM 2111 N VAL 359 9.635 -16 ATOM 2112 CA VAL 359 8.846 -16 ATOM 2113 CB VAL 359 9.747 -15 ATOM 2114 CGI VAL 359 8.898 -14 ATOM 2115 CG2 VAL 359 10.602 -16 ATOM 2116 C VAL 359 7.903 -14 ATOM 2117 O VAL 359 8.282 -14 ATOM 2118 N ASP 360 6.660 -15 ATOM 2119 CA ASP 360 5.648 -14 ATOM 2120 CB ASP 360 4.286 -14 ATOM 2121 CG ASP 360 4.162 -15 ATOM 2122 OD1 ASP 360 3.832 -15 ATOM 2123 OD2 ASP 360 4.396 -16 ATOM 2124 C ASP 360 5.632 -12 ATOM 2125 O ASP 360 5.638 -11 ATOM 2126 N LEU 361 5.639 -13
15.543 1.00 39.80 B O 16.533 1.00 36.87 B N 15.320 1.00 35.16 B C 14.982 1.00 34.71 B C 14.299 1.00 32.23 B c 14.626 1.00 29.33 B c 12.807 1.00 32.45 B c 15.484 1.00 34.05 B c 16.284 1.00 33.71 B 0 14.717 1.00 33.23 B N 14.839 1.00 30.44 B c 13.652 1.00 28.36 B c 12.934 1.00 27.74 B 0 13.441 1.00 25.82 B N 12.386 1.00 23.39 B c 12.446 1.00 23.46 B c 11.559 1.00 22.87 B 0 12.031 1.00 23.22 B c 11.020 1.00 21.85 B c 10.768 1.00 23.19 B 0 10.142 1.00 19.78 B N 8.751 1.00 18.88 B c 8.029 1.00 19.41 B c 8.203 1.00 18.91 B c 8.720 1.00 22.77 B 0 7.765 1.00 20.48 B N 8.114 1.00 19.36 B c 8.775 1.00 18.72 B 0 6.842 1.00 20.03 B N 6.191 1.00 22.21 B c 6.638 1.00 19.82 B c 6.737 1.00 20.47 B c 7.972 1.00 19.70 B c 5.590 1.00 19.94 B c 8.064 1.00 18.39 B c 5.676 1.00 19.14 B c 6.918 1.00 18.75 B c 4.672 1.00 24.66 B c 4 . 154 1.00 26.20 B 0 3.963 1.00 25.89 B N 2.520 1.00 27.05 B c 1.856 1.00 28.45 B c 2.509 1.00 28.91 B 0 0.545 1.00 29.61 B N -0.235 1.00 30.42 B c -1.702 1.00 33.04 B c -2.307 1.00 38.74 B c -3.794 1.00 43.88 B c -4.515 1.00 49.58 B N -4.921 1.00 52.78 B c -5.580 1.00 53.88 B N -4.662 1.00 53.07 B N -0.121 1.00 29.64 B C -0.635 1.00 28.09 B 0 0.543 1.00 29.30 B N 0.778 1.00 28.85 B C 2.017 1.00 27.26 B c 2.257 1.00 27.00 B 0 0.899 1.00 30.23 B c -0.727 1.00 33.15 B s 2.801 1.00 25.41 B N 3.927 1.00 24.19 B c 5.072 1.00 24.35 B c 6.197 1.00 22.54 B c 5.615 1.00 25.11 B c 3.461 1.00 23.48 B c 2.693 1.00 24.15 B 0 3.914 1.00 22.77 B N 3.504 1.00 20.61 B c 3.445 1.00 23.47 B c 2.237 1.00 26.57 B c 1. 128 1.00 25.68 B 0 2.395 1.00 27.94 B 0 4 . 475 1.00 17.89 B c 4.069 1.00 16.84 B 0 5.763 1.00 16.38 B N 307 WO 2009/026558 PCT/US2008/074097 ATOM 2127 CA LEU 361 5.770 -12 ATOM 2128 CB LEU 361 4 . 447 -11 ATOM 2129 CG LEU 361 3.2 52 -12 ATOM 2130 CDl LEU 361 2.087 -11 ATOM 2131 CD2 LEU 361 2.881 -13 ATOM 2132 C LEU 361 6.225 -12 ATOM 2133 O LEU 361 6.477 -13 ATOM 2134 N PHE 362 6.345 -11 ATOM 2135 CA PHE 362 6.792 -12 ATOM 2136 CB PHE 362 8.059 -11 ATOM 2137 CG PHE 362 9.259 -11 ATOM 2138 CDl PHE 362 10.157 -12 ATOM 2139 CD2 PHE 362 9.464 -11 ATOM 2140 CEl PHE 362 11.233 -13 ATOM 2141 CE2 PHE 362 10.534 -11 ATOM 2142 CZ PHE 362 11.423 -12 ATOM 2143 C PHE 362 5.710 -11 ATOM 2144 O PHE 362 4.720 -11 ATOM 2145 N ALA 363 5.891 -12 ATOM 2146 CA ALA 363 4.877 -12 ATOM 2147 CB ALA 363 3.7 67 -13 ATOM 2148 C ALA 363 5.509 -12 ATOM 2149 0 ALA 363 6.544 -13 ATOM 2150 N PRO 364 4.894 -12 ATOM 2151 CD PRO 364 3.855 -11 ATOM 2152 CA PRO 364 5.395 -12 ATOM 2153 CB PRO 364 4.227 -12 ATOM 2154 CG PRO 364 3.597 -10 ATOM 2155 C PRO 364 5.753 -13 ATOM 2156 O PRO 364 4.962 -14 ATOM 2157 N GLY 365 6.950 -14 ATOM 2158 CA GLY 365 7.380 -15 ATOM 2159 C GLY 365 8.373 -15 ATOM 2160 0 GLY 365 8.973 -17 ATOM 2161 N GLU 366 8.558 -15 ATOM 2162 CA GLU 366 9.498 -15 ATOM 2163 CB GLU 366 10.758 -14 ATOM 2164 CG GLU 366 11.838 -14 ATOM 2165 CD GLU 366 12.907 -13 ATOM 2166 OE1 GLU 366 13.931 -13 ATOM 2167 OE2 GLU 366 12.723 -12 ATOM 2168 C GLU 366 8.856 -14 ATOM 2169 O GLU 366 8.202 -13 ATOM 2170 N ASP 367 9.048 -15 ATOM 2171 CA ASP 367 8.400 -15 ATOM 2172 CB ASP 3 67 8.868 -14 ATOM 2173 CG ASP 367 10.172 -14 ATOM 2174 OD1 ASP 367 11.177 -13 ATOM 2175 OD2 ASP 367 10.195 -15 ATOM 2176 C ASP 367 6.898 -15 ATOM 2177 O ASP 3 67 6.273 -14 ATOM 2178 N ILE 368 6.312 -16 ATOM 2179 CA ILE 368 4 . 859 -16 ATOM 2180 CB ILE 368 4.425 -16 ATOM 2181 CG2 ILE 368 2.921 -16 ATOM 2182 CGI ILE 368 5.175 -16 ATOM 2183 CDl ILE 368 4.953 -14 ATOM 2184 C ILE 368 4.233 -17 ATOM 2185 0 ILE 368 4.365 -18 ATOM 2186 N ILE 369 3.561 -16 ATOM 2187 CA ILE 369 2.872 -17 ATOM 2188 CB ILE 369 2.562 -16 ATOM 2189 CG2 ILE 369 2.407 -14 ATOM 2190 CGI ILE 369 1.328 -16 ATOM 2191 CDl ILE 369 0.614 -15 ATOM 2192 C ILE 369 1.578 -17 ATOM 2193 0 ILE 369 0.827 -17 ATOM 2194 N GLY 370 1.326 -19 ATOM 2195 CA GLY 370 0.172 -19 ATOM 2196 C GLY 370 -0.100 -20 ATOM 2197 0 GLY 370 0.565 -21 ATOM 2198 N ALA 371 -1.063 -21 ATOM 2199 CA ALA 371 -1.526 -22 ATOM 2200 CB ALA 371 -2.705 -23 ATOM 2201 C ALA 371 -0.431 -23 ATOM 2202 0 ALA 371 0.319 -24 6.777 1.00 16.17 B C 6.946 1.00 17.23 B C 7.523 1.00 16.84 B c 7.633 1.00 16.25 B c 6.643 1.00 18.27 B c 8.128 1.00 15.83 B c 8.278 1.00 16.68 B 0 9.109 1.00 15.56 B N 10.432 1.00 14.82 B c 10.814 1.00 14 . 14 B c 10.002 1.00 12.01 B c 10.486 1.00 9.24 B c 8.738 1.00 8.63 B c 9.726 1.00 8.18 B c 7.970 1.00 7.87 B c 8.463 1.00 9.03 B c 11.450 1.00 14.66 B c 11.158 1.00 17.08 B 0 12.641 1.00 14.32 B N 13.674 1.00 15.69 B c 13.408 1.00 14.68 B c 15.025 1.00 17.04 B c 15.115 1.00 18.01 B 0 16.101 1.00 18.24 B N 16.138 1.00 17.59 B c 17.438 1.00 18.94 B c 18.339 1.00 18.02 B c 17.621 1.00 17.86 B c 17.540 1.00 20.27 B c 17.152 1.00 22.37 B 0 18.044 1.00 20.34 B N 18.138 1.00 22.18 B c 19.243 1.00 23.70 B c 19.270 1.00 23.16 B 0 20.154 1.00 25.89 B N 21.252 1.00 29.11 B c 21.023 1.00 31.40 B c 22.053 1.00 35.84 B c 22.017 1.00 40.32 B c 21.320 1.00 42.04 B 0 22.685 1.00 43.30 B 0 22.563 1.00 28.79 B c 22.642 1.00 28.23 B 0 23.586 1.00 29.00 B N 24.884 1.00 29.74 B c 25.549 1.00 33.33 B c 26.270 1.00 38.62 B c 25.839 1.00 42.20 B 0 27.272 1.00 42.52 B 0 24.771 1.00 28.66 B c 25.327 1.00 29.35 B 0 24.047 1.00 28.05 B N 23.911 1.00 26.36 B c 22.542 1.00 24.44 B c 22.359 1.00 22.78 B c 21.414 1.00 23.14 B c 21.380 1.00 21.33 B c 25.028 1.00 25.21 B c 25.076 1.00 25.00 B 0 25.940 1.00 23.47 B N 27.007 1.00 24.06 B c 28.161 1.00 24.47 B c 27.645 1.00 24.60 B c 28.901 1.00 24.42 B c 29.639 1.00 26.06 B c 26.496 1.00 23.71 B c 25.783 1.00 24.50 B 0 26.866 1.00 24.27 B N 26.357 1.00 24.97 B c 27.214 1.00 26.60 B c 28.235 1.00 27.10 B 0 26.799 1.00 27.73 B N 27.615 1.00 27.34 B c 26.946 1.00 26.39 B c 27.880 1.00 27.36 B c 26.980 1.00 28.65 B 0 308 WO 2009/026558 PCT/US2008/074097 ATOM 2203 N SER 372 -0.343 -24 ATOM 2204 CA SER 372 0.621 -25 ATOM 2205 CB SER 372 1.439 -24 ATOM 2206 OG SER 372 2.034 -26 ATOM 2207 C SER 372 -0.076 -26 ATOM 2208 O SER 372 -0.969 -26 ATOM 2209 N SER 373 0.349 -27 ATOM 2210 CA SER 373 -0.304 -29 ATOM 2211 CB SER 373 0.107 -29 ATOM 2212 OG SER 373 1.493 -30 ATOM 2213 C SER 373 0.062 -29 ATOM 2214 O SER 373 -0.443 -30 ATOM 2215 N ASP 374 0.942 -29 ATOM 2216 CA ASP 374 1.373 -29 ATOM 2217 CB ASP 374 2.410 -28 ATOM 2218 CG ASP 374 3.832 -28 ATOM 2219 OD1 ASP 374 4.016 -29 ATOM 2220 OD2 ASP 374 4.763 -28 ATOM 2221 C ASP 374 0.187 -29 ATOM 2222 O ASP 374 0.079 -30 ATOM 2223 N CYS 375 -0.696 -28 ATOM 2224 CA CYS 375 -1.976 -28 ATOM 2225 C CYS 375 -2.922 -27 ATOM 2226 0 CYS 375 -2.495 -26 ATOM 2227 CB CYS 375 -1.809 -28 ATOM 2228 SG CYS 375 -2.015 -26 ATOM 2229 N SER 376 -4.207 -27 ATOM 2230 CA SER 376 -5.221 -27 ATOM 2231 CB SER 376 -6.529 -27 ATOM 2232 OG SER 376 -6.680 -28 ATOM 2233 C SER 376 -5.455 -25 ATOM 2234 O SER 376 -6.133 -25 ATOM 2235 N THR 377 -4.892 -25 ATOM 2236 CA THR 377 -4.816 -23 ATOM 2237 CB THR 377 -5.466 -23 ATOM 2238 OG1 THR 377 -4.997 -24 ATOM 2239 CG2 THR 377 -6.974 -23 ATOM 2240 C THR 377 -3.366 -23 ATOM 2241 O THR 377 -3.047 -22 ATOM 2242 N CYS 378 -2.497 -24 ATOM 2243 CA CYS 378 -1.081 -23 ATOM 2244 C CYS 378 -0.729 -23 ATOM 2245 0 CYS 378 -1.265 -23 ATOM 2246 CB CYS 378 -0.249 -25 ATOM 2247 SG CYS 378 -0.190 -25 ATOM 2248 N PHE 379 0.169 -22 ATOM 2249 CA PHE 379 0.663 -21 ATOM 2250 CB PHE 379 0.228 -19 ATOM 2251 CG PHE 379 -1.233 -19 ATOM 2252 CDl PHE 379 -2.151 -19 ATOM 2253 CD2 PHE 379 -1.709 -19 ATOM 2254 CEl PHE 379 -3.520 -19 ATOM 2255 CE2 PHE 379 -3.072 -19 ATOM 2256 CZ PHE 379 -3.978 -19 ATOM 2257 C PHE 379 2.172 -21 ATOM 2258 O PHE 379 2.837 -21 ATOM 2259 N VAL 380 2.710 -21 ATOM 2260 CA VAL 380 4 . 127 -21 ATOM 2261 CB VAL 380 4 . 421 -22 ATOM 2262 CGI VAL 380 3.910 -23 ATOM 2263 CG2 VAL 380 5.895 -23 ATOM 2264 C VAL 380 4.526 -20 ATOM 2265 O VAL 380 3.706 -20 ATOM 2266 N SER 381 5.774 -19 ATOM 2267 CA SER 381 6.242 -19 ATOM 2268 CB SER 381 7.095 -17 ATOM 2269 OG SER 381 7.575 -17 ATOM 2270 C SER 381 7.038 -20 ATOM 2271 O SER 381 7.786 -20 ATOM 2272 N GLN 382 6.866 -19 ATOM 2273 CA GLN 382 7.558 -20 ATOM 2274 CB GLN 382 6.699 -21 ATOM 2275 CG GLN 382 6.625 -22 ATOM 2276 CD GLN 382 5.873 -24 ATOM 2277 OE1 GLN 382 5.701 -25 ATOM 2278 NE2 GLN 382 5.430 -24
29 . 126 1 . 00 27 .77 B N 29 .498 1 . 00 28 . 83 B C 30 .706 1 .00 29 . 82 B C 31, . 322 1 .00 30 .59 B 0 29 . 829 1 . 00 29 .05 B c 30 .665 1 . 00 29 .97 B 0 29 . 172 1 . 00 30 .11 B N 29 . 310 1 . 00 30 .04 B c 28 . 159 1 .00 30 .84 B c 28 .205 1 . 00 33 .39 B 0 30 . 641 1 . 00 30 . 17 B c 30 .986 1 . 00 29 . 58 B 0 31, . 385 1 .00 31 .28 B N 32 . 688 1 . 00 32 .37 B c 33 .317 1 . 00 32 .98 B c 32 .964 1 . 00 34 .09 B c 32 .042 1 . 00 35 . 12 B 0 33 . 615 1 .00 34 .70 B 0 33 .616 1 . 00 31 .98 B c 34 .403 1 . 00 33 . 02 B 0 33 . 525 1 . 00 32 .06 B N 34 .204 1 . 00 31 . 88 B c 33 .477 1, .00 30 . 87 B c 32 . 618 1, .00 28 . 42 B 0 35 . 674 1, .00 31 . 19 B c 36 . 040 1, .00 37 .01 B s 33 .807 1, . 00 32 .21 B N 32 . 954 1, . 00 33. . 14 B c 33 . 071 1, . 00 32 . 67 B c 34, . 388 1, . 00 36 .61 B 0 33 .237 1, .00 32 .73 B c 32 .474 1, . 00 33 . 18 B 0 34 , . 335 1. .00 33, . 07 B N 34 . 571 1. .00 32 .43 B c 35, .916 1, . 00 32 .44 B c 36, . 947 1, . 00 31, . 10 B 0 35, . 801 1, . 00 31. . 10 B c 34 , .549 1. .00 31, . 50 B c 35 , .061 1, . 00 30 , .92 B 0 33 , .936 1, . 00 29, .98 B N 33 , . 837 1, . 00 29, . 05 B c 32 , . 527 1, . 00 26, .98 B c 31. ,459 1, . 00 25, .69 B 0 33 , .989 1. ,00 29, . 82 B c 35 , .704 1. ,00 33 , . 15 B s 32 , . 627 1. ,00 24 , .89 B N 31. ,463 1. . 00 23. . 14 B c 31. , 530 1. .00 21. , 19 B c 31. ,289 1. .00 22 , . 53 B c 32 , .309 1. , 00 22 . .23 B c 30 . ,019 1. , 00 22 . ,19 B c 32 . , 059 1. , 00 22 . ,41 B c 29. ,764 1. , 00 20 . , 69 B c 30 , .783 1. , 00 21. , 30 B c 31. , 357 1. .00 23. .01 B c 32 . ,285 1. .00 23. .48 B 0 30 , .215 1. , 00 21. .60 B N 29. .953 1. , 00 21. , 47 B c 29. , 624 1. , 00 20 . , 54 B c 28 . .235 1. .00 19. ,96 B c 29. ,760 1. , 00 19. , 12 B c 28 . ,768 1. . 00 21. ,24 B c 27 . , 891 1. 00 21. ,49 B 0 28 . ,737 1. .00 21 . , 07 B N 27 . ,596 1. .00 23. .27 B c 28 . . 073 1. . 00 24 . .23 B c 26. . 972 1. 00 27. .50 B 0 26. . 603 1. 00 24 . 40 B c 27 . , 003 1. , 00 25. . 03 B 0 25. .310 1. .00 22 . 98 B N 24 . 294 1. .00 24 . .19 B c 23. .851 1. .00 25. .69 B c 24 . .858 1. 00 28 . .37 B c 24 . .310 1. 00 31. 99 B c 25 . , Oil 1. 00 32 . 02 B 0 23. 055 1. 00 33 . ,34 B N 309 WO 2009/026558 PCT/US2008/074097 ATOM 2279 c GLN 382 7.924 -19 ATOM 2280 0 GLN 382 7.331 -18 ATOM 2281 N SER 383 8.918 -20 ATOM 2282 CA SER 383 9.435 -19 ATOM 2283 CB SER 383 10.741 -18 ATOM 2284 OG SER 383 10.523 -17 ATOM 2285 C SER 383 9.68 6 -2 0 ATOM 2286 O SER 383 9.703 -21 ATOM 2287 N GLY 384 9.8 92 -19 ATOM 2288 CA GLY 384 9.975 -20 ATOM 2289 C GLY 384 9.031 -20 ATOM 2290 0 GLY 384 8.130 -19 ATOM 2291 N THR 385 9.240 -20 ATOM 2292 CA THR 385 8.417 -2 0 ATOM 2293 CB THR 385 9.056 -20 ATOM 2294 OG1 THR 385 9.504 -21 ATOM 2295 CG2 THR 385 10.221 -19 ATOM 2296 C THR 385 7.003 -20 ATOM 2297 O THR 385 6.094 -20 ATOM 2298 N SER 386 6.820 -21 ATOM 2299 CA SER 386 5.495 -22 ATOM 2300 CB SER 386 5.572 -23 ATOM 2301 OG SER 386 5.940 -24 ATOM 2302 C SER 386 4.591 -21 ATOM 2303 O SER 386 3.444 -20 ATOM 2304 N GLN 387 5.104 -2 0 ATOM 2305 CA GLN 387 4.283 -19 ATOM 2306 CB GLN 387 5.064 -19 ATOM 2307 CG GLN 387 6.153 -19 ATOM 2308 CD GLN 387 5.615 -21 ATOM 2309 OE1 GLN 387 4.627 -21 ATOM 2310 NE2 GLN 387 6.263 -22 ATOM 2311 C GLN 387 3.880 -18 ATOM 2312 0 GLN 387 2.777 -17 ATOM 2313 N ALA 388 4.787 -18 ATOM 2314 CA ALA 388 4.497 -17 ATOM 2315 CB ALA 388 5.740 -16 ATOM 2316 C ALA 388 3.319 -17 ATOM 2317 0 ALA 388 2.242 -16 ATOM 2318 N ALA 389 3.529 -18 ATOM 2319 CA ALA 389 2.503 -19 ATOM 2320 CB ALA 389 2.887 -2 0 ATOM 2321 C ALA 389 1. 123 -19 ATOM 2322 0 ALA 389 0.135 -18 ATOM 2323 N ALA 390 1.057 -19 ATOM 2324 CA ALA 390 -0.215 -19 ATOM 2325 CB ALA 390 -0.026 -20 ATOM 2326 C ALA 390 -0.843 -18 ATOM 2327 0 ALA 390 -2.068 -18 ATOM 2328 N HIS 391 -0.012 -17 ATOM 2329 CA HIS 391 -0.526 -15 ATOM 2330 CB HIS 391 0.615 -14 ATOM 2331 CG HIS 391 0.912 -14 ATOM 2332 CD2 HIS 391 0.636 -13 ATOM 2333 ND1 HIS 391 1.615 -15 ATOM 2334 CEl HIS 391 1.761 -14 ATOM 2335 NE2 HIS 391 1. 177 -13 ATOM 2336 C HIS 391 -1.241 -15 ATOM 2337 0 HIS 391 -2.274 -14 ATOM 2338 N VAL 392 -0.688 -16 ATOM 2339 CA VAL 392 -1.146 -15 ATOM 2340 CB VAL 392 0.007 -15 ATOM 2341 CGI VAL 392 -0.475 -15 ATOM 2342 CG2 VAL 392 1.143 -14 ATOM 2343 C VAL 392 -2.369 -16 ATOM 2344 O VAL 392 -3.269 -15 ATOM 2345 N ALA 393 -2.421 -17 ATOM 2346 CA ALA 393 -3.658 -18 ATOM 2347 CB ALA 393 -3.453 -19 ATOM 2348 C ALA 393 -4.791 -17 ATOM 2349 0 ALA 393 -5.936 -17 ATOM 2350 N GLY 394 -4.453 -17 ATOM 2351 CA GLY 394 -5.397 -16 ATOM 2352 C GLY 394 -5.878 -15 ATOM 2353 0 GLY 394 -7.082 -14 ATOM 2354 N ILE 395 -4.950 -14
23.090 1.00 24.25 B C 22.869 1.00 23.92 B O 22.328 1.00 24.93 B N 21.186 1.00 25.23 B C 21.569 1.00 24.50 B C 22.550 1.00 21.80 B 0 20.003 1.00 25.02 B c 20.165 1.00 26.23 B 0 18.818 1.00 2 5.92 B N 17.611 1.00 25.10 B c 16.534 1.00 25.74 B c 16.804 1.00 24.41 B 0 15.302 1.00 26.36 B N 14.185 1.00 2 6.63 B c 12.841 1.00 25.25 B c 12.890 1.00 23.96 B 0 12.541 1.00 25.37 B c 14.254 1.00 27.62 B c 13.554 1.00 28.58 B 0 15.099 1.00 26.33 B N 15.316 1.00 26.38 B c 16.184 1.00 26.41 B c 15.395 1.00 27.85 B 0 15.978 1.00 26.58 B c 15.572 1.00 27.11 B 0 16.998 1.00 25.64 B N 17.780 1.00 23.63 B c 18.978 1.00 22.61 B c 19.464 1.00 22.42 B c 20.096 1.00 21.76 B c 20.839 1.00 21.92 B 0 19.809 1.00 20.35 B N 16.886 1.00 23.78 B c 16.997 1.00 24.91 B 0 15.992 1.00 23.75 B N 14.972 1.00 23.70 B c 14.094 1.00 23.02 B c 14 .113 1.00 23.75 B c 14.129 1.00 24.11 B 0 13.374 1.00 22.91 B N 12.498 1.00 21.81 B c 12.086 1.00 19.84 B c 13.172 1.00 22.14 B c 12.584 1.00 22.22 B 0 14.410 1.00 22.17 B N 15.123 1.00 22.04 B c 16.506 1.00 22.25 B c 15.249 1.00 21.51 B c 15.179 1.00 21.52 B 0 15.443 1.00 20.10 B N 15.538 1.00 18.46 B c 15.771 1.00 19.36 B c 17.214 1.00 20.07 B c 17.995 1.00 19.81 B c 18.010 1.00 18.44 B N 19.216 1.00 18.95 B c 19.234 1.00 18.77 B N 14.234 1.00 16.67 B C 14.222 1.00 15.39 B 0 13.136 1.00 15.23 B N 11.815 1.00 14.91 B C 10.783 1.00 14 .04 B c 9.382 1.00 12.46 B c 11.169 1.00 12.88 B c 11.385 1.00 15.09 B c 10.722 1.00 14.21 B 0 11.789 1.00 15.37 B N 11.655 1.00 17.74 B c 12.163 1.00 18.52 B c 12.434 1.00 17.78 B c 11.980 1.00 16.51 B 0 13.606 1.00 18.67 B N 14.359 1.00 19.56 B c 13.613 1.00 20.36 B c 13.501 1.00 21.22 B 0 13.096 1.00 20.24 B N 310 WO 2009/026558 PCT/US2008/074097 ATOM 2355 CA ILE 395 -5.312 -13 ATOM 2356 CB ILE 395 -4.060 -12 ATOM 2357 CG2 ILE 395 -4.449 -11 ATOM 2358 CGI ILE 395 -3.301 -12 ATOM 2359 CDl ILE 395 -2.049 -11 ATOM 2360 C ILE 395 -6.077 -13 ATOM 2361 0 ILE 395 -6.974 -12 ATOM 2362 N ALA 396 -5.732 -14 ATOM 2363 CA ALA 396 -6.436 -15 ATOM 2364 CB ALA 396 -5.770 -16 ATOM 2365 C ALA 396 -7.885 -15 ATOM 2366 0 ALA 396 -8.809 -14 ATOM 2367 N ALA 397 -8.071 -16 ATOM 2368 CA ALA 397 -9.402 -16 ATOM 2369 CB ALA 397 -9.305 -17 ATOM 2370 C ALA 397 -10.244 -15 ATOM 2371 0 ALA 397 -11.378 -15 ATOM 2372 N MET 398 -9.686 -14 ATOM 2373 CA MET 398 -10.426 -13 ATOM 2374 CB MET 398 -9.601 -12 ATOM 2375 CG MET 398 -9.150 -12 ATOM 2376 SD MET 398 -10.147 -12 ATOM 2377 CE MET 398 -9.367 -10 ATOM 2378 C MET 398 -10.784 -12 ATOM 2379 0 MET 398 -11.925 -11 ATOM 2380 N MET 399 -9.815 -12 ATOM 2381 CA MET 399 -10.059 -11 ATOM 2382 CB MET 399 -8.741 -11 ATOM 2383 CG MET 399 -7.755 -10 ATOM 2384 SD MET 399 -6.151 -10 ATOM 2385 CE MET 399 -6.680 -9 ATOM 2386 C MET 399 -11.032 -12 ATOM 2387 0 MET 399 -11.828 -11 ATOM 2388 N LEU 400 -10.975 -13 ATOM 2389 CA LEU 400 -11.878 -14 ATOM 2390 CB LEU 400 -11.349 -15 ATOM 2391 CG LEU 400 -10.109 -15 ATOM 2392 CDl LEU 400 -9.897 -17 ATOM 2393 CD2 LEU 400 -10.273 -15 ATOM 2394 C LEU 400 -13.248 -14 ATOM 2395 O LEU 400 -14.267 -14 ATOM 2396 N SER 401 -13.284 -14 ATOM 2397 CA SER 401 -14.566 -14 ATOM 2398 CB SER 401 -14.375 -14 ATOM 2399 OG SER 401 -15.532 -15 ATOM 2400 C SER 401 -15.288 -13 ATOM 2401 O SER 401 -16.508 -13 ATOM 2402 N ALA 402 -14.523 -12 ATOM 2403 CA ALA 402 -15.106 -10 ATOM 2404 CB ALA 402 -14.124 -9 ATOM 2405 C ALA 402 -15.531 -10 ATOM 2406 0 ALA 402 -16.724 -10 ATOM 2407 N GLU 403 -14.576 -10 ATOM 2408 CA GLU 403 -14.920 -10 ATOM 2409 CB GLU 403 -14.104 -9 ATOM 2410 CG GLU 403 -13.762 -8 ATOM 2411 CD GLU 403 -12.300 -8 ATOM 2412 OE1 GLU 403 -11.906 -7 ATOM 2413 OE2 GLU 403 -11.547 -8 ATOM 2414 C GLU 403 -14.652 -12 ATOM 2415 O GLU 403 -13.554 -12 ATOM 2416 N PRO 404 -15.661 -13 ATOM 2417 CD PRO 404 -16.921 -12 ATOM 2418 CA PRO 404 -15.499 -14 ATOM 2419 CB PRO 404 -16.769 -15 ATOM 2420 CG PRO 404 -17.237 -14 ATOM 2421 C PRO 404 -15.296 -14 ATOM 2422 O PRO 404 -14.748 -15 ATOM 2423 N GLU 405 -15.727 -13 ATOM 2424 CA GLU 405 -15.601 -13 ATOM 2425 CB GLU 405 -16.583 -13 ATOM 2426 CG GLU 405 -18.044 -13 ATOM 2427 CD GLU 405 -19.001 -12 ATOM 2428 OE1 GLU 405 -20.212 -12 ATOM 2429 OE2 GLU 405 -18.553 -11 ATOM 2430 C GLU 405 -14.188 -13 12.384 1.00 20.11 B C 12.034 1.00 20.04 B C 11.302 1.00 19.78 B c 13.316 1.00 20.30 B c 13.095 1.00 19.69 B c 11.104 1.00 21.08 B c 10.691 1.00 21.99 B 0 10.473 1.00 20.99 B N 9.267 1.00 20.56 B c 8.659 1.00 20.18 B c 9.631 1.00 19.85 B c 8.995 1.00 17.95 B 0 10.677 1.00 21.02 B N 11.154 1.00 21.16 B c 12.464 1.00 17.93 B c 11.342 1.00 22.61 B c 10.875 1.00 25.02 B 0 12.014 1.00 23.67 B N 12.282 1.00 23.20 B c 13.167 1.00 24.40 B c 14.457 1.00 29.13 B c 15.879 1.00 35.63 B s 16.357 1.00 31.39 B c 10.980 1.00 23.27 B c 10.782 1.00 22.16 B 0 10.083 1.00 22.78 B N 8.843 1.00 22.76 B c 8.118 1.00 24.23 B c 8.92 8 1.00 27.83 B c 8.115 1.00 32.96 B s 6.497 1.00 29.89 B c 7.930 1.00 22.15 B c 7.218 1.00 21.59 B 0 7.957 1.00 21.52 B N 7.140 1.00 20.75 B c 6.962 1.00 18.56 B c 6.085 1.00 16.86 B c 5.826 1.00 13.64 B c 4.770 1.00 15.30 B c 7.782 1.00 22.24 B c 7.092 1.00 23.47 B 0 9.108 1.00 22.69 B N 9.786 1.00 23.81 B c 11.269 1.00 25.01 B c 11.804 1.00 25.44 B 0 9.596 1.00 23.85 B c 9.696 1.00 23.69 B 0 9.310 1.00 25.13 B N 9.016 1.00 25.64 B c 9.291 1.00 23.94 B c 7.560 1.00 28.07 B c 7.279 1.00 31.96 B 0 6.631 1.00 28.94 B N 5.204 1.00 29.12 B c 4.382 1.00 29.99 B c 5.092 1.00 33.22 B c 4.979 1.00 36.14 B c 3.941 1.00 37.63 B 0 5.918 1.00 38.88 B 0 4.657 1.00 27.95 B c 4 . 180 1.00 26.83 B 0 4.719 1.00 26.86 B N 5.442 1.00 25.89 B c 4.362 1.00 25.99 B c 4.911 1.00 25.93 B c 5.983 1.00 25.26 B c 2.868 1.00 25.55 B c 2.479 1.00 26.48 B 0 2.029 1.00 25.09 B N 0.588 1.00 25.06 B c -0.153 1.00 27.09 B c -0.031 1.00 29.66 B c -0.752 1.00 30.19 B c -0.767 1.00 31.61 B 0 -1.303 1.00 30.56 B 0 0.056 1.00 24.86 B c 311 WO 2009/026558 PCT/US2008/074097 ATOM 2431 0 GLU 405 -13.948 -13 ATOM 2432 N LEU 406 -13.256 -13 ATOM 2433 CA LEU 406 -11.870 -13 ATOM 2434 CB LEU 406 -11.000 -12 ATOM 2435 CG LEU 406 -11.111 -11 ATOM 2436 CDl LEU 406 -10.269 -11 ATOM 2437 CD2 LEU 406 -10.664 -10 ATOM 2438 C LEU 406 -11.234 -14 ATOM 2439 O LEU 406 -11.275 -15 ATOM 2440 N THR 407 -10.633 -14 ATOM 2441 CA THR 407 -9.781 -15 ATOM 2442 CB THR 407 -9.533 -14 ATOM 2443 OG1 THR 407 -8.682 -13 ATOM 2444 CG2 THR 407 -10.827 -14 ATOM 2445 C THR 407 -8.419 -15 ATOM 2446 O THR 407 -8.081 -14 ATOM 2447 N LEU 408 -7.630 -16 ATOM 2448 CA LEU 408 -6.312 -16 ATOM 2449 CB LEU 408 -5.678 -17 ATOM 2450 CG LEU 408 -4.472 -18 ATOM 2451 CDl LEU 408 -4.734 -17 ATOM 2452 CD2 LEU 408 -4 .211 -19 ATOM 2453 C LEU 408 -5.421 -15 ATOM 2454 O LEU 408 -4.552 -14 ATOM 2455 N ALA 409 -5.651 -14 ATOM 2456 CA ALA 409 -4.906 -13 ATOM 2457 CB ALA 409 -5.280 -13 ATOM 2458 C ALA 409 -5.248 -12 ATOM 2459 0 ALA 409 -4.368 -11 ATOM 2460 N GLU 410 -6.540 -12 ATOM 2461 CA GLU 410 -6.976 -10 ATOM 2462 CB GLU 410 -8.480 -10 ATOM 2463 CG GLU 410 -8.903 -10 ATOM 2464 CD GLU 410 -10.208 -10 ATOM 2465 OE1 GLU 410 -10.441 -10 ATOM 2466 OE2 GLU 410 -10.993 -11 ATOM 2467 C GLU 410 -6.583 -11 ATOM 2468 0 GLU 410 -6.332 -10 ATOM 2469 N LEU 411 -6.532 -12 ATOM 2470 CA LEU 411 -6.175 -12 ATOM 2471 CB LEU 411 -6.387 -13 ATOM 2472 CG LEU 411 -5.995 -14 ATOM 2473 CDl LEU 411 -6.881 -13 ATOM 2474 CD2 LEU 411 -6.123 -15 ATOM 2475 C LEU 411 -4.722 -12 ATOM 2476 O LEU 411 -4.369 -11 ATOM 2477 N ARG 412 -3.877 -12 ATOM 2478 CA ARG 412 -2.471 -12 ATOM 2479 CB ARG 412 -1.683 -12 ATOM 2480 CG ARG 412 -1.384 -14 ATOM 2481 CD ARG 412 -0.517 -14 ATOM 2482 NE ARG 412 0.598 -15 ATOM 2483 CZ ARG 412 0.587 -16 ATOM 2484 NH1 ARG 412 1.643 -17 ATOM 2485 NH2 ARG 412 -0.485 -17 ATOM 2486 C ARG 412 -2.327 -10 ATOM 2487 O ARG 412 -1.628 -9 ATOM 2488 N GLN 413 -3.004 -10 ATOM 2489 CA GLN 413 -2.895 -8 ATOM 2490 CB GLN 413 -3.779 -8 ATOM 2491 CG GLN 413 -3.344 -6 ATOM 2492 CD GLN 413 -1.860 -6 ATOM 2493 OE1 GLN 413 -1.485 -7 ATOM 2494 NE2 GLN 413 -1.008 -6 ATOM 2495 C GLN 413 -3.301 -7 ATOM 2496 0 GLN 413 -2.824 -6 ATOM 2497 N ARG 414 -4 .175 -8 ATOM 2498 CA ARG 414 -4.643 -7 ATOM 2499 CB ARG 414 -5.975 -8 ATOM 2500 CG ARG 414 -7.128 -7 ATOM 2501 CD ARG 414 -8.229 -7 ATOM 2502 NE ARG 414 -9.264 -6 ATOM 2503 CZ ARG 414 -9.560 -6 ATOM 2504 NH1 ARG 414 -8.904 -7 ATOM 2505 NH2 ARG 414 -10.541 -6 ATOM 2506 C ARG 414 -3.657 -7
-1.132 1.00 24.99 B O 0.922 1.00 24.30 B N 0.505 1.00 23.76 B C 1.701 1.00 21.49 B C 2.222 1.00 20.80 B C 3.464 1.00 18.92 B C 1.156 1.00 18.73 B C -0.146 1.00 23.84 B C 0.411 1.00 25.23 B O -1.315 1.00 23.77 B N -1.918 1.00 23.47 B C -3.395 1.00 21.81 B C -3.517 1.00 23.22 B O -4.089 1.00 19.79 B C -1.213 1.00 24.96 B C -0.399 1.00 26.81 B O -1.535 1.00 24.30 B N -0.929 1.00 22.60 B C -1.355 1.00 22.93 B C -0.525 1.00 24.47 B C 0.940 1.00 23.99 B C -0.732 1.00 25.90 B C -1.344 1.00 20.03 B C -0.592 1.00 16.95 B O -2.553 1.00 19.32 B N -3.065 1.00 19.43 B C -4.499 1.00 20.13 B C -2.220 1.00 20.61 B C -1.750 1.00 20.75 B O -2.012 1.00 21.62 B N -1.212 1.00 22.93 B C -1.324 1.00 25.38 B C -2.661 1.00 30.96 B C -3.125 1.00 34.21 B C -4.355 1.00 37.17 B O -2.269 1.00 35.26 B O 0.247 1.00 22.94 B C 0.92 5 1.00 23.23 B O 0.738 1.00 22.70 B N 2.129 1.00 22.90 B C 2.542 1.00 20.63 B C 4.009 1.00 20.39 B C 4.906 1.00 17.47 B C 4.375 1.00 18.76 B C 2.373 1.00 24.89 B C 3.438 1.00 24.07 B O 1.383 1.00 27.02 B N 1.496 1.00 29.77 B C 0.354 1.00 30.56 B C 0.527 1.00 32.41 B C -0.620 1.00 36.01 B C -0.152 1.00 38.01 B N -0.136 1.00 38.92 B C 0.308 1.00 38.83 B N -0.569 1.00 38.86 B N 1.436 1.00 30.73 B C 2.248 1.00 30.38 B O 0.461 1.00 33.11 B N 0.221 1.00 35.39 B C -0.948 1.00 38.60 B C -1.596 1.00 45.86 B C -1.965 1.00 49.77 B C -3.115 1.00 52.54 B O -0.989 1.00 49.77 B N 1.456 1.00 35.24 B C 1.682 1.00 36.49 B O 2.256 1.00 35.12 B N 3.500 1.00 34.96 B C 3.901 1.00 36.59 B C 3.043 1.00 39.95 B C 3.892 1.00 42.16 B C 3.125 1.00 44.38 B N 1.846 1.00 46.36 B C 1.136 1.00 48.71 B N 1.274 1.00 47.81 B N 4.646 1.00 34.00 B C 312 WO 2009/026558 PCT/US2008/074097 ATOM 2507 0 ARG 414 -3.252 -6 ATOM 2508 N LEU 415 -3.278 -9 ATOM 2509 CA LEU 415 -2.233 -9 ATOM 2510 CB LEU 415 -1.689 -10 ATOM 2511 CG LEU 415 -2.574 -11 ATOM 2512 CD1 LEU 415 -2.230 -13 ATOM 2513 CD2 LEU 415 -2.395 -11 ATOM 2514 C LEU 415 -1.091 -8 ATOM 2515 O LEU 415 -0.679 -7 ATOM 2516 N ILE 416 -0.580 -8 ATOM 2517 CA ILE 416 0.423 -7 ATOM 2518 CB ILE 416 0.655 -7 ATOM 2519 CG2 ILE 416 1.444 -5 ATOM 2520 CGI ILE 416 1.374 -8 ATOM 2521 CD1 ILE 416 1.488 -8 ATOM 2522 C ILE 416 -0.046 -6 ATOM 2523 O ILE 416 0.545 -5 ATOM 2524 N HIS 417 -1.130 -5 ATOM 2525 CA HIS 417 -1.556 -4 ATOM 2526 CB HIS 417 -2.812 -3 ATOM 2527 CG HIS 417 -3.393 -2 ATOM 2528 CD2 HIS 417 -2.908 -1 ATOM 2529 ND1 HIS 417 -4.597 -2 ATOM 2530 CEl HIS 417 -4.828 -1 ATOM 2531 NE2 HIS 417 -3.818 -0 ATOM 2532 C HIS 417 -1.811 -3 ATOM 2533 0 HIS 417 -1.646 -2 ATOM 2534 N PHE 418 -2.210 -4 ATOM 2535 CA PHE 418 -2.394 -4 ATOM 2536 CB PHE 418 -3.595 -5 ATOM 2537 CG PHE 418 -4.895 -4 ATOM 2538 CD1 PHE 418 -5.677 -5 ATOM 2539 CD2 PHE 418 -5.285 -3 ATOM 2540 CEl PHE 418 -6.822 -4 ATOM 2541 CE2 PHE 418 -6.426 -2 ATOM 2542 CZ PHE 418 -7.195 -3 ATOM 2543 C PHE 418 -1.164 -4 ATOM 2544 O PHE 418 -1.177 -4 ATOM 2545 N SER 419 -0.094 -5 ATOM 2546 CA SER 419 1.154 -5 ATOM 2547 CB SER 419 2.006 -6 ATOM 2548 OG SER 419 1.593 -7 ATOM 2549 C SER 419 1.905 -4 ATOM 2550 O SER 419 1.879 -3 ATOM 2551 N ALA 420 2.544 -4 ATOM 2552 CA ALA 420 3.554 -3 ATOM 2553 CB ALA 420 4.069 -3 ATOM 2554 C ALA 420 4.675 -3 ATOM 2555 0 ALA 420 5.089 -4 ATOM 2556 N LYS 421 5.172 -2 ATOM 2557 CA LYS 421 6.132 -2 ATOM 2558 CB LYS 421 5.557 -1 ATOM 2559 CG LYS 421 4 .124 -2 ATOM 2560 CD LYS 421 3.716 -2 ATOM 2561 CE LYS 421 2.331 -2 ATOM 2562 NZ LYS 421 1.363 -2 ATOM 2563 C LYS 421 7.468 -1 ATOM 2564 0 LYS 421 7.510 -0 ATOM 2565 N ASP 422 8.562 -2 ATOM 2566 CA ASP 422 9.873 -1 ATOM 2567 CB ASP 422 9.974 -0 ATOM 2568 CG ASP 422 10.080 -0 ATOM 2569 OD1 ASP 422 10.866 -1 ATOM 2570 OD2 ASP 422 9.381 -0 ATOM 2571 C ASP 422 10.124 -1 ATOM 2572 O ASP 422 10.463 -0 ATOM 2573 N VAL 423 9.944 -2 ATOM 2574 CA VAL 423 10.146 -2 ATOM 2575 CB VAL 423 8.831 -2 ATOM 2576 CGI VAL 423 7.775 -1 ATOM 2577 CG2 VAL 423 8.331 -3 ATOM 2578 C VAL 423 11.158 -3 ATOM 2579 O VAL 423 11.697 -3 ATOM 2580 N ILE 424 11.415 -4 ATOM 2581 CA ILE 424 12.307 -5 ATOM 2582 CB ILE 424 11.960 -6 5.270 1.00 34.78 B O 4.931 1.00 32.40 B N 5.912 1.00 31.47 B C 5.748 1.00 31.21 B C 6.346 1.00 31.92 B c 5.697 1.00 33.02 B c 7.862 1.00 30.21 B c 5.750 1.00 31.04 B c 6.711 1.00 31.86 B 0 4.530 1.00 29.96 B N 4.230 1.00 30.82 B c 2.716 1.00 30.83 B c 2.434 1.00 29.81 B c 2.178 1.00 29.19 B c 0.678 1.00 25.78 B c 4.743 1.00 30.89 B c 5.663 1.00 31.33 B 0 4 .145 1.00 31.24 B N 4.300 1.00 30.14 B c 3.469 1.00 30.66 B c 3.679 1.00 32.44 B c 3.388 1.00 33.19 B c 4.319 1.00 31.59 B N 4.417 1.00 32.26 B c 3.860 1.00 33.69 B N 5.750 1.00 29.15 B C 6.122 1.00 29.16 B 0 6.568 1.00 27.70 B N 7.992 1.00 27.83 B C 8.534 1.00 28.70 B c 8.058 1.00 29.85 B c 7.185 1.00 29.88 B c 8.393 1.00 30.40 B c 6.651 1.00 29.59 B c 7.863 1.00 31.18 B c 6.986 1.00 30.31 B c 8.777 1.00 27.12 B c 10.005 1.00 26.90 B 0 8.070 1.00 26.74 B N 8.748 1.00 26.69 B c 7.933 1.00 25.86 B c 8.188 1.00 25.35 B 0 8.983 1.00 26.68 B c 8.144 1.00 26.77 B 0 10.147 1.00 25.25 B N 10.412 1.00 24.13 B c 11.816 1.00 24.79 B c 9.439 1.00 24.87 B c 9.238 1.00 26.34 B 0 8.838 1.00 24.32 B N 7.760 1.00 25.67 B c 6.4 97 1.00 23.67 B c 6.249 1.00 23.87 B c 4.797 1.00 23.84 B c 4.550 1.00 23.52 B c 5.638 1.00 22.85 B N 8.125 1.00 27.41 B c 8.798 1.00 28.11 B 0 7.691 1.00 28.06 B N 7.844 1.00 27.60 B c 6.955 1.00 2 6.92 B c 5.489 1.00 28.56 B c 5.161 1.00 28.83 B 0 4.663 1.00 29.17 B 0 9.296 1.00 26.84 B c 9.607 1.00 26.44 B 0 10.182 1.00 25.89 B N 11.599 1.00 26.20 B c 12.396 1.00 27.67 B c 11.900 1.00 27.74 B c 12.240 1.00 28.31 B c 12.075 1.00 25.50 B c 13.168 1.00 25.97 B 0 11.239 1.00 25.87 B N 11.630 1.00 2 6.65 B c 10.893 1.00 26.26 B c 313 WO 2009/026558 PCT/US2008/074097 uuuuozuuuozuozuuuuoouozuuuozuuuuuuuzuuuuozuuuuuuuuuozuuuuuozuuuuoouozuuuoouo (N^f\|HhinCD^'TH(N X) O i—I O t—I Ο 00 'X) i—I i—i
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T. T. T T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T T. T. T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T o o o o o o o o o o o O o o o o o o o o o o o o o o o o o o o o o o o o o o o o O o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O o o o o o H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < 314 WO 2009/026558 PCT/US2008/074097 ATOM 2659 N GLN 433 20.060 -11 ATOM 2660 CA GLN 433 18.749 -11 ATOM 2661 CB GLN 433 18.879 -12 ATOM 2662 CG GLN 433 19.423 -14 ATOM 2663 CD GLN 433 18.459 -14 ATOM 2664 OE1 GLN 433 18.828 -15 ATOM 2 665 NE2 GLN 433 17.221 -14 ATOM 2666 C GLN 433 17.823 -10 ATOM 2667 0 GLN 433 16.623 -10 ATOM 2668 N ARG 434 18.373 -9 ATOM 2669 CA ARG 434 17.588 -8 ATOM 2670 CB ARG 434 18.518 -7 ATOM 2671 CG ARG 434 19.390 -7 ATOM 2672 CD ARG 434 20.174 -6 ATOM 2673 NE ARG 434 21.266 -7 ATOM 2674 CZ ARG 434 22.538 -6 ATOM 2675 NHl ARG 434 23.473 -7 ATOM 2 67 6 NH2 ARG 434 22.869 -5 ATOM 2677 C ARG 434 16.569 -7 ATOM 2678 O ARG 434 15.431 -7 ATOM 2679 N VAL 435 16.951 -7 ATOM 2680 CA VAL 435 15.975 -7 ATOM 2681 CB VAL 435 16.599 -6 ATOM 2682 CGI VAL 435 17.515 -5 ATOM 2683 CG2 VAL 435 17.315 -7 ATOM 2684 C VAL 435 14.992 -8 ATOM 2685 O VAL 435 13.890 -8 ATOM 2686 N LEU 436 15.389 -9 ATOM 2687 CA LEU 436 14.511 -10 ATOM 2688 CB LEU 436 15.312 -11 ATOM 2689 CG LEU 436 16.446 -12 ATOM 2690 CDl LEU 436 16.995 -13 ATOM 2691 CD2 LEU 436 15.952 -11 ATOM 2692 C LEU 436 13.500 -10 ATOM 2693 O LEU 436 12.351 -11 ATOM 2694 N THR 437 13.936 -10 ATOM 2695 CA THR 437 13.075 -10 ATOM 2696 CB THR 437 13.887 -11 ATOM 2697 OG1 THR 437 14.782 -12 ATOM 2698 CG2 THR 437 12.949 -11 ATOM 2699 C THR 437 12.090 -9 ATOM 2700 O THR 437 12.464 -8 ATOM 2701 N PRO 438 10.807 -10 ATOM 2702 CD PRO 438 10.282 -11 ATOM 2703 CA PRO 438 9.731 -9 ATOM 2704 CB PRO 438 8.453 -9 ATOM 2705 CG PRO 438 8.880 -11 ATOM 2706 C PRO 438 9.847 -8 ATOM 2707 O PRO 438 9.940 -9 ATOM 2708 N ASN 439 9.837 -7 ATOM 2709 CA ASN 439 9.866 -6 ATOM 2710 CB ASN 439 10.627 -5 ATOM 2711 CG ASN 439 11.355 -4 ATOM 2712 OD1 ASN 439 10.869 -4 ATOM 2713 ND2 ASN 439 12.533 -4 ATOM 2714 C ASN 439 8.434 -6 ATOM 2715 0 ASN 439 7.949 -4 ATOM 2716 N LEU 440 7.771 -7 ATOM 2717 CA LEU 440 6.378 -7 ATOM 2718 CB LEU 440 5.470 -7 ATOM 2719 CG LEU 440 5.503 -6 ATOM 2720 CDl LEU 440 4.757 -7 ATOM 2721 CD2 LEU 440 4.883 -5 ATOM 2722 C LEU 440 6.163 -7 ATOM 2723 O LEU 440 6.447 -9 ATOM 2724 N VAL 441 5.647 -7 ATOM 2725 CA VAL 441 5.096 -8 ATOM 2726 CB VAL 441 5.633 -7 ATOM 2727 CGI VAL 441 5.249 -8 ATOM 2728 CG2 VAL 441 7.139 -7 ATOM 2729 C VAL 441 3.581 -7 ATOM 2730 O VAL 441 3.078 -6 ATOM 2731 N ALA 442 2.851 -8 ATOM 2732 CA ALA 442 1.415 -8 ATOM 2733 CB ALA 442 0.938 -10 ATOM 2734 C ALA 442 0.648 -8 1.835 1.00 32.85 B N 2.205 1.00 31.54 B C 3.305 1.00 29.75 B C 2.794 1.00 28.29 B c 1.850 1.00 26.47 B c 1. 184 1.00 24.27 B 0 1.794 1.00 26.30 B N 2.645 1.00 31.04 B c 2.805 1.00 32.65 B 0 2.819 1.00 30.10 B N 3.343 1.00 28.71 B c 3.845 1.00 29.04 B c 5.012 1.00 28.41 B c 5.646 1.00 26.84 B c 6.459 1.00 27.43 B N 6.315 1.00 25.70 B c 7.088 1.00 23.11 B N 5.398 1.00 25.28 B N 2.361 1.00 27.60 B C 2.747 1.00 27.25 B 0 1. 101 1.00 27.74 B N 0.128 1.00 27.86 B C -1.199 1.00 26.45 B c -0.943 1.00 27.10 B c -1.890 1.00 27.00 B c -0.237 1.00 28.30 B c -0.709 1.00 30.16 B 0 -0.022 1.00 27.85 B N -0.307 1.00 27.26 B c -0.467 1.00 27.16 B c -1.478 1.00 25.55 B c -1.511 1.00 24.68 B c -2.849 1.00 22.51 B c 0.808 1.00 27.27 B c 0.551 1.00 28.79 B 0 2.046 1.00 25.82 B N 3.199 1.00 23.86 B c 4.494 1.00 23.41 B c 4.362 1.00 23.12 B 0 5.668 1.00 22.10 B c 3.397 1.00 22.78 B c 3.392 1.00 22.51 B 0 3.566 1.00 23.25 B N 3.511 1.00 24.11 B c 3.742 1.00 22.75 B c 3.639 1.00 23.28 B c 3.049 1.00 23.27 B c 5.099 1.00 21.97 B c 6.125 1.00 19.45 B 0 5.103 1.00 22.81 B N 6.353 1.00 23.40 B c 6.168 1.00 23.33 B c 7.424 1.00 25.22 B c 8.538 1.00 26.16 B 0 7.252 1.00 24.91 B N 6.820 1.00 24.31 B c 6.781 1.00 25.14 B 0 7.256 1.00 24.30 B N 7.690 1.00 25.09 B c 6.589 1.00 23.69 B c 5.247 1.00 24.08 B c 4.220 1.00 21.26 B c 5.401 1.00 23.50 B c 8.966 1.00 25.32 B c 9.007 1.00 24.66 B 0 10.006 1.00 25.82 B N 11.128 1.00 25.14 B c 12.479 1.00 23.66 B c 13.580 1.00 21.33 B c 12.421 1.00 23.17 B c 11.083 1.00 26.87 B c 10.773 1.00 28.65 B 0 11.384 1.00 26.88 B N 11.179 1.00 27.49 B c 10.972 1.00 27.84 B c 12.329 1.00 28.01 B c 315 WO 2009/026558 PCT/US2008/074097 ATOM 2735 0 ALA 442 0.863 -8 ATOM 2736 N ALA 443 -0.260 -7 ATOM 2737 CA ALA 443 -1.259 -6 ATOM 2738 CB ALA 443 -1.135 -5 ATOM 2739 C ALA 443 -2.662 -7 ATOM 2740 0 ALA 443 -2.873 -7 ATOM 2741 N LEU 444 -3.610 -7 ATOM 2742 CA LEU 444 -5.037 -7 ATOM 2743 CB LEU 444 -5.841 -7 ATOM 2744 CG LEU 444 -5.624 -8 ATOM 2745 CDl LEU 444 -6.078 -8 ATOM 2746 CD2 LEU 444 -6.383 -10 ATOM 2747 C LEU 444 -5.503 -5 ATOM 2748 O LEU 444 -4.915 -4 ATOM 2749 N PRO 445 -6.578 -5 ATOM 2750 CD PRO 445 -7.291 -7 ATOM 2751 CA PRO 445 -7.138 -4 ATOM 2752 CB PRO 445 -8.215 -5 ATOM 2753 CG PRO 445 -7.890 -6 ATOM 2754 C PRO 445 -7.727 -3 ATOM 2755 O PRO 445 -8.502 -4 ATOM 2756 N PRO 446 -7.357 -2 ATOM 2757 CD PRO 446 -6.431 -1 ATOM 2758 CA PRO 446 -7.984 -1 ATOM 2759 CB PRO 446 -7.269 -0 ATOM 2760 CG PRO 446 -6.736 -0 ATOM 2761 C PRO 446 -9.471 -1 ATOM 2762 O PRO 446 -10.279 -1 ATOM 2763 OXT PRO 446 -9.793 -1 TER 2764 PRO 446 ATOM 2765 CB THR 294 -8.672 -12 ATOM 2766 OG1 THR 294 -8.921 -13 ATOM 2767 CG2 THR 294 -9.367 -12 ATOM 2768 C THR 294 -6.483 -13 ATOM 2769 O THR 294 -6.465 -14 ATOM 2770 N THR 294 -6.854 -11 ATOM 2771 CA THR 294 -7.135 -12 ATOM 2772 N ASN 295 -5.945 -13 ATOM 2773 CA ASN 295 -5.062 -14 ATOM 2774 CB ASN 295 -5.516 -14 ATOM 2775 CG ASN 295 -4.655 -15 ATOM 2776 OD1 ASN 295 -3.455 -15 ATOM 2777 ND2 ASN 295 -5.271 -16 ATOM 2778 C ASN 295 -3.656 -13 ATOM 2779 0 ASN 295 -3.211 -13 ATOM 2780 N GLU 296 -2.965 -13 ATOM 2781 CA GLU 296 -1.734 -13 ATOM 2782 CB GLU 296 -1.337 -13 ATOM 2783 CG GLU 296 -2.292 -12 ATOM 2784 CD GLU 296 -3.482 -13 ATOM 2785 OE1 GLU 296 -3.596 -14 ATOM 2786 OE2 GLU 296 -4.300 -13 ATOM 2787 C GLU 296 -0.588 -13 ATOM 2788 O GLU 296 0.499 -13 ATOM 2789 N CYS 297 -0.838 -14 ATOM 2790 CA CYS 297 0.228 -15 ATOM 2791 C CYS 297 0.233 -14 ATOM 2792 0 CYS 297 1.110 -14 ATOM 2793 CB CYS 297 0.151 -16 ATOM 2794 SG CYS 297 0.339 -17 ATOM 2795 N LEU 298 -0.759 -13 ATOM 2796 CA LEU 298 -0.761 -12 ATOM 2797 CB LEU 298 -2.174 -12 ATOM 2798 CG LEU 298 -3.084 -13 ATOM 2799 CDl LEU 298 -4.519 -13 ATOM 2800 CD2 LEU 298 -2.920 -13 ATOM 2801 C LEU 298 0.202 -11 ATOM 2802 O LEU 298 0.430 -10 ATOM 2803 N ASP 299 0.781 -11 ATOM 2804 CA ASP 299 1.885 -10 ATOM 2805 CB ASP 299 1.615 -9 ATOM 2806 CG ASP 299 2.450 -8 ATOM 2807 OD1 ASP 299 2.944 -8 ATOM 2808 OD2 ASP 299 2.613 -7 ATOM 2809 C ASP 299 3.199 -11 ATOM 2810 O ASP 299 3.518 -11 13.490 1.00 27.44 B O 11.996 1.00 29.53 B N 12.950 1.00 29.76 B C 13.149 1.00 28.70 B C 12.467 1.00 30.98 B c 11.282 1.00 30.38 B 0 13.402 1.00 32.91 B N 13.095 1.00 33.56 B c 14.348 1.00 29.03 B c 15.021 1.00 26.74 B c 16.4 62 1.00 24.31 B c 14.269 1.00 25.72 B c 12.565 1.00 37.13 B c 12.869 1.00 36.31 B 0 11.766 1.00 40.64 B N 11.267 1.00 40.97 B c 11.216 1.00 43.51 B c 10.252 1.00 41.99 B c 9.998 1.00 41.69 B c 12.343 1.00 47.02 B c 13.149 1.00 47.30 B 0 12.422 1.00 50.39 B N 11.538 1.00 52.20 B c 13.418 1.00 52.13 B c 13.234 1.00 52.77 B c 11.833 1.00 53.26 B c 13.117 1.00 52.85 B c 14.075 1.00 53.37 B 0 11.911 1.00 53.26 B 0 B 38.449 1.00 44.50 EGFA c 39.043 1.00 46.09 EGFA 0 37.098 1.00 44.95 EGFA c 37.580 1.00 42.73 EGFA c 38.105 1.00 42.87 EGFA 0 37.620 1.00 43.75 EGFA N 38.303 1.00 43.33 EGFA c 36.380 1.00 40.79 EGFA N 35.774 1.00 38.54 EGFA c 34.369 1.00 38.56 EGFA c 33.767 1.00 38.98 EGFA c 34.023 1.00 39.16 EGFA 0 32.961 1.00 39.03 EGFA N 35.711 1.00 37.61 EGFA c 34.693 1.00 35.61 EGFA 0 36.828 1.00 36.47 EGFA N 37.119 1.00 36.71 EGFA c 38.574 1.00 35.44 EGFA c 39.619 1.00 33.45 EGFA c 39.915 1.00 35.35 EGFA c 39.248 1.00 35.30 EGFA 0 40.804 1.00 33.34 EGFA 0 36.151 1.00 36.70 EGFA c 36.244 1.00 36.33 EGFA 0 35.207 1.00 36.97 EGFA N 34.351 1.00 37.51 EGFA c 32.972 1.00 37.46 EGFA c 32.177 1.00 36.37 EGFA 0 34.243 1.00 38.66 EGFA c 35.863 1.00 41.23 EGFA s 32.688 1.00 38.90 EGFA N 31.478 1.00 38.94 EGFA c 31.205 1.00 38.48 EGFA c 30.877 1.00 39.20 EGFA c 31.222 1.00 38.76 EGFA c 29.400 1.00 37.53 EGFA c 31.660 1.00 40.24 EGFA c 30.742 1.00 40.91 EGFA 0 32.851 1.00 40.63 EGFA N 33.038 1.00 41.29 EGFA c 34.207 1.00 45.11 EGFA c 34.133 1.00 48.48 EGFA c 35.182 1.00 51.40 EGFA 0 33.013 1.00 50.27 EGFA 0 33.265 1.00 40.06 EGFA c 34.383 1.00 39.62 EGFA 0 316 WO 2009/026558 PCT/US2008/074097 ATOM 2811 N ASN 300 3.952 -11 ATOM 2812 CA ASN 300 5.278 -12 ATOM 2813 CB ASN 300 6.187 -11 ATOM 2814 CG ASN 300 7.613 -11 ATOM 2815 OD1 ASN 300 8.562 -11 ATOM 2816 ND2 ASN 300 7.775 -11 ATOM 2817 C ASN 300 5.256 -13 ATOM 2818 O ASN 300 6.235 -13 ATOM 2819 N ASN 301 4 .136 -14 ATOM 2820 CA ASN 301 3.977 -15 ATOM 2821 CB ASN 301 5.029 -16 ATOM 2822 CG ASN 301 4.603 -17 ATOM 2823 OD1 ASN 301 3.431 -18 ATOM 2824 ND2 ASN 301 5.554 -18 ATOM 2825 C ASN 301 4.091 -15 ATOM 2826 O ASN 301 4.368 -16 ATOM 2827 N GLY 302 3.874 -14 ATOM 2828 CA GLY 302 3.929 -14 ATOM 2829 C GLY 302 5.356 -14 ATOM 2830 0 GLY 302 5.62 0 -14 ATOM 2831 N GLY 303 6.277 -13 ATOM 2832 CA GLY 303 7.674 -13 ATOM 2833 C GLY 303 8.255 -15 ATOM 2834 0 GLY 303 9.411 -15 ATOM 2835 N CYS 304 7.448 -16 ATOM 2836 CA CYS 304 7.819 -17 ATOM 2837 C CYS 304 8.848 -18 ATOM 2838 0 CYS 304 8.667 -17 ATOM 2839 CB CYS 304 6.579 -18 ATOM 2840 SG CYS 304 5.347 -18 ATOM 2841 N SER 305 9.917 -18 ATOM 2842 CA SER 305 10.966 -19 ATOM 2843 CB SER 305 12.152 -19 ATOM 2844 OG SER 305 11.790 -21 ATOM 2845 C SER 305 10.398 -20 ATOM 2846 O SER 305 10.667 -19 ATOM 2847 N HIS 306 9.598 -21 ATOM 2848 CA HIS 306 9.060 -22 ATOM 2849 CB HIS 306 9.468 -23 ATOM 2850 CG HIS 306 10.931 -23 ATOM 2851 CD2 HIS 306 12.012 -23 ATOM 2852 ND1 HIS 306 11.420 -24 ATOM 2853 CEl HIS 306 12.739 -2 4 ATOM 2854 NE2 HIS 306 13.124 -23 ATOM 2855 C HIS 306 7.541 -22 ATOM 2856 0 HIS 306 7.014 -21 ATOM 2857 N VAL 307 6.839 -22 ATOM 2858 CA VAL 307 5.381 -22 ATOM 2859 CB VAL 307 4.793 -2 4 ATOM 2860 CGI VAL 307 3.271 -2 4 ATOM 2861 CG2 VAL 307 5.210 -2 5 ATOM 2862 C VAL 307 4.785 -22 ATOM 2863 O VAL 307 5.269 -22 ATOM 2864 N CYS 308 3.726 -21 ATOM 2865 CA CYS 308 2.902 -2 0 ATOM 2866 C CYS 308 1.562 -21 ATOM 2 8 67 0 CYS 308 1.026 -22 ATOM 2868 CB CYS 308 2.585 -19 ATOM 2869 SG CYS 308 0.778 -19 ATOM 2870 N ASN 309 1.016 -21 ATOM 2871 CA ASN 309 -0.305 -21 ATOM 2872 CB ASN 309 -0.193 -23 ATOM 2873 CG ASN 309 -1.511 -2 3 ATOM 2874 OD1 ASN 309 -2.383 -2 3 ATOM 2875 ND2 ASN 309 -1.667 -24 ATOM 2876 C ASN 309 -1.244 -2 0 ATOM 2877 O ASN 309 -1.025 -20 ATOM 2878 N ASP 310 -2.291 -20 ATOM 2879 CA ASP 310 -3.285 -19 ATOM 2880 CB ASP 310 -4.013 -19 ATOM 2881 CG ASP 310 -4.927 -17 ATOM 2882 OD1 ASP 310 -4.822 -17 ATOM 2883 OD2 ASP 310 -5.749 -17 ATOM 2884 C ASP 310 -4.297 -2 0 ATOM 2885 O ASP 310 -5.140 -20 ATOM 2886 N LEU 311 -4.206 -19
32.187 1.00 38.77 EGFA N 32.257 1.00 38.83 EGFA C 33.093 1.00 40.88 EGFA C 32.593 1.00 43.06 EGFA c 33.378 1.00 43.69 EGFA 0 31.273 1.00 44.81 EGFA N 32.843 1.00 38.88 EGFA c 33.448 1.00 38.75 EGFA 0 32.661 1.00 38.27 EGFA N 33.153 1.00 38.98 EGFA c 32.524 1.00 38.60 EGFA c 32.508 1.00 39.84 EGFA c 32.280 1.00 39.37 EGFA 0 32.748 1.00 39.66 EGFA N 34.676 1.00 39.19 EGFA c 35.265 1.00 38.65 EGFA 0 35.305 1.00 38.94 EGFA N 36.752 1.00 39.47 EGFA c 37.255 1.00 39.98 EGFA c 38.408 1.00 40.36 EGFA 0 36.381 1.00 40.10 EGFA N 36.756 1.00 41.13 EGFA c 36.912 1.00 41.77 EGFA c 37.318 1.00 43.49 EGFA 0 36.582 1.00 41.53 EGFA N 36.718 1.00 39.56 EGFA c 35.670 1.00 38.81 EGFA c 34.483 1.00 39.26 EGFA 0 36.564 1.00 38.73 EGFA c 37.890 1.00 37.07 EGFA s 36.093 1.00 37.94 EGFA N 35.149 1.00 36.26 EGFA c 35.870 1.00 34.90 EGFA c 36.529 1.00 33.63 EGFA 0 34.094 1.00 36.04 EGFA c 32.904 1.00 35.42 EGFA 0 34.547 1.00 36.85 EGFA N 33.689 1.00 36.68 EGFA c 34.237 1.00 37.58 EGFA c 34.109 1.00 38.79 EGFA c 34.423 1.00 38.86 EGFA c 33.567 1.00 39.47 EGFA N 33.550 1.00 39.63 EGFA c 34.064 1.00 39.05 EGFA N 33.566 1.00 36.61 EGFA C 32.842 1.00 36.74 EGFA 0 34.271 1.00 36.53 EGFA N 34.252 1.00 36.68 EGFA C 34.359 1.00 36.53 EGFA c 34.440 1.00 33.02 EGFA c 33.153 1.00 36.84 EGFA c 35.370 1.00 37.94 EGFA c 36.505 1.00 36.79 EGFA 0 35.019 1.00 40.08 EGFA N 35.978 1.00 41.42 EGFA c 36.159 1.00 41.00 EGFA c 35.211 1.00 40.92 EGFA 0 35.465 1.00 42.46 EGFA c 35.372 1.00 49.21 EGFA s 37.371 1.00 40.41 EGFA N 37.647 1.00 39.28 EGFA c 38.661 1.00 37.87 EGFA c 38.923 1.00 37.08 EGFA c 38.061 1.00 37.19 EGFA 0 40.116 1.00 38.27 EGFA N 38.181 1.00 40.43 EGFA c 39.260 1.00 41.33 EGFA 0 37.417 1.00 41.20 EGFA N 37.801 1.00 40.90 EGFA c 36.553 1.00 42.26 EGFA c 36.842 1.00 42.34 EGFA c 37.937 1.00 44.79 EGFA 0 35.968 1.00 41.66 EGFA 0 38.755 1.00 41.32 EGFA c 38.337 1.00 41.03 EGFA 0 40.031 1.00 41.42 EGFA N 317 WO 2009/026558 PCT/US2008/074097 ATOM 2887 CA LEU 311 -5.173 -20 ATOM 2888 CB LEU 311 -4.563 -20 ATOM 2889 CG LEU 311 -3.108 -20 ATOM 2890 CDl LEU 311 -2.561 -20 ATOM 2891 CD2 LEU 311 -2.991 -21 ATOM 2892 C LEU 311 -6.398 -19 ATOM 2893 O LEU 311 -6.479 -18 ATOM 2894 N LYS 312 -7.360 -19 ATOM 2895 CA LYS 312 -8.478 -18 ATOM 2896 CB LYS 312 -9.624 -19 ATOM 2897 CG LYS 312 -10.251 -20 ATOM 2898 CD LYS 312 -11.599 -20 ATOM 2899 CE LYS 312 -12.280 -22 ATOM 2900 NZ LYS 312 -13.550 -22 ATOM 2901 C LYS 312 -7.973 -17 ATOM 2902 0 LYS 312 -8.229 -16 ATOM 2903 N ILE 313 -7.234 -17 ATOM 2904 CA ILE 313 -6.706 -16 ATOM 2905 CB ILE 313 -6.987 -17 ATOM 2906 CG2 ILE 313 -7.416 -15 ATOM 2907 CGI ILE 313 -8.083 -18 ATOM 2908 CDl ILE 313 -9.026 -17 ATOM 2909 C ILE 313 -5.207 -16 ATOM 2910 0 ILE 313 -4.445 -17 ATOM 2911 N GLY 314 -4.797 -15 ATOM 2912 CA GLY 314 -3.396 -15 ATOM 2913 C GLY 314 -2.928 -16 ATOM 2914 0 GLY 314 -3.707 -17 ATOM 2915 N TYR 315 -1.625 -16 ATOM 2916 CA TYR 315 -1.028 -17 ATOM 2917 CB TYR 315 -0.553 -17 ATOM 2918 CG TYR 315 0.616 -16 ATOM 2919 CDl TYR 315 1.874 -16 ATOM 2920 CEl TYR 315 2.942 -15 ATOM 2921 CD2 TYR 315 0.459 -15 ATOM 2922 CE2 TYR 315 1.517 -14 ATOM 2923 cz TYR 315 2.756 -14 ATOM 2924 OH TYR 315 3.805 -13 ATOM 2925 C TYR 315 0.153 -18 ATOM 2926 O TYR 315 0.364 -18 ATOM 2927 N GLU 316 0.933 -19 ATOM 2928 CA GLU 316 2.158 -19 ATOM 2929 CB GLU 316 1.819 -21 ATOM 2930 CG GLU 316 1.030 -22 ATOM 2931 CD GLU 316 0.823 -23 ATOM 2932 OE1 GLU 316 1 .123 -23 ATOM 2933 OE2 GLU 316 0.381 -24 ATOM 2934 C GLU 316 3.041 -20 ATOM 2935 0 GLU 316 2.568 -20 ATOM 2936 N CYS 317 4.326 -20 ATOM 2937 CA CYS 317 5.195 -21 ATOM 2938 C CYS 317 5.412 -22 ATOM 2939 0 CYS 317 5.470 -23 ATOM 2940 CB CYS 317 6.538 -20 ATOM 2941 SG CYS 317 6.442 -18 ATOM 2942 N LEU 318 5.547 -2 3 ATOM 2943 CA LEU 318 5.832 -2 4 ATOM 2944 CB LEU 318 4.653 -2 5 ATOM 2945 CG LEU 318 3.328 -2 5 ATOM 2946 CDl LEU 318 2.255 -2 6 ATOM 2947 CD2 LEU 318 3.481 -25 ATOM 2948 C LEU 318 7.098 -25 ATOM 2949 O LEU 318 7.489 -24 ATOM 2950 N CYS 319 7.738 -26 ATOM 2951 CA CYS 319 9.002 -26 ATOM 2952 C CYS 319 8.993 -28 ATOM 2953 0 CYS 319 8.274 -28 ATOM 2954 CB CYS 319 10.123 -26 ATOM 2955 SG CYS 319 10.467 -24 ATOM 2956 N PRO 320 9.812 -28 ATOM 2957 CD PRO 320 10.541 -27 ATOM 2958 CA PRO 320 10.067 -2 9 ATOM 2959 CB PRO 320 11.111 -29 ATOM 2960 CG PRO 320 10.927 -27 ATOM 2961 C PRO 320 10.600 -30 ATOM 2962 O PRO 320 11.453 -30 41.044 1.00 41.31 EGFA C 42.431 1.00 38.52 EGFA C 42.498 1.00 36.88 EGFA c 43.872 1.00 37.89 EGFA c 42.182 1.00 34.94 EGFA c 40.995 1.00 42.14 EGFA c 40.185 1.00 41.25 EGFA 0 41.862 1.00 43.27 EGFA N 42.005 1.00 45.45 EGFA c 42.749 1.00 48.60 EGFA c 41.979 1.00 53.73 EGFA c 42.575 1.00 56.82 EGFA c 41.700 1.00 57.14 EGFA c 42.291 1.00 57.94 EGFA N 42.793 1.00 44 . 13 EGFA c 42.434 1.00 44.64 EGFA 0 43.860 1.00 43.02 EGFA N 44.744 1.00 41.44 EGFA c 46.217 1.00 42.03 EGFA c 46.978 1.00 40.16 EGFA c 46.283 1.00 43.15 EGFA c 47.445 1.00 43.53 EGFA c 44.521 1.00 40.70 EGFA c 45.151 1.00 42.01 EGFA 0 43.605 1.00 39.34 EGFA N 43.255 1.00 38.80 EGFA c 42.230 1.00 38.26 EGFA c 41.456 1.00 37.64 EGFA 0 42.226 1.00 38.97 EGFA N 41.405 1.00 38.95 EGFA c 40.076 1.00 37.90 EGFA c 40.208 1.00 38.39 EGFA c 39.706 1.00 38.94 EGFA c 39.803 1.00 38.15 EGFA c 40.807 1.00 38.29 EGFA c 40.910 1.00 38.40 EGFA c 40.405 1.00 38.57 EGFA c 40.526 1.00 37.81 EGFA 0 42.123 1.00 39.94 EGFA c 43.323 1.00 40.28 EGFA 0 41.364 1.00 41.83 EGFA N 41.871 1.00 43.58 EGFA c 42.721 1.00 44.75 EGFA c 41.959 1.00 48.82 EGFA c 42.761 1.00 52.94 EGFA c 43.971 1.00 57.20 EGFA 0 42.184 1.00 54.04 EGFA 0 40.701 1.00 42.80 EGFA c 39.575 1.00 44 . 00 EGFA 0 40.957 1.00 42.14 EGFA N 39.927 1.00 41.35 EGFA c 40.169 1.00 42.56 EGFA c 41.316 1.00 42.57 EGFA 0 39.925 1.00 38.97 EGFA c 39.586 1.00 35.62 EGFA s 39.089 1.00 43.52 EGFA N 39.210 1.00 43.40 EGFA c 38.689 1.00 41.86 EGFA c 39.355 1.00 41.42 EGFA c 38.937 1.00 42.17 EGFA c 40.855 1.00 41.53 EGFA c 38.453 1.00 44.60 EGFA c 37.510 1.00 44.39 EGFA 0 38.875 1.00 4 6.62 EGFA N 38.276 1.00 48.75 EGFA c 37.639 1.00 48.42 EGFA c 38.077 1.00 47.58 EGFA 0 39.317 1.00 4 9.62 EGFA c 39.923 1.00 50.75 EGFA s 36.593 1.00 49.01 EGFA N 35.842 1.00 48.55 EGFA c 36.060 1.00 49.42 EGFA c 34.972 1.00 48.61 EGFA c 34.582 1.00 48.27 EGFA c 37.165 1.00 50.82 EGFA c 37.952 1.00 50.19 EGFA 0 318 WO 2009/026558 PCT/US2008/074097 ATOM 2963 N ASP 321 10.096 -31 ATOM 2964 CA ASP 321 10.479 -32 ATOM 2965 CB ASP 321 9.810 -33 ATOM 2966 CG ASP 321 9.182 -34 ATOM 2967 OD1 ASP 321 8.807 -33 ATOM 2968 OD2 ASP 321 9.064 -35 ATOM 2969 C ASP 321 11.987 -32 ATOM 2 97 0 O ASP 321 12.599 -32 ATOM 2 971 N GLY 322 12.577 -32 ATOM 2972 CA GLY 322 14.023 -32 ATOM 2973 C GLY 322 14.592 -31 ATOM 2974 0 GLY 322 15.729 -31 ATOM 2975 N PHE 323 13.807 -30 ATOM 2 97 6 CA PHE 323 14.247 -28 ATOM 2977 CB PHE 323 13.607 -27 ATOM 2978 CG PHE 323 14.157 -28 ATOM 2 97 9 CDl PHE 323 14.250 -29 ATOM 2980 CD2 PHE 323 14.550 -27 ATOM 2981 CEl PHE 323 14.723 -2 9 ATOM 2982 CE2 PHE 323 15.024 -27 ATOM 2983 cz PHE 323 15.110 -2 8 ATOM 2984 c PHE 323 13.890 -28 ATOM 2985 0 PHE 323 13.022 -28 ATOM 2986 N GLN 324 14.567 -27 ATOM 2987 CA GLN 324 14.326 -26 ATOM 2988 CB GLN 324 15.645 -26 ATOM 2989 CG GLN 324 15.543 -2 6 ATOM 2990 CD GLN 324 16.897 -26 ATOM 2991 OE1 GLN 324 16.978 -2 6 ATOM 2992 NE2 GLN 324 17.972 -26 ATOM 2993 C GLN 324 13.729 -25 ATOM 2994 0 GLN 324 14.076 -2 4 ATOM 2995 N LEU 325 12.831 -24 ATOM 2996 CA LEU 325 12.250 -23 ATOM 2997 CB LEU 325 10.740 -23 ATOM 2998 CG LEU 325 10.036 -22 ATOM 2999 CDl LEU 325 10.139 -21 ATOM 3000 CD2 LEU 325 8.592 -22 ATOM 3001 C LEU 325 12.880 -22 ATOM 3002 O LEU 325 12.896 -22 ATOM 3003 N VAL 326 13.402 -21 ATOM 3004 CA VAL 326 14.077 -2 0 ATOM 3005 CB VAL 326 15.592 -2 0 ATOM 3006 CGI VAL 326 16.010 -21 ATOM 3007 CG2 VAL 326 15.883 -19 ATOM 3008 C VAL 326 13.418 -19 ATOM 3009 O VAL 326 12.929 -18 ATOM 3010 N ALA 327 13.394 -18 ATOM 3011 CA ALA 327 12.751 -17 ATOM 3012 CB ALA 327 13.443 -16 ATOM 3013 C ALA 327 11.270 -17 ATOM 3014 O ALA 327 10.567 -16 ATOM 3015 N GLN 328 10.813 -18 ATOM 3016 CA GLN 328 9.413 -18 ATOM 3017 CB GLN 328 8.492 -17 ATOM 3018 CG GLN 328 7.372 -18 ATOM 3019 CD GLN 328 7.288 -18 ATOM 3020 OE1 GLN 328 7.462 -19 ATOM 3021 NE2 GLN 328 7.022 -17 ATOM 3022 C GLN 328 9.050 -18 ATOM 3023 0 GLN 328 7.872 -18 ATOM 3024 N ARG 329 10.045 -18 ATOM 3025 CA ARG 329 9.759 -18 ATOM 3026 CB ARG 329 9.202 -16 ATOM 3027 CG ARG 329 10.176 -15 ATOM 3028 CD ARG 329 9.425 -14 ATOM 3029 NE ARG 329 8.174 -14 ATOM 3030 CZ ARG 329 7.271 -13 ATOM 3031 NH1 ARG 329 7.499 -12 ATOM 3032 NH2 ARG 329 6.159 -13 ATOM 3033 C ARG 329 10.921 -18 ATOM 3034 O ARG 329 10.899 -17 ATOM 3035 N ARG 330 11.925 -19 ATOM 3036 CA ARG 330 12.957 -19 ATOM 3037 CB ARG 330 14.202 -18 ATOM 3038 CG ARG 330 15.156 -18 37.234 1.00 52.17 EGFA N 38.325 1.00 52.72 EGFA C 38.187 1.00 57.23 EGFA C 39.499 1.00 61.91 EGFA c 40.332 1.00 63.09 EGFA 0 39.701 1.00 64.11 EGFA 0 38.310 1.00 51.06 EGFA c 37.246 1.00 49.86 EGFA 0 39.499 1.00 49.84 EGFA N 39.614 1.00 48.51 EGFA c 39.793 1.00 47.34 EGFA c 40.239 1.00 47.93 EGFA 0 39.445 1.00 45.29 EGFA N 39.583 1.00 42.20 EGFA c 38.517 1.00 40.51 EGFA c 37.141 1.00 38.07 EGFA c 36.610 1.00 36.97 EGFA c 36.364 1.00 37.05 EGFA c 35.330 1.00 37.63 EGFA c 35.082 1.00 36.22 EGFA c 34.561 1.00 37.83 EGFA c 40.947 1.00 41.10 EGFA c 41.631 1.00 40.98 EGFA 0 41.339 1.00 41.32 EGFA N 42.637 1.00 42.35 EGFA c 43.393 1.00 45.11 EGFA c 44.897 1.00 48.90 EGFA c 45.584 1.00 50.71 EGFA c 46.808 1.00 51.49 EGFA 0 44.793 1.00 50.40 EGFA N 42.408 1.00 41.37 EGFA c 41.439 1.00 41.39 EGFA 0 43.287 1.00 40.78 EGFA N 43.147 1.00 40.37 EGFA c 43.373 1.00 38.89 EGFA c 43.063 1.00 37.99 EGFA c 41.584 1.00 35.18 EGFA c 43.485 1.00 37.81 EGFA c 44.131 1.00 40.79 EGFA c 45.337 1.00 40.04 EGFA 0 43.618 1.00 41.36 EGFA N 44.476 1.00 42.53 EGFA c 44 . 122 1.00 41.99 EGFA c 43.201 1.00 41.24 EGFA c 43.506 1.00 41.93 EGFA c 44.385 1.00 43.44 EGFA c 43.332 1.00 43.12 EGFA 0 45.501 1.00 45.25 EGFA N 45.539 1.00 47.09 EGFA c 44.577 1.00 46.26 EGFA c 45.185 1.00 48.01 EGFA c 45.078 1.00 48.60 EGFA 0 44.997 1.00 49.94 EGFA N 44.692 1.00 51.60 EGFA c 45.563 1.00 51.40 EGFA c 46.191 1.00 53.05 EGFA c 47.666 1.00 56.41 EGFA c 48.477 1.00 58.59 EGFA 0 48.036 1.00 57.77 EGFA N 43.224 1.00 51.40 EGFA c 42.863 1.00 52.05 EGFA 0 42.376 1.00 52.02 EGFA N 40.962 1.00 53.90 EGFA c 40.719 1.00 54.36 EGFA c 40.973 1.00 55.41 EGFA c 40.909 1.00 56.46 EGFA c 41.644 1.00 57.62 EGFA N 41.681 1.00 58.17 EGFA c 41.018 1.00 57.94 EGFA N 42.390 1.00 58.09 EGFA N 40.015 1.00 54.26 EGFA C 38.881 1.00 54.09 EGFA 0 40.459 1.00 55.91 EGFA N 39.545 1.00 56.83 EGFA C 39.676 1.00 59.07 EGFA c 38.494 1.00 63.56 EGFA c 319 WO 2009/026558 PCT/US2008/074097
ATOM 3039 CD ARG 330 16.009 -17 ATOM 3040 NE ARG 330 17.205 -17 ATOM 3041 CZ ARG 330 18.101 -16 ATOM 3042 NHl ARG 330 17.931 -15 ATOM 3043 NH2 ARG 330 19.165 -16 ATOM 3044 C ARG 330 13.307 -21 ATOM 3045 O ARG 330 13.624 -21 ATOM 3046 N CYS 331 13.237 -21 ATOM 3047 CA CYS 331 13.615 -23 ATOM 3048 C CYS 331 15.046 -23 ATOM 3049 0 CYS 331 15.424 -22 ATOM 3050 CB CYS 331 12.707 -24 ATOM 3051 SG CYS 331 10.917 -23 ATOM 3052 N GLU 332 15.843 -24 ATOM 3053 CA GLU 332 17.181 -24 ATOM 3054 CB GLU 332 18.234 -23 ATOM 3055 CG GLU 332 17.872 -23 ATOM 3056 CD GLU 332 18.797 -22 ATOM 3057 OE1 GLU 332 19.367 -23 ATOM 3058 OE2 GLU 332 18.951 -21 ATOM 3059 C GLU 332 17.350 -25 ATOM 3060 O GLU 332 17.082 -26 ATOM 3061 N ASP 333 17.780 -26 ATOM 3062 CA ASP 333 17.880 -27 ATOM 3063 CB ASP 333 18.483 -28 ATOM 3064 CG ASP 333 19.649 -27 ATOM 3065 OD1 ASP 333 19.458 -26 ATOM 3066 OD2 ASP 333 20.754 -27 ATOM 3067 C ASP 333 18.756 -28 ATOM 3068 O ASP 333 18.526 -29 ATOM 3069 N ILE 334 19.769 -27 ATOM 3070 CA ILE 334 20.587 -28 ATOM 3071 CB ILE 334 20.070 -27 ATOM 3072 CG2 ILE 334 19.986 -2 8 ATOM 3073 CGI ILE 334 20.989 -26 ATOM 3074 CDl ILE 334 21.191 -25 ATOM 3075 C ILE 334 20.666 -29 ATOM 3076 0 ILE 334 21.755 -30 ATOM 3077 OXT ILE 334 19.656 -30 TER 3078 ILE 334 ATOM 3079 CA CA 1 -5.688 -15 TER 3080 CA 1 END
38.337 1.00 67.44 EGFA C 39.183 1.00 71.71 EGFA N 39.232 1.00 73.25 EGFA C 38.483 1.00 74.17 EGFA N 40.026 1.00 73.57 EGFA N 39.805 1.00 56.14 EGFA C 40.931 1.00 55.45 EGFA O 38.757 1.00 55.78 EGFA N 38.876 1.00 55.78 EGFA C 38.407 1.00 56.71 EGFA C 37.344 1.00 54.16 EGFA 0 38.024 1.00 54.71 EGFA c 38.247 1.00 52.34 EGFA s 39.210 1.00 59.67 EGFA N 38.793 1.00 63.04 EGFA c 39.677 1.00 63.37 EGFA c 41.151 1.00 64.27 EGFA c 41.891 1.00 64.91 EGFA c 42.935 1.00 64.31 EGFA 0 41.428 1.00 64.07 EGFA 0 38.811 1.00 65.33 EGFA c 39.816 1.00 64.39 EGFA 0 37.667 1.00 68.69 EGFA N 37.433 1.00 72.25 EGFA c 36.056 1.00 74.16 EGFA c 35.762 1.00 76.50 EGFA c 35.827 1.00 77.91 EGFA 0 35.476 1.00 77.38 EGFA 0 38.488 1.00 73.49 EGFA c 38.894 1.00 73.58 EGFA 0 38.903 1.00 75.52 EGFA N 40.069 1.00 77.98 EGFA c 41.320 1.00 78.68 EGFA c 42.551 1.00 78.54 EGFA c 41.585 1.00 78.89 EGFA c 40.391 1.00 77.96 EGFA c 40.363 1.00 79.11 EGFA c 40.118 1.00 79.71 EGFA 0 40.802 1.00 79.97 EGFA EGFA 0 40.122 1.00 56.81 ION c ION 320 WO 2009/026558 ATOM 1 CB THR 61 TABLE 35 7.625 -20.113 .3 2.894 1.00120.20 PCT/US2008/074097 A C ATOM 2 OG1 THR 61 7.048 -19.215 1.936 1.00120.97 A O ATOM 3 CG2 THR 61 7.446 -19.537 4 .289 1.00121.74 A C ATOM 4 C THR 61 9.869 -19.003 2.758 1.00115.49 A c ATOM 5 O THR 61 10.710 -18.870 3.648 1.00115.58 A 0 ATOM 6 N THR 61 9.741 -21.360 3.461 1.00119.24 A N ATOM 7 CA THR 61 9.132 -20.323 2.577 1.00118.55 A c ATOM 8 N ALA 62 9.546 -18.032 1.907 1.00111.50 A N ATOM 9 CA ALA 62 10.296 -16.784 1.830 1.00106.53 A C ATOM 10 CB ALA 62 10.124 -16.161 0.455 1.00108.21 A c ATOM 11 C ALA 62 9.882 -15.789 2.902 1.00102.91 A c ATOM 12 O ALA 62 8.701 -15.600 3.174 1.00101.98 A 0 ATOM 13 N THR 63 10.870 -15.145 3.501 1.00 98.29 A N ATOM 14 CA THR 63 10.624 -14.157 4.534 1.00 93.32 A c ATOM 15 CB THR 63 11.644 -14.326 5.679 1.00 92.70 A c ATOM 16 OG1 THR 63 12.973 -14.322 5.147 1.00 92.34 A 0 ATOM 17 CG2 THR 63 11.422 -15.647 6.398 1.00 92.08 A c ATOM 18 C THR 63 10.716 -12.747 3.944 1.00 89.66 A c ATOM 19 O THR 63 11.156 -12.571 2.810 1.00 90.88 A 0 ATOM 20 N PHE 64 10.280 -11.747 4.705 1.00 83.77 A N ATOM 21 CA PHE 64 10.405 -10.353 4.278 1.00 77.76 A c ATOM 22 CB PHE 64 9.065 -9.825 3.799 1.00 72.88 A c ATOM 23 CG PHE 64 9.028 -8.343 3.648 1.00 67.65 A c ATOM 24 CDl PHE 64 9.305 -7.752 2.429 1.00 66.67 A c ATOM 25 CD2 PHE 64 8.697 -7.530 4.726 1.00 66.49 A c ATOM 26 CEl PHE 64 9.251 -6.370 2.285 1.00 66.42 A c ATOM 27 CE2 PHE 64 8.640 -6.150 4.594 1.00 64.45 A c ATOM 28 CZ PHE 64 8.917 -5.567 3.374 1.00 64.76 A c ATOM 29 C PHE 64 10.936 -9.426 5.370 1.00 76.67 A c ATOM 30 O PHE 64 10.563 -9.557 6.540 1.00 76.03 A 0 ATOM 31 N HIS 65 11.787 -8.477 4.975 1.00 75.50 A N ATOM 32 CA HIS 65 12.561 -7.686 5.928 1.00 74.60 A c ATOM 33 CB HIS 65 14.003 -8.192 5.961 1.00 74.07 A c ATOM 34 CG HIS 65 14.117 -9.659 6.235 1.00 74.70 A c ATOM 35 CD2 HIS 65 13.881 -10.735 5.448 1.00 74.67 A c ATOM 36 NDl HIS 65 14.517 -10.161 7.456 1.00 75.55 A N ATOM 37 CEl HIS 65 14.523 -11.481 7.409 1.00 74.80 A c ATOM 38 NE2 HIS 65 14.141 -11.855 6.201 1.00 74.59 A N ATOM 39 C HIS 65 12.556 -6.187 5.642 1.00 73.68 A C ATOM 40 0 HIS 65 12.678 -5.755 4.498 1.00 73.21 A 0 ATOM 41 N ARG 66 12.425 -5.397 6.700 1.00 73.29 A N ATOM 42 CA ARG 66 12.508 -3.952 6.586 1.00 73.63 A C ATOM 43 CB ARG 66 11.131 -3.320 6.801 1.00 80.94 A c ATOM 44 CG ARG 66 10.664 -3.376 8.239 1.00 91.57 A c ATOM 45 CD ARG 66 9.465 -2.490 8.486 1.00102.14 A c ATOM 46 NE ARG 66 9.120 -2.4 62 9.905 1.00113.95 A N ATOM 47 CZ ARG 66 9.564 -1.551 10.763 1.00120.16 A c ATOM 48 NHl ARG 66 9.200 -1.602 12.037 1.00124.56 A N ATOM 49 NH2 ARG 66 10.368 -0.586 10.342 1.00124.67 A N ATOM 50 C ARG 66 13.482 -3.420 7.630 1.00 68.82 A C ATOM 51 O ARG 66 13.789 -4.088 8.605 1.00 69.03 A 0 ATOM 52 N CYS 67 13.974 -2.210 7.425 1.00 64.02 A N ATOM 53 CA CYS 67 14.838 -1.590 8.414 1.00 57.74 A C ATOM 54 CB CYS 67 15.397 -0.279 7.865 1.00 55.67 A c ATOM 55 SG CYS 67 16.287 0.702 9.068 1.00 43.75 A s ATOM 56 C CYS 67 14.043 -1.320 9.685 1.00 55.30 A c ATOM 57 O CYS 67 12.919 -0.825 9.630 1.00 53.23 A 0 ATOM 58 N ALA 68 14.630 -1.644 10.828 1.00 52.57 A N ATOM 59 CA ALA 68 13.953 -1.434 12.097 1.00 51.78 A c ATOM 60 CB ALA 68 14.818 -1.940 13.236 1.00 48.43 A c ATOM 61 C ALA 68 13.624 0.043 12.306 1.00 53.12 A c ATOM 62 O ALA 68 12.511 0.389 12.700 1.00 53.69 A 0 ATOM 63 N LYS 69 14.596 0.914 12.042 1.00 53.95 A N ATOM 64 CA LYS 69 14.435 2.342 12.306 1.00 53.04 A c ATOM 65 CB LYS 69 15.814 3.015 12.422 1.00 55.99 A c ATOM 66 CG LYS 69 16.931 2.058 12.899 1.00 57.69 A c ATOM 67 CD LYS 69 17.593 2.502 14.208 1.00 57.50 A c ATOM 68 CE LYS 69 17.940 1.307 15.091 1.00 57.22 A c ATOM 69 NZ LYS 69 18.773 1.709 16.260 1.00 57.57 A N ATOM 70 C LYS 69 13.620 2.975 11 .188 1.00 51.24 A c ATOM 71 0 LYS 69 14.050 3.061 10.049 1.00 49.56 A 0 ATOM 72 N ASP 70 12.429 3.424 11.537 1.00 51.12 A N ATOM 73 CA ASP 70 11.407 3.714 10.555 1.00 49.83 A c ATOM 74 CB ASP 70 10.109 4.015 11.279 1.00 54.30 A c 321 WO 2009/026558 PCT/US2008/074097 ATOM 75 CG ASP 70 8.902 3 ATOM 76 OD1 ASP 70 8.761 2 ATOM 77 OD2 ASP 70 8.109 4 ATOM 78 C ASP 70 11.715 4 ATOM 79 O ASP 70 11.398 4 ATOM 80 N PRO 71 12.322 5 ATOM 81 CD PRO 71 12.626 6 ATOM 82 CA PRO 71 12.627 7 ATOM 83 CB PRO 71 12.989 8 ATOM 84 CG PRO 71 13.420 7 ATOM 85 C PRO 71 13.734 6 ATOM 86 O PRO 71 13.979 7 ATOM 87 N TRP 72 14.380 5 ATOM 88 CA TRP 72 15.426 5 ATOM 89 CB TRP 72 16.523 4 ATOM 90 CG TRP 72 17.216 5 ATOM 91 CD2 TRP 72 18.253 4 ATOM 92 CE2 TRP 72 18.678 6 ATOM 93 CE3 TRP 72 18.863 3 ATOM 94 CDl TRP 72 17.045 6 ATOM 95 NEl TRP 72 17.923 7 ATOM 96 CZ2 TRP 72 19.684 6 ATOM 97 CZ3 TRP 72 19.860 3 ATOM 98 CH2 TRP 72 20.268 4 ATOM 99 C TRP 72 14.944 4 ATOM 100 O TRP 72 15.744 3 ATOM 101 N ARG 73 13.648 3 ATOM 102 CA ARG 73 13.065 2 ATOM 103 CB ARG 73 11.741 2 ATOM 104 CG ARG 73 11.891 1 ATOM 105 CD ARG 73 10.582 1 ATOM 106 NE ARG 73 10.042 0 ATOM 107 CZ ARG 73 8.761 0 ATOM 108 NHl ARG 73 7.911 1 ATOM 109 NH2 ARG 73 8.332 -0 ATOM 110 C ARG 73 12.840 3 ATOM 111 O ARG 73 12.572 4 ATOM 112 N LEU 74 12.966 2 ATOM 113 CA LEU 74 12.781 3 ATOM 114 CB LEU 74 14.137 3 ATOM 115 CG LEU 74 15.200 4 ATOM 116 CDl LEU 74 16.600 4 ATOM 117 CD2 LEU 74 14.945 5 ATOM 118 C LEU 74 11.885 2 ATOM 119 O LEU 74 12.341 1 ATOM 120 N PRO 75 10.595 2 ATOM 121 CD PRO 75 10.053 3 ATOM 122 CA PRO 75 9.605 1 ATOM 123 CB PRO 75 8.377 1 ATOM 124 CG PRO 75 8.581 3 ATOM 125 C PRO 75 9.306 2 ATOM 126 O PRO 75 9.277 3 ATOM 127 N GLY 76 9.090 1 ATOM 128 CA GLY 76 8.969 1 ATOM 129 C GLY 76 10.105 0 ATOM 130 0 GLY 76 10.163 0 ATOM 131 N THR 77 11.017 -0 ATOM 132 CA THR 77 12.237 -0 ATOM 133 CB THR 77 13.366 0 ATOM 134 OG1 THR 77 12.900 1 ATOM 135 CG2 THR 77 14.572 0 ATOM 136 C THR 77 12.713 -1 ATOM 137 O THR 77 12.969 -1 ATOM 138 N TYR 78 12.825 -2 ATOM 139 CA TYR 78 13.063 -4 ATOM 140 CB TYR 78 11.755 -4 ATOM 141 CG TYR 78 10.565 -4 ATOM 142 CDl TYR 78 9.907 -3 ATOM 143 CEl TYR 78 8.916 -2 ATOM 144 CD2 TYR 78 10.183 -4 ATOM 145 CE2 TYR 78 9.199 -3 ATOM 146 CZ TYR 78 8.577 -2 ATOM 147 OH TYR 78 7.659 -1 ATOM 148 C TYR 78 14.193 -4 ATOM 149 O TYR 78 14.278 -4 ATOM 150 N VAL 79 15.094 -5
10.492 1.00 60.23 A C 10.283 1.00 59.99 A O 10.087 1.00 61.75 A O 9.567 1.00 45.91 A c 8.386 1.00 43.79 A 0 10.040 1.00 43.28 A N 11.448 1.00 40.22 A c 9.148 1.00 41.43 A c 10.108 1.00 39.87 A c 11.346 1.00 39.36 A c 8.125 1.00 40.85 A c 7.204 1.00 41.69 A 0 8.279 1.00 39.17 A N 7.362 1.00 37.15 A c 8.133 1.00 33.24 A c 9.057 1.00 30.60 A c 9.959 1.00 28.45 A c 10.615 1.00 29.35 A c 10.273 1.00 24.28 A c 9.194 1.00 32.13 A c 10.132 1.00 31.43 A N 11.563 1.00 28.45 A c 11.210 1.00 29.40 A c 11.852 1.00 31.73 A c 6.286 1.00 39.33 A c 5.476 1.00 39.93 A 0 6.296 1.00 41.01 A N 5.354 1.00 41.83 A c 5.903 1.00 43.30 A c 7.263 1.00 47.92 A c 7.765 1.00 52.48 A c 6.879 1.00 56.62 A N 6.541 1.00 58.69 A c 7.021 1.00 60.74 A N 5.741 1.00 57.82 A N 4 . 024 1.00 40.96 A C 3.988 1.00 40.86 A 0 2.932 1.00 41.26 A N 1.606 1.00 43.15 A C 0.914 1.00 42.05 A c 1.776 1.00 41.09 A c 1.259 1.00 40.47 A c 1.781 1.00 36.19 A c 0.767 1.00 43.59 A c -0.180 1.00 45.64 A 0 1 . 122 1.00 42.35 A N 2.322 1.00 40.81 A c 0.465 1.00 41.19 A c 1.370 1.00 40.54 A c 2.174 1.00 39.32 A c -0.981 1.00 40.71 A c -1.329 1.00 39.79 A 0 -1.817 1.00 40.71 A N -3.250 1.00 38.99 A c -3.974 1.00 36.52 A c -5.205 1.00 35.56 A 0 -3.206 1.00 34.53 A N -3.795 1.00 35.21 A c -3.812 1.00 34.11 A c -4.462 1.00 34.86 A 0 -4.557 1.00 31.17 A c -2.996 1.00 34.73 A c -1.790 1.00 34.99 A 0 -3.655 1.00 33.72 A N -2.911 1.00 34.19 A c -2.837 1.00 32.06 A c -2.321 1.00 29.68 A c -3.152 1.00 29.12 A c -2.648 1.00 28.24 A c -0.967 1.00 28.00 A c -0.463 1.00 24.98 A c -1.307 1.00 28.24 A c -0.810 1.00 31.65 A 0 -3.557 1.00 35.43 A c -4.780 1.00 37.75 A 0 -2.731 1.00 36.65 A N 322 WO 2009/026558 PCT/US2008/074097 ATOM 151 CA VAL 79 16.068 -6 ATOM 152 CB VAL 79 17.358 -6 ATOM 153 CGI VAL 79 18.349 -7 ATOM 154 CG2 VAL 79 17.924 -4 ATOM 155 C VAL 79 15.469 -7 ATOM 156 O VAL 79 15.494 -8 ATOM 157 N VAL 80 14.915 -8 ATOM 158 CA VAL 80 14.581 -9 ATOM 159 CB VAL 80 13.775 -10 ATOM 160 CGI VAL 80 13.627 -11 ATOM 161 CG2 VAL 80 12.413 -9 ATOM 162 C VAL 80 15.878 -10 ATOM 163 O VAL 80 16.741 -10 ATOM 164 N VAL 81 16.025 -11 ATOM 165 CA VAL 81 17.173 -12 ATOM 166 CB VAL 81 17.789 -12 ATOM 167 CGI VAL 81 19.027 -13 ATOM 168 CG2 VAL 81 18.108 -10 ATOM 169 C VAL 81 16.687 -13 ATOM 170 O VAL 81 15.652 -14 ATOM 171 N LEU 82 17.419 -14 ATOM 172 CA LEU 82 16.997 -15 ATOM 173 CB LEU 82 17.176 -15 ATOM 174 CG LEU 82 16.407 -14 ATOM 175 CDl LEU 82 16.570 -14 ATOM 176 CD2 LEU 82 14.938 -14 ATOM 177 C LEU 82 17.778 -16 ATOM 178 O LEU 82 18.800 -16 ATOM 179 N LYS 83 17.268 -17 ATOM 180 CA LYS 83 17.995 -19 ATOM 181 CB LYS 83 17.184 -20 ATOM 182 CG LYS 83 17.946 -21 ATOM 183 CD LYS 83 18.130 -21 ATOM 184 CE LYS 83 18.758 -23 ATOM 185 NZ LYS 83 18.707 -23 ATOM 186 C LYS 83 19.320 -19 ATOM 187 0 LYS 83 19.366 -19 ATOM 188 N GLU 84 20.399 -19 ATOM 189 CA GLU 84 21.731 -19 ATOM 190 CB GLU 84 22.793 -19 ATOM 191 CG GLU 84 23.164 -20 ATOM 192 CD GLU 84 24.181 -20 ATOM 193 OE1 GLU 84 25.398 -20 ATOM 194 OE2 GLU 84 23.763 -2 0 ATOM 195 C GLU 84 21.899 -20 ATOM 196 0 GLU 84 21.010 -21 ATOM 197 N GLU 85 23.031 -20 ATOM 198 CA GLU 85 23.242 -21 ATOM 199 CB GLU 85 23.060 -22 ATOM 200 CG GLU 85 24 .229 -23 ATOM 201 CD GLU 85 24.788 -24 ATOM 202 OE1 GLU 85 26.009 -24 ATOM 203 OE2 GLU 85 24. Oil -25 ATOM 204 C GLU 85 22.292 -21 ATOM 205 0 GLU 85 22.400 -21 ATOM 206 N THR 86 21.364 -20 ATOM 207 CA THR 86 20.463 -19 ATOM 208 CB THR 86 19.357 -19 ATOM 209 OG1 THR 86 18.543 -19 ATOM 210 CG2 THR 86 18.483 -18 ATOM 211 C THR 86 21.208 -19 ATOM 212 O THR 86 22.160 -18 ATOM 213 N HIS 87 20.764 -19 ATOM 214 CA HIS 87 21.418 -19 ATOM 215 CB HIS 87 21.213 -20 ATOM 216 CG HIS 87 22.040 -21 ATOM 217 CD2 HIS 87 22.930 -21 ATOM 218 NDl HIS 87 22.017 -22 ATOM 219 CEl HIS 87 22.867 -23 ATOM 220 NE2 HIS 87 23.431 -23 ATOM 221 C HIS 87 20.986 -17 ATOM 222 0 HIS 87 19.822 -17 ATOM 223 N LEU 88 21.939 -17 ATOM 224 CA LEU 88 21.688 -15 ATOM 225 CB LEU 88 22.979 -15 ATOM 226 CG LEU 88 24.215 -15 -3.204 1.00 36.46 A C -2.395 1.00 37.20 A C -2.972 1.00 37.26 A C -2.383 1.00 38.46 A C -3.001 1.00 38.67 A C -1.884 1.00 35.22 A O -4.063 1.00 41.04 A N -4.028 1.00 43.11 A C -5.256 1.00 44.56 A c -5.251 1.00 47.28 A c -5.257 1.00 47.02 A c -4.016 1.00 46.29 A c -4.873 1.00 47.03 A 0 -3.034 1.00 49.18 A N -2.967 1.00 52.16 A c -1.565 1.00 51.26 A c -1.501 1.00 50.81 A c -1.202 1.00 52.80 A c -3.260 1.00 58.30 A c -2.732 1.00 58.40 A 0 -4 .105 1.00 62.94 A N -4.454 1.00 67.59 A c -5.944 1.00 64.19 A c -6.666 1.00 61.66 A c -8.164 1.00 60.74 A c -6.290 1.00 62.60 A c -3.648 1.00 73.85 A c -3.042 1.00 72.57 A 0 -3.596 1.00 82.70 A N -2.955 1.00 91.24 A c -3.050 1.00 92.11 A c -2.649 1.00 95.32 A c -1.140 1.00 96.21 A c -0.816 1.00 96.12 A c 0.629 1.00 99.11 A N -3.694 1.00 95.80 A c -4.919 1.00 98.45 A 0 -2.945 1.00100.77 A N -3.532 1.00106.04 A c -2.441 1.00108.26 A c -2.048 1.00112.62 A c -0.937 1.00116.07 A c -1.237 1.00119.19 A 0 0.241 1.00118.28 A 0 -4.512 1.00109.04 A c -4.639 1.00108.23 A 0 -5.208 1.00113.81 A N -6.261 1.00118.74 A c -5.704 1.00119.63 A c -4.870 1.00122.20 A c -5.390 1.00123.94 A c -5.246 1.00124.52 A 0 -5.947 1.00125.46 A 0 -7.441 1.00120.43 A c -8.470 1.00122.77 A 0 -7.290 1.00120.31 A N -8.373 1.00119.91 A c -7.869 1.00117.92 A c -6.917 1.00115.24 A 0 -9.021 1.00115.66 A c -9.541 1.00121.48 A c -9.353 1.00122.30 A 0 -10.752 1.00123.45 A N -11.980 1.00124.91 A c -13.090 1.00127.94 A c -12.904 1.00131.80 A c -11.937 1.00133.11 A c -13.783 1.00133.19 A N -13.366 1.00134.19 A c -12.252 1.00134.17 A N -12.473 1.00123.89 A C -12.361 1.00123.47 A 0 -13.045 1.00123.03 A N -13.574 1.00122.10 A C -14.162 1.00124.68 A c -13.273 1.00126.86 A c 323 WO 2009/026558 PCT/US2008/074097 ATOM 227 CD1 LEU 88 25.432 -14 ATOM 228 CD2 LEU 88 23.935 -14 ATOM 229 C LEU 88 20.603 -15 ATOM 230 O LEU 88 19.887 -14 ATOM 231 N SER 89 20.495 -16 ATOM 232 CA SER 89 19.381 -17 ATOM 233 CB SER 89 19.550 -18 ATOM 234 OG SER 89 19.719 -19 ATOM 235 C SER 89 18. 111 -17 ATOM 236 O SER 89 17.099 -16 ATOM 237 N GLN 90 18.185 -17 ATOM 238 CA GLN 90 17.033 -17 ATOM 239 CB GLN 90 17.300 -19 ATOM 240 CG GLN 90 17.416 -20 ATOM 241 CD GLN 90 17.691 -21 ATOM 242 OE1 GLN 90 18.790 -21 ATOM 243 NE2 GLN 90 16.693 -22 ATOM 244 C GLN 90 16.680 -16 ATOM 245 0 GLN 90 15.513 -16 ATOM 246 N SER 91 17.683 -15 ATOM 247 CA SER 91 17.472 -14 ATOM 248 CB SER 91 18.816 -13 ATOM 249 OG SER 91 19.158 -13 ATOM 250 C SER 91 16.630 -13 ATOM 251 O SER 91 15.618 -13 ATOM 252 N GLU 92 17.045 -13 ATOM 253 CA GLU 92 16.451 -13 ATOM 254 CB GLU 92 17.181 -13 ATOM 255 CG GLU 92 16.427 -12 ATOM 256 CD GLU 92 15.480 -13 ATOM 257 OE1 GLU 92 14.269 -13 ATOM 258 OE2 GLU 92 15.948 -14 ATOM 259 C GLU 92 14.953 -13 ATOM 260 0 GLU 92 14.180 -12 ATOM 261 N ARG 93 14.540 -14 ATOM 2 62 CA ARG 93 13.145 -14 ATOM 263 CB ARG 93 13.025 -16 ATOM 264 CG ARG 93 13.405 -16 ATOM 265 CD ARG 93 13.327 -18 ATOM 266 NE ARG 93 14.627 -18 ATOM 267 CZ ARG 93 14.826 -19 ATOM 268 NHl ARG 93 16.044 -2 0 ATOM 269 NH2 ARG 93 13.807 -2 0 ATOM 270 C ARG 93 12.196 -14 ATOM 271 O ARG 93 11.139 -13 ATOM 272 N THR 94 12.577 -15 ATOM 273 CA THR 94 11.852 -14 ATOM 274 CB THR 94 12.723 -14 ATOM 275 OG1 THR 94 13.153 -16 ATOM 276 CG2 THR 94 11.949 -14 ATOM 277 C THR 94 11.478 -13 ATOM 278 O THR 94 10.414 -12 ATOM 279 N ALA 95 12.361 -12 ATOM 280 CA ALA 95 12.224 -10 ATOM 281 CB ALA 95 13.581 -10 ATOM 282 C ALA 95 11.239 -10 ATOM 283 O ALA 95 10.460 -9 ATOM 284 N ARG 96 11.282 -11 ATOM 285 CA ARG 96 10.322 -10 ATOM 286 CB ARG 96 10.772 -11 ATOM 287 CG ARG 96 12.113 -11 ATOM 288 CD ARG 96 12.042 -9 ATOM 289 NE ARG 96 13.359 -9 ATOM 290 CZ ARG 96 13.603 -7 ATOM 291 NHl ARG 96 14.833 -7 ATOM 292 NH2 ARG 96 12.617 -6 ATOM 293 C ARG 96 8.985 -11 ATOM 294 O ARG 96 7.922 -10 ATOM 295 N ARG 97 9.058 -12 ATOM 296 CA ARG 97 7.876 -13 ATOM 297 CB ARG 97 8.281 -14 ATOM 298 CG ARG 97 7.103 -15 ATOM 299 CD ARG 97 7.554 -16 ATOM 300 NE ARG 97 6.539 -17 ATOM 301 CZ ARG 97 6.496 -18 ATOM 302 NHl ARG 97 5.533 -19
-13.909 1.00127.21 A C -11.890 1.00128.06 A C -14.641 1.00119.59 A C -14.882 1.00118.95 A O -15.282 1.00117.17 A N -16.174 1.00114.74 A C -16.814 1.00115.37 A C -15.825 1.00116.88 A 0 -15.341 1.00112.77 A c -15.752 1.00111.49 A 0 -14.158 1.00110.68 A N -13.279 1.00108.49 A c -12.223 1.00108.59 A c -12.811 1.00109.07 A c -11.764 1.00109.15 A c -11.212 1.00109.15 A 0 -11.491 1.00108.63 A N -12.611 1.00107.20 A c -12.589 1.00106.82 A 0 -12.078 1.00105.29 A N -11.569 1.00103.51 A c -11.370 1.00102.29 A c -10.000 1.00 98.21 A 0 -12.588 1.00103.23 A c -12.248 1.00102.98 A 0 -13.847 1.00103.82 A N -14 .884 1.00104.85 A c -16.211 1.00106.74 A c -17.447 1.00111.04 A c -18.016 1.00112.76 A c -18.143 1.00114.41 A 0 -18.336 1.00114.56 A 0 -15.055 1.00104.14 A c -15.106 1.00104.75 A 0 -15.137 1.00103.50 A N -15.445 1.00101.47 A c -15.844 1.00106.48 A c -17.298 1.00113.16 A c -17.623 1.00120.42 A c -17.516 1.00128.11 A N -16.906 1.00131.80 A c -16.858 1.00134.30 A N -16.345 1.00134.64 A N -14.286 1.00 96.81 A C -14.472 1.00 95.99 A O -13.089 1.00 91.16 A N -11.890 1.00 86.23 A C -10.640 1.00 83.21 A C -10.554 1.00 80.97 A 0 -9.388 1.00 80.14 A c -12.016 1.00 85.96 A c -11.577 1.00 85.37 A 0 -12.641 1.00 85.71 A N -12.685 1.00 87.24 A c -12.931 1.00 85.86 A c -13.758 1.00 88.89 A c -13.554 1.00 88.87 A 0 -14.909 1.00 91.47 A N -15.967 1.00 93.56 A c -17.286 1.00 97.53 A c -17.803 1.00102.81 A c -18.230 1.00108.59 A c -18.581 1.00114.78 A N -18.876 1.00118.68 A c -19.182 1.00121.30 A N -18.864 1.00121.58 A N -15.528 1.00 92.22 A C -15.818 1.00 91.98 A 0 -14.807 1.00 89.71 A N -14.245 1.00 87.42 A C -13.453 1.00 90.04 A c -12.940 1.00 94.32 A c -12.440 1.00 98.95 A c -12.666 1.00104.16 A N -13.739 1.00107.61 A c -13.860 1.00110.25 A N 324 WO 2009/026558 PCT/US2008/074097 ATOM 303 NH2 ARG 97 7.415 -18 ATOM 304 C ARG 97 7.128 -12 ATOM 305 O ARG 97 5.972 -11 ATOM 306 N LEU 98 7.799 -11 ATOM 307 CA LEU 98 7.213 -10 ATOM 308 CB LEU 98 8.281 -10 ATOM 309 CG LEU 98 8.084 -8 ATOM 310 CDl LEU 98 6.792 -8 ATOM 311 CD2 LEU 98 9.282 -8 ATOM 312 C LEU 98 6.592 -9 ATOM 313 O LEU 98 5.426 -9 ATOM 314 N GLN 99 7.376 -9 ATOM 315 CA GLN 99 6.895 -8 ATOM 316 CB GLN 99 7.986 -7 ATOM 317 CG GLN 99 7.697 -6 ATOM 318 CD GLN 99 8.960 -5 ATOM 319 OE1 GLN 99 8.930 -4 ATOM 320 NE2 GLN 99 10.092 -6 ATOM 321 C GLN 99 5.671 -8 ATOM 322 0 GLN 99 4.781 -7 ATOM 323 N ALA 100 5.645 -9 ATOM 324 CA ALA 100 4.546 -10 ATOM 325 CB ALA 100 4.904 -11 ATOM 326 C ALA 100 3.248 -10 ATOM 327 O ALA 100 2.250 -9 ATOM 328 N GLN 101 3.271 -11 ATOM 329 CA GLN 101 2.189 -10 ATOM 330 CB GLN 101 2.619 -11 ATOM 331 CG GLN 101 3.498 -12 ATOM 332 CD GLN 101 3.346 -13 ATOM 333 OE1 GLN 101 2.402 -13 ATOM 334 NE2 GLN 101 4.275 -14 ATOM 335 C GLN 101 1.888 -9 ATOM 336 0 GLN 101 0.918 -8 ATOM 337 N ALA 102 2.745 -8 ATOM 338 CA ALA 102 2.649 -7 ATOM 339 CB ALA 102 4 . 030 -6 ATOM 340 C ALA 102 1.974 -6 ATOM 341 O ALA 102 1.054 -5 ATOM 342 N ALA 103 2.440 -6 ATOM 343 CA ALA 103 1.897 -6 ATOM 344 CB ALA 103 2.489 -6 ATOM 345 C ALA 103 0.392 -6 ATOM 346 O ALA 103 -0.346 -5 ATOM 347 N ARG 104 -0.052 -7 ATOM 348 CA ARG 104 -1.458 -7 ATOM 349 CB ARG 104 -1.598 -9 ATOM 350 CG ARG 104 -1.198 -9 ATOM 351 CD ARG 104 -1.540 -11 ATOM 352 NE ARG 104 -0.642 -12 ATOM 353 CZ ARG 104 0.397 -12 ATOM 354 NHl ARG 104 1.164 -13 ATOM 355 NH2 ARG 104 0.675 -12 ATOM 356 C ARG 104 -2.373 -7 ATOM 357 O ARG 104 -3.469 -6 ATOM 358 N ARG 105 -1.935 -7 ATOM 359 CA ARG 105 -2.724 -6 ATOM 360 CB ARG 105 -2.048 -7 ATOM 361 CG ARG 105 -2.350 -8 ATOM 362 CD ARG 105 -1.519 -9 ATOM 363 NE ARG 105 -1.460 -10 ATOM 364 CZ ARG 105 -1.306 -12 ATOM 365 NHl ARG 105 -1.267 -13 ATOM 366 NH2 ARG 105 -1.191 -12 ATOM 367 C ARG 105 -2.925 -5 ATOM 368 O ARG 105 -3.706 -4 ATOM 369 N GLY 106 -2.212 -4 ATOM 370 CA GLY 106 -2.379 -3 ATOM 371 C GLY 106 -1.244 -2 ATOM 372 0 GLY 106 -1.375 -1 ATOM 373 N TYR 107 -0.126 -3 ATOM 374 CA TYR 107 1.040 -2 ATOM 375 CB TYR 107 1.454 -3 ATOM 376 CG TYR 107 0.475 -3 ATOM 377 CDl TYR 107 0.173 -1 ATOM 378 CEl TYR 107 -0.771 -1 -14.690 1.00109.39 A N -13.334 1.00 83.61 A C -13.582 1.00 83.78 A O -12.279 1.00 78.62 A N -11.378 1.00 73.43 A C -10.446 1.00 72.56 A C -10.006 1.00 71.98 A c -9.218 1.00 70.37 A c -9.171 1.00 71.13 A c -12.184 1.00 70.64 A c -12. Oil 1.00 69.36 A 0 -13.080 1.00 69.00 A N -13.861 1.00 67.29 A c -14.808 1.00 67.31 A c -15.420 1.00 66.57 A c -15.623 1.00 66.92 A c -16.068 1.00 67.28 A 0 -15.294 1.00 66.83 A N -14.660 1.00 65.61 A c -14.931 1.00 64.48 A 0 -15.024 1.00 64.28 A N -15.793 1.00 62.8 9 A c -16.201 1.00 61.93 A c -14.980 1.00 62.2 6 A c -15.364 1.00 60.92 A 0 -13.856 1.00 59.83 A N -12.897 1.00 58.75 A c -11.610 1.00 56.30 A c -11.852 1.00 55.38 A c -10.770 1.00 55.44 A c -9.989 1.00 57.12 A 0 -10.712 1.00 55.95 A N -12.638 1.00 59.50 A c -13.158 1.00 60.05 A 0 -11.843 1.00 59.21 A N -11.557 1.00 59.10 A c -11.318 1.00 56.43 A c -12.681 1.00 60.79 A c -12.447 1.00 60.89 A 0 -13.904 1.00 63.30 A N -15.052 1.00 64.47 A c -16.347 1.00 65.31 A c -15.061 1.00 64.88 A c -15.236 1.00 64.54 A 0 -14.848 1.00 65.14 A N -15.003 1.00 65.17 A c -15.097 1.00 63.37 A c -16.454 1.00 62.23 A c -16.593 1.00 61.80 A c -15.846 1.00 61.29 A N -16.387 1.00 61.76 A c -15.644 1.00 61.55 A N -17.674 1.00 61.90 A N -13.904 1.00 66.10 A C -14.195 1.00 65.62 A 0 -12.650 1.00 66.65 A N -11.546 1.00 66.20 A C -10.211 1.00 64.90 A c -9.638 1.00 65.02 A c -10.267 1.00 66.10 A c -9.365 1.00 70.31 A N -9.742 1.00 72.23 A c -8.821 1.00 73.45 A N -11.028 1.00 73.04 A N -11.703 1.00 66.79 A C -10.979 1.00 67.02 A 0 -12.650 1.00 69.01 A N -12.913 1.00 72.19 A C -12.353 1.00 73.50 A c -12.157 1.00 73.14 A 0 -12.086 1.00 75.51 A N -11.525 1.00 78.05 A c -10.235 1.00 77.61 A c -9.137 1.00 77.39 A c -8.766 1.00 77.40 A c -7.808 1.00 78.07 A c 325 WO 2009/026558 PCT/US2008/074097 ATOM 379 CD2 TYR 107 -0.195 -4 ATOM 380 CE2 TYR 107 -1.147 -3 ATOM 381 CZ TYR 107 -1.432 -2 ATOM 382 OH TYR 107 -2.392 -2 ATOM 383 C TYR 107 2.214 -2 ATOM 384 O TYR 107 2.787 -3 ATOM 385 N LEU 108 2.565 -1 ATOM 386 CA LEU 108 3.802 -1 ATOM 387 CB LEU 108 3.848 0 ATOM 388 CG LEU 108 4.652 0 ATOM 389 CDl LEU 108 4.615 2 ATOM 390 CD2 LEU 108 6.082 0 ATOM 391 C LEU 108 4.937 -1 ATOM 392 O LEU 108 4 . 827 -1 ATOM 393 N THR 109 6.018 -1 ATOM 394 CA THR 109 7.155 -2 ATOM 395 CB THR 109 7.104 -3 ATOM 396 OG1 THR 109 7.043 -4 ATOM 397 CG2 THR 109 5.897 -3 ATOM 398 C THR 109 8.461 -2 ATOM 399 O THR 109 8.508 -2 ATOM 400 N LYS 110 9.521 -1 ATOM 401 CA LYS 110 10.832 -1 ATOM 402 CB LYS 110 11.340 -0 ATOM 403 CG LYS 110 12.617 0 ATOM 404 CD LYS 110 13.088 1 ATOM 405 CE LYS 110 12.099 2 ATOM 406 NZ LYS 110 12.518 3 ATOM 407 C LYS 110 11.854 -2 ATOM 408 0 LYS 110 11.905 -2 ATOM 409 N ILE 111 12.666 -3 ATOM 410 CA ILE 111 13.853 -3 ATOM 411 CB ILE 111 14.150 -5 ATOM 412 CG2 ILE 111 15.397 -5 ATOM 413 CGI ILE 111 12.952 -5 ATOM 414 CDl ILE 111 12.768 -6 ATOM 415 C ILE 111 15.024 -2 ATOM 416 0 ILE 111 15.347 -2 ATOM 417 N LEU 112 15.655 -2 ATOM 418 CA LEU 112 16.715 -1 ATOM 419 CB LEU 112 16.689 -0 ATOM 420 CG LEU 112 15.329 -0 ATOM 421 CDl LEU 112 15.357 0 ATOM 422 CD2 LEU 112 14.962 0 ATOM 423 C LEU 112 18.069 -2 ATOM 424 O LEU 112 18.996 -1 ATOM 425 N HIS 113 18.184 -3 ATOM 426 CA HIS 113 19.458 -4 ATOM 427 CB HIS 113 20.428 -3 ATOM 428 CG HIS 113 21.807 -4 ATOM 429 CD2 HIS 113 22.500 -4 ATOM 430 NDl HIS 113 22.638 -3 ATOM 431 CEl HIS 113 23.783 -4 ATOM 432 NE2 HIS 113 23.725 -5 ATOM 433 C HIS 113 19.321 -5 ATOM 434 0 HIS 113 18.547 -5 ATOM 435 N VAL 114 20.087 -6 ATOM 436 CA VAL 114 20.031 -7 ATOM 437 CB VAL 114 19.688 -8 ATOM 438 CGI VAL 114 19.579 -9 ATOM 439 CG2 VAL 114 18.388 -7 ATOM 440 C VAL 114 21.387 -8 ATOM 441 O VAL 114 22.392 -8 ATOM 442 N PHE 115 21.415 -8 ATOM 443 CA PHE 115 22.674 -9 ATOM 444 CB PHE 115 22.500 -9 ATOM 445 CG PHE 115 22.268 -8 ATOM 446 CDl PHE 115 20.986 -7 ATOM 447 CD2 PHE 115 23.330 -7 ATOM 448 CEl PHE 115 20.766 -6 ATOM 449 CE2 PHE 115 23.120 -6 ATOM 450 CZ PHE 115 21.838 -5 ATOM 451 C PHE 115 23.217 -10 ATOM 452 O PHE 115 22.708 -11 ATOM 453 N HIS 116 24.257 -10 ATOM 454 CA HIS 116 25.087 -11 -8.512 1.00 78.22 A C -7.550 1.00 77.52 A C -7.203 1.00 78.47 A C -6.255 1.00 78.73 A 0 -12.485 1.00 80.62 A c -12.849 1.00 79.63 A 0 -12.889 1.00 83.48 A N -13.610 1.00 84 . 85 A c -14.084 1.00 86.63 A c -15.342 1.00 88.85 A c -15.564 1.00 89.67 A c -15.194 1.00 89.84 A c -12.624 1.00 84.33 A c -11.440 1.00 85.33 A 0 -13.103 1.00 82.38 A N -12.245 1.00 82.68 A c -11.700 1.00 84.37 A c -12.789 1.00 86.52 A 0 -10.830 1.00 85.93 A c -13.000 1.00 81.95 A c -14.222 1.00 79.46 A 0 -12.275 1.00 81.51 A N -12.890 1.00 81.24 A c -12.852 1.00 83.45 A c -13.662 1.00 88.37 A c -13.651 1.00 92.43 A c -14.332 1.00 95.98 A c -14.197 1.00100.67 A N -12.241 1.00 79.14 A c -11.022 1.00 79.79 A 0 -13.076 1.00 75.80 A N -12.600 1.00 72.25 A c -13.430 1.00 71.02 A c -12.898 1.00 69.49 A c -13.391 1.00 69.43 A c -12.071 1.00 67.40 A c -12.738 1.00 71.50 A c -13.841 1.00 71.60 A 0 -11.615 1.00 69.75 A N -11.598 1.00 67.25 A c -10.279 1.00 65.97 A c -9.976 1.00 66.90 A c -8.627 1.00 67.88 A c -11.092 1.00 65.29 A c -11.778 1.00 66.52 A c -12.355 1.00 65.11 A 0 -11.278 1.00 65.05 A N -11.327 1.00 66.25 A c -10.330 1.00 65.11 A c -10.387 1.00 63.95 A c -9.495 1.00 63.35 A c -11.473 1.00 63.07 A N -11.248 1.00 63.01 A c -10.056 1.00 63.38 A N -11.035 1.00 67.36 A C -10.176 1.00 67.90 A 0 -11.760 1.00 68.11 A N -11.611 1.00 69.21 A C -12.955 1.00 68.54 A c -12.775 1.00 67.55 A c -13.507 1.00 64.17 A c -11.129 1.00 71.04 A c -11.804 1.00 71.37 A 0 -9.953 1.00 73.34 A N -9.353 1.00 76.69 A c -7.856 1.00 77.67 A c -7.087 1.00 79.20 A c -6.737 1.00 79.95 A c -6.734 1.00 79.39 A c -6.052 1.00 81.16 A c -6.046 1.00 80.76 A c -5.704 1.00 82.11 A c -9.981 1.00 78.95 A c -9.739 1.00 79.39 A 0 -10.791 1.00 81.04 A N -11.131 1.00 82.56 A c 326 WO 2009/026558 PCT/US2008/074097 ATOM 455 CB HIS 116 25.073 -11 ATOM 456 CG HIS 116 25.224 -10 ATOM 457 CD2 HIS 116 26.095 -10 ATOM 458 NDl HIS 116 24.360 -9 ATOM 459 CEl HIS 116 24.689 -8 ATOM 460 NE2 HIS 116 25.737 -9 ATOM 461 C HIS 116 26.510 -11 ATOM 4 62 0 HIS 116 27.413 -10 ATOM 463 N GLY 117 26.696 -11 ATOM 464 CA GLY 117 27.997 -11 ATOM 465 C GLY 117 28.215 -12 ATOM 466 0 GLY 117 28.740 -13 ATOM 467 N LEU 118 27.834 -11 ATOM 468 CA LEU 118 28.133 -12 ATOM 469 CB LEU 118 28.931 -11 ATOM 470 CG LEU 118 28.219 -9 ATOM 471 CDl LEU 118 29.171 -9 ATOM 472 CD2 LEU 118 27.746 -8 ATOM 473 C LEU 118 26.845 -12 ATOM 474 O LEU 118 26.839 -12 ATOM 475 N LEU 119 25.749 -12 ATOM 476 CA LEU 119 24.451 -12 ATOM 477 CB LEU 119 23.998 -11 ATOM 478 CG LEU 119 22.666 -11 ATOM 479 CDl LEU 119 22.840 -12 ATOM 480 CD2 LEU 119 22.226 -10 ATOM 481 C LEU 119 23.424 -12 ATOM 482 O LEU 119 23.265 -11 ATOM 483 N PRO 120 22.717 -13 ATOM 484 CD PRO 120 22.785 -15 ATOM 485 CA PRO 120 21.706 -14 ATOM 486 CB PRO 120 21.360 -15 ATOM 487 CG PRO 120 21.598 -15 ATOM 488 C PRO 120 20.513 -13 ATOM 489 O PRO 120 20.147 -13 ATOM 490 N GLY 121 19.906 -12 ATOM 491 CA GLY 121 18.684 -11 ATOM 492 C GLY 121 18.687 -10 ATOM 493 O GLY 121 19.580 -10 ATOM 494 N PHE 122 17.689 -9 ATOM 495 CA PHE 122 17.612 -8 ATOM 496 CB PHE 122 16.813 -8 ATOM 497 CG PHE 122 15.418 -9 ATOM 498 CDl PHE 122 14.341 -8 ATOM 499 CD2 PHE 122 15.182 -10 ATOM 500 CEl PHE 122 13.056 -8 ATOM 501 CE2 PHE 122 13.906 -11 ATOM 502 CZ PHE 122 12.843 -10 ATOM 503 C PHE 122 16.990 -7 ATOM 504 O PHE 122 16.384 -7 ATOM 505 N LEU 123 17.160 -6 ATOM 506 CA LEU 123 16.489 -5 ATOM 507 CB LEU 123 17.468 -3 ATOM 508 CG LEU 123 16.892 -2 ATOM 509 CDl LEU 123 16.958 -2 ATOM 510 CD2 LEU 123 17.666 -1 ATOM 511 C LEU 123 15.342 -4 ATOM 512 O LEU 123 15.496 -4 ATOM 513 N VAL 124 14.199 -4 ATOM 514 CA VAL 124 12.982 -3 ATOM 515 CB VAL 124 11.981 -5 ATOM 516 CGI VAL 124 11.675 -5 ATOM 517 CG2 VAL 124 10.692 -4 ATOM 518 C VAL 124 12.298 -2 ATOM 519 O VAL 124 12.255 -2 ATOM 520 N LYS 125 11.751 -1 ATOM 521 CA LYS 125 10.944 -0 ATOM 522 CB LYS 125 11.382 0 ATOM 523 CG LYS 125 10.786 1 ATOM 524 CD LYS 125 11.670 2 ATOM 525 CE LYS 125 11.108 4 ATOM 526 NZ LYS 125 11.497 5 ATOM 527 C LYS 125 9.4 62 -1 ATOM 528 0 LYS 125 8.991 -1 ATOM 529 N MET 126 8.733 -1 ATOM 530 CA MET 126 7.319 -1 -12.647 1.00 86.34 A C -13.498 1.00 89.89 A C -14.496 1.00 91.04 A C -13.428 1.00 91.27 A N -14.349 1.00 92.06 A C -15. Oil 1.00 91.87 A N -10.621 1.00 80.27 A C -11.370 1.00 80.70 A O -9.330 1.00 7 6.62 A N -8.729 1.00 72.53 A C -7.406 1.00 69.71 A C -7.363 1.00 68.94 A 0 -6.310 1.00 67.10 A N -5.019 1.00 65.67 A c -4.154 1.00 64.83 A c -3.427 1.00 62.63 A c -2.418 1.00 61.32 A c -4.398 1.00 62.31 A c -4.333 1.00 64.76 A c -3.180 1.00 65.29 A 0 -5.071 1.00 63.71 A N -4.548 1.00 62.88 A c -3.549 1.00 65.56 A c -2.840 1.00 66.68 A c -1.799 1.00 68.24 A c -2.188 1.00 67.19 A c -5.682 1.00 61.76 A c -6.505 1.00 61.17 A 0 -5.739 1.00 60.22 A N -4.795 1.00 59.04 A c -6.774 1.00 58.33 A c -6.621 1.00 57.41 A c -5.181 1.00 58.24 A c -6.472 1.00 58.32 A c -5.301 1.00 60.08 A 0 -7.507 1.00 55.72 A N -7.301 1.00 51.86 A c -8.012 1.00 51.21 A c -8.803 1.00 51.96 A 0 -7.737 1.00 49.58 A N -8.383 1.00 47.46 A c -9.676 1.00 45.66 A c -9.473 1.00 44.33 A c -9.473 1.00 42.51 A c -9.268 1.00 41.45 A c -9.273 1.00 42.67 A c -9.070 1.00 37.88 A c -9.071 1.00 38.44 A c -7.486 1.00 47.82 A c -6.455 1.00 46.93 A 0 -7.882 1.00 48.30 A N -7.229 1.00 49.55 A c -6.993 1.00 50.43 A c -6.317 1.00 50.76 A c -4.803 1.00 50.11 A c -6.744 1.00 47.52 A c -8.109 1.00 49.64 A c -9.326 1.00 49.87 A 0 -7.483 1.00 50.02 A N -8.203 1.00 49.18 A c -8.182 1.00 47.70 A c -6.728 1.00 43.41 A c -8.896 1.00 46.32 A c -7.587 1.00 50.07 A c -6.362 1.00 49.64 A 0 -8.447 1.00 50.54 A N -8.021 1.00 51.53 A c -8.796 1.00 53.26 A c -8.315 1.00 55.05 A c -8.741 1.00 58.38 A c -8.255 1.00 60.15 A c -9.155 1.00 61.63 A N -8.284 1.00 51.78 A c -9.426 1.00 52.65 A 0 -7.225 1.00 51.29 A N -7.342 1.00 49.75 A c 327 WO 2009/026558 PCT/US2008/074097 ATOM 531 CB MET 126 7.119 -3 ATOM 532 CG MET 126 7.627 -4 ATOM 533 SD MET 126 7.62 6 -5 ATOM 534 CE MET 126 7.973 -6 ATOM 535 C MET 126 6.565 -1 ATOM 536 0 MET 126 7.180 -0 ATOM 537 N SER 127 5.236 -1 ATOM 538 CA SER 127 4.383 -0 ATOM 539 CB SER 127 2.917 -0 ATOM 540 OG SER 127 2.103 -0 ATOM 541 C SER 127 4.540 -1 ATOM 542 O SER 127 4.769 -3 ATOM 543 N GLY 128 4.416 -1 ATOM 544 CA GLY 128 4.503 -2 ATOM 545 C GLY 128 3.353 -3 ATOM 546 0 GLY 128 3.475 -4 ATOM 547 N ASP 129 2.241 -3 ATOM 548 CA ASP 129 1. 109 -3 ATOM 549 CB ASP 129 0.170 -3 ATOM 550 CG ASP 129 -0.675 -2 ATOM 551 OD1 ASP 129 -0.446 -1 ATOM 552 OD2 ASP 129 -1.577 -1 ATOM 553 C ASP 129 1.570 -5 ATOM 554 O ASP 129 0.985 -6 ATOM 555 N LEU 130 2.627 -5 ATOM 556 CA LEU 130 3.029 -6 ATOM 557 CB LEU 130 3.659 -6 ATOM 558 CG LEU 130 2.677 -5 ATOM 559 CDl LEU 130 3.369 -4 ATOM 560 CD2 LEU 130 2.057 -7 ATOM 561 C LEU 130 3.985 -7 ATOM 562 O LEU 130 4.656 -8 ATOM 563 N LEU 131 4.054 -7 ATOM 564 CA LEU 131 4.981 -7 ATOM 565 CB LEU 131 5.274 -7 ATOM 566 CG LEU 131 6.139 -5 ATOM 567 CDl LEU 131 5.883 -4 ATOM 568 CD2 LEU 131 7.591 -6 ATOM 569 C LEU 131 4 . 442 -9 ATOM 570 O LEU 131 5.199 -10 ATOM 571 N GLU 132 3.133 -9 ATOM 572 CA GLU 132 2.494 -10 ATOM 573 CB GLU 132 0.973 -10 ATOM 574 CG GLU 132 0.198 -11 ATOM 575 CD GLU 132 -1.324 -11 ATOM 576 OE1 GLU 132 -2.060 -12 ATOM 577 OE2 GLU 132 -1.782 -10 ATOM 578 C GLU 132 2.870 -11 ATOM 579 O GLU 132 3.437 -12 ATOM 580 N LEU 133 2.574 -10 ATOM 581 CA LEU 133 2.831 -11 ATOM 582 CB LEU 133 2.546 -10 ATOM 583 CG LEU 133 1.958 -11 ATOM 584 CDl LEU 133 1.959 -10 ATOM 585 CD2 LEU 133 2.765 -12 ATOM 586 C LEU 133 4.264 -12 ATOM 587 O LEU 133 4.491 -13 ATOM 588 N ALA 134 5.230 -11 ATOM 589 CA ALA 134 6.602 -11 ATOM 590 CB ALA 134 7.446 -10 ATOM 591 C ALA 134 7.255 -12 ATOM 592 0 ALA 134 8.214 -13 ATOM 593 N LEU 135 6.743 -12 ATOM 594 CA LEU 135 7.309 -13 ATOM 595 CB LEU 135 6.842 -13 ATOM 596 CG LEU 135 7.491 -12 ATOM 597 CDl LEU 135 6.520 -11 ATOM 598 CD2 LEU 135 8.775 -12 ATOM 599 C LEU 135 6.876 -15 ATOM 600 O LEU 135 7.490 -16 ATOM 601 N LYS 136 5.807 -15 ATOM 602 CA LYS 136 5.318 -16 ATOM 603 CB LYS 136 3.922 -16 ATOM 604 CG LYS 136 2.818 -16 ATOM 605 CD LYS 136 1.451 -16 ATOM 606 CE LYS 136 0.374 -15 -7.354 1.00 49.94 A C -6.116 1.00 51.30 A C -6.339 1.00 56.10 A S -4.675 1.00 54.16 A c -6.172 1.00 49.16 A c -5.185 1.00 47.47 A 0 -6.287 1.00 48.54 A N -5.137 1.00 46.28 A c -5.537 1.00 47.48 A c -4.375 1.00 47.10 A 0 -4.096 1.00 44 . 81 A c -4.436 1.00 44.11 A 0 -2.828 1.00 42.54 A N -1.748 1.00 39.84 A c -1.829 1.00 40.64 A c -1.378 1.00 40.33 A 0 -2.417 1.00 40.43 A N -2.637 1.00 41.66 A c -3.683 1.00 41.97 A c -3.133 1.00 45.41 A c -1.978 1.00 48.87 A 0 -3.853 1.00 45.68 A 0 -3.093 1.00 43.90 A c -2.704 1.00 46.09 A 0 -3.898 1.00 43.76 A N -4.533 1.00 45.35 A c -5.905 1.00 43.26 A c -6.978 1.00 43.78 A c -7.958 1.00 42.09 A c -7.700 1.00 40.85 A c -3.676 1.00 48.24 A c -4.167 1.00 47.63 A 0 -2.390 1.00 52.01 A N -1.541 1.00 56.99 A c -0.269 1.00 55.21 A c -0.544 1.00 53.21 A c 0.502 1.00 51.08 A c -0.589 1.00 51.08 A c -1.199 1.00 61.74 A c -1.150 1.00 62.05 A 0 -0.969 1.00 67.01 A N -0.757 1.00 70.97 A c -0.698 1.00 76.59 A c -0.504 1.00 85.24 A c -0.472 1.00 90.08 A c -0.564 1.00 93.16 A 0 -0.354 1.00 91.94 A 0 -1.946 1.00 71.12 A c -1.797 1.00 70.53 A 0 -3.133 1.00 70.73 A N -4.390 1.00 70.60 A c -5.554 1.00 67.75 A c -6.807 1.00 66.81 A c -7.933 1.00 65.64 A c -7.190 1.00 66.81 A c -4.494 1.00 72.24 A c -4.554 1.00 73.30 A 0 -4.504 1.00 73.74 A N -4.885 1.00 74.48 A c -4.889 1.00 75.03 A c -4.001 1.00 75.73 A c -4.411 1.00 73.90 A 0 -2.786 1.00 78.60 A N -1.860 1.00 81.85 A c -0.439 1.00 78.00 A c 0.306 1.00 74.37 A c 1.326 1.00 71.67 A c 0.971 1.00 72.66 A c -2.258 1.00 86.28 A c -1.857 1.00 86.58 A 0 -3.047 1.00 92.64 A N -3.560 1.00 99.95 A c -4.172 1.00101.68 A c -3.164 1.00104.97 A c -3.834 1.00108.72 A c -2.906 1.00112.39 A c 328 WO 2009/026558 PCT/US2008/074097 ATOM 607 NZ LYS 136 0.413 -16 ATOM 608 C LYS 136 6.276 -17 ATOM 609 0 LYS 136 6.599 -18 ATOM 610 N LEU 137 6.735 -16 ATOM 611 CA LEU 137 7.615 -16 ATOM 612 CB LEU 137 8.316 -15 ATOM 613 CG LEU 137 7.332 -14 ATOM 614 CDl LEU 137 8.040 -13 ATOM 615 CD2 LEU 137 6.183 -14 ATOM 616 C LEU 137 8.647 -17 ATOM 617 O LEU 137 9.098 -17 ATOM 618 N PRO 138 9.021 -18 ATOM 619 CD PRO 138 8.460 -18 ATOM 620 CA PRO 138 9.942 -19 ATOM 621 CB PRO 138 9.671 -20 ATOM 622 CG PRO 138 9.241 -19 ATOM 623 C PRO 138 11.411 -19 ATOM 624 O PRO 138 11.811 -18 ATOM 625 N HIS 139 12.203 -20 ATOM 62 6 CA HIS 139 13.634 -19 ATOM 627 CB HIS 139 14.288 -19 ATOM 628 CG HIS 139 14.255 -20 ATOM 629 CD2 HIS 139 13.765 -20 ATOM 630 NDl HIS 139 14.799 -21 ATOM 631 CEl HIS 139 14.647 -22 ATOM 632 NE2 HIS 139 14.023 -21 ATOM 633 C HIS 139 13.894 -18 ATOM 634 0 HIS 139 14.899 -18 ATOM 635 N VAL 140 12.977 -17 ATOM 636 CA VAL 140 13.104 -16 ATOM 637 CB VAL 140 11.864 -15 ATOM 638 CGI VAL 140 11.989 -14 ATOM 639 CG2 VAL 140 11.684 -15 ATOM 640 C VAL 140 13.314 -16 ATOM 641 O VAL 140 12.556 -17 ATOM 642 N ASP 141 14.334 -16 ATOM 643 CA ASP 141 14.716 -16 ATOM 644 CB ASP 141 16.243 -16 ATOM 645 CG ASP 141 16.726 -17 ATOM 646 OD1 ASP 141 15.931 -17 ATOM 647 OD2 ASP 141 17.908 -17 ATOM 648 C ASP 141 14.141 -15 ATOM 649 O ASP 141 13.682 -16 ATOM 650 N TYR 142 14.192 -14 ATOM 651 CA TYR 142 13.602 -13 ATOM 652 CB TYR 142 14.327 -13 ATOM 653 CG TYR 142 15.789 -12 ATOM 654 CDl TYR 142 16.173 -11 ATOM 655 CEl TYR 142 17.505 -11 ATOM 656 CD2 TYR 142 16.787 -13 ATOM 657 CE2 TYR 142 18.119 -13 ATOM 658 CZ TYR 142 18.470 -12 ATOM 659 OH TYR 142 19.804 -11 ATOM 660 C TYR 142 13.717 -12 ATOM 661 O TYR 142 14.582 -12 ATOM 662 N ILE 143 12.847 -11 ATOM 663 CA ILE 143 12.880 -9 ATOM 664 CB ILE 143 11.558 -9 ATOM 665 CG2 ILE 143 11.539 -8 ATOM 666 CGI ILE 143 11.377 -10 ATOM 667 CDl ILE 143 10.176 -10 ATOM 668 C ILE 143 13.122 -8 ATOM 669 0 ILE 143 12.432 -8 ATOM 670 N GLU 144 14.090 -7 ATOM 671 CA GLU 144 14.306 -6 ATOM 672 CB GLU 144 15.774 -6 ATOM 673 CG GLU 144 15.934 -6 ATOM 674 CD GLU 144 17.360 -6 ATOM 675 OE1 GLU 144 18.061 -7 ATOM 676 OE2 GLU 144 17.774 -4 ATOM 677 C GLU 144 13.832 -5 ATOM 678 0 GLU 144 13.848 -5 ATOM 679 N GLU 145 13.399 -4 ATOM 680 CA GLU 145 12.995 -3 ATOM 681 CB GLU 145 11.828 -2 ATOM 682 CG GLU 145 11.463 -1 -1.572 1.00114.91 A N -4.613 1.00104.36 A C -4.616 1.00104.13 A O -5.495 1.00109.27 A N -6.589 1.00112.82 A C -7.149 1.00113.33 A C -7.588 1.00114.59 A c -8.463 1.00113.74 A c -8.343 1.00113.79 A c -6.163 1.00113.26 A c -5.017 1.00116.86 A 0 -7.090 1.00111.23 A N -8.452 1.00111.87 A c -6.891 1.00109.31 A c -8.091 1.00110.49 A c -9.157 1.00111.00 A c -6.815 1.00106.05 A c -7.378 1.00104.55 A 0 -6.124 1.00103.94 A N -5.942 1.00101.12 A c -7.275 1.00106.04 A c -8.326 1.00110.34 A c -9.589 1.00112.17 A c -8.133 1.00112.32 A N -9.232 1.00113.63 A c -10.130 1.00113.61 A N -4.885 1.00 95.84 A C -4.166 1.00 95.18 A 0 -4.794 1.00 87.12 A N -3.881 1.00 78.27 A C -3.945 1.00 76.69 A c -2.963 1.00 76.29 A c -5.340 1.00 76.45 A c -2.425 1.00 73.68 A c -1.886 1.00 74.17 A 0 -1.790 1.00 67.84 A N -0.421 1.00 61.64 A c -0.307 1.00 60.92 A c 1.077 1.00 60.19 A c 2.038 1.00 62.25 A 0 1.204 1.00 57.97 A 0 0.605 1.00 58.24 A c 1.677 1.00 56.40 A 0 0.269 1.00 54.75 A N 1.087 1.00 50.27 A c 2.429 1.00 49.53 A c 2.337 1.00 50.08 A c 2.243 1.00 49.37 A c 2.179 1.00 45.77 A c 2.364 1.00 48.54 A c 2.300 1.00 48.20 A c 2.209 1.00 47.16 A c 2.162 1.00 47.82 A 0 0.335 1.00 48.09 A c -0.520 1.00 48.03 A 0 0.650 1.00 46.96 A N 0.002 1.00 45.43 A c -0.718 1.00 43.93 A c -1.213 1.00 42.29 A c -1.877 1.00 44.21 A c -2.765 1.00 43.87 A c 1.010 1.00 45.82 A c 2.024 1.00 47.06 A 0 0.740 1.00 45.93 A N 1.634 1.00 45.04 A c 2.033 1.00 44.77 A c 3.525 1.00 46.74 A c 3.944 1.00 49.18 A c 4.293 1.00 49.24 A 0 3.927 1.00 48.88 A 0 1.075 1.00 44.39 A c -0.133 1.00 45.65 A 0 1.970 1.00 43.72 A N 1.568 1.00 42.02 A c 2.427 1.00 43.89 A c 2.287 1.00 46.61 A c 329 WO 2009/026558 PCT/US2008/074097 ATOM 683 CD GLU 145 10.678 -0 ATOM 684 OE1 GLU 145 11.226 -0 ATOM 685 OE2 GLU 145 9.518 -0 ATOM 686 C GLU 145 14.168 -2 ATOM 687 O GLU 145 14.794 -2 ATOM 688 N ASP 146 14.459 -1 ATOM 689 CA ASP 146 15.592 -0 ATOM 690 CB ASP 146 15.517 0 ATOM 691 CG ASP 146 16.890 0 ATOM 692 OD1 ASP 146 17.912 0 ATOM 693 OD2 ASP 146 16.936 1 ATOM 694 C ASP 146 15.607 0 ATOM 695 O ASP 146 14.557 0 ATOM 696 N SER 147 16.801 0 ATOM 697 CA SER 147 16.970 1 ATOM 698 CB SER 147 17.033 0 ATOM 699 OG SER 147 17.929 1 ATOM 700 C SER 147 18.232 2 ATOM 701 O SER 147 19.248 2 ATOM 702 N SER 148 18.165 3 ATOM 703 CA SER 148 19.235 4 ATOM 704 CB SER 148 18.746 5 ATOM 705 OG SER 148 17.859 6 ATOM 706 C SER 148 20.513 4 ATOM 707 O SER 148 20.469 3 ATOM 708 N VAL 149 21.653 4 ATOM 709 CA VAL 149 22.893 4 ATOM 710 CB VAL 149 23.937 3 ATOM 711 CGI VAL 149 23.389 2 ATOM 712 CG2 VAL 149 24.289 3 ATOM 713 C VAL 149 23.479 5 ATOM 714 O VAL 149 23.208 6 ATOM 715 N PHE 150 24.277 6 ATOM 716 CA PHE 150 24.789 7 ATOM 717 CB PHE 150 24.070 7 ATOM 718 CG PHE 150 22.611 7 ATOM 719 CDl PHE 150 21.804 6 ATOM 720 CD2 PHE 150 22.034 9 ATOM 721 CEl PHE 150 20.433 6 ATOM 722 CE2 PHE 150 20.676 9 ATOM 723 CZ PHE 150 19.867 8 ATOM 724 C PHE 150 26.287 7 ATOM 725 O PHE 150 26.819 6 ATOM 726 N ALA 151 26.952 8 ATOM 727 CA ALA 151 28.330 8 ATOM 728 CB ALA 151 28.763 10 ATOM 729 C ALA 151 28.460 8 ATOM 730 0 ALA 151 27.541 8 ATOM 731 N GLN 152 29.593 8 ATOM 732 CA GLN 152 29.904 8 ATOM 733 CB GLN 152 30.119 6 ATOM 734 CG GLN 152 28.947 5 ATOM 735 CD GLN 152 27.627 6 ATOM 736 OE1 GLN 152 27.453 6 ATOM 737 NE2 GLN 152 26.690 6 ATOM 738 C GLN 152 31.141 9 ATOM 739 0 GLN 152 31.946 8 ATOM 740 OXT GLN 152 31.277 10 TER 741 GLN 152 ATOM 742 CB SER 153 56.497 17 ATOM 743 OG SER 153 57.007 16 ATOM 744 C SER 153 54.149 16 ATOM 745 O SER 153 53.706 16 ATOM 746 N SER 153 54.578 18 ATOM 747 CA SER 153 55.014 17 ATOM 748 N ILE 154 53.900 15 ATOM 749 CA ILE 154 53.158 14 ATOM 750 CB ILE 154 53.840 13 ATOM 751 CG2 ILE 154 53.052 11 ATOM 752 CGI ILE 154 55.262 12 ATOM 753 CDl ILE 154 55.319 12 ATOM 754 C ILE 154 51.719 14 ATOM 755 0 ILE 154 51.448 14 ATOM 756 N PRO 155 50.775 13 ATOM 757 CD PRO 155 50.980 13 ATOM 758 CA PRO 155 49.363 13 3.478 1.00 47.51 A C 4.601 1.00 48.29 A O 3.294 1.00 49.39 A 0 1.730 1.00 40.96 A c 2.795 1.00 38.91 A 0 0.661 1.00 40.13 A N 0.625 1.00 38.49 A c -0.651 1.00 39.89 A c -1.178 1.00 40.94 A c -0.697 1.00 41.19 A 0 -2.085 1.00 41.04 A 0 1.853 1.00 36.42 A c 2.406 1.00 37.06 A 0 2.262 1.00 33.43 A N 3.480 1.00 33.76 A c 4.675 1.00 30.49 A c 5.653 1.00 34.97 A 0 3.436 1.00 34.29 A c 2.835 1.00 32.95 A 0 4 . 084 1.00 33.24 A N 3.973 1.00 30.80 A c 4 . 486 1.00 30.12 A c 3.555 1.00 30.98 A 0 4.704 1.00 29.06 A c 5.749 1.00 28.62 A 0 4.141 1.00 26.45 A N 4.882 1.00 26.25 A c 4.236 1.00 28.16 A c 4.231 1.00 27.27 A c 2.826 1.00 26.42 A c 4.976 1.00 26.13 A c 4 . 132 1.00 23.35 A 0 6.024 1.00 27.27 A N 6.408 1.00 26.72 A c 7.654 1.00 23.59 A c 7.489 1.00 23.95 A c 7.709 1.00 24.72 A c 7.112 1.00 25.04 A c 7.557 1.00 26.92 A c 6.957 1.00 27.24 A c 7.181 1.00 27.37 A c 6.714 1.00 27.96 A c 7.379 1.00 26.24 A 0 6.256 1.00 27.06 A N 6.627 1.00 29.75 A c 6.132 1.00 29.52 A c 8.149 1.00 32.40 A c 8.876 1.00 34.17 A 0 8.634 1.00 33.63 A N 10.060 1.00 34.27 A c 10.632 1.00 32.18 A c 10.408 1.00 32.72 A c 10.972 1.00 28.64 A c 12.193 1.00 21.85 A 0 10.075 1.00 27.12 A N 10.346 1.00 37.30 A c 11.216 1.00 38.53 A 0 9.725 1.00 38.27 A 0 A 14.876 1.00115.65 B c 13.585 1.00117.41 B 0 14.361 1.00110.66 B c 13.214 1.00110.93 B 0 16.192 1.00114.12 B N 14.839 1.00113.11 B c 15.245 1.00107.72 B N 14.877 1.00104.32 B C 15.430 1.00107.91 B c 15.029 1.00109.50 B c 14.887 1.00111.40 B c 13.381 1.00116.02 B c 15.383 1.00100.10 B c 16.506 1.00 97.82 B 0 14.553 1.00 96.93 B N 13.131 1.00 95.03 B c 14.940 1.00 91.06 B c 330 WO 2009/026558 PCT/US2008/074097 ATOM 759 CB PRO 155 48.678 13 ATOM 760 CG PRO 155 49.602 13 ATOM 761 C PRO 155 49.187 12 ATOM 7 62 O PRO 155 49.609 11 ATOM 7 63 N TRP 156 48.553 13 ATOM 764 CA TRP 156 48.441 12 ATOM 765 CB TRP 156 47.418 12 ATOM 766 CG TRP 156 45.987 12 ATOM 7 67 CD2 TRP 156 45.260 11 ATOM 768 CE2 TRP 156 43.956 11 ATOM 769 CE3 TRP 156 45.588 10 ATOM 770 CDl TRP 156 45.113 13 ATOM 771 NEl TRP 156 43.892 12 ATOM 772 CZ2 TRP 156 42.980 10 ATOM 773 CZ3 TRP 156 44.620 9 ATOM 774 CH2 TRP 156 43.331 9 ATOM 775 C TRP 156 48.043 10 ATOM 776 O TRP 156 48.377 10 ATOM 777 N ASN 157 47.329 10 ATOM 778 CA ASN 157 46.667 9 ATOM 779 CB ASN 157 45.359 9 ATOM 780 CG ASN 157 45.544 10 ATOM 781 OD1 ASN 157 45.730 10 ATOM 782 ND2 ASN 157 45.491 12 ATOM 783 C ASN 157 47.526 8 ATOM 784 0 ASN 157 47.284 7 ATOM 785 N LEU 158 48.523 9 ATOM 786 CA LEU 158 49.500 8 ATOM 787 CB LEU 158 50.192 9 ATOM 788 CG LEU 158 49.313 9 ATOM 789 CDl LEU 158 50.117 10 ATOM 790 CD2 LEU 158 48.795 8 ATOM 791 C LEU 158 50.523 7 ATOM 792 O LEU 158 51.132 6 ATOM 793 N GLU 159 50.692 8 ATOM 794 CA GLU 159 51.581 8 ATOM 795 CB GLU 159 51.771 9 ATOM 796 CG GLU 159 52.326 9 ATOM 797 CD GLU 159 53.837 9 ATOM 798 OE1 GLU 159 54.432 9 ATOM 799 OE2 GLU 159 54.436 8 ATOM 800 C GLU 159 51.013 7 ATOM 801 0 GLU 159 51.761 6 ATOM 802 N ARG 160 49.688 6 ATOM 803 CA ARG 160 49.012 5 ATOM 804 CB ARG 160 47.604 6 ATOM 805 CG ARG 160 46.908 5 ATOM 806 CD ARG 160 47.510 5 ATOM 807 NE ARG 160 47.759 7 ATOM 808 CZ ARG 160 46.859 7 ATOM 809 NHl ARG 160 47.178 9 ATOM 810 NH2 ARG 160 45.644 7 ATOM 811 C ARG 160 48.921 4 ATOM 812 O ARG 160 48.769 3 ATOM 813 N ILE 161 48.996 4 ATOM 814 CA ILE 161 49.033 3 ATOM 815 CB ILE 161 48.143 3 ATOM 816 CG2 ILE 161 46.691 3 ATOM 817 CGI ILE 161 48.548 4 ATOM 818 CDl ILE 161 47.707 4 ATOM 819 C ILE 161 50.464 2 ATOM 820 0 ILE 161 50.711 1 ATOM 821 N THR 162 51.406 3 ATOM 822 CA THR 162 52.823 3 ATOM 823 CB THR 162 53.593 4 ATOM 824 OG1 THR 162 53.175 4 ATOM 825 CG2 THR 162 55.085 4 ATOM 826 C THR 162 53.457 2 ATOM 827 O THR 162 53.682 3 ATOM 828 N PRO 163 53.769 1 ATOM 829 CD PRO 163 53.698 0 ATOM 830 CA PRO 163 54.269 1 ATOM 831 CB PRO 163 54.318 -0 ATOM 832 CG PRO 163 54.471 -0 ATOM 833 C PRO 163 55.634 1 ATOM 834 O PRO 163 56.310 2 13.666 1.00 92.51 B C 12.564 1.00 94.48 B C 16.085 1.00 85.90 B c 15.983 1.00 86.91 B 0 17.166 1.00 78.41 B N 18.366 1.00 71.33 B c 19.335 1.00 67.02 B c 18.982 1.00 64.20 B c 19.254 1.00 62.56 B c 18.760 1.00 61.45 B c 19.865 1.00 61.09 B c 18.351 1.00 63.97 B c 18.214 1.00 62.71 B N 18.861 1.00 59.75 B c 19.962 1.00 59.49 B c 19.463 1.00 60.30 B c 18.036 1.00 69.39 B c 18.766 1.00 69.00 B 0 16.930 1.00 68.55 B N 16.621 1.00 67.01 B c 15.890 1.00 65.67 B c 14.714 1.00 64.99 B c 13.578 1.00 64.19 B 0 14.978 1.00 63.63 B N 15.786 1.00 66.89 B c 15.748 1.00 66.52 B 0 15.104 1.00 67.36 B N 14.416 1.00 69.81 B c 13.314 1.00 67.04 B c 12.140 1.00 64.16 B c 11.209 1.00 61.97 B c 11.395 1.00 61.15 B c 15.442 1.00 72.86 B c 15.287 1.00 73.28 B 0 16.500 1.00 76.18 B N 17.597 1.00 78.78 B c 18.499 1.00 80.32 B c 19.870 1.00 87.64 B c 19.872 1.00 92.62 B c 20.971 1.00 96.21 B 0 18.778 1.00 97.33 B 0 18.399 1.00 78.60 B c 18.967 1.00 78.52 B 0 18.428 1.00 78.98 B N 19.253 1.00 80.10 B c 19.609 1.00 77.90 B c 20.602 1.00 74.99 B c 21.973 1.00 72.60 B c 22.225 1.00 72.12 B N 22.734 1.00 70.97 B c 22.921 1.00 69.95 B N 23.068 1.00 67.47 B N 18.602 1.00 82.37 B C 19.288 1.00 81.03 B 0 17.280 1.00 87.22 B N 16.598 1.00 93.06 B C 15.341 1.00 91.27 B c 15.742 1.00 91.17 B c 14.408 1.00 90.97 B c 13.157 1.00 89.92 B c 16.221 1.00 98.36 B c 15.512 1.00 98.21 B 0 16.714 1.00104.69 B N 16.580 1.00111.43 B c 16.012 1.00112.56 B c 14.663 1.00112.68 B 0 16.043 1.00113.86 B c 17.913 1.00117.00 B c 18.787 1.00115.50 B 0 18.070 1.00123.18 B N 16.959 1.00126.42 B c 19.302 1.00128.43 B c 18.957 1.00129.86 B c 17.477 1.00129.27 B c 19.745 1.00133.09 B c 18.995 1.00133.34 B 0 331 WO 2009/026558 PCT/US2008/074097
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O. O. O. O. O. O. UJ UJ UJ UJ UJ UJ UJ UJ C < < C < < C h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι C < < < < < < >H >H >H >H >H >H >H >H >H >H >H >H UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ M M M cn cn cn cn cn cn cn cn X X 04 04 04 04 04 04 04 .-1 .-1 .-1 .-1 .-1 .-1 .-1 .-1 > > > > > > > CJ CJ CJ CJ CJ CJ CJ CJ CJ > > > > > > > H H H H H H H H H H H H h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι h-Ι .-1 h-Ι < < < < < < < < H Eh t—1 CN t—1 CN t—1 CN t—1 CN t—1 t—1 CN CN t—1 (N t—1 Q < CQ (0 < CQ CO Q U C CQ c> c> C CQ CO Q ω UJ < CQ C> c> < CQ CO U UJ U UJ ΕΝ X C CQ CO Q Q C CQ CO Q Q O' CQ CO f 1 f 1 O' Z CJ CJ CJ CJ CJ o Z CJ CJ CJ CJ CJ CJ o z CJ CJ CJ CJ CJ o Z CJ CJ CJ CJ o o CJ o Z CJ CJ CJ CJ CJ O Z CJ CJ CJ CJ CJ CJ CJ CJ o CJ o Z CJ CJ CJ CJ CJ CJ o Z CJ CJ CJ CJ CJ CJ O z CJ CJ CJ o o CJ o Z CJ LO CO O' CO <J\ O i—1 CN ro lO co O' CO o t—1 CN ro lO UO Γ" CO σ. O t—1 CN ro lO UO r> CO <J\ O t—1 CN ro lO UO r> CO O t—1 CN ro lO UO Γ" CO σ. O t—1 (N ro lO UO r> CO o t—1 CN ro lO UO Γ" CO O ro ro ro ro ro lO lO lO lO lO lO lO lO lO lO UO UO uo UO UO UO UO Ci> UO r> Γ" r> Γ" r> r> Γ" Γ" Γ" CO CO CO CO CO CO CO CO CO CO σ. σ. σ. <T> σ. σ. <T\ <T> σ. σ. o o O o o O o o o o t—1 CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO σ. σ. <T> <T> <T> σ. <T> σ. <T> <T> <T\ T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T T. T T. T T T T T T T T T T T T T T T T T T T T T T T T o o o o o O o o O O o O o O o O O o o o o o o o o o O o o o o o o O o o o o O o o O O o O o o o o o o o o O o o o o o o o o o o o o o o o o o o o O O o H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H Fh < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < 332 WO 2009/026558 PCT/US2008/074097 ATOM 911 CB THR 187 31.427 11 ATOM 912 OG1 THR 187 32.779 11 ATOM 913 CG2 THR 187 30.692 11 ATOM 914 C THR 187 32.376 10 ATOM 915 O THR 187 33.222 9 ATOM 916 N SER 188 32.247 11 ATOM 917 CA SER 188 33.194 11 ATOM 918 CB SER 188 32.696 12 ATOM 919 OG SER 188 31.476 13 ATOM 920 C SER 188 34.544 12 ATOM 921 O SER 188 34.634 12 ATOM 922 N ILE 189 35.592 12 ATOM 923 CA ILE 189 36.948 12 ATOM 924 CB ILE 189 37.794 11 ATOM 92 5 CG2 ILE 189 39.070 11 ATOM 92 6 CGI ILE 189 37.018 9 ATOM 927 CD1 ILE 189 37.195 9 ATOM 92 8 C ILE 189 37.643 13 ATOM 92 9 0 ILE 189 37.635 13 ATOM 930 N GLN 190 38.254 14 ATOM 931 CA GLN 190 39.228 15 ATOM 932 CB GLN 190 39.485 16 ATOM 933 CG GLN 190 40.325 17 ATOM 934 CD GLN 190 40.435 18 ATOM 935 OE1 GLN 190 41.333 19 ATOM 936 NE2 GLN 190 39.519 19 ATOM 937 C GLN 190 40.529 14 ATOM 938 0 GLN 190 41.373 14 ATOM 939 N SER 191 40.694 13 ATOM 940 CA SER 191 41.750 12 ATOM 941 CB SER 191 41.455 11 ATOM 942 OG SER 191 41.141 12 ATOM 943 C SER 191 43.127 13 ATOM 944 O SER 191 44.137 12 ATOM 945 N ASP 192 43.175 14 ATOM 946 CA ASP 192 44.462 15 ATOM 947 CB ASP 192 44.475 16 ATOM 948 CG ASP 192 43.554 17 ATOM 949 OD1 ASP 192 42.863 17 ATOM 950 OD2 ASP 192 43.521 17 ATOM 951 C ASP 192 44.964 16 ATOM 952 O ASP 192 45.887 17 ATOM 953 N HIS 193 44.371 16 ATOM 954 CA HIS 193 44.968 16 ATOM 955 CB HIS 193 44.239 16 ATOM 956 CG HIS 193 44.367 17 ATOM 957 CD2 HIS 193 43.639 18 ATOM 958 ND1 HIS 193 45.324 16 ATOM 959 CEl HIS 193 45.180 17 ATOM 960 NE2 HIS 193 44.164 18 ATOM 961 C HIS 193 46.434 16 ATOM 962 0 HIS 193 46.780 15 ATOM 963 N ARG 194 47.305 17 ATOM 964 CA ARG 194 48.720 16 ATOM 965 CB ARG 194 49.606 18 ATOM 966 CG ARG 194 49.614 18 ATOM 967 CD ARG 194 51.028 18 ATOM 968 NE ARG 194 51.653 19 ATOM 969 CZ ARG 194 51.872 20 ATOM 970 NHl ARG 194 52.447 21 ATOM 971 NH2 ARG 194 51.515 20 ATOM 972 C ARG 194 48.973 15 ATOM 973 O ARG 194 49.986 14 ATOM 974 N GLU 195 48.038 15 ATOM 975 CA GLU 195 48.202 14 ATOM 976 CB GLU 195 47.253 14 ATOM 977 CG GLU 195 47.374 13 ATOM 978 CD GLU 195 48.483 14 ATOM 979 OE1 GLU 195 49.400 14 ATOM 980 OE2 GLU 195 48.434 13 ATOM 981 C GLU 195 47.955 13 ATOM 982 0 GLU 195 48.557 12 ATOM 983 N ILE 196 47.080 12 ATOM 984 CA ILE 196 46.715 11 ATOM 985 CB ILE 196 45.258 11 ATOM 986 CG2 ILE 196 45.079 11 0.071 1.00 28.27 B C 0.392 1.00 31.09 B O 1.376 1.00 29.63 B c -1.964 1.00 28.24 B c -2.167 1.00 27.28 B 0 -2.734 1.00 29.91 B N -3.786 1.00 35.55 B c -4.687 1.00 36.16 B c -4.223 1.00 37.67 B 0 -3.185 1.00 39.38 B c -2.014 1.00 39.88 B 0 -3.994 1.00 42.96 B N -3.530 1.00 45.75 B c -3.594 1.00 46.16 B c -2.810 1.00 45.77 B c -3.020 1.00 44.55 B c -1.550 1.00 46.37 B c -4.392 1.00 48.83 B c -5.62 6 1.00 48.75 B 0 -3.735 1.00 52.85 B N -4.382 1.00 55.02 B c -3.516 1.00 57.93 B c -4.212 1.00 64.58 B c -3.438 1.00 67.20 B c -3.678 1.00 70.49 B 0 -2.506 1.00 70.62 B N -4.551 1.00 54.50 B c -3.673 1.00 54.01 B 0 -5.678 1.00 54.52 B N -5.761 1.00 54.55 B c -6.895 1.00 51.67 B c -8.102 1.00 44.78 B 0 -5.936 1.00 55.93 B c -5.770 1.00 54.97 B 0 -6.272 1.00 58.49 B N -6.511 1.00 61.41 B c -7.881 1.00 56.12 B c -7.957 1.00 51.17 B c -6.959 1.00 50.15 B 0 -9.023 1.00 44.73 B 0 -5.424 1.00 66.24 B c -5.663 1.00 65.77 B 0 -4.234 1.00 73.45 B N -3.023 1.00 81.62 B c -1.793 1.00 82.94 B c -0.574 1.00 84.93 B c -0.155 1.00 86.25 B c 0.392 1.00 85.89 B N 1.356 1.00 87.01 B c 1.048 1.00 87.56 B N -2.985 1.00 86.32 B C -3.506 1.00 89.16 B 0 -2.377 1.00 90.27 B N -2.396 1.00 94.87 B C -2.003 1.00103.52 B c -0.519 1.00114.19 B c 0.039 1.00122.81 B c -0.052 1.00129.82 B N 0.992 1.00133.99 B c 0.822 1.00136.60 B N 2.206 1.00136.97 B N -1.450 1.00 92.97 B C -1.547 1.00 93.22 B 0 -0.539 1.00 90.26 B N 0.483 1.00 87.06 B C 1.644 1.00 87.51 B c 2.814 1.00 89.28 B c 3.778 1.00 88.92 B c 3.402 1.00 88.50 B 0 4.927 1.00 90.60 B 0 -0.074 1.00 84.15 B c 0.377 1.00 84.55 B 0 -1.065 1.00 79.94 B N -1.609 1.00 77.04 B c -1.261 1.00 76.26 B c 0.241 1.00 73.41 B c 333 WO 2009/026558 PCT/US2008/074097 ATOM 987 CGI ILE 196 44.319 12 ATOM 988 CDl ILE 196 42.868 11 ATOM 989 C ILE 196 46.881 11 ATOM 990 0 ILE 196 46.491 10 ATOM 991 N GLU 197 47.456 12 ATOM 992 CA GLU 197 47.596 12 ATOM 993 CB GLU 197 48.293 13 ATOM 994 CG GLU 197 49.760 14 ATOM 995 CD GLU 197 50.448 15 ATOM 996 OE1 GLU 197 51.690 15 ATOM 997 OE2 GLU 197 49.752 16 ATOM 998 C GLU 197 48.356 11 ATOM 999 0 GLU 197 49.454 11 ATOM 1000 N GLY 198 47.749 10 ATOM 1001 CA GLY 198 48.355 9 ATOM 1002 C GLY 198 47.946 8 ATOM 1003 0 GLY 198 48.153 7 ATOM 1004 N ARG 199 47.352 8 ATOM 1005 CA ARG 199 47.126 7 ATOM 1006 CB ARG 199 47.618 7 ATOM 1007 CG ARG 199 49.106 7 ATOM 1008 CD ARG 199 49.602 8 ATOM 1009 NE ARG 199 51.056 8 ATOM 1010 CZ ARG 199 51.760 8 ATOM 1011 NHl ARG 199 53.079 8 ATOM 1012 NH2 ARG 199 51.138 8 ATOM 1013 C ARG 199 45.680 6 ATOM 1014 O ARG 199 45.382 5 ATOM 1015 N VAL 200 44.786 7 ATOM 1016 CA VAL 200 43.364 7 ATOM 1017 CB VAL 200 42.529 8 ATOM 1018 CGI VAL 200 41.049 7 ATOM 1019 CG2 VAL 200 42.861 8 ATOM 1020 C VAL 200 42.859 7 ATOM 1021 O VAL 200 42.698 8 ATOM 1022 N MET 201 42.601 5 ATOM 1023 CA MET 201 42.062 5 ATOM 1024 CB MET 201 42.500 4 ATOM 1025 CG MET 201 42.155 4 ATOM 1026 SD MET 201 40.673 3 ATOM 1027 CE MET 201 40.321 3 ATOM 1028 C MET 201 40.554 5 ATOM 1029 0 MET 201 39.950 5 ATOM 1030 N VAL 202 39.940 6 ATOM 1031 CA VAL 202 38.504 6 ATOM 1032 CB VAL 202 38.121 8 ATOM 1033 CGI VAL 202 36.670 8 ATOM 1034 CG2 VAL 202 38.421 9 ATOM 1035 C VAL 202 37.768 6 ATOM 1036 O VAL 202 37.839 6 ATOM 1037 N THR 203 37.069 5 ATOM 1038 CA THR 203 36.356 4 ATOM 1039 CB THR 203 35.896 2 ATOM 1040 OG1 THR 203 34.699 3 ATOM 1041 CG2 THR 203 36.987 2 ATOM 1042 C THR 203 35.139 4 ATOM 1043 O THR 203 34.806 6 ATOM 1044 N ASP 204 34.477 4 ATOM 1045 CA ASP 204 33.344 5 ATOM 1046 CB ASP 204 33.337 4 ATOM 1047 CG ASP 204 34.107 3 ATOM 1048 OD1 ASP 204 33.557 2 ATOM 1049 OD2 ASP 204 35.265 3 ATOM 1050 C ASP 204 32.043 4 ATOM 1051 O ASP 204 30.981 4 ATOM 1052 N PHE 205 32.124 4 ATOM 1053 CA PHE 205 30.941 3 ATOM 1054 CB PHE 205 31.305 2 ATOM 1055 CG PHE 205 30.137 1 ATOM 1056 CDl PHE 205 29.870 2 ATOM 1057 CD2 PHE 205 29.246 1 ATOM 1058 CEl PHE 205 28.727 2 ATOM 1059 CE2 PHE 205 28.100 0 ATOM 1060 CZ PHE 205 27.839 1 ATOM 1061 C PHE 205 30.202 4 ATOM 1062 O PHE 205 30.717 5 -1.844 1.00 74.97 B C -1.783 1.00 75.89 B C -3.125 1.00 76.54 B c -3.743 1.00 74.38 B 0 -3.729 1.00 77.49 B N -5.181 1.00 78.27 B c -5.637 1.00 79.61 B c -5.283 1.00 85.72 B c -5.934 1.00 88.78 B c -6.079 1.00 89.81 B 0 -6.299 1.00 90.86 B 0 -5.701 1.00 76.80 B c -5.248 1.00 76.81 B 0 -6.653 1.00 75.14 B N -7.202 1.00 72.34 B c -6.493 1.00 70.89 B c -7.013 1.00 69.29 B 0 -5.312 1.00 71.26 B N -4.436 1.00 70.32 B c -3.031 1.00 74.10 B c -3.006 1.00 83.59 B c -1.650 1.00 91.99 B c -1.592 1.00100.21 B N -0.487 1.00104.98 B c -0.516 1.00108.28 B N 0.646 1.00109.18 B N -4.378 1.00 67.21 B C -3.777 1.00 67.23 B 0 -5.001 1.00 63.27 B N -5.016 1.00 58.38 B C -4.274 1.00 57.40 B c -4.484 1.00 55.82 B c -2.799 1.00 55.70 B c -6.442 1.00 56.33 B c -7.095 1.00 56.53 B 0 -6.924 1.00 55.20 B N -8.260 1.00 55.32 B c -8.830 1.00 55.79 B c -10.283 1.00 58.69 B c -10.522 1.00 64.01 B s -12.296 1.00 63.64 B c -8.163 1.00 53.91 B c -7.440 1.00 55.03 B 0 -8.875 1.00 53.21 B N -8.744 1.00 52.50 B c -8.828 1.00 47.24 B c -9.158 1.00 41.41 B c -7.509 1.00 41.18 B c -9.813 1.00 54.26 B c -10.992 1.00 54.98 B 0 -9.394 1.00 55.90 B N -10.336 1.00 59.12 B c -9.690 1.00 57.76 B c -8.924 1.00 55.18 B 0 -8.768 1.00 55.56 B c -10.855 1.00 61.90 B c -10.382 1.00 63.12 B 0 -11.839 1.00 64.10 B N -12.446 1.00 66.16 B c -13.941 1.00 70.85 B c -14.280 1.00 77.17 B c -14.052 1.00 77.27 B 0 -14.764 1.00 80.38 B 0 -11.797 1.00 64.17 B c -12.413 1.00 66.46 B 0 -10.547 1.00 60.33 B N -9.848 1.00 57.09 B c -8.904 1.00 58.44 B c -8.137 1.00 58.36 B c -6.867 1.00 59.33 B c -8.722 1.00 60.27 B c -6.192 1.00 60.30 B c -8.054 1.00 61.35 B c -6.787 1.00 61.17 B c -9.055 1.00 54.53 B c -8.077 1.00 52.72 B 0 334 WO 2009/026558 PCT/US2008/074097 ATOM 1063 N GLU 206 28.981 5 ATOM 1064 CA GLU 206 28.152 6 ATOM 1065 CB GLU 206 28.037 7 ATOM 1066 CG GLU 206 27.201 8 ATOM 1067 CD GLU 206 27.691 9 ATOM 1068 OE1 GLU 206 27.017 10 ATOM 1069 OE2 GLU 206 28.748 9 ATOM 1070 C GLU 206 2 6.7 63 5 ATOM 1071 0 GLU 206 25.986 5 ATOM 1072 N ASN 207 26.459 5 ATOM 1073 CA ASN 207 25.086 4 ATOM 1074 CB ASN 207 24.857 3 ATOM 1075 CG ASN 207 23.494 2 ATOM 1076 OD1 ASN 207 23.376 2 ATOM 1077 ND2 ASN 207 22.446 3 ATOM 1078 C ASN 207 24.736 5 ATOM 1079 O ASN 207 25.011 5 ATOM 1080 N VAL 208 24.131 6 ATOM 1081 CA VAL 208 23.780 7 ATOM 1082 CB VAL 208 24.660 9 ATOM 1083 CGI VAL 208 26.124 8 ATOM 1084 CG2 VAL 208 24.436 9 ATOM 1085 C VAL 208 22.327 8 ATOM 1086 O VAL 208 21.841 8 ATOM 1087 N PRO 209 21.599 8 ATOM 1088 CD PRO 209 21.915 7 ATOM 1089 CA PRO 209 20.289 8 ATOM 1090 CB PRO 209 19.697 8 ATOM 1091 CG PRO 209 20.892 8 ATOM 1092 C PRO 209 20.387 10 ATOM 1093 O PRO 209 21.474 11 ATOM 1094 N GLU 210 19.235 11 ATOM 1095 CA GLU 210 19.148 12 ATOM 1096 CB GLU 210 17.762 12 ATOM 1097 CG GLU 210 17.373 12 ATOM 1098 CD GLU 210 16.081 12 ATOM 1099 OE1 GLU 210 15.148 13 ATOM 1100 OE2 GLU 210 16.003 13 ATOM 1101 C GLU 210 19.427 13 ATOM 1102 0 GLU 210 19.150 12 ATOM 1103 N GLU 211 19.979 14 ATOM 1104 CA GLU 211 20.047 15 ATOM 1105 CB GLU 211 20.886 16 ATOM 1106 CG GLU 211 22.143 16 ATOM 1107 CD GLU 211 23.166 15 ATOM 1108 OE1 GLU 211 23.159 15 ATOM 1109 OE2 GLU 211 23.980 14 ATOM 1110 C GLU 211 18.619 16 ATOM 1111 0 GLU 211 17.769 16 ATOM 1112 N ASP 212 18.356 16 ATOM 1113 CA ASP 212 17.104 16 ATOM 1114 CB ASP 212 17.006 16 ATOM 1115 CG ASP 212 15.875 17 ATOM 1116 OD1 ASP 212 15.010 18 ATOM 1117 OD2 ASP 212 15.861 17 ATOM 1118 C ASP 212 17.094 18 ATOM 1119 O ASP 212 17.763 19 ATOM 1120 N GLY 213 16.330 18 ATOM 1121 CA GLY 213 16.248 19 ATOM 1122 C GLY 213 15.807 21 ATOM 1123 0 GLY 213 16.199 22 ATOM 1124 N THR 214 14.996 20 ATOM 1125 CA THR 214 14.552 21 ATOM 1126 CB THR 214 13.732 21 ATOM 1127 OG1 THR 214 14.618 20 ATOM 1128 CG2 THR 214 12.684 20 ATOM 1129 C THR 214 15.788 22 ATOM 1130 O THR 214 15.720 23 ATOM 1131 N ARG 215 16.908 21 ATOM 1132 CA ARG 215 17.994 21 ATOM 1133 CB ARG 215 17.946 20 ATOM 1134 CG ARG 215 18.150 21 ATOM 1135 CD ARG 215 17.327 20 ATOM 1136 NE ARG 215 17.244 19 ATOM 1137 CZ ARG 215 17.219 18 ATOM 1138 NH1 ARG 215 17.135 17
-9.478 1.00 52.93 B N -8.774 1.00 51.13 B C -9.595 1.00 53.70 B C -8.934 1.00 57.85 B c -9.245 1.00 59.92 B c -8.839 1.00 61.92 B 0 -9.893 1.00 60.90 B 0 -8.513 1.00 47.24 B c -9.429 1.00 47.31 B 0 -7.254 1.00 43.16 B N -6.854 1.00 37.74 B c -6.593 1.00 39.88 B c -7.059 1.00 41.36 B c -7.914 1.00 40.04 B 0 -6.523 1.00 39.17 B N -5.60 6 1.00 34.09 B c -4.484 1.00 32.93 B 0 -5.814 1.00 31.06 B N -4.719 1.00 28.94 B c -4.728 1.00 29.67 B c -4.589 1.00 30.43 B c -6.006 1.00 24.70 B c -4.864 1.00 29.88 B c -5.973 1.00 31.23 B 0 -3.747 1.00 31.45 B N -2.406 1.00 31.28 B c -3.785 1.00 28.45 B c -2.426 1.00 28.25 B c -1.549 1.00 30.42 B c -4.020 1.00 29.17 B c -4.003 1.00 27.51 B 0 -4.220 1.00 32.85 B N -4.455 1.00 33.71 B c -4.962 1.00 39.61 B c -6.302 1.00 51.73 B c -6.857 1.00 61.74 B c -6.064 1.00 64.35 B 0 -8.097 1.00 67.46 B 0 -3.202 1.00 31.17 B c -2.089 1.00 28.89 B 0 -3.398 1.00 29.36 B N -2.333 1.00 30.97 B c -2.766 1.00 31.25 B c -3.591 1.00 33.76 B c -2.829 1.00 36.82 B c -1.576 1.00 37.51 B 0 -3.485 1.00 39.74 B 0 -2.014 1.00 32.21 B c -2.900 1.00 32.92 B 0 -0.746 1.00 33.11 B N -0.326 1.00 31.22 B c 1.207 1.00 33.18 B c 1.788 1.00 37.82 B c 1.032 1.00 38.10 B 0 3.030 1.00 39.62 B 0 -0.805 1.00 29.26 B c -0.228 1.00 27.81 B 0 -1.863 1.00 27.67 B N -2.4 63 1.00 26.36 B c -1.576 1.00 26.31 B c -1.805 1.00 23.54 B 0 -0.561 1.00 29.38 B N 0.380 1.00 32.08 B c 1.535 1.00 32.59 B c 2.414 1.00 33.19 B 0 1.027 1.00 32.64 B c 1.033 1.00 33.20 B c 1.613 1.00 34.45 B 0 0.965 1.00 32.69 B N 1.903 1.00 32.87 B c 2.987 1.00 31.54 B c 4.372 1.00 31.05 B c 5.370 1.00 31.52 B c 5.060 1.00 30.75 B N 6.004 1.00 31.15 B c 5.704 1.00 24.64 B N 335 WO 2009/026558 PCT/US2008/074097 ATOM 1139 NH2 ARG 215 17.290 18.708 7.274 1.00 33.67 B N ATOM 1140 C ARG 215 19.395 22.043 1.285 1.00 33.56 B C ATOM 1141 O ARG 215 20.372 22.345 1.974 1.00 32.49 B O ATOM 1142 N PHE 216 19.488 21.768 -0.012 1.00 35.28 B N ATOM 1143 CA PHE 216 20.788 21.626 -0.657 1.00 38.92 B C ATOM 1144 CB PHE 216 20.867 20.293 -1.390 1.00 35.82 B C ATOM 1145 CG PHE 216 22.161 20.080 -2.116 1.00 30.16 B c ATOM 1146 CDl PHE 216 22.198 20.076 -3.499 1.00 25.91 B c ATOM 1147 CD2 PHE 216 23.337 19.866 -1.411 1.00 30.02 B c ATOM 1148 CEl PHE 216 23.383 19.862 -4.179 1.00 25.89 B c ATOM 1149 CE2 PHE 216 24.539 19.647 -2.083 1.00 30.04 B c ATOM 1150 CZ PHE 216 24.565 19.646 -3.471 1.00 2 6.63 B c ATOM 1151 C PHE 216 21.128 22.726 -1.640 1.00 42.83 B c ATOM 1152 O PHE 216 20.336 23.043 -2.528 1.00 43.81 B 0 ATOM 1153 N HIS 217 22.326 23.284 -1.498 1.00 47.52 B N ATOM 1154 CA HIS 217 22.812 24.292 -2.431 1.00 52.66 B c ATOM 1155 CB HIS 217 22.869 25.642 -1.731 1.00 50.71 B c ATOM 1156 CG HIS 217 21.531 26.130 -1.273 1.00 50.46 B c ATOM 1157 CD2 HIS 217 21.019 26.293 -0.030 1.00 50.17 B c ATOM 1158 NDl HIS 217 20.531 26.491 -2.152 1.00 49.45 B N ATOM 1159 CEl HIS 217 19.461 26.854 -1.467 1.00 50.58 B c ATOM 1160 NE2 HIS 217 19.729 26.743 -0.178 1.00 48.98 B N ATOM 1161 C HIS 217 24.180 23.930 -2.979 1.00 57.43 B C ATOM 1162 0 HIS 217 25.180 24.121 -2.308 1.00 59.37 B 0 ATOM 1163 N ARG 218 24.216 23.419 -4.206 1.00 64.96 B N ATOM 1164 CA ARG 218 25.442 22.892 -4.802 1.00 72.47 B C ATOM 1165 CB ARG 218 25.220 22.646 -6.300 1.00 78.99 B c ATOM 1166 CG ARG 218 26.190 21.661 -6.954 1.00 90.87 B c ATOM 1167 CD ARG 218 25.535 20.276 -7.165 1.00101.66 B c ATOM 1168 NE ARG 218 26.490 19.288 -7.654 1.00114.14 B N ATOM 1169 CZ ARG 218 26.150 18.068 -8.073 1.00121.60 B c ATOM 1170 NHl ARG 218 24.872 17.680 -8.065 1.00127.19 B N ATOM 1171 NH2 ARG 218 27.081 17.221 -8.505 1.00127.03 B N ATOM 1172 C ARG 218 26.608 23.862 -4.603 1.00 73.27 B C ATOM 1173 O ARG 218 27.765 23.464 -4.575 1.00 74.75 B 0 ATOM 1174 N GLN 219 26.274 25.134 -4.441 1.00 73.30 B N ATOM 1175 CA GLN 219 27.223 26.237 -4.488 1.00 70.94 B C ATOM 1176 CB GLN 219 26.467 27.502 -4.879 1.00 75.90 B c ATOM 1177 CG GLN 219 25.114 27.586 -4.175 1.00 83.68 B c ATOM 1178 CD GLN 219 24.098 28.401 -4.942 1.00 89.19 B c ATOM 1179 OE1 GLN 219 22.915 28.422 -4.599 1.00 94.35 B 0 ATOM 1180 NE2 GLN 219 24.554 29.083 -5.991 1.00 93.47 B N ATOM 1181 C GLN 219 27.926 26.450 -3.151 1.00 66.77 B c ATOM 1182 0 GLN 219 29.042 26.950 -3.105 1.00 65.68 B 0 ATOM 1183 N ALA 220 27.250 26.096 -2.065 1.00 62.72 B N ATOM 1184 CA ALA 220 27.798 26.247 -0.724 1.00 58.15 B c ATOM 1185 CB ALA 220 26.714 26.721 0.250 1.00 58.33 B c ATOM 1186 C ALA 220 28.304 24.897 -0.295 1.00 55.57 B c ATOM 1187 0 ALA 220 29.020 24.768 0.694 1.00 54.79 B 0 ATOM 1188 N SER 221 27.901 23.882 -1.046 1.00 52.69 B N ATOM 1189 CA SER 221 28.148 22.512 -0.657 1.00 48.98 B c ATOM 1190 CB SER 221 27.234 21.572 -1.442 1.00 48.25 B c ATOM 1191 OG SER 221 27.591 20.221 -1.196 1.00 52.95 B 0 ATOM 1192 C SER 221 29.612 22.145 -0.876 1.00 45.54 B c ATOM 1193 O SER 221 30.244 22.604 -1.823 1.00 43.51 B 0 ATOM 1194 N LYS 222 30.140 21.329 0.029 1.00 43.16 B N ATOM 1195 CA LYS 222 31.494 20.805 -0.064 1.00 4 0.62 B c ATOM 1196 CB LYS 222 32.293 21.215 1 .176 1.00 42.07 B c ATOM 1197 CG LYS 222 32.478 22.733 1.292 1.00 45.25 B c ATOM 1198 CD LYS 222 32.723 23.204 2.724 1.00 48.85 B c ATOM 1199 CE LYS 222 34.164 22.947 3.161 1.00 51.16 B c ATOM 1200 NZ LYS 222 34.554 23.815 4.315 1.00 55.09 B N ATOM 1201 C LYS 222 31.409 19.285 -0.183 1.00 38.00 B c ATOM 1202 0 LYS 222 31.643 18.554 0.777 1.00 35.80 B 0 ATOM 1203 N CYS 223 31.073 18.833 -1.383 1.00 36.43 B N ATOM 1204 CA CYS 223 30.694 17.455 -1.618 1.00 37.63 B c ATOM 1205 C CYS 223 31.746 16.399 -1.325 1.00 36.41 B c ATOM 1206 0 CYS 223 31.424 15.223 -1.246 1.00 36.97 B 0 ATOM 1207 CB CYS 223 30.228 17.288 -3.057 1.00 37.34 B c ATOM 1208 SG CYS 223 28.629 18.083 -3.444 1.00 45.36 B s ATOM 1209 N ASP 224 32.998 16.808 -1.173 1.00 35.94 B N ATOM 1210 CA ASP 224 34.088 15.846 -1.114 1.00 34.10 B c ATOM 1211 CB ASP 224 35.177 16.192 -2.129 1.00 33.40 B c ATOM 1212 CG ASP 224 34.719 16.017 -3.560 1.00 33.62 B c ATOM 1213 OD1 ASP 224 33.643 15.412 -3.775 1.00 33.19 B 0 ATOM 1214 OD2 ASP 224 35.445 16.478 -4.468 1.00 33.20 B 0 336 WO 2009/026558 PCT/US2008/074097 ATOM 1215 c ASP 224 34.712 15 ATOM 1216 0 ASP 224 35.558 14 ATOM 1217 N SER 225 34.311 16 ATOM 1218 CA SER 225 34.855 16 ATOM 1219 CB SER 225 33.947 17 ATOM 1220 OG SER 225 33.806 17 ATOM 1221 C SER 225 35.119 15 ATOM 1222 O SER 225 36.241 15 ATOM 1223 N HIS 226 34.091 14 ATOM 1224 CA HIS 226 34.120 13 ATOM 1225 CB HIS 226 32.688 13 ATOM 1226 CG HIS 226 32.582 11 ATOM 1227 CD2 HIS 226 32.413 11 ATOM 1228 ND1 HIS 226 32.571 10 ATOM 1229 CEl HIS 226 32.397 9 ATOM 1230 NE2 HIS 226 32.299 10 ATOM 1231 C HIS 226 34.969 12 ATOM 1232 0 HIS 226 35.771 11 ATOM 1233 N GLY 227 34.801 12 ATOM 1234 CA GLY 227 35.568 10 ATOM 1235 C GLY 227 37.021 11 ATOM 1236 0 GLY 227 37.911 10 ATOM 1237 N THR 228 37.282 12 ATOM 1238 CA THR 228 38.658 12 ATOM 1239 CB THR 228 38.732 14 ATOM 1240 OG1 THR 228 37.899 14 ATOM 1241 CG2 THR 228 40.151 14 ATOM 1242 C THR 228 39.526 12 ATOM 1243 O THR 228 40.704 12 ATOM 1244 N HIS 229 38.923 13 ATOM 1245 CA HIS 229 39.562 13 ATOM 1246 CB HIS 229 38.653 13 ATOM 1247 CG HIS 229 39.267 13 ATOM 1248 CD2 HIS 229 39.884 14 ATOM 1249 ND1 HIS 229 39.261 12 ATOM 1250 CEl HIS 229 39.846 13 ATOM 1251 NE2 HIS 229 40.232 14 ATOM 1252 C HIS 229 39.841 11 ATOM 1253 0 HIS 229 40.891 11 ATOM 1254 N LEU 230 38.914 10 ATOM 1255 CA LEU 230 39.074 9 ATOM 1256 CB LEU 230 37.769 8 ATOM 1257 CG LEU 230 36.876 8 ATOM 1258 CD1 LEU 230 35.554 8 ATOM 1259 CD2 LEU 230 37.653 8 ATOM 1260 C LEU 230 40.166 8 ATOM 1261 O LEU 230 40.971 7 ATOM 1262 N ALA 231 40.206 8 ATOM 1263 CA ALA 231 41.387 8 ATOM 1264 CB ALA 231 41.272 9 ATOM 1265 C ALA 231 42.629 9 ATOM 1266 0 ALA 231 43.650 8 ATOM 1267 N GLY 232 42.520 10 ATOM 1268 CA GLY 232 43.612 11 ATOM 1269 C GLY 232 44.108 10 ATOM 1270 0 GLY 232 45.328 10 ATOM 1271 N VAL 233 43.195 9 ATOM 1272 CA VAL 233 43.666 8 ATOM 1273 CB VAL 233 42.533 8 ATOM 1274 CGI VAL 233 43.009 7 ATOM 1275 CG2 VAL 233 42.113 10 ATOM 1276 C VAL 233 44.294 7 ATOM 1277 O VAL 233 45.170 7 ATOM 1278 N VAL 234 43.875 7 ATOM 1279 CA VAL 234 44.338 5 ATOM 1280 CB VAL 234 43.514 5 ATOM 1281 CGI VAL 234 44.048 3 ATOM 1282 CG2 VAL 234 42.055 5 ATOM 1283 C VAL 234 45.776 5 ATOM 1284 O VAL 234 46.623 5 ATOM 1285 N SER 235 46.053 6 ATOM 1286 CA SER 235 47.283 6 ATOM 1287 CB SER 235 47.056 5 ATOM 1288 OG SER 235 4 6.021 6 ATOM 1289 C SER 235 47.784 8 ATOM 1290 O SER 235 48.595 8 0.258 1.00 34.14 B C 0.532 1.00 34.57 B O 1. 116 1.00 31.75 B N 2.468 1.00 31.41 B C 3.351 1.00 30.07 B C 4.627 1.00 34.20 B 0 3.184 1.00 30.28 B c 3.603 1.00 30.27 B 0 3.338 1.00 29.35 B N 4.272 1.00 29.88 B c 4.527 1.00 30.92 B c 5.236 1.00 32.20 B c 6.548 1.00 32.53 B c 4.568 1.00 32.58 B N 5.436 1.00 31.14 B c 6.645 1.00 31.62 B N 3.748 1.00 32.22 B C 4 . 493 1.00 32.16 B 0 2.465 1.00 32.20 B N 1.869 1.00 31.70 B C 1.607 1.00 31.69 B c 1.821 1.00 34.79 B 0 1. 145 1.00 29.42 B N 0.843 1.00 29.53 B c 0.270 1.00 27.13 B c -0.891 1.00 28.15 B 0 -0.146 1.00 25.42 B c 2.105 1.00 29.67 B c 2.059 1.00 30.29 B 0 3.229 1.00 27.72 B N 4.525 1.00 27.44 B c 5.573 1.00 25.75 B c 6.936 1.00 26.14 B c 7.572 1.00 23.57 B c 7.821 1.00 23.19 B N 8.945 1.00 25.43 B c 8.820 1.00 23.55 B N 4.895 1.00 29.45 B C 5.477 1.00 29.48 B 0 4.553 1.00 29.61 B N 4.877 1.00 30.30 B C 4.682 1.00 31.34 B c 5.886 1.00 32.18 B c 5.753 1.00 31.32 B c 7.135 1.00 30.90 B c 4.082 1.00 31.00 B c 4.664 1.00 30.12 B 0 2.770 1.00 30.56 B N 1.975 1.00 31.98 B c 0.541 1.00 32.60 B c 2.633 1.00 31.45 B c 2.771 1.00 31.71 B 0 3.042 1.00 30.90 B N 3.717 1.00 33.63 B c 4.953 1.00 35.98 B c 5.231 1.00 35.65 B 0 5.717 1.00 35.53 B N 6.881 1.00 37.07 B c 7.908 1.00 35.57 B c 8.968 1.00 32.92 B c 8.582 1.00 34.02 B c 6.440 1.00 37.64 B c 7.102 1.00 39.28 B 0 5.313 1.00 38.29 B N 5.008 1.00 39.89 B c 3.886 1.00 36.19 B c 3.661 1.00 33.10 B c 4.258 1.00 34.67 B c 4.558 1.00 43.08 B c 4.997 1.00 43.79 B 0 3.682 1.00 44.77 B N 2.910 1.00 46.23 B c 1.620 1.00 44.76 B c 0.839 1.00 42.23 B 0 2.590 1.00 48.21 B c 1.684 1.00 48.69 B 0 337 WO 2009/026558 PCT/US2008/074097 ATOM 1291 N GLY 236 47.304 9.130 3.345 1.00 49.94 B N ATOM 1292 CA GLY 236 47.832 10.469 3.192 1.00 52.58 B C ATOM 1293 C GLY 236 49.332 10.484 3.393 1.00 53.64 B C ATOM 1294 0 GLY 236 49.845 9.799 4.279 1.00 53.07 B 0 ATOM 1295 N ARG 237 50.030 11.272 2.577 1.00 55.39 B N ATOM 1296 CA ARG 237 51.495 11.329 2.611 1.00 56.99 B c ATOM 1297 CB ARG 237 52.010 12.277 1.517 1.00 58.98 B c ATOM 1298 CG ARG 237 52.163 11.617 0.149 1.00 64.90 B c ATOM 1299 CD ARG 237 52.103 12.625 -0.988 1.00 70.94 B c ATOM 1300 NE ARG 237 52.670 12.109 -2.229 1.00 78.50 B N ATOM 1301 CZ ARG 237 51.961 11.550 -3.203 1.00 82.50 B c ATOM 1302 NH1 ARG 237 52.563 11.111 -4.299 1.00 86.46 B N ATOM 1303 NH2 ARG 237 50.653 11.425 -3.079 1.00 84.78 B N ATOM 1304 C ARG 237 52.083 11.730 3.967 1.00 55.17 B C ATOM 1305 O ARG 237 53.036 11.123 4 . 434 1.00 53.63 B O ATOM 1306 N ASP 238 51.499 12.742 4.599 1.00 55.50 B N ATOM 1307 CA ASP 238 52.045 13.309 5.831 1.00 53.79 B C ATOM 1308 CB ASP 238 52.199 14.832 5.692 1.00 57.66 B C ATOM 1309 CG ASP 238 53.374 15.241 4.779 1.00 61.12 B c ATOM 1310 OD1 ASP 238 54.346 14.462 4.622 1.00 60.35 B 0 ATOM 1311 OD2 ASP 238 53.323 16.362 4.219 1.00 63.48 B 0 ATOM 1312 C ASP 238 51.199 13.008 7.063 1.00 50.51 B c ATOM 1313 O ASP 238 51.606 13.315 8.178 1.00 50.36 B 0 ATOM 1314 N ALA 239 50.022 12.425 6.857 1.00 47.11 B N ATOM 1315 CA ALA 239 49.095 12.138 7.950 1.00 44.37 B C ATOM 1316 CB ALA 239 48.060 13.257 8.077 1.00 38.70 B C ATOM 1317 C ALA 239 48.394 10.798 7.734 1.00 44.34 B C ATOM 1318 0 ALA 239 47.540 10.399 8.524 1.00 44.60 B O ATOM 1319 N GLY 240 48.751 10.109 6.656 1.00 44.64 B N ATOM 1320 CA GLY 240 48.206 8.784 6.427 1.00 46.73 B C ATOM 1321 C GLY 240 48.697 7.731 7.411 1.00 48.30 B C ATOM 1322 0 GLY 240 49.718 7.914 8.086 1.00 49.76 B 0 ATOM 1323 N VAL 241 47.969 6.624 7.501 1.00 48.91 B N ATOM 1324 CA VAL 241 48.395 5.502 8.323 1.00 50.59 B c ATOM 1325 CB VAL 241 47.190 4.674 8.818 1.00 51.60 B c ATOM 1326 CGI VAL 241 47.677 3.372 9.448 1.00 51.09 B c ATOM 1327 CG2 VAL 241 46.370 5.482 9.824 1.00 50.77 B c ATOM 1328 C VAL 241 49.293 4.602 7.490 1.00 51.82 B c ATOM 1329 O VAL 241 50.505 4.561 7.690 1.00 52.95 B 0 ATOM 1330 N ALA 242 48.685 3.885 6.552 1.00 52.19 B N ATOM 1331 CA ALA 242 49.427 3.079 5.596 1.00 53.00 B c ATOM 1332 CB ALA 242 48.617 1.854 5.210 1.00 50.35 B c ATOM 1333 C ALA 242 49.728 3.915 4.360 1.00 54.75 B c ATOM 1334 0 ALA 242 49.099 3.743 3.311 1.00 55.41 B 0 ATOM 1335 N LYS 243 50.693 4.818 4 . 494 1.00 57.04 B N ATOM 1336 CA LYS 243 51.026 5.750 3.427 1.00 59.49 B C ATOM 1337 CB LYS 243 52.189 6.644 3.865 1.00 62.11 B C ATOM 1338 CG LYS 243 52.031 7.180 5.285 1.00 64.29 B C ATOM 1339 CD LYS 243 53.160 8.135 5.673 1.00 64.68 B C ATOM 1340 CE LYS 243 52.959 8.684 7.088 1.00 65.19 B C ATOM 1341 NZ LYS 243 54.113 9.505 7.542 1.00 65.01 B N ATOM 1342 C LYS 243 51.400 4.993 2.158 1.00 60.19 B C ATOM 1343 0 LYS 243 52.058 3.951 2.211 1.00 60.85 B O ATOM 1344 N GLY 244 50.970 5.509 1.013 1.00 59.50 B N ATOM 1345 CA GLY 244 51.328 4.867 -0.238 1.00 58.54 B C ATOM 1346 C GLY 244 50.309 3.847 -0.704 1.00 58.79 B C ATOM 1347 0 GLY 244 50.189 3.605 -1.908 1.00 59.80 B 0 ATOM 1348 N ALA 245 49.571 3.254 0.235 1.00 56.96 B N ATOM 1349 CA ALA 245 48.507 2.321 -0.116 1.00 53.85 B c ATOM 1350 CB ALA 245 47.545 2.160 1.038 1.00 53.74 B c ATOM 1351 C ALA 245 47.777 2.848 -1.340 1.00 51.91 B c ATOM 1352 0 ALA 245 47.669 4.055 -1.544 1.00 50.88 B 0 ATOM 1353 N SER 246 47.292 1.929 -2.158 1.00 49.93 B N ATOM 1354 CA SER 246 46.958 2.244 -3.534 1.00 48.39 B c ATOM 1355 CB SER 246 47.694 1.276 -4.455 1.00 50.45 B c ATOM 1356 OG SER 246 47.393 1.537 -5.808 1.00 55.36 B 0 ATOM 1357 C SER 246 45.461 2.124 -3.737 1.00 46.93 B c ATOM 1358 O SER 246 44.965 1.082 -4.167 1.00 46.77 B 0 ATOM 1359 N MET 247 44.745 3.204 -3.444 1.00 46.10 B N ATOM 1360 CA MET 247 43.304 3.138 -3.195 1.00 42.61 B c ATOM 1361 CB MET 247 42.901 4.220 -2.210 1.00 41.03 B c ATOM 1362 CG MET 247 43.382 3.946 -0.814 1.00 41.28 B c ATOM 1363 SD MET 247 42.988 5.289 0.244 1.00 41.25 B s ATOM 1364 CE MET 247 41.356 5.749 -0.392 1.00 44.40 B c ATOM 1365 C MET 247 42.401 3.226 -4.401 1.00 40.94 B c ATOM 1366 0 MET 247 42.695 3.891 -5.385 1.00 40.67 B 0 338 WO 2009/026558 PCT/US2008/074097 ATOM 1367 N ARG 248 41.279 2 ATOM 1368 CA ARG 248 40.247 2 ATOM 1369 CB ARG 248 40.098 1 ATOM 1370 CG ARG 248 41.411 0 ATOM 1371 CD ARG 248 41.305 -0 ATOM 1372 NE ARG 248 41.744 -0 ATOM 1373 CZ ARG 248 40.919 -0 ATOM 1374 NH1 ARG 248 41.407 -0 ATOM 1375 NH2 ARG 248 39.606 -0 ATOM 1376 C ARG 248 38.950 3 ATOM 1377 O ARG 248 38.554 2 ATOM 1378 N SER 249 38.297 4 ATOM 1379 CA SER 249 37.070 4 ATOM 1380 CB SER 249 37.144 6 ATOM 1381 OG SER 249 36.827 6 ATOM 1382 C SER 249 35.844 4 ATOM 1383 O SER 249 35.908 4 ATOM 1384 N LEU 250 34.740 4 ATOM 1385 CA LEU 250 33.421 3 ATOM 1386 CB LEU 250 32.789 2 ATOM 1387 CG LEU 250 33.376 1 ATOM 1388 CDl LEU 250 34.903 1 ATOM 1389 CD2 LEU 250 32.710 0 ATOM 1390 C LEU 250 32.597 5 ATOM 1391 O LEU 250 32.872 5 ATOM 1392 N ARG 251 31.599 5 ATOM 1393 CA ARG 251 30.750 6 ATOM 1394 CB ARG 251 30.669 7 ATOM 1395 CG ARG 251 30.297 9 ATOM 1396 CD ARG 251 29.335 9 ATOM 1397 NE ARG 251 28.997 11 ATOM 1398 CZ ARG 251 28.209 12 ATOM 1399 NH1 ARG 251 27.697 11 ATOM 1400 NH2 ARG 251 27.919 13 ATOM 1401 C ARG 251 29.329 6 ATOM 1402 O ARG 251 28.442 6 ATOM 1403 N VAL 252 29.127 5 ATOM 1404 CA VAL 252 27.852 5 ATOM 1405 CB VAL 252 27.993 4 ATOM 1406 CGI VAL 252 28.692 3 ATOM 1407 CG2 VAL 252 28.721 4 ATOM 1408 C VAL 252 27.199 6 ATOM 1409 O VAL 252 26.128 6 ATOM 1410 N LEU 253 27.840 7 ATOM 1411 CA LEU 253 27.232 8 ATOM 1412 CB LEU 253 28.058 8 ATOM 1413 CG LEU 253 28.172 7 ATOM 1414 CDl LEU 253 28.840 8 ATOM 1415 CD2 LEU 253 26.769 7 ATOM 1416 C LEU 253 27.099 9 ATOM 1417 O LEU 253 28.061 10 ATOM 1418 N ASN 254 25.924 10 ATOM 1419 CA ASN 254 25.798 11 ATOM 1420 CB ASN 254 24.346 12 ATOM 1421 CG ASN 254 23.416 12 ATOM 1422 OD1 ASN 254 23.809 12 ATOM 1423 ND2 ASN 254 22.161 11 ATOM 1424 C ASN 254 26.339 12 ATOM 1425 0 ASN 254 26.926 12 ATOM 1426 N CYS 255 26.151 14 ATOM 1427 CA CYS 255 26.802 15 ATOM 1428 C CYS 255 26.204 15 ATOM 1429 0 CYS 255 26.793 16 ATOM 1430 CB CYS 255 26.629 16 ATOM 1431 SG CYS 255 27.276 16 ATOM 1432 N GLN 256 25.033 14 ATOM 1433 CA GLN 256 24.396 15 ATOM 1434 CB GLN 256 22.874 15 ATOM 1435 CG GLN 256 22.359 16 ATOM 1436 CD GLN 256 21.063 16 ATOM 1437 OE1 GLN 256 20.388 15 ATOM 1438 NE2 GLN 256 20.710 18 ATOM 1439 C GLN 256 24.767 13 ATOM 1440 0 GLN 256 24.233 13 ATOM 1441 N GLY 257 25.690 13 ATOM 1442 CA GLY 257 26.200 11 -4.305 1.00 40.61 B N -5.312 1.00 42.13 B C -6.012 1.00 46.07 B C -6.591 1.00 52.02 B c -7.134 1.00 60.10 B c -8.524 1.00 68.77 B N -9.560 1.00 74.48 B c -10.795 1.00 78.20 B N -9.364 1.00 76.74 B N -4.601 1.00 39.77 B C -3.609 1.00 40.40 B 0 -5.073 1.00 35.62 B N -4.404 1.00 31.39 B C -3.983 1.00 28.56 B c -5.066 1.00 27.85 B 0 -5.272 1.00 28.48 B c -6.498 1.00 27.14 B 0 -4.612 1.00 25.37 B N -5.234 1.00 25.79 B c -4.928 1.00 26.82 B c -5.646 1.00 27.29 B c -5.464 1.00 25.27 B c -5.115 1.00 28.81 B c -4.585 1.00 24.78 B c -3.439 1.00 27.07 B 0 -5.285 1.00 22.58 B N -4.664 1.00 20.82 B c -5.554 1.00 18.39 B c -4.774 1.00 20.45 B c -5.561 1.00 21.67 B c -4.839 1.00 19.94 B N -5.331 1.00 22.92 B c -6.542 1.00 22.45 B N -4.610 1.00 28.30 B N -4.295 1.00 20.66 B C -5.156 1.00 16.50 B 0 -3.000 1.00 21.54 B N -2.482 1.00 21.20 B C -1.688 1.00 19.63 B c -2.525 1.00 17.44 B c -0.374 1.00 18.14 B c -1.552 1.00 21.35 B c -1.029 1.00 24.50 B 0 -1.333 1.00 20.92 B N -0.550 1.00 20.41 B c 0.698 1.00 19.82 B c 1.711 1.00 22.59 B c 2.980 1.00 21.86 B c 2.020 1.00 21.15 B c -1.334 1.00 20.52 B c -1.956 1.00 19.48 B 0 -1.303 1.00 21.23 B N -1.964 1.00 23.98 B c -2.349 1.00 26.23 B c -1.157 1.00 25.36 B c -0.039 1.00 23.00 B 0 -1.398 1.00 28.55 B N -1.102 1.00 25.22 B c -0.028 1.00 24.34 B 0 -1.571 1.00 25.88 B N -0.916 1.00 28.48 B c 0.466 1.00 29.01 B c 1.330 1.00 30.18 B 0 -1.724 1.00 28.76 B c -3.442 1.00 36.42 B s 0.685 1.00 28.37 B N 1.973 1.00 28.98 B c 1.820 1.00 28.59 B c 2.025 1.00 27.47 B c 1.300 1.00 25.99 B c 0.843 1.00 27.71 B 0 1. 182 1.00 21.77 B N 2.901 1.00 28.76 B c 4.005 1.00 28.16 B 0 2.447 1.00 29.54 B N 3.280 1.00 28.50 B c 339 WO 2009/026558 PCT/US2008/074097 ATOM 1443 c GLY 257 25.263 10.774 3.347 1.00 29.00 B C ATOM 1444 0 GLY 257 25.513 9.795 4 . 060 1.00 27.09 B O ATOM 1445 N LYS 258 24.169 10.872 2.600 1.00 30.82 B N ATOM 1446 CA LYS 258 23.143 9.844 2.595 1.00 31.63 B C ATOM 1447 CB LYS 258 21.757 10.497 2.455 1.00 32.83 B C ATOM 1448 CG LYS 258 20.572 9.539 2.594 1.00 35.03 B c ATOM 1449 CD LYS 258 19.575 10.016 3.632 1.00 33.55 B c ATOM 1450 CE LYS 258 18.826 11.265 3.169 1.00 38.29 B c ATOM 1451 NZ LYS 258 17.669 10.963 2.256 1.00 33.52 B N ATOM 1452 C LYS 258 23.420 8.904 1.433 1.00 30.72 B c ATOM 1453 0 LYS 258 23.941 9.323 0.390 1.00 31.26 B 0 ATOM 1454 N GLY 259 23.089 7.633 1.627 1.00 28.86 B N ATOM 1455 CA GLY 259 23.292 6.635 0.586 1.00 28.66 B c ATOM 1456 C GLY 259 22.214 5.590 0.739 1.00 27.16 B c ATOM 1457 0 GLY 259 21.327 5.774 1.556 1.00 29.64 B 0 ATOM 1458 N THR 260 22.263 4 . 499 -0.010 1.00 25.94 B N ATOM 1459 CA THR 260 21.243 3.470 0.174 1.00 24.06 B c ATOM 1460 CB THR 260 20.185 3.497 -0.956 1.00 23.07 B c ATOM 1461 OG1 THR 260 20.716 2.860 -2.120 1.00 23.27 B 0 ATOM 14 62 CG2 THR 260 19.803 4.929 -1.294 1.00 23.82 B c ATOM 1463 C THR 260 21.803 2.059 0.254 1.00 23.68 B c ATOM 1464 O THR 260 22.853 1.774 -0.299 1.00 23.66 B 0 ATOM 1465 N VAL 261 21.083 1. 174 0.938 1.00 24.37 B N ATOM 1466 CA VAL 261 21.509 -0.201 1.075 1.00 24.48 B c ATOM 1467 CB VAL 261 20.511 -1.049 1.868 1.00 24.12 B c ATOM 1468 CGI VAL 261 20.950 -2.486 1.814 1.00 22.98 B c ATOM 1469 CG2 VAL 261 20.445 -0.589 3.307 1.00 26.24 B c ATOM 1470 C VAL 261 21.664 -0.856 -0.276 1.00 25.55 B c ATOM 1471 O VAL 261 22.598 -1.631 -0.476 1.00 25.67 B 0 ATOM 1472 N SER 2 62 20.754 -0.560 -1.202 1.00 25.26 B N ATOM 1473 CA SER 2 62 20.823 -1.198 -2.510 1.00 28.13 B c ATOM 1474 CB SER 2 62 19.559 -0.928 -3.301 1.00 26.07 B c ATOM 1475 OG SER 2 62 19.262 0.447 -3.272 1.00 30.83 B 0 ATOM 1476 C SER 2 62 22.038 -0.704 -3.293 1.00 30.74 B c ATOM 1477 O SER 2 62 22.734 -1.485 -3.974 1.00 30.74 B 0 ATOM 1478 N GLY 263 22.296 0.594 -3.172 1.00 32.08 B N ATOM 1479 CA GLY 263 23.413 1.196 -3.876 1.00 34.48 B c ATOM 1480 C GLY 2 63 24.735 0.711 -3.328 1.00 35.11 B c ATOM 1481 0 GLY 263 25.684 0.517 -4.075 1.00 36.07 B 0 ATOM 1482 N THR 264 24.801 0.514 -2.019 1.00 34.36 B N ATOM 1483 CA THR 264 26.023 0.040 -1.409 1.00 34.13 B c ATOM 1484 CB THR 264 25.886 -0.023 0.126 1.00 32.04 B c ATOM 1485 OG1 THR 264 25.904 1.301 0.657 1.00 29.99 B 0 ATOM 1486 CG2 THR 264 27.019 -0.816 0.741 1.00 30.83 B c ATOM 1487 C THR 264 26.216 -1.361 -1.942 1.00 36.25 B c ATOM 1488 O THR 264 27.305 -1.749 -2.384 1.00 36.88 B 0 ATOM 1489 N LEU 265 25.122 -2.112 -1.900 1.00 36.49 B N ATOM 1490 CA LEU 265 25.119 -3.489 -2.338 1.00 36.94 B c ATOM 1491 CB LEU 265 23.682 -3.980 -2.408 1.00 38.26 B c ATOM 1492 CG LEU 265 23.306 -5.152 -1.522 1.00 36.02 B c ATOM 1493 CDl LEU 265 21.836 -5.460 -1.766 1.00 37.13 B c ATOM 1494 CD2 LEU 265 24.178 -6.351 -1.857 1.00 36.13 B c ATOM 1495 C LEU 265 25.773 -3.583 -3.711 1.00 36.28 B c ATOM 1496 O LEU 265 26.781 -4.256 -3.885 1.00 36.69 B 0 ATOM 1497 N ILE 266 25.196 -2.891 -4.683 1.00 36.29 B N ATOM 1498 CA ILE 266 25.706 -2.929 -6.044 1.00 35.45 B c ATOM 1499 CB ILE 266 24.879 -1.982 -6.950 1.00 31.67 B c ATOM 1500 CG2 ILE 266 25.385 -2.047 -8.363 1.00 29.36 B c ATOM 1501 CGI ILE 266 23.390 -2.379 -6.899 1.00 31.50 B c ATOM 1502 CDl ILE 266 22.469 -1.530 -7.756 1.00 25.14 B c ATOM 1503 C ILE 266 27.197 -2.546 -6.067 1.00 37.49 B c ATOM 1504 0 ILE 266 27.964 -3.033 -6.904 1.00 37.39 B 0 ATOM 1505 N GLY 267 27.612 -1.694 -5.134 1.00 37.97 B N ATOM 1506 CA GLY 267 29.013 -1.332 -5.061 1.00 38.87 B c ATOM 1507 C GLY 267 29.894 -2.504 -4.644 1.00 41.23 B c ATOM 1508 0 GLY 2 67 31.043 -2.618 -5.086 1.00 42.31 B 0 ATOM 1509 N LEU 268 29.367 -3.375 -3.787 1.00 41.65 B N ATOM 1510 CA LEU 268 30.122 -4.524 -3.298 1.00 42.08 B c ATOM 1511 CB LEU 268 29.424 -5.170 -2.095 1.00 42.22 B c ATOM 1512 CG LEU 268 29.354 -4.290 -0.844 1.00 43.99 B c ATOM 1513 CDl LEU 268 28.426 -4.921 0.173 1.00 43.26 B c ATOM 1514 CD2 LEU 268 30.756 -4.085 -0.276 1.00 42.42 B c ATOM 1515 C LEU 268 30.204 -5.529 -4.416 1.00 43.00 B c ATOM 1516 O LEU 268 31.120 -6.352 -4.451 1.00 41.06 B 0 ATOM 1517 N GLU 269 29.238 -5.460 -5.331 1.00 43.87 B N ATOM 1518 CA GLU 269 29.213 -6.378 -6.459 1.00 46.33 B c 340 WO 2009/026558 PCT/US2008/074097
ATOM 1519 CB GLU 269 27.818 -6.445 -7.064 1.00 43.85 B ATOM 1520 CG GLU 269 27.622 -7.621 -7.999 1.00 42.78 B ATOM 1521 CD GLU 269 26.619 -7.328 -9.103 1.00 43.42 B ATOM 1522 OEl GLU 269 25.667 -6.554 -8.869 1.00 42.07 B ATOM 1523 OE2 GLU 269 26.788 -7.873 -10.214 1.00 45.39 B ATOM 1524 C GLU 269 30.220 -5.929 -7.517 1.00 48.39 B ATOM 1525 O GLU 269 30.919 -6.754 -8.110 1.00 4 9.72 B ATOM 1526 N PHE 270 30.297 -4.619 -7.739 1.00 49.23 B ATOM 1527 CA PHE 270 31.364 -4.030 -8.538 1.00 48.36 B ATOM 1528 CB PHE 270 31.211 -2.505 -8.522 1.00 47.34 B ATOM 1529 CG PHE 270 32.293 -1.761 -9.257 1.00 48.28 B ATOM 1530 CD1 PHE 270 32.085 -1.306 -10.552 1.00 48.57 B ATOM 1531 CD2 PHE 270 33.504 -1.475 -8.641 1.00 46.97 B ATOM 1532 CEl PHE 270 33.059 -0.581 -11.217 1.00 46.26 B ATOM 1533 CE2 PHE 270 34.479 -0.752 -9.302 1.00 47.34 B ATOM 1534 CZ PHE 270 34.254 -0.306 -10.591 1.00 47.47 B ATOM 1535 C PHE 270 32.730 -4.454 -7.976 1.00 48.75 B ATOM 1536 O PHE 270 33.635 -4.802 -8.727 1.00 48.85 B ATOM 1537 N ILE 271 32.882 -4.442 -6.658 1.00 49.09 B ATOM 1538 CA ILE 271 34.162 -4.801 -6.071 1.00 51.75 B ATOM 1539 CB ILE 271 34.193 -4.501 -4.566 1.00 52.01 B ATOM 1540 CG2 ILE 271 35.275 -5.324 -3.886 1.00 49.86 B ATOM 1541 CGI ILE 271 34.422 -3.005 -4.346 1.00 52.71 B ATOM 1542 CD1 ILE 271 34.765 -2.638 -2.916 1.00 54.18 B ATOM 1543 C ILE 271 34.484 -6.272 -6.291 1.00 54.91 B ATOM 1544 O ILE 271 35.629 -6.627 -6.577 1.00 54.18 B ATOM 1545 N ARG 272 33.467 -7.121 -6.164 1.00 58.06 B ATOM 1546 CA ARG 272 33.610 -8.557 -6.376 1.00 60.91 B ATOM 1547 CB ARG 272 32.333 -9.274 -5.934 1.00 62.27 B ATOM 1548 CG ARG 272 32.265 -10.749 -6.317 1.00 62.63 B ATOM 1549 CD ARG 272 33.258 -11.598 -5.531 1.00 62.94 B ATOM 1550 NE ARG 272 33.136 -13.000 -5.914 1.00 66.12 B ATOM 1551 CZ ARG 272 34.131 -13.878 -5.876 1.00 67.67 B ATOM 1552 NHl ARG 272 33.923 -15.132 -6.252 1.00 67.95 B ATOM 1553 NH2 ARG 272 35.329 -13.503 -5.456 1.00 69.21 B ATOM 1554 C ARG 272 33.870 -8.846 -7.847 1.00 62.21 B ATOM 1555 O ARG 272 34.764 -9.616 -8.196 1.00 63.03 B ATOM 1556 N LYS 273 33.074 -8.221 -8.701 1.00 62.61 B ATOM 1557 CA LYS 273 33.251 -8.323 -10.132 1.00 64.08 B ATOM 1558 CB LYS 273 32.341 -7.313 -10.825 1.00 64 .38 B ATOM 1559 CG LYS 273 32.239 -7.493 -12.320 1.00 67.49 B ATOM 1560 CD LYS 273 31.427 -8.739 -12.660 1.00 73.19 B ATOM 1561 CE LYS 273 29.976 -8.594 -12.216 1.00 75.81 B ATOM 1562 NZ LYS 273 29.238 -7.554 -13.000 1.00 81.17 B ATOM 1563 C LYS 273 34.708 -8.048 -10.482 1.00 65.41 B ATOM 1564 0 LYS 273 35.328 -8.792 -11.229 1.00 66.02 B ATOM 1565 N SER 274 35.253 -6.974 -9.925 1.00 68.14 B ATOM 1566 CA SER 274 36.656 -6.628 -10.118 1.00 69.59 B ATOM 1567 CB SER 274 37.015 -5.384 -9.310 1.00 67.55 B ATOM 1568 OG SER 274 36.241 -4.284 -9.727 1.00 67.09 B ATOM 1569 C SER 274 37.551 -7.764 -9.670 1.00 71.55 B ATOM 1570 O SER 274 38.246 -8.373 -10.475 1.00 72.19 B ATOM 1571 N GLN 275 37.525 -8.040 -8.372 1.00 74.22 B ATOM 1572 CA GLN 275 38.417 -9.023 -7.777 1.00 77.85 B ATOM 1573 CB GLN 275 37.936 -9.379 -6.369 1.00 76.85 B ATOM 1574 CG GLN 275 38.908 -10.221 -5.574 1.00 76.18 B ATOM 1575 CD GLN 275 38.196 -11.209 -4.675 1.00 76.76 B ATOM 1576 OEl GLN 275 37.049 -11.572 -4.928 1.00 77.71 B ATOM 1577 NE2 GLN 275 38.870 -11.648 -3.619 1.00 76.78 B ATOM 1578 C GLN 275 38.524 -10.289 -8.629 1.00 80.71 B ATOM 1579 0 GLN 275 39.545 -10.967 -8.606 1.00 80.41 B ATOM 1580 N LEU 276 37.481 -10.602 -9.388 1.00 84.76 B ATOM 1581 CA LEU 276 37.564 -11.713 -10.324 1.00 89.24 B ATOM 1582 CB LEU 276 36.204 -11.978 -10.971 1.00 87.78 B ATOM 1583 CG LEU 276 35.112 -12.504 -10.039 1.00 87.27 B ATOM 1584 CD1 LEU 276 33.844 -12.767 -10.833 1.00 85.86 B ATOM 1585 CD2 LEU 276 35.591 -13.768 -9.351 1.00 85.57 B ATOM 1586 C LEU 276 38.598 -11.420 -11.405 1.00 92.06 B ATOM 1587 O LEU 276 39.735 -11.884 -11.324 1.00 94.30 B ATOM 1588 N VAL 277 38.206 -10.638 -12.406 1.00 94.47 B ATOM 1589 CA VAL 277 39.058 -10.389 -13.567 1.00 96.12 B ATOM 1590 CB VAL 277 38.306 -9.555 -14.652 1.00 95.15 B ATOM 1591 CGI VAL 277 37.071 -10.292 -15.118 1.00 93.14 . B ATOM 1592 CG2 VAL 277 37.928 -8.196 -14.109 1.00 93.32 B ATOM 1593 C VAL 277 40.378 -9.686 -13.222 1.00 97.93 B ATOM 1594 O VAL 277 41.159 -9.353 -14.107 1.00 97.39 B
2 CJ 341 c c c 0 0 c 0
N c c c c c c c c c 0
N c c c c c c 0
N c c c c
N c
N
N
C 0
N
C c c c c
N c 0 c 0 c 0
N c c c c 0
N c 0
N c c c c c c 0
N c c c c c 0 ATOM 1595 N GLN 278 40.630 -9.467 -11.939 1.00101.32 ATOM 1596 CA GLN 278 41.830 -8.754 -11.522 1.00105.97 ATOM 1597 CB GLN 278 41.490 -7.782 -10.392 1.00105.35 ATOM 1598 CG GLN 278 41.943 -6.352 -10.628 1.00103.69 ATOM 1599 CD GLN 278 41.433 -5.404 -9.557 1.00102.60 ATOM 1600 OE1 GLN 278 41.461 -4.182 -9.726 1.00101.28 ATOM 1601 NE2 GLN 278 40.959 -5.965 -8.447 1.00100.13 ATOM 1602 C GLN 278 42.909 -9.723 -11.057 1.00108.32 ATOM 1603 0 GLN 278 42.614 -10.809 -10.563 1.00109.28 ATOM 1604 N PRO 279 44.181 -9.335 -11.206 1.00109.09 ATOM 1605 CD PRO 279 44.637 -8.017 -11.676 1.00107.47 ATOM 1606 CA PRO 279 45.300 -10.176 -10.768 1.00110.86 ATOM 1607 CB PRO 279 46.530 -9.402 -11.226 1.00107.87 ATOM 1608 CG PRO 279 46.078 -7.984 -11.247 1.00106.50 ATOM 1609 C PRO 279 45.271 -10.355 -9.257 1.00111.43 ATOM 1610 O PRO 279 44.978 -9.413 -8.520 1.00113.76 ATOM 1611 N VAL 280 45.588 -11.564 -8.804 1.00110.51 ATOM 1612 CA VAL 280 45.386 -11.947 -7.411 1.00109.51 ATOM 1613 CB VAL 280 45.741 -13.435 -7.179 1.00111.61 ATOM 1614 CGI VAL 280 44.843 -14.319 -8.025 1.00112.81 ATOM 1615 CG2 VAL 280 47.198 -13.688 -7.524 1.00113.25 ATOM 1616 C VAL 280 46.188 -11.099 -6.434 1.00106.06 ATOM 1617 O VAL 280 47.391 -10.925 -6.583 1.00106.05 ATOM 1618 N GLY 281 45.502 -10.572 -5.429 1.00102.30 ATOM 1619 CA GLY 281 46.161 -9.771 -4.420 1.00 96.08 ATOM 1620 C GLY 281 45.214 -9.508 -3.272 1.00 90.39 ATOM 1621 0 GLY 281 44.008 -9.683 -3.415 1.00 91.92 ATOM 1622 N PRO 282 45.731 -9.088 -2.114 1.00 85.97 ATOM 1623 CD PRO 282 47.160 -8.858 -1.846 1.00 87.84 ATOM 162 4 CA PRO 282 44.896 -8.825 -0.937 1.00 80.46 ATOM 162 5 CB PRO 282 45.908 -8.715 0.199 1.00 84.08 ATOM 162 6 CG PRO 282 47.160 -8.263 -0.471 1.00 87.49 ATOM 1627 C PRO 282 44.049 -7.556 -1.086 1.00 74.39 ATOM 162 8 O PRO 282 44.553 -6.508 -1.516 1.00 72.54 ATOM 1629 N LEU 283 42.767 -7.655 -0.730 1.00 68.07 ATOM 1630 CA LEU 283 41.861 -6.508 -0.783 1.00 61.93 ATOM 1631 CB LEU 283 40.682 -6.782 -1.726 1.00 60.52 ATOM 1632 CG LEU 283 41.009 -7.186 -3.163 1.00 60.95 ATOM 1633 CD1 LEU 283 39.834 -6.834 -4.064 1.00 60.01 ATOM 1634 CD2 LEU 283 42.266 -6.475 -3.631 1.00 62.63 ATOM 1635 C LEU 283 41.315 -6.118 0.585 1.00 57.20 ATOM 1636 O LEU 283 40.773 -6.943 1.316 1.00 54.88 ATOM 1637 N VAL 284 41.472 -4.844 0.919 1.00 52.54 ATOM 1638 CA VAL 284 40.759 -4.245 2.037 1.00 47.36 ATOM 1639 CB VAL 284 41.674 -3.304 2.846 1.00 45.36 ATOM 1640 CGI VAL 284 40.929 -2.737 4 . 029 1.00 45.93 ATOM 1641 CG2 VAL 284 42.887 -4.050 3.322 1.00 42.54 ATOM 1642 C VAL 284 39.591 -3.440 1 . 473 1.00 44.41 ATOM 1643 O VAL 284 39.694 -2.814 0.419 1.00 44.27 ATOM 1644 N VAL 285 38.465 -3.472 2.166 1.00 41.51 ATOM 1645 CA VAL 285 37.341 -2.636 1.769 1.00 38.92 ATOM 1646 CB VAL 285 36.171 -3.503 1.299 1.00 37.13 ATOM 1647 CGI VAL 285 35.051 -2.645 0.775 1.00 35.52 ATOM 1648 CG2 VAL 285 36.660 -4.442 0.240 1.00 36.78 ATOM 1649 C VAL 285 36.935 -1.794 2.975 1.00 35.14 ATOM 1650 O VAL 285 36.583 -2.329 4.033 1.00 36.12 ATOM 1651 N LEU 286 37.024 -0.480 2.835 1.00 29.16 ATOM 1652 CA LEU 286 36.689 0.388 3.943 1.00 27.92 ATOM 1653 CB LEU 286 37.665 1.552 4.026 1.00 24.63 ATOM 1654 CG LEU 286 37.299 2.689 4.975 1.00 23.37 ATOM 1655 CD1 LEU 286 37.193 2.208 6.431 1.00 21.39 ATOM 1656 CD2 LEU 286 38.360 3.758 4 . 829 1.00 23.59 ATOM 1657 C LEU 286 35.278 0.908 3.742 1.00 28.41 ATOM 1658 O LEU 286 34.984 1.517 2.714 1.00 29.12 ATOM 1659 N LEU 287 34.414 0.663 4.726 1.00 28.37 ATOM 1660 CA LEU 287 32.998 1.003 4.635 1.00 28.51 ATOM 1661 CB LEU 287 32.175 -0.275 4.784 1.00 32.94 ATOM 1662 CG LEU 287 32.022 -1.197 3.572 1.00 36.53 ATOM 1663 CD1 LEU 287 31.746 -2.615 4.052 1.00 37.57 ATOM 1664 CD2 LEU 287 30.878 -0.692 2.667 1.00 37.50 ATOM 1665 C LEU 287 32.560 2.022 5.701 1.00 26.32 ATOM 1666 O LEU 287 31.825 1.682 6.636 1.00 25.55 ATOM 1667 N PRO 288 32.989 3.285 5.564 1.00 25.64 ATOM 1668 CD PRO 288 33.477 3.896 4.314 1.00 26.22 ATOM 1669 CA PRO 288 32.781 4.299 6.603 1.00 25.01 ATOM 1670 CB PRO 288 33.736 5.411 6.196 1.00 25.67
2 CJ WO 2009/026558 PCT/US2008/074097
B N
B C
B C
B C
B C B 0
B N
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C B 0
B B
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C
B C B 0
B N
B C
B C
B ' C B C
B C
B C B 0
B N
B C
B C
B C 342 WO 2009/026558 PCT/US2008/074097 ATOM 1671 CG PRO 288 33.688 5.361 4.683 1.00 24.95 B C ATOM 1672 C PRO 288 31.336 4.799 6.659 1.00 24.78 B C ATOM 1673 O PRO 288 31.099 6.009 6.677 1.00 24.06 B 0 ATOM 1674 N LEU 289 30.381 3.871 6.682 1.00 24.21 B N ATOM 1675 CA LEU 289 28.961 4.213 6.708 1.00 24.93 B c ATOM 1676 CB LEU 289 28.414 4 .234 5.277 1.00 21.80 B c ATOM 1677 CG LEU 289 28.726 2.999 4.424 1.00 21.73 B c ATOM 1678 CDl LEU 289 27.882 1.824 4.854 1.00 22.83 B c ATOM 1679 CD2 LEU 289 28.461 3.318 2.970 1.00 21.63 B c ATOM 1680 C LEU 289 28.165 3.210 7.557 1.00 25.83 B c ATOM 1681 O LEU 289 28.615 2.087 7.787 1.00 26.10 B 0 ATOM 1682 N ALA 290 26.987 3.613 8.022 1.00 26.31 B N ATOM 1683 CA ALA 290 26.088 2.683 8.709 1.00 25.80 B c ATOM 1684 CB ALA 290 26.142 2.912 10.220 1.00 22.49 B c ATOM 1685 C ALA 290 24.658 2.860 8.220 1.00 27.47 B c ATOM 1686 0 ALA 290 24.266 3.938 7.756 1.00 26.91 B 0 ATOM 1687 N GLY 291 23.881 1.789 8.327 1.00 29.54 B N ATOM 1688 CA GLY 291 22.435 1.910 8.311 1.00 30.47 B c ATOM 1689 C GLY 291 21.837 1.040 9.397 1.00 31.26 B c ATOM 1690 0 GLY 291 22.557 0.577 10.275 1.00 31.62 B 0 ATOM 1691 N GLY 2 92 20.530 0.801 9.340 1.00 33.20 B N ATOM 1692 CA GLY 2 92 19.939 -0.177 10.239 1.00 31.71 B c ATOM 1693 C GLY 292 20.446 -1.550 9.851 1.00 32.14 B c ATOM 1694 0 GLY 292 20.856 -1.719 8.707 1.00 31.02 B 0 ATOM 1695 N TYR 293 20.437 -2.508 10.784 1.00 33.24 B N ATOM 1696 CA TYR 293 20.782 -3.900 10.476 1.00 33.89 B c ATOM 1697 CB TYR 293 20.391 -4.856 11.627 1.00 36.33 B c ATOM 1698 CG TYR 293 20.208 -6.306 11.192 1.00 37.79 B c ATOM 1699 CDl TYR 293 21.258 -7.219 11.258 1.00 38.75 B c ATOM 1700 CEl TYR 293 21.117 -8.501 10.764 1.00 38.29 B c ATOM 1701 CD2 TYR 293 19.008 -6.730 10.631 1.00 38.47 B c ATOM 1702 CE2 TYR 293 18.853 -7.998 10.139 1.00 37.87 B c ATOM 1703 CZ TYR 293 19.905 -8.884 10.200 1.00 40.01 B c ATOM 1704 OH TYR 293 19.731 -10.145 9.667 1.00 40.12 B 0 ATOM 1705 C TYR 293 20.064 -4.318 9.208 1.00 34.23 B c ATOM 1706 O TYR 293 18.855 -4.168 9.090 1.00 32.68 B 0 ATOM 1707 N SER 294 20.831 -4.825 8.252 1.00 36.49 B N ATOM 1708 CA SER 294 20.296 -5.257 6.971 1.00 37.92 B c ATOM 1709 CB SER 294 20.802 -4.365 5.842 1.00 37.02 B c ATOM 1710 OG SER 294 20.222 -4.748 4.601 1.00 36.27 B 0 ATOM 1711 C SER 294 20.785 -6.666 6.730 1.00 40.68 B c ATOM 1712 O SER 294 21.995 -6.919 6.637 1.00 39.86 B 0 ATOM 1713 N ARG 295 19.848 -7.593 6.621 1.00 43.03 B N ATOM 1714 CA ARG 295 20.250 -8.969 6.436 1.00 44.95 B c ATOM 1715 CB ARG 295 19.035 -9.900 6.559 1.00 46.57 B c ATOM 1716 CG ARG 295 18.604 -10.555 5.276 1.00 49.25 B c ATOM 1717 CD ARG 295 18.893 -12.030 5.331 1.00 51.43 B c ATOM 1718 NE ARG 295 17.661 -12.797 5.434 1.00 54.06 B N ATOM 1719 CZ ARG 295 17.620 -14.104 5.653 1.00 54.98 B c ATOM 1720 NH1 ARG 295 18.751 -14.786 5.790 1.00 56.63 B N ATOM 1721 NH2 ARG 295 16.449 -14.722 5.733 1.00 55.08 B N ATOM 1722 C ARG 295 20.925 -9.084 5.069 1.00 43.35 B C ATOM 1723 O ARG 295 21.975 -9.718 4.948 1.00 44.39 B 0 ATOM 1724 N VAL 296 20.353 -8.446 4.053 1.00 40.22 B N ATOM 1725 CA VAL 296 20.917 -8.555 2.715 1.00 41.05 B C ATOM 1726 CB VAL 296 20.026 -7.833 1.653 1.00 41.81 B c ATOM 1727 CGI VAL 296 19.931 -6.339 1.964 1.00 43.65 B c ATOM 1728 CG2 VAL 296 20.590 -8.056 0.251 1.00 41.55 B c ATOM 1729 C VAL 296 22.342 -7.981 2.665 1.00 41.93 B c ATOM 1730 O VAL 296 23.240 -8.588 2.058 1.00 40.42 B 0 ATOM 1731 N LEU 297 22.555 -6.833 3.317 1.00 40.51 B N ATOM 1732 CA LEU 297 23.873 -6.198 3.334 1.00 39.85 B c ATOM 1733 CB LEU 297 23.808 -4.809 3.992 1.00 36.62 B c ATOM 1734 CG LEU 297 25.093 -3.965 4.013 1.00 33.08 B c ATOM 1735 CDl LEU 297 25.497 -3.593 2.611 1.00 32.37 B c ATOM 1736 CD2 LEU 297 24.875 -2.712 4.827 1.00 32.91 B c ATOM 1737 C LEU 297 24.850 -7.073 ’ 4.100 1.00 41.61 B c ATOM 1738 O LEU 297 26.014 -7.193 3.724 1.00 42.84 B ’’ 0 ATOM 1739 N ASN 298 24.381 -7.699 5.173 1.00 43.04 B N ATOM 1740 CA ASN 298 25.259 -8.577 5.935 1.00 44.53 B c ATOM 1741 CB ASN 298 24.556 -9.083 7.192 1.00 43.88 B c ATOM 1742 CG ASN 298 24.704 -8.136 8.358 1.00 43.04 B c ATOM 1743 OD1 ASN 298 24.706 -6.919 8.186 1.00 43.95 . B 0 ATOM 1744 ND2 ASN 298 24.837 -8.689 9.554 1.00 42.99 B N ATOM 1745 C ASN 298 25.710 -9.756 5.083 1.00 45.13 ' B c ATOM 1746 0 ASN 298 26.889 -10.114 5.074 1.00 47.16 B 0 343 WO 2009/026558 PCT/US2008/074097
ATOM 1747 N ALA 299 24.763 -10.345 4.363 1.00 44.07 B ATOM 1748 CA ALA 299 25.055 -11.440 3.456 1.00 43.47 B ATOM 1749 CB ALA 299 23.842 -11.721 2.605 1.00 42.59 B ATOM 1750 C ALA 299 26.245 -11.098 2.562 1.00 43.77 B ATOM 1751 0 ALA 299 27.290 -11.760 2.616 1.00 43.07 B ATOM 1752 N ALA 300 26.071 -10.056 1.747 1.00 42.89 B ATOM 1753 CA ALA 300 27.083 -9.631 0.782 1.00 41.86 B ATOM 1754 CB ALA 300 26.675 -8.321 0.123 1.00 37.77 B ATOM 1755 C ALA 300 28.419 -9.459 1.474 1.00 42.97 B ATOM 1756 0 ALA 300 29.466 -9.787 0.917 1.00 44 . 18 B ATOM 1757 N CYS 301 28.398 -8.947 2.694 1.00 44.23 B ATOM 1758 CA CYS 301 29.648 -8.840 3.414 1.00 45.71 B ATOM 1759 CB CYS 301 29.430 -8.131 4.738 1.00 45.13 B ATOM 1760 SG CYS 301 29.438 -6.352 4.500 1.00 43.18 B ATOM 1761 C CYS 301 30.228 -10.224 3.612 1.00 47.63 B ATOM 1762 O CYS 301 31.383 -10.466 3.287 1.00 47.12 B ATOM 1763 N GLN 302 29.402 -11.137 4 .111 1.00 51.11 B ATOM 1764 CA GLN 302 29.784 -12.532 4.238 1.00 54 .23 B ATOM 1765 CB GLN 302 28.601 -13.345 4.729 1.00 55.02 B ATOM 1766 CG GLN 302 28.766 -14.830 4.489 1.00 57.93 B ATOM 1767 CD GLN 302 27.821 -15.644 5.325 1.00 59.06 B ATOM 1768 OE1 GLN 302 26.660 -15.823 4.964 1.00 60.77 B ATOM 1769 NE2 GLN 302 28.307 -16.140 6.460 1.00 61.10 B ATOM 1770 C GLN 302 30.290 -13.132 2.929 1.00 56.72 B ATOM 1771 0 GLN 302 31.296 -13.840 2.913 1.00 56.31 B ATOM 1772 N ARG 303 29.596 -12.862 1.830 1.00 59.07 B ATOM 1773 CA ARG 303 30.067 -13.342 0.542 1.00 62.00 B ATOM 1774 CB ARG 303 29.103 -12.924 -0.564 1.00 65.78 B ATOM 1775 CG ARG 303 29.606 -13.207 -1.966 1.00 73.70 B ATOM 1776 CD ARG 303 30.386 -14.512 -2.031 1.00 81.75 B ATOM 1777 NE ARG 303 30.633 -14.969 -3.399 1.00 89.51 B ATOM 1778 CZ ARG 303 31.436 -15.984 -3.699 1.00 94.37 B ATOM 1779 NH1 ARG 303 31.611 -16.348 -4.963 1.00 98.35 B ATOM 1780 NH2 ARG 303 32.070 -16.631 -2.727 1.00 97.91 B ATOM 1781 C ARG 303 31.477 -12.811 0.255 1.00 61.71 B ATOM 1782 O ARG 303 32.407 -13.602 0.077 1.00 62.96 B ATOM 1783 N LEU 304 31.647 -11.488 0.227 1.00 59.43 B ATOM 1784 CA LEU 304 32.971 -10.898 0.007 1.00 57.53 B ATOM 1785 CB LEU 304 32.891 -9.371 -0.032 1.00 54.34 B ATOM 1786 CG LEU 304 32.255 -8.734 -1.268 1.00 52.05 B ATOM 1787 CDl LEU 304 32.077 -7.257 -1.037 1.00 52.38 B ATOM 1788 CD2 LEU 304 33.112 -8.967 -2.490 1.00 50.60 B ATOM 1789 C LEU 304 33.997 -11.309 1.066 1.00 57.95 B ATOM 1790 O LEU 304 35.203 -11.297 0.809 1.00 57.93 B ATOM 1791 N ALA 305 33.531 -11.666 2.257 1.00 58.05 B ATOM 1792 CA ALA 305 34.442 -12.134 3.287 1.00 59.23 B ATOM 1793 CB ALA 305 33.734 -12.190 4.635 1.00 56.74 B ATOM 1794 C ALA 305 34.965 -13.515 2.905 1.00 61.55 B ATOM 1795 0 ALA 305 36.163 -13.785 3.025 1.00 60.10 B ATOM 1796 N ARG 306 34.061 -14.374 2.428 1.00 65.01 B ATOM 1797 CA ARG 306 34.389 -15.766 2.098 1.00 67.69 B ATOM 1798 CB ARG 306 33.117 -16.562 1.772 1.00 70.93 B ATOM 1799 CG ARG 306 32.222 -16.781 2.978 1.00 76.23 B ATOM 1800 CD ARG 306 31.075 -17.736 2.703 1.00 81.71 B ATOM 1801 NE ARG 306 30.394 -18.093 3.948 1.00 88.37 B ATOM 1802 CZ ARG 306 29.232 -18.738 4.016 1.00 91.88 B ATOM 1803 NH1 ARG 306 28.693 -19.016 5.202 1.00 93.39 B ATOM 1804 NH2 ARG 306 28.609 -19.102 2.899 1.00 94.36 B ATOM 1805 C ARG 306 35.348 -15.843 0.921 1.00 66.50 B ATOM 1806 O ARG 306 36.274 -16.655 0.911 1.00 67.91 B ATOM 1807 N ALA 307 35.119 -14.989 -0.068 1.00 63.54 B ATOM 1808 CA ALA 307 36.020 -14.861 -1.205 1.00 59.80 B ATOM 1809 CB ALA 307 35.355 -14.024 -2.301 1.00 57.91 B ATOM 1810 C ALA 307 37.357 -14.232 -0.804 1.00 57.82 B ATOM 1811 0 ALA 307 38.131 -13.823 -1.660 1.00 59.09 B ATOM 1812 N GLY 308 37.626 -14 .134 , 0.492 1.00 54.92 B ATOM 1813 CA GLY 308 38.963 -13.757 0.909 1.00 51.44 B ATOM 1814 C GLY 308 39.210 -12.286 1. 178 1.00 49.16 B ATOM 1815 0 GLY 308 40.329 -11.899 1.516 1.00 48.32 B ATOM 1816 N VAL 309 38.180 -11.456 1.047 1.00 48.13 B ATOM 1817 CA VAL 309 38.370 -10.021 1.235 1.00 46.11 B ATOM 1818 CB VAL 309 37.356 -9.209 0.421 1.00 44.93 B ATOM 1819 CGI VAL 309 37.720 -7.748 0.489 1.00 44.68 . B ATOM 1820 CG2 VAL 309 37.329 -9.689 -1.027 1.00 42.19 B ATOM 1821 C VAL 309 38.264 -9.607 2.704 1.00 46.55 B ATOM 1822 O VAL 309 37.516 -10.209 3.472 1.00 49.09 B
N C C C 0 N C C C 0 N C C S C 0 N C C C C 0 N C 0 N C C C C N C
22UOZU C C C C C 0 N C C C 0 N C C C C N C N N C 0 N C C C 0 N C C 0 N C C C C C 0 344 WO 2009/026558 PCT/US2008/074097
ATOM 1823 N VAL 310 39.030 -8.587 3.091 1.00 45.59 B ATOM 1824 CA VAL 310 38.948 -8.015 4 . 437 1.00 44.13 B ATOM 1825 CB VAL 310 40.353 -7.668 4.994 1.00 45.86 B ATOM 1826 CGI VAL 310 40.219 -6.873 6.295 1.00 46.71 B ATOM 1827 CG2 VAL 310 41.164 -8.939 5.221 1.00 4 6.65 B ATOM 1828 C VAL 310 38.125 -6.726 4.433 1.00 42.98 B ATOM 1829 O VAL 310 38.601 -5.679 3.982 1.00 43.01 B ATOM 1830 N LEU 311 36.898 -6.799 4.942 1.00 41.73 B ATOM 1831 CA LEU 311 36.047 -5.612 5.081 1.00 38.57 B ATOM 1832 CB LEU 311 34.578 -5.978 4.883 1.00 38.91 B ATOM 1833 CG LEU 311 34.197 -6.356 3.455 1.00 41.16 B ATOM 1834 CDl LEU 311 35.473 -6.615 2.644 1.00 43.08 B ATOM 1835 CD2 LEU 311 33.280 -7.585 3.481 1.00 40.54 B ATOM 1836 C LEU 311 36.210 -4.974 6.448 1.00 3 6.32 B ATOM 1837 O LEU 311 35.990 -5.630 7.471 1.00 33.22 B ATOM 1838 N VAL 312 36.598 -3.696 6.454 1.00 36.10 B ATOM 1839 CA VAL 312 36.634 -2.901 7.682 1.00 36.13 B ATOM 1840 CB VAL 312 37.971 -2.156 7.835 1.00 33.57 B ATOM 1841 CGI VAL 312 37.949 -1.274 9.061 1.00 30.27 B ATOM 1842 CG2 VAL 312 39.094 -3.163 7.964 1.00 34.18 B ATOM 1843 C VAL 312 35.507 -1.893 7.646 1.00 37.18 B ATOM 1844 O VAL 312 35.316 -1.213 6.643 1.00 39.23 B ATOM 1845 N THR 313 34.740 -1.803 8.728 1.00 37.86 B ATOM 1846 CA THR 313 33.611 -0.882 8.744 1.00 37.25 B ATOM 1847 CB THR 313 32.291 -1.645 8.538 1.00 36.13 B ATOM 1848 OG1 THR 313 31.263 -0.721 8.168 1.00 37.57 B ATOM 1849 CG2 THR 313 31.887 -2.358 9.814 1.00 33.52 B ATOM 1850 C THR 313 33.531 -0.102 10.053 1.00 36.40 B ATOM 1851 O THR 313 34.036 -0.561 11.079 1.00 36.86 B ATOM 1852 N ALA 314 32.894 1.071 10.008 1.00 34.34 B ATOM 1853 CA ALA 314 32.627 1.873 11.205 1.00 31.94 B ATOM 1854 CB ALA 314 32.299 3.285 10.802 1.00 32.67 B ATOM 1855 C ALA 314 31.488 1.308 12.050 1.00 31.52 B ATOM 1856 0 ALA 314 30.443 0.911 11.521 1.00 31.50 B ATOM 1857 N ALA 315 31.682 1.295 13.364 1.00 31.10 B ATOM 1858 CA ALA 315 30.728 0.667 14.277 1.00 32.53 B ATOM 1859 CB ALA 315 31.354 0.496 15.654 1.00 30.26 B ATOM 1860 C ALA 315 29.437 1.468 14.400 1.00 35.34 B ATOM 1861 0 ALA 315 28.383 0.913 14.708 1.00 36.03 B ATOM 1862 N GLY 316 29.520 2.774 14.165 1.00 36.52 B ATOM 1863 CA GLY 316 28.340 3.606 14.262 1.00 37.34 B ATOM 1864 C GLY 316 28.494 4.613 15.378 1.00 38.62 B ATOM 1865 0 GLY 316 29.157 4.317 16.376 1.00 41.26 B ATOM 1866 N ASN 317 27.870 5.782 15.216 1.00 38.59 B ATOM 1867 CA ASN 317 28.134 6.964 16.041 1.00 38.47 B ATOM 1868 CB ASN 317 28.289 8.205 15.168 1.00 38.39 B ATOM 1869 CG ASN 317 29.539 8.187 14.381 1.00 39.27 B ATOM 1870 OD1 ASN 317 30.506 7.535 14.764 1.00 40.16 B ATOM 1871 ND2 ASN 317 29.548 8.902 13.268 1.00 40.64 B ATOM 1872 C ASN 317 27.033 7.264 17.029 1.00 38.47 B ATOM 1873 0 ASN 317 26.906 8.408 17.488 1.00 37.31 B ATOM 1874 N PHE 318 26.217 6.272 17.343 1.00 38.66 B ATOM 1875 CA PHE 318 24.974 6.581 18.027 1.00 39.58 B ATOM 1876 CB PHE 318 23.816 5.899 17.304 1.00 38.09 B ATOM 1877 CG PHE 318 23.744 6.244 15.839 1.00 35.73 B ATOM 1878 CDl PHE 318 23.340 7.502 15.430 1.00 33.00 B ATOM 1879 CD2 PHE 318 24.089 5.313 14.869 1.00 34.65 B ATOM 1880 CEl PHE 318 23.280 7.821 14.083 1.00 30.08 B ATOM 1881 CE2 PHE 318 24.026 5.640 13.516 1.00 32.23 B ATOM 1882 CZ PHE 318 23.620 6.893 13.132 1.00 28.85 B ATOM 1883 C PHE 318 24.987 6.218 19.499 1.00 39.58 B ATOM 1884 O PHE 318 23.973 6.342 20.172 1.00 39.71 B ATOM 1885 N ARG 319 26.150 5.800 19.996 1.00 41.36 B ATOM 1886 CA ARG 319 26.316 5.383 21.392 1.00 43.43 B ATOM 1887 CB ARG 319 26.128 6.579 22.341 1.00 44.77 B ATOM 1888 CG ARG 319 26.990 6.509 .2 3.603 1.00 48.54 B ATOM 1889 CD ARG 319 26.728 7.651 24.620 1.00 51.31 B ATOM 1890 NE ARG 319 27.431 7.397 25.884 1.00 55.25 B ATOM 1891 CZ ARG 319 28.457 8 . 111 26.349 1.00 58.43 B ATOM 1892 NHl ARG 319 28.914 9.152 25.661 1.00 59.31 B ATOM 1893 NH2 ARG 319 29.051 7.763 27.490 1.00 57.79 B ATOM 1894 C ARG 319 25.308 4.271 21.720 1.00 43.91 B ATOM 1895 O ARG 319 24.741 4.212 22.820 1.00 44.45 . B ATOM 1896 N ASP 320 25.101 3.396 20.743 1.00 43.13 B ATOM 1897 CA ASP 320 24.102 2.348 20.809 1.00 43.73 ' B ATOM 1898 CB ASP 320 23.065 2.577 19.715 1.00 42.02 B zuuuuuozuuouuozuuuozuuuozuuozuuuozuozu 345
N
C c c c c 0
N c c c c c c 0 c c c c c c c c 0
N c c c c
' N c
N
N
C 0
N
C c ATOM 1899 CG ASP 320 21.795 1.807 19.954 1.00 45.94 ATOM 1900 OD1 ASP 320 21.657 1.219 21.049 1.00 48.90 ATOM 1901 OD2 ASP 320 20.926 1.785 19.048 1.00 48 . 43 ATOM 1902 C ASP 320 24.826 1.020 20.580 1.00 45.02 ATOM 1903 O ASP 320 26.034 1.010 20.291 1.00 45.17 ATOM 1904 N ASP 321 24.111 -0.095 20.714 1.00 45.07 ATOM 1905 CA ASP 321 24.692 -1.392 20.387 1.00 46.17 ATOM 1906 CB ASP 321 23.789 -2.522 20.884 1.00 47.34 ATOM 1907 CG ASP 321 24.383 -3.898 20.619 1.00 51.14 ATOM 1908 OD1 ASP 321 25.355 -3.996 19.828 1.00 51.98 ATOM 1909 OD2 ASP 321 23.888 -4.892 21.202 1.00 53.20 ATOM 1910 C ASP 321 24.899 -1.522 18.871 1.00 46.01 ATOM 1911 O ASP 321 23.972 -1.311 18.081 1.00 46.19 ATOM 1912 N ALA 322 26.118 -1.879 18.473 1.00 45.06 ATOM 1913 CA ALA 322 26.484 -1.976 17.059 1.00 44.18 ATOM 1914 CB ALA 322 27.964 -2.302 16.936 1.00 42.98 ATOM 1915 C ALA 322 25.666 -3. Oil 16.2 92 1.00 44.26 ATOM 1916 0 ALA 322 25.483 -2.898 15.082 1.00 42.38 ATOM 1917 N CYS 323 25.170 -4.020 16.996 1.00 4 6.17 ATOM 1918 CA CYS 323 24.540 -5.154 16.335 1.00 47.75 ATOM 1919 C CYS 323 23.225 -4.782 15.655 1.00 47.19 ATOM 192 0 0 CYS 323 22.621 -5.596 14.947 1.00 49.21 ATOM 1921 CB CYS 323 24.302 -6.277 17.337 1.00 47.92 ATOM 1922 SG CYS 323 25.755 -6.815 18.317 1.00 57.92 ATOM 1923 N LEU 324 22.786 -3.547 15.859 1.00 44 . 42 ATOM 1924 CA LEU 324 21.537 -3.106 15.275 1.00 41.95 ATOM 1925 CB LEU 324 20.781 -2.256 16.288 1.00 42.78 ATOM 192 6 CG LEU 324 19.899 -3.109 17.215 1.00 42.58 ATOM 1927 CDl LEU 324 20.409 -4.537 17.241 1.00 41.91 ATOM 1928 CD2 LEU 324 19.893 -2.514 18.621 1.00 41.27 ATOM 192 9 C LEU 324 21.746 -2.348 13.969 1.00 41.25 ATOM 1930 O LEU 324 20.801 -1.845 13.367 1.00 38.50 ATOM 1931 N TYR 325 22.992 -2.299 13.519 1.00 40.98 ATOM 1932 CA TYR 325 23.347 -1.560 12.315 1.00 39.73 ATOM 1933 CB TYR 325 24.155 -0.328 12.696 1.00 37.77 ATOM 1934 CG TYR 325 23.499 0.517 13.742 1.00 33.29 ATOM 1935 CDl TYR 325 22.650 1.557 13.377 1.00 34.00 ATOM 1936 CEl TYR 325 22.022 2.334 14.321 1.00 33.26 ATOM 1937 CD2 TYR 325 23.709 0.271 15.086 1.00 30.61 ATOM 1938 CE2 TYR 325 23.087 1.038 16.039 1.00 33.72 ATOM 1939 CZ TYR 325 22.239 2.074 15.649 1.00 33.01 ATOM 1940 OH TYR 325 21.597 2.844 16.588 1.00 32.19 ATOM 1941 C TYR 325 24.188 -2.407 11.377 1.00 40.49 ATOM 1942 O TYR 325 25.078 -3.134 11.823 1.00 41.28 ATOM 1943 N SER 326 23.936 -2.294 10.080 1.00 40.51 ATOM 1944 CA SER 326 24.848 -2.889 9.106 1.00 41.58 ATOM 1945 CB SER 326 24.062 -3.730 8.093 1.00 4 2.97 ATOM 1946 OG SER 326 23.315 -4.736 8.753 1.00 42.86 ATOM 1947 C SER 326 25.653 -1.791 8.393 1.00 41.09 ATOM 1948 O SER 326 25.202 -0.655 8.270 1.00 42.79 ATOM 1949 N PRO 327 26.860 -2.123 7.924 1.00 40.03 ATOM 1950 CD PRO 327 27.684 -1.256 7.0 62 1.00 39.65 ATOM 1951 CA PRO 327 27.418 -3.473 8.060 1.00 38.97 ATOM 1952 CB PRO 327 28.303 -3.620 6.821 1.00 38.89 ATOM 1953 CG PRO 327 28.693 -2.200 6.454 1.00 38.79 ATOM 1954 C PRO 327 28.168 -3.781 9.358 1.00 37.64 ATOM 1955 O PRO 327 28.985 -4.697 9.392 1.00 38.69 ATOM 1956 N ALA 328 27.890 -3.037 10.424 1.00 35.56 ATOM 1957 CA ALA 328 28.624 -3.219 11.672 1.00 34.25 ATOM 1958 CB ALA 328 28.270 -2.119 12.651 1.00 31.78 ATOM 1959 C ALA 328 28.316 -4.571 12.287 1.00 34.71 ATOM 1960 0 ALA 328 29.181 -5.236 12.848 1.00 32.22 ATOM 1961 N SER 329 27.064 -4.972 12.185 1.00 37.03 ATOM 1962 CA SER 329 26.602 -6.104 12.955 1.00 39.06 ATOM 1963 CB SER 329 25.068 -6.120 13.024 1.00 39.81 ATOM 1964 OG SER 329 24.482 -6.166 11.734 1.00 39.62 ATOM 1965 C SER 329 27.123 -7.343 12.282 1.00 39.36 ATOM 1966 O SER 329 27.029 -8.439 12.827 1.00 41.11 ATOM 1967 N ALA 330 27.691 -7.163 11.096 1.00 38.72 ATOM 1968 CA ALA 330 28.173 -8.304 10.324 1.00 39.45 ATOM 1969 CB ALA 330 28.489 -7.871 8.901 1.00 36.46 ATOM 1970 C ALA 330 29.391 -8.988 10.962 1.00 40.24 ATOM 1971 0 ALA 330 30.410 -8.355 11.276 1.00 39.63 ATOM 1972 N PRO 331 29.287 -10.308 11.159 1.00 41.42 ATOM 1973 CD PRO 331 28.083 -11.075 10.788 1.00 42.18 ATOM 1974 CA PRO 331 30.275 -11.147 11.842 1.00 42.22
2 CJ WO 2009/026558 PCT/US2008/074097
B C B 0 B 0
B C B 0
B B
B C
B C B 0 B 0
B C B 0
B N
B C
B C
B C B 0
B N
B C
B C B 0
B C
B S
B N
B C
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C
B C
B C
B C B 0
B C B 0
B N
B C
B C B 0
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C B 0
B N
B C
B C B 0
B C
B ' 0 B N
B C
B C
B C B 0
B N
B C
B C 346 WO 2009/026558 PCT/US2008/074097 ATOM 1975 CB PRO 331 29.609 -12 ATOM 1976 CG PRO 331 28.163 -12 ATOM 1977 C PRO 331 31.613 -11 ATOM 1978 O PRO 331 32.677 -11 ATOM 1979 N GLU 332 31.552 -11 ATOM 1980 CA GLU 332 32.755 -11 ATOM 1981 CB GLU 332 32.432 -12 ATOM 1982 CG GLU 332 31.067 -12 ATOM 1983 CD GLU 332 30.035 -13 ATOM 1984 OE1 GLU 332 30.196 -14 ATOM 1985 OE2 GLU 332 29.058 -12 ATOM 1986 C GLU 332 33.344 -10 ATOM 1987 0 GLU 332 34.237 -10 ATOM 1988 N VAL 333 32.832 -9 ATOM 1989 CA VAL 333 33.361 -7 ATOM 1990 CB VAL 333 32.211 -6 ATOM 1991 CGI VAL 333 32.749 -5 ATOM 1992 CG2 VAL 333 31.545 -7 ATOM 1993 C VAL 333 34.169 -7 ATOM 1994 O VAL 333 33.864 -7 ATOM 1995 N ILE 334 35.193 -6 ATOM 1996 CA ILE 334 35.937 -5 ATOM 1997 CB ILE 334 37.403 -5 ATOM 1998 CG2 ILE 334 38.148 -4 ATOM 1999 CGI ILE 334 38.108 -6 ATOM 2000 CDl ILE 334 38.789 -7 ATOM 2001 C ILE 334 35.276 -4 ATOM 2002 0 ILE 334 35.264 -3 ATOM 2003 N THR 335 34.724 -4 ATOM 2004 CA THR 335 33.899 -3 ATOM 2005 CB THR 335 32.565 -3 ATOM 2006 OG1 THR 335 31.900 -4 ATOM 2007 CG2 THR 335 31.676 -2 ATOM 2008 C THR 335 34.653 -2 ATOM 2009 O THR 335 35.212 -3 ATOM 2010 N VAL 336 34.695 -1 ATOM 2011 CA VAL 336 35.676 -0 ATOM 2012 CB VAL 336 36.670 0 ATOM 2013 CGI VAL 336 37.660 1 ATOM 2014 CG2 VAL 336 37.398 -0 ATOM 2015 C VAL 336 35.029 0 ATOM 2016 O VAL 336 34.361 1 ATOM 2017 N GLY 337 35.239 0 ATOM 2018 CA GLY 337 34.802 1 ATOM 2019 C GLY 337 35.746 2 ATOM 2020 0 GLY 337 36.780 2 ATOM 2021 N ALA 338 35.391 3 ATOM 2022 CA ALA 338 36.217 5 ATOM 2023 CB ALA 338 35.435 6 ATOM 2024 C ALA 338 36.667 5 ATOM 2025 0 ALA 338 35.876 5 ATOM 2026 N THR 339 37.944 5 ATOM 2027 CA THR 339 38.479 6 ATOM 2028 CB THR 339 39.537 5 ATOM 2029 OG1 THR 339 40.599 5 ATOM 2030 CG2 THR 339 38.907 3 ATOM 2031 C THR 339 39.154 7 ATOM 2032 O THR 339 39.425 7 ATOM 2033 N ASN 340 39.422 8 ATOM 2034 CA ASN 340 40.081 9 ATOM 2035 CB ASN 340 39.285 10 ATOM 2036 CG ASN 340 39.236 10 ATOM 2037 OD1 ASN 340 39.719 9 ATOM 2038 ND2 ASN 340 38.651 11 ATOM 2039 C ASN 340 41.515 9 ATOM 2040 0 ASN 340 42.037 8 ATOM 2041 N ALA 341 42.134 10 ATOM 2042 CA ALA 341 43.538 10 ATOM 2043 CB ALA 341 43.997 12 ATOM 2044 C ALA 341 43.801 10 ATOM 2045 0 ALA 341 44.954 10 ATOM 2046 N GLN 342 42.730 9 ATOM 2047 CA GLN 342 42.838 9 ATOM 2048 CB GLN 342 41.779 9 ATOM 2049 CG GLN 342 41.374 11 ATOM 2050 CD GLN 342 42.561 12 11.881 1.00 42.39 B C 11.698 1.00 42.38 B C 11.112 1.00 42.21 B c 11.727 1.00 41.29 B 0 9.797 1.00 42.77 B N 9.014 1.00 45.40 B _c 7.825 1.00 46.55 B c 7.218 1.00 50.46 B c 7.573 1.00 52.20 B c 7.128 1.00 50.77 B 0 8.292 1.00 52.83 B 0 8.551 1.00 45.69 B c 7.698 1.00 47.38 B 0 9.129 1.00 4 5.52 B N 8.92 6 1.00 44.61 B c 8.689 1.00 43.61 B c 8.738 1.00 43.34 B c 7.350 1.00 42.09 B c 10.148 1.00 44.86 B c 11.283 1.00 44.91 B 0 9.915 1.00 43.56 B N 11.009 1.00 42.14 B c 10.618 1.00 41.32 B c 11.771 1.00 39.45 B c 10.323 1.00 42.05 B c 11.528 1.00 41.74 B c 11.391 1.00 42.30 B c 10.617 1.00 44.99 B 0 12.593 1.00 40.57 B N 13.012 1.00 39.86 B c 13.560 1.00 38.34 B c 12.527 1.00 35.93 B 0 14.016 1.00 37.95 B c 14.064 1.00 39.84 B c 14.999 1.00 40.88 B 0 13.903 1.00 39.68 B N 14.628 1.00 38.86 B c 13.674 1.00 36.14 B c 14.475 1.00 34.81 B c 12.830 1.00 34.08 B c 15.455 1.00 39.97 B c 14.923 1.00 41.64 B 0 16.763 1.00 40.20 B N 17.606 1.00 39.73 B c 17.486 1.00 39.43 B c 16.820 1.00 39.46 B 0 18.126 1.00 39.12 B N 18.096 1.00 38.05 B c 17.479 1.00 34.55 B c 19.509 1.00 38.46 B c 20.451 1.00 39.47 B 0 19.651 1.00 39.40 B N 20.922 1.00 42.52 B c 21.517 1.00 44.20 B c 20.576 1.00 46.75 B 0 21.861 1.00 45.49 B c 20.684 1.00 44.11 B c 19.542 1.00 43.96 B 0 21.767 1.00 46.79 B N 21.685 1.00 48.44 B c 22.465 1.00 46.64 B c 23.943 1.00 45.72 B c 24.401 1.00 43.67 B 0 24.706 1.00 4 5.68 B N 22.210 1.00 47.97 B c 22.482 1.00 46.71 B 0 22.337 1.00 49.51 B N 22.688 1.00 51.79 B c 22.534 1.00 49.71 B c 24.110 1.00 54.25 B c 24.547 1.00 54.89 B 0 24.829 1.00 56.61 B N 26.158 1.00 58.83 . B c 27.084 1.00 60.38 B c 26.715 1.00 63.15 B c 26.637 1.00 65.06 B c 347 WO 2009/026558 PCT/US2008/074097
ATOM 2051 OE1 GLN 342 42.539 13.276 25.918 1.00 66.99 B ATOM 2052 NE2 GLN 342 43.616 11.939 27.381 1.00 66.05 B ATOM 2053 C GLN 342 42.660 7.832 26.105 1.00 59.71 B ATOM 2054 0 GLN 342 42.625 7.165 27.143 1.00 59.74 B ATOM 2055 N ASP 343 42.547 7.289 24.895 1.00 59.69 B ATOM 2056 CA ASP 343 42.193 5.888 24.706 1.00 59.97 B ATOM 2057 CB ASP 343 43.276 4.988 25.315 1.00 60.43 B ATOM 2058 CG ASP 343 44.410 4.685 24.328 1.00 62.18 B ATOM 2059 OD1 ASP 343 44.125 4.483 23.130 1.00 61.55 B ATOM 2060 OD2 ASP 343 45.591 4.644 24.739 1.00 64.06 B ATOM 2061 C ASP 343 40.804 5.552 25.281 1.00 59.58 B ATOM 2062 0 ASP 343 40.562 4.440 25.756 1.00 58.20 B ATOM 2063 N GLN 344 39.896 6.527 25.218 1.00 58.40 B ATOM 2064 CA GLN 344 38.531 6.362 25.712 1.00 5 6.68 B ATOM 2065 CB GLN 344 38.226 7.428 26.768 1.00 57.01 B ATOM 2066 CG GLN 344 38.911 7.171 28.100 1.00 59.32 B ATOM 2067 CD GLN 344 38.507 5.837 28.714 1.00 61.30 B ATOM 2068 OE1 GLN 344 37.395 5.687 29.225 1.00 61.08 B ATOM 2069 NE2 GLN 344 39.410 4.858 28.660 1.00 61.88 B ATOM 2070 C GLN 344 37.473 6.420 24.607 1.00 54.73 B ATOM 2071 0 GLN 344 37.713 6.939 23.520 1.00 55.32 B ATOM 2072 N PRO 345 36.276 5.887 24.884 1.00 52.34 B ATOM 2073 CD PRO 345 35.864 5.218 26.130 1.00 52.86 B ATOM 2074 CA PRO 345 35.208 5.872 23.881 1.00 51.32 B ATOM 2075 CB PRO 345 34.080 5.115 24.572 1.00 52.46 B ATOM 2076 CG PRO 345 34.752 4.348 25.676 1.00 53.13 B ATOM 2077 C PRO 345 34.782 7.278 23.486 1.00 48.74 B ATOM 2078 O PRO 345 34.501 8.114 24.345 1.00 47.73 B ATOM 2079 N VAL 346 34.732 7.535 22.185 1.00 46.48 B ATOM 2080 CA VAL 346 34.432 8.875 21.700 1.00 45.16 B ATOM 2081 CB VAL 346 34.719 8.994 20.195 1.00 44.09 B ATOM 2082 CGI VAL 346 33.991 10.203 19.640 1.00 45.77 B ATOM 2083 CG2 VAL 346 36.215 9.134 19.961 1.00 43.38 B ATOM 2084 C VAL 346 32.989 9.327 21.953 1.00 43.26 B ATOM 2085 O VAL 346 32.032 8.604 21.695 1.00 43.80 B ATOM 2086 N THR 347 32.833 10.535 22.466 1.00 40.93 B ATOM 2087 CA THR 347 31.529 11.168 22.437 1.00 38.99 B ATOM 2088 CB THR 347 31.267 11.969 23.727 1.00 38.98 B ATOM 2089 OG1 THR 347 32.410 12.783 24.025 1.00 39.16 B ATOM 2090 CG2 THR 347 31.000 11.024 24.877 1.00 37.77 B ATOM 2091 C THR 347 31.437 12.095 21.225 1.00 36.77 B ATOM 2092 O THR 347 32.324 12.917 20.981 1.00 35.24 B ATOM 2093 N LEU 348 30.359 11.933 20.463 1.00 34.41 B ATOM 2094 CA LEU 348 30.085 12.764 19.300 1.00 32.42 B ATOM 2095 CB LEU 348 29.981 11.869 18.057 1.00 30.11 B ATOM 2096 CG LEU 348 31.248 11.02 3 17.803 1.00 29.43 B ATOM 2097 CDl LEU 348 30.916 9.801 16.981 1.00 26.50 B ATOM 2098 CD2 LEU 348 32.315 11.869 17.112 1.00 25.20 B ATOM 2099 C LEU 348 28.760 13.441 19.609 1.00 31.86 B ATOM 2100 O LEU 348 27.766 12.7 62 19.801 1.00 33.15 B ATOM 2101 N GLY 349 28.735 14.764 19.702 1.00 31.16 B ATOM 2102 CA GLY 349 27.519 15.402 20.194 1.00 32.64 B ATOM 2103 C GLY 349 27.086 14.817 21.534 1.00 32.03 B ATOM 2104 0 GLY 349 27.831 14.868 22.484 1.00 34.71 B ATOM 2105 N THR 350 25.895 14.251 21.642 1.00 33.25 B ATOM 2106 CA THR 350 25.549 13.563 22.890 1.00 32.37 B ATOM 2107 CB THR 350 24.172 14.014 23.433 1.00 31.72 B ATOM 2108 OG1 THR 350 23.142 13.664 22.502 1.00 33.43 B ATOM 2109 CG2 THR 350 24.156 15.502 23.644 1.00 32.71 B ATOM 2110 C THR 350 25.553 12.039 22 .721 1.00 31.43 B ATOM 2111 O THR 350 25.330 11.292 23.679 1.00 30.78 B ATOM 2112 N LEU 351 25.808 11.586 21.497 1.00 29.11 B ATOM 2113 CA LEU 351 26.001 10.177 21.238 1.00 27.69 B ATOM 2114 CB LEU 351 25.421 9.831 19.878 1.00 27.14 B ATOM 2115 CG LEU 351 23.939 10.206 19.774 1.00 28.37 B ATOM 2116 CDl LEU 351 23.314 9.489 18.590 1.00 29.77 B ATOM 2117 CD2 LEU 351 23.218 9.806 21.054 1.00 27.08 B ATOM 2118 C LEU 351 27.482 9.824 21.298 1.00 29.91 B ATOM 2119 O LEU 351 28.173 10.139 22.277 1.00 31.43 B ATOM 2120 N GLY 352 27.981 9.178 20.248 1.00 30.92 B ATOM 2121 CA GLY 352 29.376 8.774 20.232 1.00 30.77 B ATOM 2122 C GLY 352 29.534 7.340 19.770 1.00 30.80 B ATOM 2123 0 GLY 352 28.656 6.788 19.104 1.00 31.81 . B ATOM 2124 N THR 353 30.647 6.715 20.121 1.00 30.12 B ATOM 2125 CA THR 353 30.980 5.456 19.488 1.00 30.91 B ATOM 2126 CB THR 353 32.410 5.035 19.835 1.00 29.91 B
2 CJ ο
N
C 0
N
C c c 0 0 c 0
N c c c c 0
N c 0
N c c c c c 0 c c c c 0
N c c 0 c c 0
N c c c c c c 0
N c c 0
N c c 0 c c 0
N c c c c c c 0
N c c 0
N c c 348 WO 2009/026558 PCT/US2008/074097 ATOM 2127 OG1 THR 353 32.743 3.818 19.152 1.00 26.96 B O ATOM 2128 CG2 THR 353 32.539 4.829 21.332 1.00 31.40 B C ATOM 2129 C THR 353 30.020 4.381 19.955 1.00 32.86 B C ATOM 2130 O THR 353 29.869 4 .171 21.162 1.00 32.88 B 0 ATOM 2131 N ASN 354 29.371 3.710 19.002 1.00 32.48 B N ATOM 2132 CA ASN 354 28.714 2.430 19.277 1.00 34.53 B c ATOM 2133 CB ASN 354 28.125 1.825 17.994 1.00 32.64 B c ATOM 2134 CG ASN 354 26.811 2.451 17.611 1.00 32.64 B c ATOM 2135 OD1 ASN 354 26.421 3.484 18.158 1.00 34.86 B 0 ATOM 2136 ND2 ASN 354 26.116 1.838 16.669 1.00 30.53 B N ATOM 2137 C ASN 354 29.656 1.399 19.910 1.00 34.76 B c ATOM 2138 O ASN 354 30.882 1.558 19.919 1.00 32.98 B 0 ATOM 2139 N PHE 355 29.059 0.326 20.413 1.00 36.79 B N ATOM 2140 CA PHE 355 29.770 -0.671 21.207 1.00 39.22 B c ATOM 2141 CB PHE 355 29.805 -0.217 22.661 1.00 39.08 B c ATOM 2142 CG PHE 355 28.478 0.292 23.150 1.00 39.28 B c ATOM 2143 CDl PHE 355 28.297 1.635 23.433 1.00 37.87 B c ATOM 2144 CD2 PHE 355 27.399 -0.570 23.280 1.00 39.36 B c ATOM 2145 CEl PHE 355 27.073 2.107 23.831 1.00 38.35 B c ATOM 2146 CE2 PHE 355 26.166 -0.100 23.681 1.00 39.17 B c ATOM 2147 CZ PHE 355 26.004 1.241 23.955 1.00 38.97 B c ATOM 2148 C PHE 355 29.058 -2.022 21.128 1.00 41.42 B c ATOM 2149 O PHE 355 28.135 -2.222 20.327 1.00 42.06 B 0 ATOM 2150 N GLY 356 29.472 -2.945 21.985 1.00 43.05 B N ATOM 2151 CA GLY 356 28.791 -4.217 22.030 1.00 4 6.32 B c ATOM 2152 C GLY 356 29.615 -5.316 21.418 1.00 49.86 B c ATOM 2153 0 GLY 356 30.734 -5.080 20.960 1.00 49.34 B 0 ATOM 2154 N ARG 357 29.067 -6.525 21.415 1.00 52.59 B N ATOM 2155 CA ARG 357 29.853 -7.687 21.050 1.00 55.32 B c ATOM 2156 CB ARG 357 29.054 -8.957 21.316 1.00 56.96 B c ATOM 2157 CG ARG 357 27.733 -9.016 20.601 1.00 57.12 B c ATOM 2158 CD ARG 357 26.958 -10.270 20.970 1.00 60.05 B c ATOM 2159 NE ARG 357 25.646 -10.272 20.324 1.00 66.70 B N ATOM 2160 CZ ARG 357 25.436 -10.567 19.041 1.00 69.70 B c ATOM 2161 NHl ARG 357 24.202 -10.535 18.550 1.00 71.70 B N ATOM 2162 NH2 ARG 357 26.455 -10.900 18.249 1.00 70.96 B N ATOM 2163 C ARG 357 30.282 -7.628 19.584 1.00 55.87 B C ATOM 2164 O ARG 357 31.312 -8.195 19.208 1.00 58.14 B 0 ATOM 2165 N CYS 358 29.493 -6.925 18.770 1.00 53.84 B N ATOM 2166 CA CYS 358 29.711 -6.841 17.328 1.00 50.17 B C ATOM 2167 C CYS 358 30.828 -5.854 16.927 1.00 48.24 B c ATOM 2168 0 CYS 358 31.055 -5.601 15.744 1.00 46.71 B 0 ATOM 2169 CB CYS 358 28.381 -6.484 16.648 1.00 50.59 B c ATOM 2170 SG CYS 358 27.087 -7.713 17.021 1.00 53.47 B s ATOM 2171 N VAL 359 31.531 -5.306 17.912 1.00 46.32 B N ATOM 2172 CA VAL 359 32.716 -4.503 17.630 1.00 45.82 B c ATOM 2173 CB VAL 359 32.806 -3.282 18.567 1.00 44.83 B c ATOM 2174 CGI VAL 359 34.050 -2.469 18.240 1.00 42.10 B c ATOM 2175 CG2 VAL 359 31.541 -2.426 18.436 1.00 44.41 B c ATOM 2176 C VAL 359 33.968 -5.344 17.829 1.00 46.74 B c ATOM 2177 O VAL 359 34.087 -6.061 18.821 1.00 48.03 B 0 ATOM 2178 N ASP 360 34.908 -5.262 16.893 1.00 46.35 B N ATOM 2179 CA ASP 360 36.122 -6.067 16.991 1.00 44.78 B c ATOM 2180 CB ASP 360 36.624 -6.448 15.597 1.00 44.72 B c ATOM 2181 CG ASP 360 35.649 -7.354 14.859 1.00 46.97 B c ATOM 2182 OD1 ASP 360 35.617 -8.576 15.133 1.00 48.10 B 0 ATOM 2183 OD2 ASP 360 34.902 -6.842 14.005 1.00 49.17 B 0 ATOM 2184 C ASP 360 37.197 -5.326 17.756 1.00 43.17 B c ATOM 2185 O ASP 360 38.004 -5.931 18.438 1.00 44.20 B 0 ATOM 2186 N LEU 361 37.192 -4.008 17.653 1.00 42.15 B N ATOM 2187 CA LEU 361 38.119 -3.190 18.417 1.00 42.07 B c ATOM 2188 CB LEU 361 39.577 -3.571 18.098 1.00 42.02 B c ATOM 2189 CG LEU 361 40.202 -3.182 16.739 1.00 43.57 B c ATOM 2190 CDl LEU 361 41.713 -3.002 16.874 1.00 42.62 B c ATOM 2191 CD2 LEU 361 39.894 -4.237 15.704 1.00 41.99 B c ATOM 2192 C LEU 361 37.879 -1.715 18.092 1.00 42.18 B c ATOM 2193 O LEU 361 36.995 -1.375 17.297 1.00 40.87 B 0 ATOM 2194 N PHE 362 38.669 -0.850 18.717 1.00 42.23 B N ATOM 2195 CA PHE 362 38.589 0.587 18.498 1.00 43.61 B c ATOM 2196 CB PHE 362 38.373 1.307 19.834 1.00 42.71 B c ATOM 2197 CG PHE 362 37.078 0.961 20.497 1.00 43.77 B c ATOM 2198 CDl PHE 362 36.206 1.953 20.907 1.00 44 . 12 B c ATOM 2199 CD2 PHE 362 36.716 -0.361 20.688 1.00 43.83 . B c ATOM 2200 CEl PHE 362 34.987 1.627 21.494 1.00 44.59 B c ATOM 2201 CE2 PHE 3 62 35.505 -0.693 21.272 1.00 44.45 ' B c ATOM 2202 CZ PHE 362 34.640 0.300 21.677 1.00 43.51 B c 349 WO 2009/026558 PCT/US2008/074097 ATOM 2203 c PHE 362 39.873 1 ATOM 2204 0 PHE 3 62 40.813 0 ATOM 2205 N ALA 363 39.896 2 ATOM 2206 CA ALA 363 41.108 3 ATOM 2207 CB ALA 363 41.400 2 ATOM 2208 C ALA 363 40.849 4 ATOM 2209 0 ALA 363 39.703 4 ATOM 2210 N PRO 364 41.909 5 ATOM 2211 CD PRO 364 43.317 5 ATOM 2212 CA PRO 364 41.721 6 ATOM 2213 CB PRO 364 43.094 7 ATOM 2214 CG PRO 364 44.027 6 ATOM 2215 C PRO 364 40.669 7 ATOM 2216 O PRO 364 40.728 6 ATOM 2217 N GLY 365 39.716 8 ATOM 2218 CA GLY 365 38.632 8 ATOM 2219 C GLY 365 38.112 9 ATOM 2220 0 GLY 365 37.095 10 ATOM 2221 N GLU 366 38.798 10 ATOM 2222 CA GLU 366 38.454 11 ATOM 2223 CB GLU 366 38.184 11 ATOM 2224 CG GLU 366 37.350 13 ATOM 2225 CD GLU 366 37.236 13 ATOM 2226 OE1 GLU 366 36.271 12 ATOM 2227 OE2 GLU 366 38.120 13 ATOM 2228 C GLU 366 39.627 12 ATOM 2229 0 GLU 366 40.750 12 ATOM 2230 N ASP 367 39.375 13 ATOM 2231 CA ASP 367 40.416 14 ATOM 2232 CB ASP 367 41.114 15 ATOM 2233 CG ASP 367 42.050 16 ATOM 2234 OD1 ASP 367 41.637 17 ATOM 2235 OD2 ASP 367 43.200 16 ATOM 2236 C ASP 367 41.442 14 ATOM 2237 O ASP 367 42.648 14 ATOM 2238 N ILE 368 40.977 13 ATOM 2239 CA ILE 368 41.924 13 ATOM 2240 CB ILE 368 41.340 11 ATOM 2241 CG2 ILE 368 42.346 11 ATOM 2242 CGI ILE 368 40.900 10 ATOM 2243 CDl ILE 368 41.884 10 ATOM 2244 C ILE 368 42.275 14 ATOM 2245 0 ILE 368 41.392 14 ATOM 2246 N ILE 369 43.558 14 ATOM 2247 CA ILE 369 43.975 15 ATOM 2248 CB ILE 369 45.308 16 ATOM 2249 CG2 ILE 369 46.469 15 ATOM 2250 CGI ILE 369 45.366 17 ATOM 2251 CDl ILE 369 46.541 18 ATOM 2252 C ILE 369 44.140 14 ATOM 2253 0 ILE 369 44.605 13 ATOM 2254 N GLY 370 43.747 15 ATOM 2255 CA GLY 370 43.750 14 ATOM 2256 C GLY 370 43.444 15 ATOM 2257 0 GLY 370 43.140 16 ATOM 2258 N ALA 371 43.524 15 ATOM 2259 CA ALA 371 43.276 15 ATOM 2260 CB ALA 371 43.233 15 ATOM 2261 C ALA 371 41.974 16 ATOM 2262 0 ALA 371 40.945 16 ATOM 2263 N SER 372 42.009 18 ATOM 2264 CA SER 372 40.774 18 ATOM 2265 CB SER 372 40.803 20 ATOM 2266 OG SER 372 39.646 20 ATOM 2267 C SER 372 40.489 19 ATOM 2268 O SER 372 41.357 19 ATOM 2269 N SER 373 39.256 19 ATOM 2270 CA SER 373 38.922 19 ATOM 2271 CB SER 373 37.592 18 ATOM 2272 OG SER 373 36.498 19 ATOM 2273 C SER 373 38.846 20 ATOM 2274 O SER 373 38.728 21 ATOM 2275 N ASP 374 38.922 21 ATOM 2276 CA ASP 374 38.882 23 ATOM 2277 CB ASP 374 39.132 23 ATOM 2278 CG ASP 374 37.900 23 17.844 1.00 4 3.97 B C 17.648 1.00 44.43 B O 17.498 1.00 44.29 B N 17.043 1.00 42.94 B C 15.606 1.00 41.34 B C 17.170 1.00 42.78 B c 17.259 1.00 40.55 B 0 17.184 1.00 44.63 B N 16.940 1.00 45.92 B c 17.314 1.00 45.95 B c 16.984 1.00 45.73 B c 17.301 1.00 45.76 B c 16.329 1.00 47.71 B c 15.138 1.00 46.96 B 0 16.839 1.00 48.81 B N 16.016 1.00 50.95 B c 16.425 1.00 52.82 B c 15.896 1.00 54.20 B 0 17.367 1.00 53.12 B N 17.772 1.00 53.18 B c 19.284 1.00 55.16 B c 19.757 1.00 57.81 B c 21.288 1.00 59.11 B c 21.874 1.00 59.52 B 0 21.902 1.00 58.89 B 0 17.416 1.00 51.60 B c 17.799 1.00 53.06 B 0 16.663 1.00 50.68 B N 16.377 1.00 48.72 B c 17.680 1.00 51.98 B c 17.506 1.00 55.60 B c 16.888 1.00 57.07 B 0 17.998 1.00 57.74 B 0 15.403 1.00 45.06 B c 15.614 1.00 44.79 B 0 14.337 1.00 40.15 B N 13.417 1.00 35.41 B c 12.776 1.00 32.03 B c 11.818 1.00 30.65 B c 13.860 1.00 28.33 B c 14.993 1.00 22.93 B c 12.318 1.00 35.65 B c 11.584 1.00 34.20 B 0 12.209 1.00 33.12 B N 11.180 1.00 31.13 B c 11.529 1.00 31.54 B c 11.000 1.00 29.64 B c 10.875 1.00 31.98 B c 11.339 1.00 32.59 B c 9.867 1.00 30.83 B c 9.850 1.00 31.37 B 0 8.773 1.00 30.51 B N 7.482 1.00 32.26 B c 6.365 1.00 32.89 B c 6.619 1.00 33.94 B 0 5.126 1.00 32.44 B N 3.937 1.00 31.69 B c 2.699 1.00 28.10 B c 4.029 1.00 32.16 B c 4 . 402 1.00 34.89 B 0 3.684 1.00 31.83 B N 3.552 1.00 31.63 B c 4.414 1.00 29.79 B c 4 . 140 1.00 27.55 B 0 2.121 1.00 31.94 B c 1.428 1.00 33.59 B 0 1.681 1.00 33.37 B N 0.285 1.00 32.32 B c -0.069 1.00 29.34 B c 0.624 1.00 29.96 B 0 0.034 1.00 32.38 B c -1 . 111 1.00 28.01 B 0 1 .120 1.00 35.17 . B N 1.040 1.00 38.35 B c 2.416 1.00 39.54 B c 3.316 1.00 42.83 B c 350 WO 2009/026558 PCT/US2008/074097 ATOM 2279 OD1 ASP 374 36.992 22 ATOM 2280 OD2 ASP 374 37.837 24 ATOM 2281 C ASP 374 39.910 23 ATOM 2282 O ASP 374 39.578 24 ATOM 2283 N CYS 375 41.159 23 ATOM 2284 CA CYS 375 42.150 23 ATOM 2285 C CYS 375 43.162 22 ATOM 2286 0 CYS 375 43.130 21 ATOM 2287 CB CYS 375 42.836 24 ATOM 2288 SG CYS 375 44.265 24 ATOM 2289 N SER 376 44.059 22 ATOM 2290 CA SER 376 44.898 21 ATOM 2291 CB SER 376 45.615 21 ATOM 2292 OG SER 376 46.458 22 ATOM 2293 C SER 376 45.947 20 ATOM 2294 O SER 376 46.542 19 ATOM 2295 N THR 377 46.216 21 ATOM 2296 CA THR 377 47.278 21 ATOM 2297 CB THR 377 48.426 22 ATOM 2298 OG1 THR 377 47.982 23 ATOM 2299 CG2 THR 377 48.869 22 ATOM 2300 C THR 377 46.685 21 ATOM 2301 O THR 377 47.349 21 ATOM 2302 N CYS 378 45.416 21 ATOM 2303 CA CYS 378 44.663 22 ATOM 2304 C CYS 378 44.469 20 ATOM 2305 0 CYS 378 44.251 19 ATOM 2306 CB CYS 378 43.310 22 ATOM 2307 SG CYS 378 43.483 24 ATOM 2308 N PHE 379 44.573 20 ATOM 2309 CA PHE 379 44.255 19 ATOM 2310 CB PHE 379 45.438 19 ATOM 2311 CG PHE 379 46.518 18 ATOM 2312 CDl PHE 379 47.646 19 ATOM 2313 CD2 PHE 379 46.411 17 ATOM 2314 CEl PHE 379 48.652 18 ATOM 2315 CE2 PHE 379 47.405 16 ATOM 2316 CZ PHE 379 48.529 17 ATOM 2317 C PHE 379 43.062 20 ATOM 2318 O PHE 379 42.756 21 ATOM 2319 N VAL 380 42.391 19 ATOM 2320 CA VAL 380 41.339 19 ATOM 2321 CB VAL 380 39.963 19 ATOM 2322 CGI VAL 380 39.411 18 ATOM 2323 CG2 VAL 380 39.017 20 ATOM 2324 C VAL 380 41.200 18 ATOM 2325 O VAL 380 41.609 17 ATOM 2326 N SER 381 40.620 18 ATOM 2327 CA SER 381 40.349 17 ATOM 2328 CB SER 381 40.716 18 ATOM 2329 OG SER 381 40.806 17 ATOM 2330 C SER 381 38.869 17 ATOM 2331 O SER 381 37.958 17 ATOM 2332 N GLN 382 38.645 15 ATOM 2333 CA GLN 382 37.298 15 ATOM 2334 CB GLN 382 36.971 14 ATOM 2335 CG GLN 382 37.028 15 ATOM 2336 CD GLN 382 36.169 15 ATOM 2337 OE1 GLN 382 35.414 16 ATOM 2338 NE2 GLN 382 36.269 14 ATOM 2339 C GLN 382 37.155 14 ATOM 2340 0 GLN 382 38.134 13 ATOM 2341 N SER 383 35.936 13 ATOM 2342 CA SER 383 35.651 12 ATOM 2343 CB SER 383 35.265 13 ATOM 2344 OG SER 383 36.295 14 ATOM 2345 C SER 383 34.550 11 ATOM 2346 O SER 383 33.657 12 ATOM 2347 N GLY 384 34.626 10 ATOM 2348 CA GLY 384 33.608 9 ATOM 2349 C GLY 384 34.158 8 ATOM 2350 0 GLY 384 35.375 8 ATOM 2351 N THR 385 33.285 7 ATOM 2352 CA THR 385 33.784 5 ATOM 2353 CB THR 385 32.691 4 ATOM 2354 OG1 THR 385 31.490 5 3.091 1.00 44.31 B O 4.261 1.00 46.41 B O 0.047 1.00 39.30 B C -0.846 1.00 40.00 B O 0.189 1.00 39.54 B N -0.807 1.00 41.25 B C -0.892 1.00 42.24 B C -0.071 1.00 44.57 B 0 -0.423 1.00 42.60 B c 0.698 1.00 43.30 B s -1.872 1.00 40.33 B N -2.254 1.00 37.25 B c -3.573 1.00 39.26 B c -3.441 1.00 40.65 B 0 -1.222 1.00 35.77 B c -1.319 1.00 34.73 B 0 -0.259 1.00 34.14 B N 0.710 1.00 32.96 B c 0.603 1.00 29.40 B c 1.082 1.00 29.82 B 0 -0.842 1.00 24.15 B c 2.103 1.00 34.62 B c 3.099 1.00 34.86 B 0 2.138 1.00 35.87 B N 3.364 1.00 39.20 B c 4 . 157 1.00 38.82 B c 3.583 1.00 38.85 B 0 3.006 1.00 41.18 B c 2.585 1.00 47.55 B s 5.481 1.00 40.10 B N 6.404 1.00 40.73 B c 7.336 1.00 42.07 B c 6.711 1.00 44.32 B c 6.174 1.00 45.53 B c 6.667 1.00 44.45 B c 5.601 1.00 48.10 B c 6.100 1.00 45.09 B c 5.567 1.00 46.79 B c 7.268 1.00 40.73 B c 7.438 1.00 39.27 B 0 7.827 1.00 41.60 B N 8.814 1.00 41.83 B c 8.147 1.00 39.80 B c 7.62 5 1.00 37.70 B c 9.128 1.00 38.24 B c 9.787 1.00 42.06 B c 9.496 1.00 40.84 B 0 10.944 1.00 43.79 B N 11.936 1.00 45.78 B c 13.330 1.00 46.59 B c 14.279 1.00 51.19 B 0 11.900 1.00 45.40 B c 11.746 1.00 43.60 B 0 12.035 1.00 46.71 B N 12.031 1.00 47.56 B c 10.648 1.00 47.78 B c 9.630 1.00 53.25 B c 8.438 1.00 56.07 B c 7.989 1.00 58.19 B 0 7.905 1.00 57.86 B N 13.041 1.00 47.35 B c 13.362 1.00 49.75 B 0 13.538 1.00 44.94 B N 14.426 1.00 42.17 B c 15.810 1.00 40.00 B c 16.353 1.00 35.61 B 0 13.903 1.00 41.99 B c 13.174 1.00 40.39 B 0 14.295 1.00 42.52 B N 13.907 1.00 42.23 B c 13.905 1.00 41.28 B c 13.941 1.00 39.89 B 0 13.862 1.00 40.09 . B N 13.746 1.00 41.46 B c 13.979 1.00 40.99 B c 13.268 1.00 41.65 B 0 351 WO 2009/026558 PCT/US2008/074097
ATOM 2355 CG2 THR 385 32.414 4.731 15.454 1.00 41.03 B ATOM 2356 C THR 385 34.405 5.741 12.375 1.00 43.11 B ATOM 2357 O THR 385 35.218 4.836 12.187 1.00 45.39 B ATOM 2358 N SER 386 34.043 6.579 11.414 1.00 42.03 B ATOM 2359 CA SER 386 34.672 6.478 10.112 1.00 40.89 B ATOM 2360 CB SER 386 34.002 7.424 9.132 1.00 42.12 B ATOM 2361 OG SER 386 32.735 6.907 8.763 1.00 45.70 B ATOM 2 3 62 C SER 386 36.167 6.760 10.182 1.00 39.87 B ATOM 2363 O SER 386 36.960 6.079 9.529 1.00 38.99 B ATOM 2364 N GLN 387 36.563 7.747 10.979 1.00 38.57 B ATOM 2365 CA GLN 387 37.986 8.019 11.164 1.00 38.45 B ATOM 2366 CB GLN 387 38.179 9.266 12.025 1.00 38.28 B ATOM 2367 CG GLN 387 37.233 10.404 11.670 1.00 37.87 B ATOM 2368 CD GLN 387 37.271 10.745 10.198 1.00 37.13 B ATOM 2369 OE1 GLN 387 38.334 10.910 9.629 1.00 41.19 B ATOM 2370 NE2 GLN 387 36.107 10.849 9.575 1.00 38.64 B ATOM 2371 C GLN 387 38.641 6.810 11.846 1.00 38.88 B ATOM 2372 0 GLN 387 39.767 6.427 11.518 1.00 39.69 B ATOM 2373 N ALA 388 37.922 6.199 12.786 1.00 37.00 B ATOM 2374 CA ALA 388 38.434 5.042 13.507 1.00 34.63 B ATOM 2375 CB ALA 388 37.467 4.654 14.623 1.00 31.74 B ATOM 2376 C ALA 388 38.647 3.865 12.556 1.00 34.56 B ATOM 2377 0 ALA 388 39.647 3.155 12.640 1.00 35.06 B ATOM 2378 N ALA 389 37.702 3.657 11.648 1.00 34.57 B ATOM 2379 CA ALA 389 37.788 2.550 10.703 1.00 33.13 B ATOM 2380 CB ALA 389 36.454 2.356 9.991 1.00 32.48 B ATOM 2381 C ALA 389 38.883 2.795 9.680 1.00 33.71 B ATOM 2382 0 ALA 389 39.514 1.855 9.214 1.00 34.66 B ATOM 2383 N ALA 390 39.109 4.056 9.319 1.00 34.06 B ATOM 2384 CA ALA 390 40.198 4.367 8.407 1.00 35.02 B ATOM 2385 CB ALA 390 40.296 5.872 8.210 1.00 32.15 B ATOM 2386 C ALA 390 41.523 3.795 8.973 1.00 35.11 B ATOM 2387 0 ALA 390 42.236 3.071 8.279 1.00 33.97 B ATOM 2388 N HIS 391 41.820 4.092 10.238 1.00 34.71 B ATOM 2389 CA HIS 391 43.073 3.661 10.846 1.00 37.06 B ATOM 2390 CB HIS 391 43.133 4.076 12.321 1.00 37.89 B ATOM 2391 CG HIS 391 43.435 5.52 8 12.536 1.00 41.44 B ATOM 2392 CD2 HIS 391 44.268 6.146 13.407 1.00 42.12 B ATOM 2393 NDl HIS 391 42.808 6.534 11.833 1.00 41.80 B ATOM 2394 CEl HIS 391 43.237 7.707 12.263 1.00 42.62 B ATOM 2395 NE2 HIS 391 44 .124 7.501 13.219 1.00 42.69 B ATOM 2396 C HIS 391 43.230 2.152 10.749 1.00 37.12 B ATOM 2397 0 HIS 391 44.272 1.646 10.336 1.00 38.23 B ATOM 2398 N VAL 392 42.191 1.429 11.142 1.00 36.22 B ATOM 2399 CA VAL 392 42.251 -0.016 11.115 1.00 33.77 B ATOM 2400 CB VAL 392 40.988 -0.62 6 11.701 1.00 31.11 B ATOM 2401 CGI VAL 392 40.991 -2.135 11.491 1.00 27.16 B ATOM 2402 CG2 VAL 392 40.905 -0.282 13.170 1.00 28.41 B ATOM 2403 C VAL 392 42.401 -0.488 9.681 1.00 34.43 B ATOM 2404 O VAL 392 43.086 -1.479 9.415 1.00 35.64 B ATOM 2405 N ALA 393 41.758 0.227 8.759 1.00 33.11 B ATOM 2406 CA ALA 393 41.821 -0.130 7.354 1.00 33.65 B ATOM 2407 CB ALA 393 40.934 0.809 6.525 1.00 31.34 B ATOM 2408 C ALA 393 43.278 -0.025 6.911 1.00 34.97 B ATOM 2409 0 ALA 393 43.755 -0.830 6.105 1.00 33.98 B ATOM 2410 N GLY 394 43.977 0.969 7.454 1.00 35.70 B ATOM 2411 CA GLY 394 45.345 1.232 7.045 1.00 36.60 B ATOM 2412 C GLY 394 46.253 0.163 7.604 1.00 38.29 B ATOM 2413 0 GLY 394 47.080 -0.405 6.887 1.00 37.89 B ATOM 2414 N ILE 395 46.080 -0.123 8.890 1.00 39.54 B ATOM 2415 CA ILE 395 46.869 -1.141 9.553 1.00 39.77 B ATOM 2416 CB ILE 395 46.439 -1.312 11.010 1.00 39.22 B ATOM 2417 CG2 ILE 395 47.192 -2.480 11.636 1.00 36.68 B ATOM 2418 CGI ILE 395 46.666 -0.005 11.780 1.00 37.42 B ATOM 2419 CDl ILE 395 46.141 -0.037 13.210 1.00 34.61 B ATOM 2420 C ILE 395 46.634 -2.441 8.824 1.00 41.71 B ATOM 2421 0 ILE 395 47.568 -3.143 8.476 1.00 43.58 B ATOM 2422 N ALA 396 45.376 -2.756 8.578 1.00 43.04 B ATOM 2423 CA ALA 396 45.054 -3.961 7.833 1.00 45.09 B ATOM 2424 CB ALA 396 43.574 -3.968 7.464 1.00 43.55 B ATOM 2425 C ALA 396 45.903 -4.019 6.573 1.00 46.33 B ATOM 2426 0 ALA 396 46.203 -5.099 6.062 1.00 47.54 B ATOM 2427 N ALA 397 46.276 -2.844 6.073 1.00 48.10 . B ATOM 2428 CA ALA 397 46.967 -2.743 4.797 1.00 49.04 B ATOM 2429 CB ALA 397 46.744 -1.374 4 .195 1.00 47.71 ' B ATOM 2430 C ALA 397 48.454 -3.004 4.968 1.00 50.53 B c c 0 N c c 0 c 0 zuuuuozuozuuuozuuuozuuuozuuuuzuzu 0 N c c c c c 0 N c c c 0 N c c 0 N c c c c c c 0 N c c c 0 N c c c 352 WO 2009/026558 PCT/US2008/074097 ATOM 2431 0 ALA 397 49.049 -3 ATOM 2432 N MET 398 49.045 -2 ATOM 2433 CA MET 398 50.423 -2 ATOM 2434 CB MET 398 50.750 -1 ATOM 2435 CG MET 398 50.318 -0 ATOM 2436 SD MET 398 51.552 0 ATOM 2437 CE MET 398 51.735 -0 ATOM 2438 C MET 398 50.607 -4 ATOM 2439 0 MET 398 51.606 -4 ATOM 2440 N MET 399 49.624 -4 ATOM 2441 CA MET 399 49.743 -6 ATOM 2442 CB MET 399 48.808 -6 ATOM 2443 CG MET 399 49.220 -5 ATOM 2444 SD MET 399 48.186 -5 ATOM 2445 CE MET 399 47.122 -7 ATOM 2446 C MET 399 49.471 -7 ATOM 2447 0 MET 399 50.184 -8 ATOM 2448 N LEU 400 48.444 -6 ATOM 2449 CA LEU 400 48.212 -7 ATOM 2450 CB LEU 400 46.845 -7 ATOM 2451 CG LEU 400 45.716 -8 ATOM 2452 CDl LEU 400 44 . 429 -7 ATOM 2453 CD2 LEU 400 46.061 -9 ATOM 2454 C LEU 400 49.304 -7 ATOM 2455 O LEU 400 49.422 -8 ATOM 2456 N SER 401 50.103 -6 ATOM 2457 CA SER 401 51.162 -5 ATOM 2458 CB SER 401 51.500 -4 ATOM 2459 OG SER 401 52.416 -4 ATOM 2460 C SER 401 52.398 -6 ATOM 2461 O SER 401 53.097 -7 ATOM 2 4 62 N ALA 402 52.659 -6 ATOM 2463 CA ALA 402 53.724 -7 ATOM 2464 CB ALA 402 53.906 -7 ATOM 2465 C ALA 402 53.383 -9 ATOM 2466 0 ALA 402 54.068 -9 ATOM 2467 N GLU 403 52.312 -9 ATOM 2468 CA GLU 403 51.893 -11 ATOM 2469 CB GLU 403 51.516 -11 ATOM 2470 CG GLU 403 52.532 -11 ATOM 2471 CD GLU 403 52.184 -10 ATOM 2472 OE1 GLU 403 51.312 -10 ATOM 2473 OE2 GLU 403 52.782 -9 ATOM 2474 C GLU 403 50.694 -11 ATOM 2475 O GLU 403 49.560 -11 ATOM 2476 N PRO 404 50.930 -11 ATOM 2477 CD PRO 404 52.238 -11 ATOM 2478 CA PRO 404 49.823 -11 ATOM 2479 CB PRO 404 50.514 -11 ATOM 2480 CG PRO 404 51.883 -10 ATOM 2481 C PRO 404 48.826 -12 ATOM 2482 O PRO 404 47.623 -12 ATOM 2483 N GLU 405 49.332 -13 ATOM 2484 CA GLU 405 48.497 -14 ATOM 2485 CB GLU 405 49.339 -15 ATOM 2486 CG GLU 405 49.728 -15 ATOM 2487 CD GLU 405 50.509 -17 ATOM 2488 OE1 GLU 405 51.337 -17 ATOM 2489 OE2 GLU 405 50.294 -18 ATOM 2490 C GLU 405 47.772 -14 ATOM 2491 O GLU 405 47.171 -15 ATOM 2492 N LEU 406 47.818 -13 ATOM 2493 CA LEU 406 47.071 -13 ATOM 2494 CB LEU 406 47.211 -12 ATOM 2495 CG LEU 406 48.424 -12 ATOM 2496 CDl LEU 406 48.719 -10 ATOM 2497 CD2 LEU 406 48.144 -13 ATOM 2498 C LEU 406 45.605 -14 ATOM 2499 O LEU 406 45.077 -13 ATOM 2500 N THR 407 44.948 -14 ATOM 2501 CA THR 407 43.540 -15 ATOM 2502 CB THR 407 43.229 -16 ATOM 2503 OG1 THR 407 43.044 -16 ATOM 2504 CG2 THR 407 44.382 -17 ATOM 2505 C THR 407 42.660 -14 ATOM 2506 O THR 407 43.125 -13 4 . 174 1.00 51.84 B O 6.000 1.00 51.67 B N 6.388 1.00 53.66 B C 7.687 1.00 54.03 B C 7.716 1.00 56.66 B c 7.036 1.00 60.87 B s 5.342 1.00 61.35 B c 6.601 1.00 55.46 B c 6.183 1.00 56.38 B 0 7.243 1.00 55.72 B N 7.642 1.00 56.05 B c 8.822 1.00 52.69 B c 10.083 1.00 49.75 B c 11.517 1.00 43.73 B s 10.807 1.00 41.37 B c 6.496 1.00 58.09 B c 6.328 1.00 60.78 B 0 5.705 1.00 60.18 B N 4.503 1.00 61.96 B c 3.905 1.00 60.96 B c 4.218 1.00 59.67 B c 3.591 1.00 59.61 B c 3.677 1.00 59.08 B c 3.483 1.00 65.48 B c 2.473 1.00 65.74 B 0 3.743 1.00 69.84 B N 2.811 1.00 75.12 B c 2.937 1.00 76.14 B c 1.931 1.00 82.39 B 0 3.112 1.00 77.81 B c 2.197 1.00 77.60 B 0 4.405 1.00 80.22 B N 4.858 1.00 81.56 B c 6.365 1.00 81.70 B c 4.492 1.00 83.56 B c 3.687 1.00 83.97 B 0 5.071 1.00 86.39 B N 4.781 1.00 90.62 B c 6.072 1.00 94.08 B c 7.195 1.00101.30 B c 8.179 1.00105.07 B c 9.047 1.00107.17 B 0 8.087 1.00107.51 B 0 3.849 1.00 8 9.62 B c 4.298 1.00 89.74 B 0 2.535 1.00 87.70 B N 1.863 1.00 82.55 B c 1.574 1.00 8 6.92 B c 0.221 1.00 82.11 B c 0.453 1.00 81.28 B c 1.817 1.00 8 6.62 B c 1.699 1.00 89.69 B 0 2.170 1.00 84.71 B N 2.216 1.00 82.30 B c 1.885 1.00 83.56 B c 0.415 1.00 84.66 B c 0.076 1.00 86.54 B c -0.862 1.00 86.91 B 0 0.742 1.00 88.12 B 0 3.549 1.00 80.19 B c 3.800 1.00 79.93 B 0 4.402 1.00 78.24 B N 5.648 1.00 76.72 B c 6.410 1.00 74.80 B c 7.327 1.00 74.00 B c 7.740 1.00 73.34 B c 8.52 9 1.00 74.12 B c 5.365 1.00 76.33 B " c 4.330 1.00 77.41 B 0 6.291 1.00 75.06 B N 6.126 1.00 73.55 B c 6.668 1.00 72.50 B c 8.088 1.00 70.12 . B 0 6.372 1.00 7 0.92 B c 6.866 1.00 73.16 ' B c 7.762 1.00 71.83 B 0 353 WO 2009/026558 PCT/US2008/074097
ATOM 2507 N LEU 408 41.390 -14.039 6.472 1.00 72.79 B ATOM 2508 CA LEU 408 40.370 -13.276 7.176 1.00 71.72 B ATOM 2509 CB LEU 408 38.987 -13.813 6.797 1.00 70.47 B ATOM 2510 CG LEU 408 37.747 -12.922 6.92 0 1.00 69.40 B ATOM 2511 CDl LEU 408 37.916 -11.902 8.053 1.00 67.99 B ATOM 2512 CD2 LEU 408 37.528 -12.232 5.584 1.00 69.52 B ATOM 2513 C LEU 408 40.589 -13.449 8.677 1.00 71.42 B ATOM 2514 O LEU 408 40.722 -12.474 9.419 1.00 71.69 B ATOM 2515 N ALA 409 40.640 -14.707 9.107 1.00 70.70 B ATOM 2516 CA ALA 409 40.632 -15.048 10.525 1.00 69.24 B ATOM 2517 CB ALA 409 40.137 -16.485 10.701 1.00 68.18 B ATOM 2518 C ALA 409 41.997 -14.867 11.192 1.00 68.50 B ATOM 2519 0 ALA 409 42.080 -14.711 12.409 1.00 67.64 B ATOM 2520 N GLU 410 43.060 -14.882 10.394 1.00 68.72 B ATOM 2521 CA GLU 410 44.407 -14.683 10.918 1.00 69.75 B ATOM 2522 CB GLU 410 45.442 -15.290 9.970 1.00 69.56 B ATOM 2523 CG GLU 410 45.349 -16.800 9.836 1.00 70.17 B ATOM 2524 CD GLU 410 46.369 -17.356 8.868 1.00 70.08 B ATOM 2525 OE1 GLU 410 46.232 -18.532 8.455 1.00 71.00 B ATOM 2526 OE2 GLU 410 47.309 -16.610 8.521 1.00 70.53 B ATOM 2527 C GLU 410 44.734 -13.209 11.132 1.00 70.53 B ATOM 2528 O GLU 410 45.324 -12.838 12.151 1.00 70.22 B ATOM 2529 N LEU 411 44.362 -12.371 10.168 1.00 70.72 B ATOM 2530 CA LEU 411 44.614 -10.941 10.292 1.00 70.59 B ATOM 2531 CB LEU 411 44.163 -10.203 9.028 1.00 69.74 B ATOM 2532 CG LEU 411 44.300 -8.676 8.969 1.00 67.81 B ATOM 2533 CDl LEU 411 44.390 -8.235 7.528 1.00 66.98 B ATOM 2534 CD2 LEU 411 43.113 -8.014 9.634 1.00 67.36 B ATOM 2535 C LEU 411 43.821 -10.460 11.484 1.00 71.74 B ATOM 2536 O LEU 411 44.301 -9.662 12.289 1.00 71.67 B ATOM 2537 N ARG 412 42.603 -10.970 11.597 1.00 73.60 B ATOM 2538 CA ARG 412 41.745 -10.648 12.719 1.00 76.27 B ATOM 2539 CB ARG 412 40.459 -11.455 12.617 1.00 73.69 B ATOM 2540 CG ARG 412 39.320 -10.901 13.422 1.00 70.65 B ATOM 2541 CD ARG 412 38.098 -11.772 13.268 1.00 67.93 B ATOM 2542 NE ARG 412 36.875 -10.988 13.159 1.00 66.79 B ATOM 2543 CZ ARG 412 36.239 -10.764 12.017 1.00 66.69 B ATOM 2544 NHl ARG 412 35.130 -10.042 12.007 1.00 65.72 B ATOM 2545 NH2 ARG 412 36.717 -11.264 10.885 1.00 68.01 B ATOM 2546 C ARG 412 42.488 -11.005 13.997 1.00 80.83 B ATOM 2547 O ARG 412 42.543 -10.216 14.930 1.00 80.65 B ATOM 2548 N GLN 413 43.077 -12.196 14.018 1.00 86.79 B ATOM 2549 CA GLN 413 43.835 -12.665 15.170 1.00 92.24 B ATOM 2550 CB GLN 413 44.276 -14.114 14.951 1.00 94.97 B ATOM 2551 CG GLN 413 44.915 -14.766 16.170 1.00 99.47 B ATOM 2552 CD GLN 413 44.028 -14.675 17.399 1.00102.34 B ATOM 2553 OE1 GLN 413 44.204 -13.792 18.245 1.00103.95 B ATOM 2554 NE2 GLN 413 43.062 -15.588 17.501 1.00104 .17 B ATOM 2555 C GLN 413 45.062 -11.792 15.410 1.00 94.56 B ATOM 2556 0 GLN 413 45.477 -11.580 16.550 1.00 95.17 B ATOM 2557 N ARG 414 45.638 -11.288 14.324 1.00 97.12 B ATOM 2558 CA ARG 414 46.857 -10.498 14.405 1.00 98.76 B ATOM 2559 CB ARG 414 47.512 -10.401 13.029 1.00101.11 B ATOM 2560 CG ARG 414 48.259 -11.653 12.624 1.00104.98 B ATOM 2561 CD ARG 414 49.105 -11.403 11.395 1.00109.69 B ATOM 2562 NE ARG 414 50.249 -12.307 11.305 1.00114.56 B ATOM 2563 CZ ARG 414 50.158 -13.631 11.227 1.00118.01 B ATOM 2564 NHl ARG 414 48.968 -14.220 11.233 1.00120.46 B ATOM 2565 NH2 ARG 414 51.258 -14.367 11.131 1.00120.17 B ATOM 2566 C ARG 414 46.611 -9.102 14.950 1.00 98.39 B ATOM 2567 O ARG 414 47.365 -8.619 15.794 1.00 98.42 B ATOM 2568 N LEU 415 45.556 -8.457 14.465 1.00 98.39 B ATOM 2569 CA LEU 415 45.194 -7.126 14.934 1.00 99.38 B ATOM 2570 CB LEU 415 43.926 -6.639 14.239 1.00 96.98 B ATOM 2571 CG LEU 415 44.046 -6.188 12.784 1.00 94.64 B ATOM 2572 CDl LEU 415 42.667 -5.991 .12.184 1.00 93.57 B ATOM 2573 CD2 LEU 415 44.838 -4.905 12.725 1.00 93.89 B ATOM 2574 C LEU 415 44.964 -7.142 16.430 1.00102.00 B ATOM 2575 O LEU 415 45.363 -6.224 17.130 1.00100.71 B ATOM 2576 N ILE 416 44.325 -8.200 16.916 1.00106.93 B ATOM 2577 CA ILE 416 43.995 -8.306 18.332 1.00111.24 B ATOM 2578 CB ILE 416 43.220 -9.593 18.642 1.00109.49 B ATOM 2579 CG2 ILE 416 42.848 -9.620 20.110 1.00107.39 . B ATOM 2580 CGI ILE 416 41.958 -9.668 17.789 1.00109.48 B ATOM 2581 CDl ILE 416 41.160 -10.926 18.002 1.00110.78 ' B ATOM 2582 C ILE 416 45.253 -8.319 19.179 1.00114.47 B
2 CJ 354
N
C c c c c c 0
N c c c 0
N c c c c 0 0 c 0
N c c c c c c 0
N c c c c
N c N 0
N
C
C c c 0
N c 0
N c c c c
N c
N
N
C 0
N
C c c c c c 0
N c c c c c c
ATOM 2583 0 ILE 416 45.367 -7.568 20.146 1.00117.39 B ATOM 2584 N HIS 417 46.195 -9.181 18.812 1.00116.77 B ATOM 2585 CA HIS 417 47.420 -9.315 19.578 1.00117.72 B ATOM 2586 CB HIS 417 48.350 -10.343 18.929 1.00124.49 B ATOM 2587 CG HIS 417 49.677 -10.471 19.611 1.00130.81 B ATOM 2588 CD2 HIS 417 50.035 -11.091 20.760 1.00133.74 B ATOM 2589 NDl HIS 417 50.829 -9.905 19.107 1.00133.21 B ATOM 2590 CEl HIS 417 51.839 -10.170 19.916 1.00135.24 B ATOM 2591 NE2 HIS 417 51.384 -10.888 20.928 1.00135.71 B ATOM 2592 C HIS 417 48.125 -7.976 19.669 1.00115.09 B ATOM 2593 0 HIS 417 48.408 -7.491 20.761 1.00113.36 B ATOM 2594 N PHE 418 48.394 -7.371 18.517 1.00112.88 B ATOM 2595 CA PHE 418 49.206 -6.162 18.469 1.00110.87 B ATOM 2596 CB PHE 418 49.750 -5.943 17.059 1.00115.25 B ATOM 2597 CG PHE 418 51.070 -6.611 16.814 1.00121.12 B ATOM 2598 CDl PHE 418 51.145 -7.792 16.098 1.00123.17 B ATOM 2599 CD2 PHE 418 52.238 -6.059 17.312 1.00123.35 B ATOM 2600 CEl PHE 418 52.359 -8.408 15.884 1.00125.37 B ATOM 2601 CE2 PHE 418 53.456 -6.672 17.101 1.00125.90 B ATOM 2602 CZ PHE 418 53.514 -7.852 16.383 1.00126.36 B ATOM 2603 C PHE 418 48.472 -4.913 18.927 1.00106.04 B ATOM 2604 O PHE 418 49.033 -3.820 18.896 1.00106.28 B ATOM 2605 N SER 419 47.224 -5.084 19.353 1.00 99.46 B ATOM 2606 CA SER 419 46.413 -3.987 19.875 1.00 92.29 B ATOM 2607 CB SER 419 44.937 -4.359 19.839 1.00 90.97 B ATOM 2608 OG SER 419 44.506 -4.607 18.522 1.00 89.32 B ATOM 2609 C SER 419 46.781 -3.652 21.311 1.00 88.83 B ATOM 2610 O SER 419 46.976 -4.547 22.124 1.00 89.15 B ATOM 2611 N ALA 420 46.858 -2.363 21.627 1.00 85.37 B ATOM 2612 CA ALA 420 47.016 -1.927 23.010 1.00 81.97 B ATOM 2613 CB ALA 420 47.044 -0.406 23.082 1.00 81.91 B ATOM 2614 C ALA 420 45.842 -2.469 23.816 1.00 79.89 B ATOM 2615 0 ALA 420 44.713 -2.475 23.330 1.00 79.29 B ATOM 2616 N LYS 421 46.100 -2.92 6 25.039 1.00 77.60 B ATOM 2617 CA LYS 421 45.101 -3.706 25.762 1.00 76.65 B ATOM 2618 CB LYS 421 45.629 -5.120 26.005 1.00 75.21 B ATOM 2619 CG LYS 421 46.034 -5.842 24.730 1.00 74.25 B ATOM 2620 CD LYS 421 45.404 -7.221 24.634 1.00 72.30 B ATOM 2 621 CE LYS 421 45.912 -7.973 23.414 1.00 71.65 B ATOM 2622 NZ LYS 421 47.403 -7.974 23.350 1.00 69.08 B ATOM 2 62 3 C LYS 421 44.606 -3.108 27.080 1.00 76.30 B ATOM 2 62 4 0 LYS 421 45.388 -2.590 27.874 1.00 75.81 B ATOM 2 62 5 N ASP 422 43.292 -3.193 27.291 1.00 76.07 B ATOM 2 62 6 CA ASP 422 42.654 -2.840 28.557 1.00 75.90 B ATOM 2627 CB ASP 422 43.025 -3.859 29.635 1.00 76.51 B ATOM 2628 CG ASP 422 42.547 -5.259 29.293 1.00 77.29 B ATOM 2629 OD1 ASP 422 41.496 -5.684 29.823 1.00 77.24 B ATOM 2630 OD2 ASP 422 43.218 -5.936 28.485 1.00 78.52 B ATOM 2631 C ASP 422 42.978 -1.434 29.032 1.00 75.72 B ATOM 2632 0 ASP 422 43.111 -1.185 30.231 1.00 75.77 B ATOM 2633 N VAL 423 43.094 -0.516 28.078 1.00 75.77 B ATOM 2634 CA VAL 423 43.330 0.893 28.373 1.00 75.46 B ATOM 2635 CB VAL 423 44.279 1.52 9 27.323 1.00 74.23 B ATOM 2636 CGI VAL 423 45.572 0.739 27.256 1.00 73.29 B ATOM 2637 CG2 VAL 423 43.616 1.555 25.953 1.00 72.59 B ATOM 2638 C VAL 423 42.008 1.666 28.385 1.00 75.67 B ATOM 2639 0 VAL 423 41.911 2.734 28.997 1.00 75.74 B ATOM 2640 N ILE 424 40.999 1.118 27.706 1.00 74.56 B ATOM 2641 CA ILE 424 39.674 1.733 27.641 1.00 74.42 B ATOM 2642 CB ILE 424 38.810 1.097 26.512 1.00 73.36 B ATOM 2643 CG2 ILE 424 37.506 1.865 26.345 1.00 74.09 B ATOM 2644 CGI ILE 424 39.558 1.125 25.183 1.00 71.55 B ATOM 2645 CDl ILE 424 38.737 0.586 24.031 1.00 68.53 B ATOM 2646 C ILE 424 38.934 1.52 6 28.969 1.00 74.42 B ATOM 2647 0 ILE 424 38.736 0.384 29.397 1.00 74.56 B ATOM 2648 N ASN 425 38.516 2.612 .29.618 1.00 73.22 B ATOM 2649 CA ASN 425 37.707 2.466 30.822 1.00 73.77 B ATOM 2650 CB ASN 425 37.545 3.803 31.550 1.00 72.83 B ATOM 2651 CG ASN 425 36.794 3.659 32.863 1.00 71.81 B ATOM 2652 OD1 ASN 425 35.814 2.92 5 32.949 1.00 72.71 B ATOM 2653 ND2 ASN 425 37.258 4.350 33.891 1.00 71.45 B ATOM 2654 C ASN 425 36.338 1.944 30.426 1.00 74.65 B ATOM 2655 0 ASN 425 35.618 2.603 29.686 1.00 74.07 . B ATOM 2656 N GLU 426 35.976 0.766 30.924 1.00 76.81 B ATOM 2657 CA GLU 426 34.741 0.111 30.501 1.00 79.15 B ATOM 2658 CB GLU 426 34.712 -1.337 30.986 1.00 80.99 B ο N C c c c N c N C 0 N C c c c c c c c c 0 N c c 0 c 0
2 CJ WO 2009/026558 PCT/US2008/074097 355 c c 0
N c c c c c
N c 0
N c c c 0 0 c 0
N c c c c c 0
N c c c c c c 0
N c c c 0
N c 0
N c c ATOM 2659 CG GLU 426 35.579 -2.282 30.184 1.00 83.84 ATOM 2660 CD GLU 426 35.147 -3.729 30.345 1.00 86.17 ATOM 2661 OE1 GLU 426 35.400 -4.529 29.418 1.00 87.57 ATOM 2662 OE2 GLU 426 34.551 -4.063 31.395 1.00 85.46 ATOM 2663 C GLU 426 33.480 0.824 30.984 1.00 79.50 ATOM 2664 0 GLU 426 32.386 0.569 30.474 1.00 80.47 ATOM 2665 N ALA 427 33.637 1.722 31.956 1.00 78.27 ATOM 2666 CA ALA 427 32.501 2.376 32.599 1.00 76.26 ATOM 2667 CB ALA 427 32.936 2.969 33.924 1.00 75.03 ATOM 2668 C ALA 427 31.835 3.4 52 31.740 1.00 75.60 ATOM 2669 0 ALA 427 30.987 4.205 32.224 1.00 75.77 ATOM 2670 N TRP 428 32.226 3.530 30.473 1.00 74.75 ATOM 2671 CA TRP 428 31.555 4.397 29.512 1.00 74.44 ATOM 2672 CB TRP 428 32.542 4.811 28.423 1.00 74.02 ATOM 2673 CG TRP 428 32.114 5.942 27.534 1.00 73.99 ATOM 2674 CD2 TRP 428 31.476 5.843 26.247 1.00 74.18 ATOM 2675 CE2 TRP 428 31.407 7.143 25.715 1.00 73.61 ATOM 2676 CE3 TRP 428 30.968 4.781 25.492 1.00 74.77 ATOM 2677 CDl TRP 428 32.379 7.258 27.723 1.00 73.84 ATOM 2678 NEl TRP 428 31.963 7.988 26.637 1.00 74.39 ATOM 2 67 9 CZ2 TRP 428 30.853 7.414 24.462 1.00 72 .79 ATOM 2680 CZ3 TRP 428 30.417 5.055 24.245 1.00 74.68 ATOM 2681 CH2 TRP 428 30.367 6.362 23.746 1.00 73.12 ATOM 2682 C TRP 428 30.424 3.579 28.905 1.00 74.60 ATOM 2683 O TRP 428 29.370 4 . 106 28.555 1.00 73.81 ATOM 2684 N PHE 429 30.656 2.276 28.799 1.00 75.15 ATOM 2685 CA PHE 429 29.715 1.370 28.146 1.00 76.08 ATOM 2686 CB PHE 429 30.447 0.117 27.654 1.00 75.20 ATOM 2687 CG PHE 429 31.632 0.409 26.773 1.00 73.39 ATOM 2688 CDl PHE 429 32.897 -0.041 27.119 1.00 72.50 ATOM 2689 CD2 PHE 429 31.478 1.127 25.594 1.00 72.64 ATOM 2690 CEl PHE 429 33.989 0.214 26.304 1.00 71.63 ATOM 2691 CE2 PHE 429 32.562 1.386 24.775 1.00 72.20 ATOM 2692 CZ PHE 429 33.822 0.928 25.131 1.00 71.45 ATOM 2693 C PHE 429 28.588 0.958 29.083 1.00 76.15 ATOM 2694 O PHE 429 28.820 0.627 30.242 1.00 76.42 ATOM 2695 N PRO 430 27.346 0.961 28.587 1.00 7 6.64 ATOM 2696 CD PRO 430 26.911 1.204 27.203 1.00 76.64 ATOM 2697 CA PRO 430 26.237 0.571 29.458 1.00 78.80 ATOM 2698 CB PRO 430 25.006 0.663 28.549 1.00 77.13 ATOM 2699 CG PRO 430 25.536 0.602 27.168 1.00 76.00 ATOM 2700 C PRO 430 26.445 -0.825 30.039 1.00 80.99 ATOM 2701 O PRO 430 26.865 -1.747 29.341 1.00 81.23 ATOM 2702 N GLU 431 26.140 -0.961 31.325 1.00 83.65 ATOM 2703 CA GLU 431 26.550 -2.107 32.130 1.00 85.46 ATOM 2704 CB GLU 431 25.639 -2.199 33.363 1.00 89.78 ATOM 2705 CG GLU 431 26.071 -3.227 34.405 1.00 95.94 ATOM 2706 CD GLU 431 25.317 -3.091 35.721 1.00 98.87 ATOM 2707 OE1 GLU 431 25.879 -3.512 36.758 1.00100.92 ATOM 2708 OE2 GLU 431 24.174 -2.570 35.717 1.00100.66 ATOM 2709 C GLU 431 26.569 -3.446 31.388 1.00 83.87 ATOM 2710 0 GLU 431 27.593 -4.133 31.337 1.00 83.49 ATOM 2711 N ASP 4 32 25.429 -3.799 30.808 1.00 81.63 ATOM 2712 CA ASP 4 32 25.220 -5.121 30.232 1.00 79.14 ATOM 2713 CB ASP 432 23.722 -5.335 29.977 1.00 79.86 ATOM 2714 CG ASP 4 32 22.998 -4.047 29.596 1.00 79.96 ATOM 2715 OD1 ASP 432 23.092 -3.046 30.346 1.00 79.78 ATOM 2716 OD2 ASP 432 22.329 -4.039 28.542 1.00 79.18 ATOM 2717 C ASP 432 26.009 -5.339 28.944 1.00 77.30 ATOM 2718 O ASP 432 26.070 -6.451 28.413 1.00 76.75 ATOM 2719 N GLN 433 26.612 -4.268 28.445 1.00 75.05 ATOM 2720 CA GLN 433 27.378 -4.327 27.213 1.00 72.42 ATOM 2721 CB GLN 433 27.122 -3.074 26.375 1.00 71.49 ATOM 2722 CG GLN 433 25.835 -3.110 25.591 1.00 70.56 ATOM 2723 CD GLN 433 25.896 -4.114 24.468 1.00 71.25 ATOM 2724 OE1 GLN 433 24.888 -4.442 .23.845 1.00 71.67 ATOM 2725 NE2 GLN 433 27.091 -4.615 24.204 1.00 72.06 ATOM 2726 C GLN 433 28.867 -4.461 27.484 1.00 71.41 ATOM 2727 0 GLN 433 29.608 -4.934 26.627 1.00 71.95 ATOM 2728 N ARG 434 29.296 -4.047 28.675 1.00 69.73 ATOM 2729 CA ARG 434 30.717 -3.900 28.985 1.00 68.37 ATOM 2730 CB ARG 434 30.900 -3.423 30.424 1.00 68.00 ATOM 2731 CG ARG 434 30.438 -2.003 30.678 1.00 68.67 ATOM 2732 CD ARG 434 31.044 -1.449 31.956 1.00 69.05 ATOM 2733 NE ARG 434 30.069 -0.678 32.713 1.00 70.49 ATOM 2734 CZ ARG 434 29.112 -1.228 33.449 1.00 72.47
2 CJ WO 2009/026558 PCT/US2008/074097
B C
B C B 0 B 0
B C
B , 0 B N
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C
B C
B C
B N
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C
B C B 0
B N
B C
B C
B C
B C B 0 B 0
B C B 0
B N
B C
B C
B C B 0 B 0
B C B 0
B N
B C
B C
B C
B C B 0
B N B " C B 0
B B
B C
B C
B C
B N
B C 356 WO 2009/026558 PCT/US2008/074097 ATOM 2735 NHl ARG 434 28.255 -0 ATOM 2736 NH2 ARG 434 29.018 -2 ATOM 2737 C ARG 434 31.510 -5 ATOM 2738 O ARG 434 32.589 -5 ATOM 2739 N VAL 435 30.981 -6 ATOM 2740 CA VAL 435 31.681 -7 ATOM 2741 CB VAL 435 30.884 -8 ATOM 2742 CGI VAL 435 30.754 -8 ATOM 2743 CG2 VAL 435 29.498 -8 ATOM 2744 C VAL 435 31.934 -7 ATOM 2745 O VAL 435 32.990 -8 ATOM 2746 N LEU 436 30.971 -7 ATOM 2747 CA LEU 436 31.051 -8 ATOM 2748 CB LEU 436 29.648 -7 ATOM 2749 CG LEU 436 28.556 -8 ATOM 2750 CDl LEU 436 27.225 -8 ATOM 2751 CD2 LEU 436 28.970 -10 ATOM 2752 C LEU 436 31.976 -7 ATOM 2753 O LEU 436 32.655 -7 ATOM 2754 N THR 437 31.988 -5 ATOM 2755 CA THR 437 32.728 -4 ATOM 2756 CB THR 437 32.403 -3 ATOM 2757 OG1 THR 437 31.009 -3 ATOM 2758 CG2 THR 437 33.216 -2 ATOM 2759 C THR 437 34 .229 -5 ATOM 2760 O THR 437 34.822 -4 ATOM 2761 N PRO 438 34.862 -5 ATOM 2762 CD PRO 438 34.210 -5 ATOM 2763 CA PRO 438 36.283 -5 ATOM 2764 CB PRO 438 36.515 -6 ATOM 2765 CG PRO 438 35.187 -6 ATOM 2766 C PRO 438 37.156 -4 ATOM 2767 O PRO 438 37.476 -3 ATOM 2768 N ASN 439 37.553 -4 ATOM 2769 CA ASN 439 38.460 -3 ATOM 2770 CB ASN 439 38.716 -3 ATOM 2771 CG ASN 439 39.413 -2 ATOM 2772 OD1 ASN 439 40.452 -2 ATOM 2773 ND2 ASN 439 38.846 -1 ATOM 2774 C ASN 439 39.769 -3 ATOM 2775 O ASN 439 40.655 -4 ATOM 2776 N LEU 440 39.877 -3 ATOM 2777 CA LEU 440 41.041 -3 ATOM 2778 CB LEU 440 40.833 -4 ATOM 2779 CG LEU 440 41.127 -5 ATOM 2780 CDl LEU 440 40.647 -6 ATOM 2781 CD2 LEU 440 42.614 -5 ATOM 2782 C LEU 440 41.263 -1 ATOM 2783 O LEU 440 40.359 -1 ATOM 2784 N VAL 441 42.461 -1 ATOM 2785 CA VAL 441 42.772 -0 ATOM 2786 CB VAL 441 43.250 1 ATOM 2787 CGI VAL 441 43.613 2 ATOM 2788 CG2 VAL 441 42.174 1 ATOM 2789 C VAL 441 43.857 -0 ATOM 2790 O VAL 441 45.021 -0 ATOM 2791 N ALA 442 43.472 -0 ATOM 2792 CA ALA 442 44.369 -0 ATOM 2793 CB ALA 442 43.740 -0 ATOM 2794 C ALA 442 45.743 -0 ATOM 2795 0 ALA 442 45.908 0 ATOM 2796 N ALA 443 46.730 -0 ATOM 2797 CA ALA 443 48.092 -0 ATOM 2798 CB ALA 443 48.802 -0 ATOM 2799 C ALA 443 48.838 -1 ATOM 2800 0 ALA 443 48.650 -2 ATOM 2801 N LEU 444 49.677 -0 ATOM 2802 CA LEU 444 50.523 -1 ATOM 2803 CB LEU 444 51.269 0 ATOM 2804 CG LEU 444 50.583 0 ATOM 2805 CDl LEU 444 51.176 1 ATOM 2806 CD2 LEU 444 50.739 -0 ATOM 2807 C LEU 444 51.523 -2 ATOM 2808 O LEU 444 51.990 -1 ATOM 2809 N PRO 445 51.854 -3 ATOM 2810 CD PRO 445 51.177 -3 34.113 1.00 73.59 B N 33.521 1.00 73.57 B N 28.795 1.00 68.33 B C 28.190 1.00 68.56 B O 29.319 1.00 67.14 B N 29.233 1.00 66.36 B C 29.945 1.00 66.62 B c 31.431 1.00 64.88 B c 29.307 1.00 64.17 B c 27.776 1.00 65.17 B c 27.442 1.00 66.15 B 0 26.910 1.00 63.04 B N 25.497 1.00 61.71 B c 24.871 1.00 62.24 B c 25.561 1.00 61.83 B c 24.823 1.00 60.35 B c 25.593 1.00 60.07 B c 24.675 1.00 59.12 B c 23.759 1.00 57.04 B 0 25.000 1.00 57.08 B N 24.207 1.00 56.21 B c 24.648 1.00 53.88 B c 24.442 1.00 55.23 B 0 23.858 1.00 50.77 B c 24.338 1.00 55.95 B c 25.374 1.00 56.67 B 0 23.274 1.00 54.46 B N 21.990 1.00 54.63 B c 23.244 1.00 53.85 B c 21.807 1.00 52.36 B c 21.329 1.00 52.88 B c 23.581 1.00 54.24 B c 22.721 1.00 55.50 B 0 24.835 1.00 54.28 B N 25.203 1.00 54.38 B c 26.700 1.00 53.17 B c 27.206 1.00 52.95 B c 26.674 1.00 54.56 B 0 28.233 1.00 52.08 B N 24.417 1.00 55.78 B c 24.814 1.00 57.73 B 0 23.295 1.00 5 6.06 B N 22.397 1.00 55.86 B c 21.379 1.00 55.14 B c 21.783 1.00 54.08 B c 20.684 1.00 51.94 B c 22.028 1.00 53.63 B c 21.627 1.00 56.41 B c 20.947 1.00 56.93 B 0 21.717 1.00 56.47 B N 20.944 1.00 56.91 B c 21.851 1.00 55.91 B c 21.009 1.00 55.40 B c 22.864 1.00 54.73 B c 19.916 1.00 58.09 B c 20.272 1.00 58.32 B 0 18.643 1.00 60.35 B N 17.576 1.00 62.99 B c 16.219 1.00 62.78 B c 17.630 1.00 65.68 B c 18.121 1.00 65.64 B 0 17.113 1.00 69.73 B N 17.028 1.00 74.87 B c 18.356 1.00 70.53 B c 15.923 1.00 79.99 B c 15.726 1.00 81.17 B 0 15.196 1.00 8 6.92 B N 14.185 1.00 94.56 B c 13.404 1.00 91.22 B c 12.150 1.00 88.84 B c 11.774 1.00 86.05 B c 11.017 1.00 85.93 B c 14.840 1.00100.27 . B c 15.955 1.00101.97 B 0 14.155 1.00102.71 B N 12.942 1.00102.47 B c 357 WO 2009/026558 PCT/US2008/074097 ATOM 2811 CA PRO 445 52.880 -4 ATOM 2812 CB PRO 445 52.808 -5 ATOM 2813 CG PRO 445 51.472 -5 ATOM 2814 C PRO 445 54.257 -3 ATOM 2815 O PRO 445 54.698 -2 ATOM 2816 N PRO 446 54.952 -3 ATOM 2817 CD PRO 446 54.384 -3 ATOM 2818 CA PRO 446 56.374 -3 ATOM 2819 CB PRO 446 56.702 -3 ATOM 2820 CG PRO 446 55.580 -3 ATOM 2821 C PRO 446 57.221 -4 ATOM 2822 O PRO 446 58.166 -3 ATOM 2823 N SER 447 56.864 -5 ATOM 2824 CA SER 447 57.519 -6 ATOM 2825 CB SER 447 58.228 -7 ATOM 2826 OG SER 447 57.298 -8 ATOM 2827 C SER 447 56.556 -7 ATOM 2828 O SER 447 55.822 -8 ATOM 2829 OXT SER 447 56.535 -7 TER 2830 SER 447 ATOM 2831 CB GLU 1 3.711 32 ATOM 2832 CG GLU 1 3.439 33 ATOM 2833 CD GLU 1 4.640 34 ATOM 2834 OE1 GLU 1 4.445 35 ATOM 2835 OE2 GLU 1 5.780 34 ATOM 2836 C GLU 1 4.715 30 ATOM 2837 0 GLU 1 4 .120 29 ATOM 2838 N GLU 1 5.502 32 ATOM 2839 CA GLU 1 4.317 31 ATOM 2840 N SER 2 5.722 29 ATOM 2841 CA SER 2 6.323 28 ATOM 2842 CB SER 2 7.056 28 ATOM 2843 OG SER 2 6.217 28 ATOM 2844 C SER 2 5.320 27 ATOM 2845 O SER 2 4.159 27 ATOM 2846 N VAL 3 5.771 26 ATOM 2847 CA VAL 3 4.917 25 ATOM 2848 CB VAL 3 5.242 24 ATOM 2849 CGI VAL 3 6.704 24 ATOM 2850 CG2 VAL 3 4.319 23 ATOM 2851 C VAL 3 5.069 24 ATOM 2852 O VAL 3 4.315 23 ATOM 2853 N LEU 4 6.051 24 ATOM 2854 CA LEU 4 6.090 23 ATOM 2855 CB LEU 4 7.521 23 ATOM 2856 CG LEU 4 8.079 22 ATOM 2857 CD1 LEU 4 9.349 21 ATOM 2858 CD2 LEU 4 7.052 20 ATOM 2859 C LEU 4 5.547 24 ATOM 2860 O LEU 4 6.084 25 ATOM 2861 N THR 5 4.490 24 ATOM 2 8 62 CA THR 5 3.856 24 ATOM 2863 CB THR 5 2.350 24 ATOM 2864 OG1 THR 5 1.842 23 ATOM 2865 CG2 THR 5 2.075 26 ATOM 2866 C THR 5 4 . 069 24 ATOM 2867 O THR 5 3.962 22 ATOM 2868 N GLN 6 4.378 24 ATOM 2869 CA GLN 6 4.589 24 ATOM 2870 CB GLN 6 6.057 24 ATOM 2871 CG GLN 6 7.018 25 ATOM 2872 CD GLN 6 8.361 25 ATOM 2873 OE1 GLN 6 8.433 24 ATOM 2874 NE2 GLN 6 9.430 25 ATOM 2875 C GLN 6 4.202 25 ATOM 2876 0 GLN 6 4.228 26 ATOM 2877 N PRO 7 3.861 25 ATOM 2878 CD PRO 7 4.220 24 ATOM 2879 CA PRO 7 3.326 26 ATOM 2880 CB PRO 7 3.116 25 ATOM 2881 CG PRO 7 4 . 129 24 ATOM 2882 C PRO 7 4.305 27 ATOM 2883 O PRO 7 5.506 27 ATOM 2884 N PRO 8 3.791 28 ATOM 2885 CD PRO 8 2.356 28 ATOM 2886 CA PRO 8 4.604 29 14.611 1.00108.96 B c 13.598 1.00103.83 B c 12.969 1.00101.93 B c 14.618 1.00113.37 B c 13.611 1.00112.80 B 0 15.760 1.00116.22 B .N 17.095 1.00119.98 B C 15.797 1.00122.39 B C 17.291 1.00122.57 B C 17.975 1.00120.33 B C 15.017 1.00125.56 B c 14.326 1.00129.91 B 0 15.111 1.00131.30 B N 14.335 1.00136.24 B c 15.270 1.00141.23 B c 15.952 1.00144.06 B 0 13.423 1.00141.04 B c 13.934 1.00131.68 B 0 12.201 1.00113.76 B 0 B 16.970 1.00138.52 L31H c 16.919 1.00141.85 L31H c 16.438 1.00143.45 L31H c 15.860 1.00143.83 L31H 0 16.635 1.00143.91 L31H 0 18.137 1.00130.94 L31H c 17.346 1.00131.43 L31H 0 18.664 1.00135.71 L31H N 18.288 1.00134.83 L31H c 18.902 1.00125.13 L31H N 18.781 1.00119.15 L31H c 20.080 1.00120.98 L31H c 21.212 1.00124.69 L31H 0 18.440 1.00113.88 L31H c 18.849 1.00112.42 L31H 0 17.688 1.00107.83 L31H N 17.342 1.00101.42 L31H c 15.924 1.00101.94 L31H c 15.839 1.00102.39 L31H c 15.579 1.00102.00 L31H c 18.375 1.00 95.09 L31H c 18.386 1.00 95.30 L31H 0 19.252 1.00 87.11 L31H N 20.483 1.00 80.33 L31H c 20.799 1.00 78.74 L31H c 19.989 1.00 75.03 L31H c 20.651 1.00 73.88 L31H c 19.908 1.00 73.52 L31H c 21.646 1.00 76.28 L31H c 21.962 1.00 74.35 L31H 0 22.288 1.00 72.42 L31H N 23.388 1.00 67.66 L31H c 23.143 1.00 65.52 L31H c 22.591 1.00 64.87 L31H 0 22.184 1.00 64.39 L31H c 24.761 1.00 65.49 L31H c 24.936 1.00 65.15 L31H 0 25.730 1.00 64.29 L31H N 27.114 1.00 63.73 L31H c 27.326 1.00 61.83 L31H c 27.379 1.00 59.76 L31H c 26.745 1.00 60.41 L31H c 25.554 1.00 61.76 L31H 0 27.540 1.00 58.87 L31H N 28.074 1.00 64.47 L31H c 27.702 1.00 64.01 L31H 0 29.330 1.00 66.46 L31H N 30.038 1.00 67.84 L31H c 30.254 1.00 65.35 L31H c 31.547 1.00 65.91 L31H c 31.494 1.00 67.09 L31H c 30.442 1.00 64.17 L31H c 30.222 1.00 65.08 . L31H 0 30.834 1.00 63.81 L31H N 30.785 1.00 61.18 ' L31H c 31.085 1.00 63.42 L31H c 358 WO 2009/026558 PCT/US2008/074097 ATOM 2887 CB PRO 8 3.577 30 ATOM 2888 CG PRO 8 2.367 30 ATOM 2889 C PRO 8 5.369 29 ATOM 2890 O PRO 8 6.443 30 ATOM 2891 N SER 9 4.798 29 ATOM 2 8 92 CA SER 9 5.182 29 ATOM 2893 CB SER 9 4.466 30 ATOM 2894 OG SER 9 4 . 887 30 ATOM 2895 C SER 9 4.866 27 ATOM 2896 O SER 9 3.784 27 ATOM 2897 N VAL 10 5.837 27 ATOM 2898 CA VAL 10 5.607 26 ATOM 2899 CB VAL 10 6.233 25 ATOM 2900 CGI VAL 10 5.360 24 ATOM 2901 CG2 VAL 10 7.633 25 ATOM 2902 C VAL 10 6.224 26 ATOM 2903 O VAL 10 6.939 27 ATOM 2904 N SER 11 5.917 26 ATOM 2905 CA SER 11 6.542 26 ATOM 2906 CB SER 11 6.227 27 ATOM 2907 OG SER 11 4.873 28 ATOM 2908 C SER 11 6.107 25 ATOM 2909 O SER 11 4.965 24 ATOM 2910 N GLY 12 7.055 25 ATOM 2911 CA GLY 12 6.799 24 ATOM 2912 C GLY 12 7.831 24 ATOM 2913 0 GLY 12 8.833 25 ATOM 2914 N ALA 13 7.608 24 ATOM 2915 CA ALA 13 8.553 24 ATOM 2916 CB ALA 13 7.914 24 ATOM 2917 C ALA 13 9.824 23 ATOM 2918 O ALA 13 9.863 22 ATOM 2919 N PRO 14 10.891 24 ATOM 2920 CD PRO 14 11.122 25 ATOM 2921 CA PRO 14 12.071 23 ATOM 2922 CB PRO 14 13.043 23 ATOM 2923 CG PRO 14 12.608 25 ATOM 2924 C PRO 14 11.699 21 ATOM 2925 O PRO 14 10.950 21 ATOM 2926 N GLY 15 12.211 20 ATOM 2927 CA GLY 15 11.854 19 ATOM 2928 C GLY 15 10.772 18 ATOM 2929 0 GLY 15 10.696 17 ATOM 2930 N GLN 16 9.936 19 ATOM 2931 CA GLN 16 8.802 19 ATOM 2932 CB GLN 16 7.661 20 ATOM 2933 CG GLN 16 6.908 20 ATOM 2934 CD GLN 16 5.727 21 ATOM 2935 OE1 GLN 16 4.583 20 ATOM 2936 NE2 GLN 16 5.994 22 ATOM 2937 C GLN 16 9.123 18 ATOM 2938 0 GLN 16 10.101 19 ATOM 2939 N ARG 17 8.278 17 ATOM 2940 CA ARG 17 8.411 17 ATOM 2941 CB ARG 17 8.093 16 ATOM 2942 CG ARG 17 8.223 15 ATOM 2943 CD ARG 17 7.961 14 ATOM 2944 NE ARG 17 7.644 13 ATOM 2945 CZ ARG 17 6.444 13 ATOM 2946 NHl ARG 17 5.440 14 ATOM 2947 NH2 ARG 17 6.239 13 ATOM 2948 C ARG 17 7.481 18 ATOM 2949 O ARG 17 6.403 18 ATOM 2950 N VAL 18 7.930 18 ATOM 2951 CA VAL 18 7.210 19 ATOM 2952 CB VAL 18 7.816 20 ATOM 2953 CGI VAL 18 7.832 21 ATOM 2954 CG2 VAL 18 9.222 20 ATOM 2955 C VAL 18 7.320 18 ATOM 2956 O VAL 18 8 . 181 17 ATOM 2957 N THR 19 6.451 19 ATOM 2958 CA THR 19 6.657 18 ATOM 2959 CB THR 19 5.694 17 ATOM 2960 OG1 THR 19 4.376 18 ATOM 2961 CG2 THR 19 5.687 16 ATOM 2962 C THR 19 6.4 65 20 31.075 1.00 61.24 L31H c 30.395 1.00 60.71 L31H c 32.411 1.00 63.36 L31H c 32.568 1.00 63.66 L31H 0 33.365 1.00 63.25 L31H N 34.757 1.00 63.19 L31H c 35.350 1.00 60.99 L31H c 36.678 1.00 57.73 L31H 0 35.578 1.00 64.48 L31H c 35.478 1.00 65.45 L31H 0 36.382 1.00 63.89 L31H N 37.362 1.00 63.42 L31H c 36.910 1.00 63.39 L31H c 35.836 1.00 62.57 L31H c 36.349 1.00 63.77 L31H c 38.670 1.00 63.10 L31H c 38.708 1.00 62.36 L31H 0 39.741 1.00 63.31 L31H N 41.035 1.00 64.07 L31H c 41.545 1.00 65.21 L31H c 41.310 1.00 68.61 L31H 0 42.059 1.00 63.28 L31H c 42.068 1.00 63.10 L31H 0 42.903 1.00 62.91 L31H N 43.992 1.00 62.96 L31H c 45.040 1.00 62.06 L31H c 44.706 1.00 62.73 L31H 0 46.295 1.00 59.54 L31H N 47.341 1.00 57.29 L31H c 48.692 1.00 54.68 L31H c 47.217 1.00 57.41 L31H c 46.462 1.00 57.04 L31H 0 47.938 1.00 56.71 L31H N 48.702 1.00 56.70 L31H c 47.937 1.00 57.23 L31H c 48.860 1.00 57.17 L31H c 48.806 1.00 55.90 L31H c 48.464 1.00 58.32 L31H c 49.432 1.00 58.21 L31H 0 47.817 1.00 60.26 L31H N 48.195 1.00 62.96 L31H c 47.332 1.00 65.28 L31H c 47.221 1.00 64.05 L31H 0 46.710 1.00 68.62 L31H N 45.926 1.00 71.60 L31H c 45.957 1.00 75.87 L31H c 47.252 1.00 82.09 L31H c 47.177 1.00 87.55 L31H c 46.977 1.00 90.03 L31H 0 47.326 1.00 89.14 L31H N 44.471 1.00 70.08 L31H c 43.902 1.00 69.52 L31H 0 43.876 1.00 68.13 L31H N 42.471 1.00 66.35 L31H c 42.248 1.00 65.46 L31H c 40.804 1.00 65.51 L31H c 40.688 1.00 66.05 L31H c 39.326 1.00 68.32 L31H N 38.764 1.00 71.52 L31H c 39.446 1.00 73.00 L31H N 37.526 1.00 72.19 L31H N 41.620 1.00 65.81 L31H C 42.068 1.00 64.65 L31H 0 40.392 1.00 64.40 L31H N 39.411 1.00 63.29 L31H C 39.293 1.00 65.09 L31H c 40.648 1.00 65.44 L31H c 38.727 1.00 66.78 L31B c 38.044 1.00 62.02 L31H c 37.838 1.00 60.97 L31H 0 37.112 1.00 61.73 L31H N 35.712 1.00 61.82 L31H c 35.261 1.00 61.35 . L31H c 35.116 1.00 60.99 L31H 0 36.264 1.00 61.60 ' L31H c 34.781 1.00 63.20 L31H c 359 WO 2009/026558 PCT/US2008/074097 ATOM 2963 0 THR 19 5.754 21 ATOM 2964 N ILE 20 7.113 20 ATOM 2965 CA ILE 20 6.843 20 ATOM 2966 CB ILE 20 8.089 21 ATOM 2967 CG2 ILE 20 7.815 22 ATOM 2968 CGI ILE 20 8.487 22 ATOM 2969 CD1 ILE 20 9.698 23 ATOM 2970 C ILE 20 6.432 20 ATOM 2971 0 ILE 20 6.787 18 ATOM 2972 N SER 21 5.682 20 ATOM 2973 CA SER 21 4.990 19 ATOM 2974 CB SER 21 3.536 19 ATOM 2975 OG SER 21 3.435 19 ATOM 2976 C SER 21 5.058 20 ATOM 2977 O SER 21 4.306 21 ATOM 2978 N CYS 22 5.945 19 ATOM 2979 CA CYS 22 6.069 20 ATOM 2980 C CYS 22 5.038 19 ATOM 2981 0 CYS 22 5.077 18 ATOM 2982 CB CYS 22 7.483 19 ATOM 2983 SG CYS 22 8.208 20 ATOM 2984 N THR 23 4 . 117 20 ATOM 2985 CA THR 23 3.184 19 ATOM 2986 CB THR 23 1.713 19 ATOM 2987 OG1 THR 23 1.553 21 ATOM 2988 CG2 THR 23 1.337 19 ATOM 2989 C THR 23 3.492 19 ATOM 2990 O THR 23 3.929 20 ATOM 2991 N GLY 24 3.269 18 ATOM 2992 CA GLY 24 3.772 19 ATOM 2993 C GLY 24 2.763 18 ATOM 2994 0 GLY 24 1.659 19 ATOM 2995 N SER 25 3.157 18 ATOM 2996 CA SER 25 2.299 17 ATOM 2997 CB SER 25 1.914 18 ATOM 2998 OG SER 25 2.996 19 ATOM 2999 C SER 25 3.025 16 ATOM 3000 O SER 25 4.250 16 ATOM 3001 N SER 26 2.274 16 ATOM 3002 CA SER 26 2.812 14 ATOM 3003 CB SER 26 1.695 14 ATOM 3004 OG SER 26 1.213 15 ATOM 3005 C SER 26 3.939 15 ATOM 3006 O SER 26 4.438 14 ATOM 3007 N SER 27 4.333 16 ATOM 3008 CA SER 27 5.432 17 ATOM 3009 CB SER 27 5.100 18 ATOM 3010 OG SER 27 5.675 19 ATOM 3011 C SER 27 6.732 17 ATOM 3012 O SER 27 7.776 17 ATOM 3013 N ASN 28 6.664 16 ATOM 3014 CA ASN 28 7.861 16 ATOM 3015 CB ASN 28 8.044 18 ATOM 3016 CG ASN 28 6.746 18 ATOM 3017 OD1 ASN 28 6.023 19 ATOM 3018 ND2 ASN 28 6.444 18 ATOM 3019 C ASN 28 7.858 15 ATOM 3020 0 ASN 28 8.286 14 ATOM 3021 N ILE 29 7.377 16 ATOM 3022 CA ILE 29 7.398 15 ATOM 3023 CB ILE 29 6.712 15 ATOM 3024 CG2 ILE 29 6.839 14 ATOM 3025 CGI ILE 29 7.353 17 ATOM 3026 CD1 ILE 29 6.811 17 ATOM 3027 C ILE 29 6.686 13 ATOM 3028 0 ILE 29 7.096 12 ATOM 3029 N GLY 30 5.617 14 ATOM 3030 CA GLY 30 4.897 12 ATOM 3031 C GLY 30 5.367 12 ATOM 3032 0 GLY 30 4.609 11 ATOM 3033 N ALA 31 6.623 12 ATOM 3034 CA ALA 31 7.179 12 ATOM 3035 CB ALA 31 7.541 13 ATOM 3036 C ALA 31 8.405 11 ATOM 3037 0 ALA 31 9.124 11 ATOM 3038 N GLY 32 8.634 11
35.124 1.00 64.11 L31H 0 33.613 1.00 62.60 L31H N 32.512 1.00 62.83 L31H C 32.198 1.00 63.61 L31H c 31.032 1.00 65.17 L31H c 33.429 1.00 64.22 L31H c 33.213 1.00 64.62 L31H c 31.275 1.00 63.78 L31H c 31.162 1.00 62.92 L31H 0 30.354 1.00 64.09 L31H N 29.336 1.00 64.86 L31H c 29.754 1.00 63.74 L31H c 31.163 1.00 64.14 L31H 0 27.887 1.00 65.67 L31H c 27.489 1.00 68.38 L31H 0 27.099 1.00 64.14 L31H N 25.671 1.00 63.02 L31H c 24.866 1.00 63.37 L31H c 24.848 1.00 62.28 L31H 0 25.210 1.00 61.52 L31H c 23.808 1.00 61.05 L31H s 24.202 1.00 64.37 L31H N 23.290 1.00 64.83 L31H c 23.634 1.00 65.15 L31H c 23.655 1.00 65.49 L31H 0 25.006 1.00 65.92 L31H c 21.852 1.00 64.35 L31H c 21.596 1.00 64.00 L31H 0 20.917 1.00 62.67 L31H N 19.572 1.00 61.57 L31H c 18.472 1.00 61.13 L31H c 18.532 1.00 62.34 L31H 0 17.461 1.00 61.63 L31H N 16.319 1.00 62.41 L31H c 15.557 1.00 62.65 L31H c 14.770 1.00 64.84 L31H 0 15.362 1.00 62.86 L31H c 15.416 1.00 63.34 L31H 0 14.474 1.00 62.26 L31H N 13.695 1.00 62.09 L31H c 12.899 1.00 62.24 L31H c 11.880 1.00 60.48 L31H 0 12.735 1.00 62.28 L31H c 12.006 1.00 61.32 L31H 0 12.717 1.00 62.13 L31H N 11.854 1.00 61.96 L31H c 11.141 1.00 61.55 L31H c 11.804 1.00 57.20 L31H 0 12.642 1.00 61.99 L31H c 12.072 1.00 62.44 L31H 0 13.950 1.00 60.60 L31H N 14.785 1.00 59.48 L31H c 15.486 1.00 59.78 L31H c 15.983 1.00 58.38 L31H c 15.235 1.00 58.36 L31H 0 17.250 1.00 58.43 L31H N 15.822 1.00 59.65 L31H c 15.548 1.00 57.88 L31H 0 17.019 1.00 61.65 L31H N 18.123 1.00 64.05 L31H c 19.384 1.00 63.61 L31H c 20.530 1.00 65.10 L31H c 19.781 1.00 63.17 L31H c 21.061 1.00 61.54 L31H c 17.730 1.00 65.35 L31H c 18.120 1.00 65.26 L31H 0 16.953 1.00 66.80 L31H N 16.472 1.00 69.29 L31H c 15.093 1.00 70.79 L31H c 14.308 1.00 73.79 L31H 0 14.783 1.00 70.57 L31H N 13.496 1.00 68.69 L31H c 12.705 1.00 69.46 . L31H c 13.689 1.00 67.46 L31H c 12.737 1.00 66.80 L31H 0 14.930 1.00 65.06 L31H N 360 WO 2009/026558 PCT/US2008/074097 ATOM 3039 CA GLY 32 9.744 10 ATOM 3040 C GLY 32 10.998 10 ATOM 3041 O GLY 32 12.018 10 ATOM 3042 N TYR 33 10.923 12 ATOM 3043 CA TYR 33 12.055 13 ATOM 3044 CB TYR 33 11.947 14 ATOM 3045 CG TYR 33 11.990 14 ATOM 3046 CD1 TYR 33 13.156 13 ATOM 3047 CE1 TYR 33 13.196 13 ATOM 3048 CD2 TYR 33 10.857 14 ATOM 3049 CE2 TYR 33 10.886 14 ATOM 3050 CZ TYR 33 12.063 13 ATOM 3051 OH TYR 33 12.120 13 ATOM 3052 C TYR 33 12.064 13 ATOM 3053 O TYR 33 11.014 13 ATOM 3054 N ASP 34 13.251 13 ATOM 3055 CA ASP 34 13.417 13 ATOM 3056 CB ASP 34 14.791 12 ATOM 3057 CG ASP 34 14.910 11 ATOM 3058 OD1 ASP 34 15.934 10 ATOM 3059 OD2 ASP 34 13.989 10 ATOM 3060 C ASP 34 13.269 14 ATOM 3061 0 ASP 34 13.605 15 ATOM 3062 N VAL 35 12.798 14 ATOM 3063 CA VAL 35 12.738 16 ATOM 3064 CB VAL 35 11.457 16 ATOM 3065 CGI VAL 35 11.532 17 ATOM 3066 CG2 VAL 35 10.256 16 ATOM 3067 C VAL 35 13.908 16 ATOM 3068 0 VAL 35 14.232 15 ATOM 3069 N HIS 36 14.534 17 ATOM 3070 CA HIS 36 15.642 17 ATOM 3071 CB HIS 36 16.868 18 ATOM 3072 CG HIS 36 17. 111 17 ATOM 3073 CD2 HIS 36 17.089 17 ATOM 3074 ND1 HIS 36 17.489 15 ATOM 3075 CE1 HIS 36 17.689 15 ATOM 3076 NE2 HIS 36 17.454 16 ATOM 3077 C HIS 36 15.167 18 ATOM 3078 0 HIS 36 14.271 19 ATOM 3079 N TRP 37 15.753 19 ATOM 3080 CA TRP 37 15.326 20 ATOM 3081 CB TRP 37 14.601 19 ATOM 3082 CG TRP 37 13.257 18 ATOM 3083 CD2 TRP 37 11.982 19 ATOM 3084 CE2 TRP 37 11.002 18 ATOM 3085 CE3 TRP 37 11.571 20 ATOM 3086 CD1 TRP 37 13.006 17 ATOM 3087 NE1 TRP 37 11.651 17 ATOM 3088 CZ2 TRP 37 9.640 18 ATOM 3089 CZ3 TRP 37 10.220 21 ATOM 3090 CH2 TRP 37 9.269 20 ATOM 3091 C TRP 37 16.485 21 ATOM 3092 0 TRP 37 17.541 20 ATOM 3093 N TYR 38 16.285 22 ATOM 3094 CA TYR 38 17.362 23 ATOM 3095 CB TYR 38 17.771 24' ATOM 3096 CG TYR 38 18.088 23 ATOM 3097 CD1 TYR 38 17.073 23 ATOM 3098 CE1 TYR 38 17.364 22 ATOM 3099 CD2 TYR 38 19.409 23 ATOM 3100 CE2 TYR 38 19.713 22 ATOM 3101 CZ TYR 38 18.688 22 ATOM 3102 OH TYR 38 19.009 21 ATOM 3103 C TYR 38 17.007 24 ATOM 3104 0 TYR 38 15.897 24 ATOM 3105 N GLN 39 17.974 24 ATOM 3106 CA GLN 39 17.837 25 ATOM 3107 CB GLN 39 18.437 24 ATOM 3108 CG GLN 39 18.538 25 ATOM 3109 CD GLN 39 19.329 24 ATOM 3110 OE1 GLN 39 20.550 24 ATOM 3111 NE2 GLN 39 18.635 23 ATOM 3112 C GLN 39 18.567 26 ATOM 3113 0 GLN 39 19.650 26 ATOM 3114 N GLN 40 17.965 27
15.212 1.00 61.49 L31H c 15.632 1.00 60.15 L31H c 15.972 1.00 58.78 L31H 0 15.608 1.00 57.00 L31H N 15.974 1.00 52.69 L31H c 15.255 1.00 50.83 L31H c 13.741 1.00 49.75 L31H c 13.099 1.00 49.31 L31H c 11.729 1.00 48.18 L31H c 12.959 1.00 47.71 L31H c 11.583 1.00 47.03 L31H c 10.979 1.00 48.69 L31H c 9.62 9 1.00 50.47 L31H 0 17.487 1.00 50.76 L31H c 18 . 111 1.00 52.52 L31H 0 18.074 1.00 48.14 L31H N 19.531 1.00 45.26 L31H c 19.920 1.00 45.18 L31H c 19.734 1.00 44.74 L31H c 20.197 1.00 43.60 L31H 0 19.133 1.00 45.00 L31H 0 20.165 1.00 45.11 L31H c 19.564 1.00 44 . 68 L31H 0 21.407 1.00 44 . 99 L31H N 22.178 1.00 4 3.90 L31H c 22.997 1.00 44 .15 L31H c 23.965 1.00 43.72 L31H c 22.050 1.00 44 .74 L31H c 23.128 1.00 43.44 L31H c 23.888 1.00 42.76 L31H 0 23.075 1.00 43.03 L31H N 23.956 1.00 42.46 L31H c 23.124 1.00 42.43 L31H c 21.912 1.00 43.91 L31H c 20.587 1.00 43.23 L31H c 21.995 1.00 43.31 L31H N 20.778 1.00 41.56 L31H c 19.906 1.00 41.42 L31H N 24 .796 1.00 42.73 L31H C 24.363 1.00 44 .22 L31H 0 25.981 1.00 43.29 L31H N 26.916 1.00 43.33 L31H C 28.124 1.00 45.93 L31H c 27.843 1.00 49.34 L31H c 28.015 1.00 50.13 L31H c 27.743 1.00 51.37 L31H c 28.378 1.00 52.24 L31H c 27.471 1.00 51.27 L31H c 27.412 1.00 51.06 L31H N 27.826 1.00 52.35 L31H c 28.457 1.00 52.72 L31H c 28.182 1.00 52.64 L31H c 27.457 1.00 43.28 L31H c 27.809 1.00 42.97 L31H 0 27.560 1.00 43.01 L31H N 28.014 1.00 43.05 L31H c 26.901 1.00 38.88 L31H c 25.624 1.00 33.77 L31H c 24 .743 1.00 28.65 L31H c 23.583 1.00 25.10 L31H c 25.305 1.00 32.66 L31H c 24.144 1.00 29.28 L31H c 23.289 1.00 27.75 L31H c 22.127 1.00 26.39 L31H 0 29.234 1.00 46.95 L31H c 29.357 1.00 48.67 L31H 0 30.127 1.00 49.84 L31H N 31.281 1.00 52.09 L31H c 32.506 1.00 52.21 L31H c 33.725 1.00 54.03 L31H c 34.840 1.00 55.27 L31H c 34.907 1.00 56.25 L31H 0 35.722 1.00 55.16 . L31H N 30.999 1.00 54.46 L31H c 30.401 1.00 52.58 L31H 0 31.415 1.00 57.66 L31H N 361 WO 2009/026558 PCT/US2008/074097 ATOM 3115 CA GLN 40 18.592 28 ATOM 3116 CB GLN 40 17.964 29 ATOM 3117 CG GLN 40 18.774 30 ATOM 3118 CD GLN 40 18.186 31 ATOM 3119 OE1 GLN 40 16.964 31 ATOM 3120 NE2 GLN 40 19.066 32 ATOM 3121 C GLN 40 18.451 29 ATOM 3122 0 GLN 40 17.384 30 ATOM 3123 N LEU 41 19.533 29 ATOM 3124 CA LEU 41 19.607 30 ATOM 3125 CB LEU 41 20.938 30 ATOM 3126 CG LEU 41 21.403 28 ATOM 3127 CDl LEU 41 22.063 28 ATOM 3128 CD2 LEU 41 22.382 28 ATOM 3129 C LEU 41 19.507 31 ATOM 3130 O LEU 41 20.261 32 ATOM 3131 N PRO 42 18.562 32 ATOM 3132 CD PRO 42 17.570 32 ATOM 3133 CA PRO 42 18.400 34 ATOM 3134 CB PRO 42 17.306 34 ATOM 3135 CG PRO 42 16.529 33 ATOM 3136 C PRO 42 19.718 34 ATOM 3137 O PRO 42 20.413 34 ATOM 3138 N GLY 43 20.066 35 ATOM 3139 CA GLY 43 21.333 36 ATOM 3140 C GLY 43 22.437 35 ATOM 3141 0 GLY 43 23.581 35 ATOM 3142 N THR 44 22.106 34 ATOM 3143 CA THR 44 23.093 33 ATOM 3144 CB THR 44 23.760 32 ATOM 3145 OG1 THR 44 24.190 33 ATOM 3146 CG2 THR 44 24.981 31 ATOM 3147 C THR 44 22.492 32 ATOM 3148 O THR 44 21.270 32 ATOM 3149 N ALA 45 23.375 32 ATOM 3150 CA ALA 45 22.990 31 ATOM 3151 CB ALA 45 24.237 30 ATOM 3152 C ALA 45 22.222 29 ATOM 3153 0 ALA 45 22.384 29 ATOM 3154 N PRO 46 21.366 29 ATOM 3155 CD PRO 46 20.704 29 ATOM 3156 CA PRO 46 20.794 28 ATOM 3157 CB PRO 46 19.846 27 ATOM 3158 CG PRO 46 19.452 29 ATOM 3159 C PRO 46 21.872 26 ATOM 3160 0 PRO 46 22.848 26 ATOM 3161 N LYS 47 21.696 26 ATOM 3162 CA LYS 47 22.559 24 ATOM 3163 CB LYS 47 23.201 24 ATOM 3164 CG LYS 47 23.152 23 ATOM 3165 CD LYS 47 23.908 23 ATOM 3166 CE LYS 47 23.940 22 ATOM 3167 NZ LYS 47 22.786 21 ATOM 3168 C LYS 47 21.695 23 ATOM 3169 0 LYS 47 20.528 23 ATOM 3170 N LEU 48 22.256 22 ATOM 3171 CA LEU 48 21.549 21 ATOM 3172 CB LEU 48 22.369 20 ATOM 3173 CG LEU 48 21.898 19 ATOM 3174 CDl LEU 48 20.513 19 ATOM 3175 CD2 LEU 48 22.951 18 ATOM 3176 C LEU 48 21.291 20 ATOM 3177 0 LEU 48 22.205 20 ATOM 3178 N LEU 49 20.046 20 ATOM 3179 CA LEU 49 19.604 19 ATOM 3180 CB LEU 49 18.407 20 ATOM 3181 CG LEU 49 17.894 19 ATOM 3182 CDl LEU 49 18.888 20 ATOM 3183 CD2 LEU 49 16.481 20 ATOM 3184 C LEU 49 19.197 18 ATOM 3185 0 LEU 49 19.422 17 ATOM 3186 N ILE 50 18.567 17 ATOM 3187 CA ILE 50 18.181 16 ATOM 3188 CB ILE 50 16.872 16 ATOM 3189 CG2 ILE 50 16.229 14 ATOM 3190 CGI ILE 50 17.156 15 31.254 1.00 61.56 L31H c 30.092 1.00 59.03 L31H c 29.713 1.00 56.95 L31H c 28.563 1.00 56.21 L31H c 28.405 1.00 55.30 L31H 0 27.756 1.00 53.83 L31H N 32.525 1.00 66.50 L31H c 32.813 1.00 66.89 L31H 0 33.285 1.00 72.91 L31H N 34.389 1.00 79.05 L31H c 35.108 1.00 79.25 L31H c 35.224 1.00 81.00 L31H c 33.916 1.00 80.82 L31H c 36.379 1.00 80.82 L31H c 33.773 1.00 82.23 L31H c 32.859 1.00 83.72 L31H 0 34.251 1.00 83.71 L31H N 35.313 1.00 84 .10 L31H c 33.646 1.00 84.51 L31H c 34.497 1.00 83.82 L31H c 35.057 1.00 83.24 L31H c 33.692 1.00 84 .11 L31H c 34.709 1.00 84 .12 L31H 0 32.576 1.00 83.31 L31H N 32.487 1.00 82.03 L31H c 31.823 1.00 81.46 L31H c 31.732 1.00 81.22 L31H 0 31.357 1.00 79.80 L31H N 30.668 1.00 75.75 L31H c 31.624 1.00 76.28 L31H c 32.799 1.00 76.33 L31H 0 30.959 1.00 75.30 L31H c 29.512 1.00 72.48 L31H c 29.352 1.00 73.96 L31H 0 28.709 1.00 66.86 L31H N 27.635 1.00 60.76 L31H c 26.885 1.00 57.60 L31H c 28.145 1.00 56.71 L31H c 29.294 1.00 54.89 L31H 0 27.290 1.00 54.07 L31H N 26.134 1.00 53.12 L31H c 27.590 1.00 51.10 L31H c 26.420 1.00 49.83 L31H c 25.977 1.00 51.00 L31H c 27.708 1.00 48.33 L31H c 26.969 1.00 45.76 L31H 0 28.665 1.00 46.26 L31H N 28.792 1.00 43.92 L31H c 30.189 1.00 4 5.52 L31H c 30.910 1.00 48.84 L31H c 32.248 1.00 49.89 L31H c 32.922 1.00 54.13 L31H c 33.858 1.00 56.30 L31H N 28.560 1.00 42.72 L31H c 28.967 1.00 42.20 L31H 0 27.875 1.00 41.33 L31H N 27.651 1.00 39.44 L31H c 26.729 1.00 36.39 L31H c 26.538 1.00 33.98 L31H c 25.858 1.00 30.93 L31H c 25.716 1.00 31.01 L31H c 28.978 1.00 39.99 L31H c 29.813 1.00 37.73 L31H 0 29.155 1.00 40.04 L31H N 30.395 1.00 40.75 L31H c 30.968 1.00 41.14 L31H c 32.320 1.00 43.03 L31H c 33.442 1.00 40.83 L3 Iff c 32.556 1.00 41.04 L31H c 30.196 1.00 42.11 L31H c 31.071 1.00 43.22 L31H 0 29.060 1.00 42.58 L31H N 28.714 1.00 43.24 . L31H c 29.406 1.00 43.38 L31H c 28.663 1.00 41.25 L31H c 30.855 1.00 42.23 L31H c 362 WO 2009/026558 PCT/US2008/074097 ATOM 3191 CD1 ILE 50 16.212 14 ATOM 3192 c ILE 50 18.005 16 ATOM 3193 0 ILE 50 17.188 16 ATOM 3194 N SER 51 18.759 15 ATOM 3195 CA SER 51 18.711 15 ATOM 3196 CB SER 51 20.130 14 ATOM 3197 OG SER 51 20.939 14 ATOM 3198 C SER 51 17.991 13 ATOM 3199 O SER 51 17.737 12 ATOM 3200 N GLY 52 17.648 13 ATOM 3201 CA GLY 52 17.056 12 ATOM 3202 C GLY 52 15.903 11 ATOM 3203 0 GLY 52 15.778 10 ATOM 3204 N ASN 53 15.069 12 ATOM 3205 CA ASN 53 13.841 12 ATOM 3206 CB ASN 53 13.102 11 ATOM 3207 CG ASN 53 12.894 11 ATOM 3208 OD1 ASN 53 12.568 12 ATOM 3209 ND2 ASN 53 13.081 10 ATOM 3210 C ASN 53 14.102 12 ATOM 3211 0 ASN 53 13.345 12 ATOM 3212 N SER 54 15.177 11 ATOM 3213 CA SER 54 15.289 10 ATOM 3214 CB SER 54 14.677 9 ATOM 3215 OG SER 54 15.248 8 ATOM 3216 C SER 54 16.709 10 ATOM 3217 O SER 54 16.905 10 ATOM 3218 N ASN 55 17.692 11 ATOM 3219 CA ASN 55 19.087 11 ATOM 3220 CB ASN 55 19.938 10 ATOM 3221 CG ASN 55 19.450 9 ATOM 3222 OD1 ASN 55 19.565 8 ATOM 3223 ND2 ASN 55 18.898 9 ATOM 3224 C ASN 55 19.700 12 ATOM 3225 0 ASN 55 19.502 13 ATOM 3226 N ARG 56 20.457 12 ATOM 3227 CA ARG 56 21.089 13 ATOM 3228 CB ARG 56 20.883 13 ATOM 3229 CG ARG 56 19.439 13 ATOM 3230 CD ARG 56 19.324 12 ATOM 3231 NE ARG 56 19.736 11 ATOM 3232 CZ ARG 56 20.967 10 ATOM 3233 NHl ARG 56 21.260 9 ATOM 3234 NH2 ARG 56 21.908 11 ATOM 3235 C ARG 56 22.587 13 ATOM 3236 O ARG 56 23.318 12 ATOM 3237 N PRO 57 23.070 14 ATOM 3238 CD PRO 57 22.322 15 ATOM 3239 CA PRO 57 24.519 14 ATOM 3240 CB PRO 57 24.656 16 ATOM 3241 CG PRO 57 23.346 16 ATOM 3242 C PRO 57 25.064 14 ATOM 3243 O PRO 57 24.490 15 ATOM 3244 N SER 58 26.166 14 ATOM 3245 CA SER 58 26.803 14 ATOM 3246 CB SER 58 28.198 13 ATOM 3247 OG SER 58 29.072 14 ATOM 3248 C SER 58 26.917 15 ATOM 3249 O SER 58 27.172 16 ATOM 3250 N GLY 59 26.732 16 ATOM 3251 CA GLY 59 26.434 17 ATOM 3252 C GLY 59 24.984 17 ATOM 3253 0 GLY 59 24.676 17 ATOM 3254 N VAL 60 24.089 17 ATOM 3255 CA VAL 60 22.662 17 ATOM 3256 CB VAL 60 21.850 17 ATOM 3257 CGI VAL 60 20.391 17 ATOM 3258 CG2 VAL 60 22.336 18 ATOM 3259 C VAL 60 22.277 15 ATOM 3260 O VAL 60 22.498 14 ATOM 3261 N PRO 61 21.706 16 ATOM 3262 CD PRO 61 21.552 17 ATOM 3263 CA PRO 61 21.353 14 ATOM 3264 CB PRO 61 21.030 15 ATOM 3265 CG PRO 61 21.652 17 ATOM 3266 C PRO 61 20.172 14 31.385 1.00 43.01 L31H c 27.213 1.00 45.56 L31H c 26.569 1.00 43.85 L31H 0 26.673 1.00 48.30 L31H N 25.246 1.00 49.71 L31H c 24.675 1.00 49.26 L31H c 25.403 1.00 52.11 L31H 0 24.961 1.00 50.08 L31H c 25.865 1.00 50.16 L31H 0 23.695 1.00 51.31 L31H N 23.284 1.00 52.07 L31H c 24.164 1.00 54.09 L31H c 24.499 1.00 54.32 L31H 0 24.551 1.00 55.48 L31H N 25.310 1.00 55.60 L31H c 24.751 1.00 52.09 L31H c 23.248 1.00 49.39 L31H c 22.692 1.00 50.31 L31H 0 22.584 1.00 46.57 L31H N 26.799 1.00 56.53 L31H c 27.647 1.00 57.59 L31H 0 27.115 1.00 58.06 L31H N 28.421 1.00 59.90 L31H c 28.357 1.00 60.64 L31H c 27.315 1.00 59.19 L31H 0 29.000 1.00 62.28 L31H c 30.055 1.00 62.32 L31H 0 28.330 1.00 64.32 L31H N 28.744 1.00 67.64 L31H c 27.545 1.00 67.43 L31H c 2 6.8 92 1.00 67.97 L31H c 27.458 1.00 66.43 L31H 0 25.695 1.00 68.44 L31H N 29.401 1.00 69.95 L31H c 28.937 1.00 71.67 L31H 0 30.477 1.00 72.79 L31H N 31.238 1.00 75.45 L31H c 32.739 1.00 77.48 L31H c 33.188 1.00 83.20 L31H c 34.637 1.00 88.80 L31H c 34.816 1.00 95.67 L31H N 35.153 1.00 99.28 L31H c 35.293 1.00100.99 L31H N 35.352 1.00101.75 L31H N 30.978 1.00 75.94 L31H C 31.139 1.00 76.36 L31H 0 30.586 1.00 76.18 L31H N 30.039 1.00 75.75 L31H C 30.545 1.00 77.03 L31H c 29.859 1.00 75.92 L31H c 29.176 1.00 75.20 L31H c 31.965 1.00 77.22 L31H c 32.832 1.00 78.83 L31H 0 32.208 1.00 76.68 L31H N 33.521 1.00 75.29 L31H c 33.488 1.00 75.46 L31H c 32.675 1.00 72.13 L31H 0 33.910 1.00 73.26 L31H c 33.067 1.00 73.30 L31H 0 35.192 1.00 71.02 L31H N 35.623 1.00 66.74 L31H c 36.062 1.00 63.73 L31H c 37.181 1.00 63.24 L31H 0 35.182 1.00 60.90 L31H N 35.480 1.00 58.68 L31H c 34.178 1.00 57.78 L31H c 34.475 1.00 56.47 L31H c 33.268 1.00 58.00 L31H c 36.325 1.00 58.24 L31H c 35.923 1.00 55.12 L31H 0 37.519 1.00 58.08 L31H N 38.137 1.00 57.75 L31H c 38.459 1.00 58.26 . L31H c 39.760 1.00 58.11 L31H c 39.600 1.00 58.28 L31H c 37.976 1.00 58.36 L31H c 363 WO 2009/026558 PCT/US2008/074097 ATOM 32 67 0 PRO 61 19.438 14 ATOM 3268 N ASP 62 19.991 12 ATOM 3269 CA ASP 62 18.872 12 ATOM 3270 CB ASP 62 19.073 10 ATOM 3271 CG ASP 62 19.202 10 ATOM 3272 OD1 ASP 62 19.770 9 ATOM 3273 OD2 ASP 62 18.742 11 ATOM 3274 C ASP 62 17.587 12 ATOM 3275 O ASP 62 16.500 12 ATOM 3276 N ARG 63 17.721 13 ATOM 3277 CA ARG 63 16.561 14 ATOM 3278 CB ARG 63 17.006 15 ATOM 3279 CG ARG 63 17.583 15 ATOM 3280 CD ARG 63 17.748 16 ATOM 3281 NE ARG 63 18.504 17 ATOM 3282 CZ ARG 63 18.006 18 ATOM 3283 NHl ARG 63 16.741 19 ATOM 3284 NH2 ARG 63 18.779 19 ATOM 3285 C ARG 63 15.761 15 ATOM 3286 O ARG 63 14.541 15 ATOM 3287 N PHE 64 16.471 15 ATOM 3288 CA PHE 64 15.873 15 ATOM 3289 CB PHE 64 16.782 16 ATOM 3290 CG PHE 64 17.058 17 ATOM 3291 CDl PHE 64 16.251 19 ATOM 3292 CD2 PHE 64 18.131 18 ATOM 3293 CEl PHE 64 16.507 20 ATOM 3294 CE2 PHE 64 18.394 19 ATOM 3295 CZ PHE 64 17.577 20 ATOM 3296 C PHE 64 15.690 14 ATOM 3297 O PHE 64 16.627 13 ATOM 3298 N SER 65 14.495 14 ATOM 3299 CA SER 65 14 .223 13 ATOM 3300 CB SER 65 13.755 12 ATOM 3301 OG SER 65 12.887 12 ATOM 3302 C SER 65 13.182 13 ATOM 3303 O SER 65 12.299 14 ATOM 3304 N GLY 66 13.303 13 ATOM 3305 CA GLY 66 12.403 13 ATOM 3306 C GLY 66 11.674 12 ATOM 3307 0 GLY 66 11.973 11 ATOM 3308 N SER 67 10.708 12 ATOM 3309 CA SER 67 9.993 11 ATOM 3310 CB SER 67 9.188 10 ATOM 3311 OG SER 67 8.017 11 ATOM 3312 C SER 67 9.067 11 ATOM 3313 O SER 67 8.618 13 ATOM 3314 N LYS 68 8.797 11 ATOM 3315 CA LYS 68 8.024 11 ATOM 3316 CB LYS 68 8.933 11 ATOM 3317 CG LYS 68 8.182 11 ATOM 3318 CD LYS 68 9.093 11 ATOM 3319 CE LYS 68 8.287 10 ATOM 3320 NZ LYS 68 9.135 10 ATOM 3321 C LYS 68 6.949 10 ATOM 3322 0 LYS 68 7.141 9 ATOM 3323 N SER 69 5.817 10 ATOM 3324 CA SER 69 4.696 9 ATOM 3325 CB SER 69 3.870 9 ATOM 3326 OG SER 69 2.891 8 ATOM 3327 C SER 69 3.822 10 ATOM 3328 O SER 69 3.270 11 ATOM 3329 N GLY 70 3.694 9 ATOM 3330 CA GLY 70 2.820 10 ATOM 3331 C GLY 70 3.285 11 ATOM 3332 0 GLY 70 4.269 11 ATOM 3333 N THR 71 2.587 12 ATOM 3334 CA THR 71 2.895 14 ATOM 3335 CB THR 71 1.685 14 ATOM 3336 OG1 THR 71 0.597 14 ATOM 3337 CG2 THR 71 1.289 13 ATOM 3338 C THR 71 3.328 15 ATOM 3339 O THR 71 3.385 16 ATOM 3340 N SER 72 3.628 14 ATOM 3341 CA SER 72 4.041 15 ATOM 3342 CB SER 72 2.875 15 37.074 1.00 56.83 L31H 0 38.579 1.00 58.64 L31H N 38.205 1.00 59.95 L31H C 38.707 1.00 62.80 L31H c 40.234 1.00 67.16 L31H c 40.700 1.00 67.81 L31H .0 40.969 1.00 69.22 L31H 0 38.758 1.00 58.55 L31H c 38.530 1.00 57.80 L31H 0 39.487 1.00 57.77 L31H N 39.933 1.00 57.68 L31H c 40.781 1.00 59.02 L31H c 42.130 1.00 60.91 L31H c 42.979 1.00 64.55 L31H c 42.280 1.00 67.17 L31H N 41.915 1.00 67.43 L31H c 42.178 1.00 67.62 L31H N 41.297 1.00 67.50 L31H N 38.734 1.00 56.49 L31H C 38.817 1.00 56.13 L31H 0 37.632 1.00 55.21 L31H N 36.360 1.00 54.46 L31H C 35.623 1.00 53.69 L31H c 36.385 1.00 51.65 L31H c 36.220 1.00 50.28 L31H c 37.269 1.00 50.64 L31H c 36.920 1.00 48.84 L31H c 37.974 1.00 48.98 L31H c 37.798 1.00 48.52 L31H c 35.459 1.00 53.96 L31H c 35.262 1.00 53.07 L31H 0 34.896 1.00 54.00 L31H N 33.970 1.00 54.18 L31H c 34.748 1.00 53.56 L31H c 35.802 1.00 52.90 L31H 0 32.927 1.00 54.21 L31H c 33.202 1.00 54.41 L31H 0 31.725 1.00 54.11 L31H N 30.649 1.00 53.71 L31H c 30.103 1.00 54.08 L31H c 30.478 1.00 54.45 L31H 0 29.224 1.00 54.58 L31H N 28.591 1.00 55.72 L31H c 29.632 1.00 55.62 L31H c 30.019 1.00 57.25 L31H 0 27.496 1.00 56.30 L31H c 27.535 1.00 55.91 L31H 0 26.515 1.00 56.98 L31H N 25.347 1.00 57.91 L31H c 24.118 1.00 57.46 L31H c 22.801 1.00 56.11 L31H c 21.637 1.00 56.19 L31H c 20.368 1.00 55.24 L31H c 19.137 1.00 51.72 L31H N 25.084 1.00 59.65 L31H c 25.340 1.00 60.17 L31H 0 24.564 1.00 61.33 L31H N 24.280 1.00 61.60 L31H c 25.550 1.00 60.95 L31H c 25.352 1.00 59.59 L31H 0 23.203 1.00 61.91 L31H c 23.397 1.00 64.14 L31H 0 22.071 1.00 60.05 L31H N 21.018 1.00 56.96 L31H c 20.447 1.00 56.37 L31H c 19.709 1.00 56.19 L31H 0 20.786 1.00 55.57 L31H N 20.212 1.00 55.61 L31H' c 19.503 1.00 54.53 L31H c 20.428 1.00 56.64 L31H 0 18.316 1.00 54.65 L31H c 21.289 1.00 56.84 L31H c 21.061 1.00 57.59 . L31H 0 22.470 1.00 57.58 L31H N 23.579 1.00 57.61 ' L31H c 24.542 1.00 57.91 L31H c 364 WO 2009/026558 PCT/US2008/074097 ATOM 3343 OG SER 72 2.211 14.410 24.795 1.00 58.50 L31H 0 ATOM 3344 C SER 72 5.221 14.830 24.323 1.00 57.22 L31H c ATOM 3345 O SER 72 5.757 13.796 23.937 1.00 57.93 L31H 0 ATOM 3346 N ALA 73 5.625 15.502 25.392 1.00 56.55 L31H N ATOM 3347 CA ALA 73 6.766 15.073 26.187 1.00 56.17 L31H c ATOM 3348 CB ALA 73 8.063 15.426 25.466 1.00 55.12 L31H c ATOM 3349 C ALA 73 6.681 15.802 27.514 1.00 56.46 L31H c ATOM 3350 O ALA 73 5.891 16.719 27.659 1.00 56.55 L31H 0 ATOM 3351 N SER 74 7.484 15.401 28.487 1.00 58.75 L31H N ATOM 3352 CA SER 74 7.588 16.178 29.716 1.00 60.34 L31H c ATOM 3353 CB SER 74 6.575 15.712 30.738 1.00 60.09 L31H c ATOM 3354 OG SER 74 6.962 16.205 32.010 1.00 58.83 L31H 0 ATOM 3355 C SER 74 8.953 16.163 30.389 1.00 60.92 L31H c ATOM 3356 O SER 74 9.735 15.224 30.228 1.00 63.33 L31H 0 ATOM 3357 N LEU 75 9.216 17.211 31.162 1.00 59.31 L31H N ATOM 3358 CA LEU 75 10.383 17.259 32.032 1.00 58.44 L31H c ATOM 3359 CB LEU 75 11.150 18.574 31.803 1.00 59.47 L31H c ATOM 3360 CG LEU 75 12.456 18.834 32.565 1.00 57.74 L31H c ATOM 3361 CD1 LEU 75 13.397 17.653 32.379 1.00 58.12 L31H c ATOM 3362 CD2 LEU 75 13.102 20.118 32.067 1.00 56.35 L31H c ATOM 3363 C LEU 75 9.924 17.163 33.492 1.00 58.84 L31H c ATOM 3364 O LEU 75 9.086 17.945 33.938 1.00 58.64 L31H 0 ATOM 3365 N ALA 76 10.470 16.201 34.226 1.00 59.13 L31H N ATOM 3366 CA ALA 76 10.194 16.059 35.650 1.00 60.32 L31H c ATOM 3367 CB ALA 76 9.776 14.632 35.951 1.00 59.16 L31H c ATOM 3368 C ALA 76 11.427 16.423 36.480 1.00 61.43 L31H c ATOM 3369 O ALA 76 12.535 15.935 36.220 1.00 62.96 L31H 0 ATOM 3370 N ILE 77 11.237 17.278 37.482 1.00 61.31 L31H N ATOM 3371 CA ILE 77 12.317 17.597 38.413 1.00 61.17 L31H c ATOM 3372 CB ILE 77 12.624 19.120 38.434 1.00 61.96 L31H c ATOM 3373 CG2 ILE 77 13.872 19.387 39.253 1.00 61.34 L31H c ATOM 3374 CGI ILE 77 12.863 19.633 37.015 1.00 61.57 L31H c ATOM 3375 CD1 ILE 77 13.330 21.061 36.956 1.00 60.74 L31H c ATOM 3376 C ILE 77 11.932 17.163 39.821 1.00 60.56 L31H c ATOM 3377 0 ILE 77 10.914 17.592 40.341 1.00 60.68 L31H 0 ATOM 3378 N THR 78 12.733 16.315 40.447 1.00 60.81 L31H N ATOM 3379 CA THR 78 12.422 15.930 41.815 1.00 63.27 L31H c ATOM 3380 CB THR 78 12.493 14.402 41.993 1.00 62.92 L31H c ATOM 3381 OG1 THR 78 13.677 13.902 41.366 1.00 65.95 L31H 0 ATOM 3382 CG2 THR 78 11.287 13.739 41.375 1.00 62.85 L31H c ATOM 3383 C THR 78 13.315 16.603 42.861 1.00 64.30 L31H c ATOM 3384 O THR 78 14.312 17.251 42.523 1.00 63.28 L31H 0 ATOM 3385 N GLY 79 12.929 16.460 44.128 1.00 64.43 L31H N ATOM 3386 CA GLY 79 13.737 16.961 45.222 1.00 64.73 L31H c ATOM 3387 C GLY 79 14.187 18.371 44.944 1.00 65.69 L31H c ATOM 3388 0 GLY 79 15.382 18.678 44.980 1.00 66.58 L31H 0 ATOM 3389 N LEU 80 13.219 19.233 44.662 1.00 66.28 L31H N ATOM 3390 CA LEU 80 13.501 20.552 44.116 1.00 67.14 L31H c ATOM 3391 CB LEU 80 12.182 21.315 43.940 1.00 66.33 L31H c ATOM 3392 CG LEU 80 12.006 22.208 42.707 1.00 65.90 L31H c ATOM 3393 CD1 LEU 80 12.826 21.693 41.522 1.00 64.85 L31H c ATOM 3394 CD2 LEU 80 10.531 22.256 42.364 1.00 63.32 L31H c ATOM 3395 C LEU 80 14.473 21.333 45.008 1.00 67.62 L31H c ATOM 3396 O LEU 80 14.247 21.501 46.203 1.00 66.07 L31H 0 ATOM 3397 N GLN 81 15.571 21.782 44.412 1.00 69.02 L31H N ATOM 3398 CA GLN 81 16.511 22.664 45.090 1.00 71.32 L31H c ATOM 3399 CB GLN 81 17.956 22.251 44.784 1.00 71.81 L31H c ATOM 3400 CG GLN 81 18.387 20.908 45.359 1.00 72.58 L31H c ATOM 3401 CD GLN 81 19.656 20.370 44.703 1.00 73.31 L31H c ATOM 3402 OE1 GLN 81 20.123 20.900 43.695 1.00 73.31 L31H 0 ATOM 3403 NE2 GLN 81 20.212 19.309 45.274 1.00 75.44 L31H N ATOM 3404 C GLN 81 16.262 24.082 44.586 1.00 71.73 L31H c ATOM 3405 0 GLN 81 15.703 24.269 43.508 1.00 71.27 L31H 0 ATOM 3406 N ALA 82 16.675 25.076 45.365 1.00 73.50 L31H N ATOM 3407 CA ALA 82 16.338 26.464 45.064 1.00 75.37 L31H c ATOM 3408 CB ALA 82 16.599 27.340 46.277 1.00 76.64 L31H c ATOM 3409 C ALA 82 17.146 26.961 43.882 1.00 76.22 L31H c ATOM 3410 O ALA 82 16.703 27.823 43.123 1.00 76.26 L31H' 0 ATOM 3411 N GLU 83 18.336 26.399 43.732 1.00 76.93 L31H N ATOM 3412 CA GLU 83 19.222 26.755 42.645 1.00 77.92 L31H c ATOM 3413 CB GLU 83 20.657 26.390 43.025 1.00 82.68 L31H c ATOM 3414 CG GLU 83 21.235 27.232 44.165 1.00 90.24 L31H c ATOM 3415 CD GLU 83 20.590 26.959 45.522 1.00 94.97 . L31H c ATOM 3416 OE1 GLU 83 20.480 25.777 45.917 1.00 99.12 L31H 0 ATOM 3417 OE2 GLU 83 20.199 27.934 46.199 1.00 98.16 L31H 0 ATOM 3418 C GLU 83 18.802 26.050 41.356 1.00 75.65 L31H c 365 WO 2009/026558 PCT/US2008/074097 ATOM 3419 0 GLU 83 19.563 25 ATOM 3420 N ASP 84 17.579 25 ATOM 3421 CA ASP 84 16.981 24 ATOM 3422 CB ASP 84 16.245 23 ATOM 3423 CG ASP 84 17.181 22 ATOM 3424 OD1 ASP 84 18.176 22 ATOM 3425 OD2 ASP 84 16.935 21 ATOM 3426 C ASP 84 16.032 25 ATOM 3427 O ASP 84 15.559 25 ATOM 3428 N GLU 85 15.765 27 ATOM 3429 CA GLU 85 14.955 28 ATOM 3430 CB GLU 85 14.859 29 ATOM 3431 CG GLU 85 14.009 30 ATOM 3432 CD GLU 85 13.407 31 ATOM 3433 OEl GLU 85 13.686 32 ATOM 3434 OE2 GLU 85 12.650 30 ATOM 3435 C GLU 85 15.585 28 ATOM 3436 0 GLU 85 16.765 28 ATOM 3437 N ALA 86 14.795 28 ATOM 3438 CA ALA 86 15.285 28 ATOM 3439 CB ALA 86 16.519 28 ATOM 3440 C ALA 86 14.251 28 ATOM 3441 0 ALA 86 13.093 28 ATOM 3442 N ASP 87 14.691 29 ATOM 3443 CA ASP 87 13.868 29 ATOM 3444 CB ASP 87 14.125 30 ATOM 3445 CG ASP 87 13.594 31 ATOM 3446 OD1 ASP 87 12.788 31 ATOM 3447 OD2 ASP 87 13.983 32 ATOM 3448 C ASP 87 14.154 27 ATOM 3449 O ASP 87 15.285 27 ATOM 3450 N TYR 88 13.113 26 ATOM 3451 CA TYR 88 13.207 25 ATOM 3452 CB TYR 88 12.560 24 ATOM 3453 CG TYR 88 13.368 24 ATOM 3454 CDl TYR 88 12.958 24 ATOM 3455 CEl TYR 88 13.767 24 ATOM 3456 CD2 TYR 88 14.599 23 ATOM 3457 CE2 TYR 88 15.411 23 ATOM 3458 CZ TYR 88 15.000 24 ATOM 3459 OH TYR 88 15.849 24 ATOM 3460 C TYR 88 12.585 25 ATOM 3461 O TYR 88 11.539 26 ATOM 3462 N TYR 89 13.262 25 ATOM 3463 CA TYR 89 12.795 25 ATOM 3464 CB TYR 89 13.607 26 ATOM 3465 CG TYR 89 13.533 27 ATOM 3466 CDl TYR 89 14.474 28 ATOM 3467 CEl TYR 89 14.466 29 ATOM 3468 CD2 TYR 89 12.567 28 ATOM 3469 CE2 TYR 89 12.548 29 ATOM 3470 CZ TYR 89 13.507 30 ATOM 3471 OH TYR 89 13.533 31 ATOM 3472 C TYR 89 12.955 23 ATOM 3473 O TYR 89 13.932 23 ATOM 3474 N CYS 90 11.988 23 ATOM 3475 CA CYS 90 12.106 22 ATOM 3476 C CYS 90 12.345 22 ATOM 3477 0 CYS 90 12.111 23 ATOM 3478 CB CYS 90 10.848 21 ATOM 3479 SG CYS 90 9.280 22 ATOM 3480 N GLN 91 12.802 21 ATOM 3481 CA GLN 91 13.132 21 ATOM 3482 CB GLN 91 14.568 22 ATOM 3483 CG GLN 91 15.174 21 ATOM 3484 CD GLN 91 16.675 21 ATOM 3485 OEl GLN 91 17.231 21 ATOM 3486 NE2 GLN 91 17.343 22 ATOM 3487 C GLN 91 12.964 20 ATOM 3488 0 GLN 91 13.317 19 ATOM 3489 N SER 92 12.433 20 ATOM 3490 CA SER 92 12.363 19 ATOM 3491 CB SER 92 10.977 18 ATOM 3492 OG SER 92 10.870 17 ATOM 3493 C SER 92 12.679 19 ATOM 3494 O SER 92 12.694 20 40.395 1.00 74.80 L31H 0 41.351 1.00 73.41 L31H N 40.145 1.00 71.11 L31H C 40.471 1.00 70.69 L31H c 40.499 1.00 70.12 L31H c 39.741 1.00 70.45 L31H 0 41.271 1.00 67.92 L31H 0 39.495 1.00 69.37 L31H c 38.385 1.00 69.35 L31H 0 40.197 1.00 67.68 L31H N 39.653 1.00 65.89 L31H c 40.680 1.00 67.36 L31H c 40.250 1.00 69.50 L31H c 41.433 1.00 71.65 L31H c 41.596 1.00 73.05 L31H 0 42.200 1.00 73.05 L31H 0 38.346 1.00 63.80 L31H c 38.316 1.00 62.73 L31H 0 37.270 1.00 61.53 L31H N 35.949 1.00 58.22 L31H c 35.595 1.00 59.72 L31H c 34.819 1.00 56.10 L31H c 35.037 1.00 55.00 L31H 0 33.608 1.00 53.32 L31H N 32.415 1.00 51.34 L31H c 31.475 1.00 51.11 L31H c 32.020 1.00 53.30 L31H c 32.972 1.00 53.43 L31H 0 31.491 1.00 55.18 L31H 0 31.675 1.00 51.29 L31H c 31.221 1.00 50.39 L31H 0 31.544 1.00 4 9.52 L31H N 30.848 1.00 49.11 L31H c 31.706 1.00 48.57 L31H c 32.957 1.00 47.75 L31H c 34.188 1.00 47.35 L31H c 35.309 1.00 46.21 L31H c 32.884 1.00 47.54 L31H c 33.986 1.00 4 6.69 L31H c 35.197 1.00 4 6.67 L31H c 36.274 1.00 43.55 L31H 0 29.457 1.00 49.99 L31H c 29.257 1.00 50.31 L31H 0 28.490 1.00 49.96 L31H N 27.115 1.00 51.75 L31H c 26.259 1.00 53.70 L31H c 26.644 1.00 5 6.56 L31H c 27.509 1.00 57.34 L31H c 27.814 1.00 58.06 L31H c 26.095 1.00 56.23 L31H c 26.396 1.00 57.93 L31H c 27.257 1.00 58.84 L31H c 27.547 1.00 59.54 L31H 0 26.541 1.00 52.19 L31H c 26.830 1.00 51.07 L31H 0 25.722 1.00 51.93 L31H N 24.939 1.00 51.12 L31H c 23.460 1.00 50.42 L31H c 22.983 1.00 50.17 L31H 0 25.097 1.00 53.40 L31H c 24 .728 1.00 51.64 L31H s 22.733 1.00 49.04 L31H N 21.320 1.00 46.80 L31H c 21.204 1.00 46.39 L31H c 19.822 1.00 43.37 L31H c 19.925 1.00 43.12 L31H c 20.604 1.00 42.92 L31H 0 19.273 1.00 41.91 L31B N 20.531 1.00 46.33 L31H c 21.015 1.00 45.84 L31H 0 19.313 1.00 45.77 L31H N 18.381 1.00 45.24 L31H c 18.438 1.00 45.03 , L31H c 17.537 1.00 47.80 ' L31H 0 16.937 1.00 45.02 ' L31H c 16.622 1.00 44.46 L31H 0 366 WO 2009/026558 PCT/US2008/074097 ATOM 3495 N TYR 93 12.948 18.695 16.073 1.00 44.70 L31H N ATOM 3496 CA TYR 93 13.093 18.933 14.640 1.00 43.04 L31H C ATOM 3497 CB TYR 93 13.960 17.835 13.993 1.00 40.79 L31H C ATOM 3498 CG TYR 93 14.200 18.002 12.493 1.00 38.37 L31H c ATOM 3499 CDl TYR 93 15.219 18.832 12.014 1.00 36.91 L31H c ATOM 3500 CEl TYR 93 15.435 19.013 10.642 1.00 32.83 L31H c ATOM 3501 CD2 TYR 93 13.400 17.349 11.558 1.00 35.95 L31H c ATOM 3502 CE2 TYR 93 13.609 17.521 10.180 1.00 35.00 L31H c ATOM 3503 CZ TYR 93 14.631 18.360 9.732 1.00 34.67 L31H c ATOM 3504 OH TYR 93 14.833 18.558 8.381 1.00 32.18 L31H 0 ATOM 3505 C TYR 93 11.692 18.892 14.055 1.00 43.84 L31H c ATOM 3506 O TYR 93 10.820 18.220 14.592 1.00 42.51 L31H 0 ATOM 3507 N ASP 94 11.482 19.615 12.964 1.00 45.57 L31H N ATOM 3508 CA ASP 94 10.186 19.654 12.308 1.00 47.61 L31H c ATOM 3509 CB ASP 94 9.550 21.027 12.531 1.00 49.33 L31H c ATOM 3510 CG ASP 94 8.067 21.041 12.222 1.00 51.78 L31H c ATOM 3511 OD1 ASP 94 7.277 21.314 13.156 1.00 52.86 L31H 0 ATOM 3512 OD2 ASP 94 7.693 20.783 11.056 1.00 51.71 L31H 0 ATOM 3513 C ASP 94 10.399 19.402 10.818 1.00 48.27 L31H c ATOM 3514 O ASP 94 11.058 20.187 10.141 1.00 48.27 L31H 0 ATOM 3515 N SER 95 9.848 18.312 10.299 1.00 49.99 L31H N ATOM 3516 CA SER 95 10.228 17.877 8.964 1.00 52.79 L31H c ATOM 3517 CB SER 95 9.7 62 16.446 8.702 1.00 52.89 L31H c ATOM 3518 OG SER 95 8.526 16.436 8.005 1.00 54.06 L31H 0 ATOM 3519 C SER 95 9.663 18.797 7.890 1.00 55.32 L31H c ATOM 3520 O SER 95 10.082 18.735 6.734 1.00 56.36 L31H 0 ATOM 3521 N SER 96 8.712 19.649 8.261 1.00 57.01 L31H N ATOM 3522 CA SER 96 8.219 20.657 7.330 1.00 59.06 L31H c ATOM 3523 CB SER 96 6.765 20.981 7.624 1.00 57.61 L31H c ATOM 3524 OG SER 96 6.662 21.651 8.865 1.00 56.06 L31H 0 ATOM 3525 C SER 96 9.048 21.943 7.412 1.00 61.43 L31H c ATOM 3526 O SER 96 9.380 22.542 6.391 1.00 63.10 L31H 0 ATOM 3527 N LEU 97 9.380 22.369 8.62 5 1.00 62.38 L31H N ATOM 3528 CA LEU 97 10.125 23.608 8.802 1.00 63.01 L31H c ATOM 3529 CB LEU 97 9.970 24.118 10.238 1.00 66.93 L31H c ATOM 3530 CG LEU 97 8.521 24.274 10.714 1.00 69.67 L31H c ATOM 3531 CDl LEU 97 8.477 25.078 12.010 1.00 69.75 L31H c ATOM 3532 CD2 LEU 97 7.709 24.963 9.636 1.00 69.77 L31H c ATOM 3533 C LEU 97 11.606 23.422 8.477 1.00 61.49 L31H c ATOM 3534 O LEU 97 12.307 24.384 8.146 1.00 59.90 L31H 0 ATOM 3535 N SER 98 12.073 22.181 8.577 1.00 58.39 L31H N ATOM 3536 CA SER 98 13.452 21.858 8.262 1.00 55.51 L31H c ATOM 3537 CB SER 98 13.793 22.338 6.856 1.00 56.09 L31H c ATOM 3538 OG SER 98 13.189 21.493 5.898 1.00 59.25 L31H 0 ATOM 3539 C SER 98 14.422 22.457 9.264 1.00 53.09 L31H c ATOM 3540 O SER 98 15.576 22.727 8.945 1.00 51.29 L31H 0 ATOM 3541 N GLY 99 13.950 22.663 10.484 1.00 51.30 L31H N ATOM 3542 CA GLY 99 14.827 23.149 11.532 1.00 50.67 L31H c ATOM 3543 C GLY 99 14.406 22.584 12.868 1.00 50.25 L31H c ATOM 3544 0 GLY 99 13.335 21.998 12.991 1.00 49.46 L31H 0 ATOM 3545 N SER 100 15.245 22.754 13.877 1.00 50.20 L31H N ATOM 3546 CA SER 100 14.920 22.233 15.193 1.00 50.66 L31H c ATOM 3547 CB SER 100 16.177 21.667 15.858 1.00 51.28 L31H c ATOM 3548 OG SER 100 16.337 20.294 15.521 1.00 52.02 L31H 0 ATOM 3549 C SER 100 14.294 23.321 16.055 1.00 50.29 L31H c ATOM 3550 O SER 100 14.995 24.184 16.582 1.00 50.01 L31H 0 ATOM 3551 N VAL 101 12.970 23.266 16.190 1.00 48.60 L31H N ATOM 3552 CA VAL 101 12.189 24.384 16.701 1.00 4 7.52 L31H c ATOM 3553 CB VAL 101 10.881 24.535 15.918 1.00 46.73 L31H c ATOM 3554 CGI VAL 101 11.192 24.568 14.442 1.00 47.59 L31H c ATOM 3555 CG2 VAL 101 9.920 23.403 16.256 1.00 45.46 L31H c ATOM 3556 C VAL 101 11.853 24.264 18.184 1.00 47.82 L31H c ATOM 3557 O VAL 101 11.604 23.167 18.691 1.00 48.23 L31H 0 ATOM 3558 N PHE 102 11.841 25.399 18.876 1.00 46.37 L31H N ATOM 3559 CA PHE 102 11.718 25.388 20.318 1.00 47.35 L31H c ATOM 3560 CB PHE 102 12.631 26.421 20.932 1.00 44.20 L31H c ATOM 3561 CG PHE 102 14.061 26.242 20.590 1.00 41.82 L31H c ATOM 3562 CDl PHE 102 14.551 26.688 19.380 1.00 39.65 L31H‘ c ATOM 3563 CD2 PHE 102 14.944 25.730 21.522 1.00 4 0.97 L31H c ATOM 3564 CEl PHE 102 15.893 26.641 19.113 1.00 38.50 L31H c ATOM 3565 CE2 PHE 102 16.292 25.680 21.260 1.00 38.80 L31H c ATOM 35 66 CZ PHE 102 16.769 26.139 20.057 1.00 39.41 L31H c ATOM 3567 C PHE 102 10.315 25.646 20.828 1.00 50.48 . L31H c ATOM 3568 O PHE 102 9.402 25.958 20.067 1.00 52.07 L31H 0 ATOM 3569 N GLY 103 10.166 25.515 22.140 1.00 53.14 L31H N ATOM 3570 CA GLY 103 8.894 25.767 22.779 1.00 55.97 L31H c 367 WO 2009/026558 ATOM 3571 C GLY 103 8.882 27.133 23.425 1.00 57.19 PCT/US2008/074097 L31H C ATOM 3572 0 GLY 103 9.941 27.744 23.611 1.00 56.34 L31H 0 ATOM 3573 N GLY 104 7.679 27.606 23.761 1.00 58.19 L31H N ATOM 3574 CA GLY 104 7.525 28.924 24.349 1.00 58.63 L31H C ATOM 3575 C GLY 104 8.458 29.139 25.523 1.00 59.14 L31H c ATOM 3576 0 GLY 104 9.114 30.177 25.626 1.00 59.20 L31H 0 ATOM 3577 N GLY 105 8.532 28.151 26.406 1.00 60.02 L31H N ATOM 3578 CA GLY 105 9.420 28.257 27.547 1.00 61.89 L31H c ATOM 3579 C GLY 105 8.647 28.213 28.850 1.00 63.99 L31H c ATOM 3580 0 GLY 105 7.412 28.344 28.866 1.00 65.05 L31H 0 ATOM 3581 N THR 106 9.369 28.016 29.951 1.00 63.25 L31H N ATOM 3582 CA THR 106 8.743 28.026 31.264 1.00 61.53 L31H c ATOM 3583 CB THR 106 8.311 26.620 31.690 1.00 60.33 L31H c ATOM 3584 OG1 THR 106 7.374 26.095 30.740 1.00 60.09 L31H 0 ATOM 3585 CG2 THR 106 7.661 26.667 33.058 1.00 58.71 L31H c ATOM 3586 C THR 106 9.652 28.608 32.342 1.00 62.44 L31H c ATOM 3587 O THR 106 10.829 28.256 32.458 1.00 61.28 L31H 0 ATOM 3588 N LYS 107 9.087 29.522 33.122 1.00 63.21 L31H N ATOM 3589 CA LYS 107 9.755 30.039 34.299 1.00 62.64 L31H c ATOM 3590 CB LYS 107 9.161 31.391 34.689 1.00 64.98 L31H c ATOM 3591 CG LYS 107 9.643 31.922 36.030 1.00 67.60 L31H c ATOM 3592 CD LYS 107 10.962 32.670 35.901 1.00 72.42 L31H c ATOM 3593 CE LYS 107 11.213 33.560 37.126 1.00 76.31 L31H c ATOM 3594 NZ LYS 107 12.373 34.501 36.969 1.00 79.44 L31H N ATOM 3595 C LYS 107 9.543 29.042 35.426 1.00 61.19 L31H c ATOM 3596 0 LYS 107 8.401 28.794 35.846 1.00 62.04 L31H 0 ATOM 3597 N LEU 108 10.638 28.457 35.904 1.00 57.46 L31H N ATOM 3598 CA LEU 108 10.570 27.633 37.102 1.00 53.84 L31H c ATOM 3599 CB LEU 108 11.556 26.466 37.040 1.00 54.15 L31H c ATOM 3600 CG LEU 108 11.541 25.642 38.328 1.00 50.02 L31H c ATOM 3601 CDl LEU 108 10.186 25.017 38.503 1.00 50.06 L31H c ATOM 3602 CD2 LEU 108 12.597 24.589 38.290 1.00 51.57 L31H c ATOM 3603 C LEU 108 10.902 28.478 38.309 1.00 53.02 L31H c ATOM 3604 O LEU 108 12.016 28.981 38.440 1.00 51.31 L31H 0 ATOM 3605 N THR 109 9.925 28.629 39.192 1.00 52.73 L31H N ATOM 3606 CA THR 109 10.118 29.355 40.440 1.00 52.49 L31H c ATOM 3607 CB THR 109 9.000 30.416 40.628 1.00 52.18 L31H c ATOM 3608 OG1 THR 109 9.260 31.542 39.777 1.00 50.86 L31H 0 ATOM 3609 CG2 THR 109 8.918 30.866 42.076 1.00 53.04 L31H c ATOM 3610 C THR 109 10.113 28.375 41.617 1.00 53.48 L31H c ATOM 3611 O THR 109 9.120 27.680 41.851 1.00 51.71 L31H 0 ATOM 3612 N VAL 110 11.228 28.304 42.342 1.00 54.50 L31H N ATOM 3613 CA VAL 110 11.286 27.475 43.546 1.00 56.59 L31H c ATOM 3614 CB VAL 110 12.727 26.972 43.863 1.00 55.19 L31H c ATOM 3615 CGI VAL 110 12.700 26.076 45.091 1.00 51.04 L31H c ATOM 3616 CG2 VAL 110 13.302 26.227 42.673 1.00 54.74 L31H c ATOM 3617 C VAL 110 10.824 28.353 44.690 1.00 59.73 L31H c ATOM 3618 O VAL 110 11.501 29.312 45.047 1.00 59.28 L31H 0 ATOM 3619 N LEU 111 9.670 28.027 45.260 1.00 63.84 L31H N ATOM 3 62 0 CA LEU 111 8.976 28.955 46.141 1.00 69.11 L31H c ATOM 3621 CB LEU 111 7.519 28.520 46.288 1.00 64.19 L31H c ATOM 3622 CG LEU 111 6.819 28.414 44.932 1.00 60.56 L31H c ATOM 3623 CDl LEU 111 5.553 27.609 45.066 1.00 58.84 L31H c ATOM 3624 CD2 LEU 111 6.546 29.800 44.386 1.00 55.98 L31H c ATOM 3625 C LEU 111 9.645 29.066 47.503 1.00 75.53 L31H c ATOM 3626 O LEU 111 9.702 28.101 48.259 1.00 78.23 L31H 0 ATOM 3627 N GLY 112 10.159 30.254 47.801 1.00 81.81 L31H N ATOM 3628 CA GLY 112 10.745 30.510 49.103 1.00 90.35 L31H c ATOM 3629 C GLY 112 10.012 31.619 49.837 1.00 95.92 L31H c ATOM 3630 0 GLY 112 10.472 32.096 50.874 1.00 95.75 L31H 0 ATOM 3631 N GLN 113 8.870 32.029 49.287 1.00102.79 L31H N ATOM 3632 CA GLN 113 8.019 33.058 49.885 1.00110.31 L31H c ATOM 3633 CB GLN 113 8.334 34.429 49.280 1.00113.77 L31H c ATOM 3634 CG GLN 113 9.794 34.826 49.315 1.00118.20 L31H c ATOM 3635 CD GLN 113 10.067 36.072 48.494 1.00120.53 L31H c ATOM 3636 OE1 GLN 113 9.723 37.186 48.896 1.00121.11 L31H 0 ATOM 3637 NE2 GLN 113 10.687 35.890 47.332 1.00121.57 L31H N ATOM 3638 C GLN 113 6.545 32.727 49.625 1.00113.82 L31H’ c ATOM 3639 0 GLN 113 6.214 32.017 48.679 1.00113.64 L31H 0 ATOM 3640 N PRO 114 5.640 33.248 50.462 1.00117.28 L31H N ATOM 3641 CD PRO 114 5.936 34.027 51.673 1.00117.03 L31H c ATOM 3642 CA PRO 114 4.210 32.935 50.357 1.00119.60 L31H c ATOM 3643 CB PRO 114 3.609 33.570 51.609 1.00119.09 . L31H c ATOM 3644 CG PRO 114 4.761 33.732 52.542 1.00118.20 L31H c ATOM 3645 C PRO 114 3.566 33.484 49.094 1.00121.80 ' L31H c ATOM 3646 O PRO 114 4.237 34.052 48.239 1.00122.55 L31H 0 368 WO 2009/026558 PCT/US2008/074097 ATOM 3647 N LYS 115 2.254 33.304 48.988 1.00123.51 L31H N ATOM 3648 CA LYS 115 1.465 33.997 47.980 1.00124.74 L31H C ATOM 3649 CB LYS 115 -0.025 33.715 48.192 1.00125.92 L31H C ATOM 3650 CG LYS 115 -0.961 34.837 47.740 1.00125.60 L31H c ATOM 3651 CD LYS 115 -1.039 34.958 46.224 1.00124.69 L31H c ATOM 3652 CE LYS 115 -1.896 33.860 45.617 1.00124.00 L31H c ATOM 3653 NZ LYS 115 -3.289 33.894 46.139 1.00123.01 L31H "n" ATOM 3654 C LYS 115 1.722 35.492 48.094 1.00125.34 L31H c ATOM 3655 0 LYS 115 2.067 35.988 49.166 1.00126.21 L31H 0 ATOM 3656 N ALA 116 1.559 36.206 46.986 1.00125.78 L31H N ATOM 3657 CA ALA 116 1.657 37.657 46.994 1.00125.51 L31H c ATOM 3658 CB ALA 116 3.117 38.080 46.981 1.00124.48 L31H c ATOM 3659 C ALA 116 0.933 38.250 45.794 1.00125.03 L31H c ATOM 3660 0 ALA 116 1.418 38.161 44.667 1.00125.35 L31H 0 ATOM 3661 N ALA 117 -0.229 38.848 46.043 1.00123.76 L31H N ATOM 3662 CA ALA 117 -0.939 39.596 45. Oil 1.00120.64 L31H c ATOM 3663 CB ALA 117 -2.425 39.662 45.336 1.00124.29 L31H c ATOM 3664 C ALA 117 -0.352 41.001 44.940 1.00117.39 L31H c ATOM 3665 0 ALA 117 -0.156 41.654 45.964 1.00117.55 L31H 0 ATOM 3666 N PRO 118 -0.051 41.480 43.724 1.00113.58 L31H N ATOM 3667 CD PRO 118 -0.303 40.835 42.425 1.00113.39 L31H c ATOM 3668 CA PRO 118 0.628 42.768 43.574 1.00109.03 L31H c ATOM 3669 CB PRO 118 1.009 42.804 42.096 1.00110.84 L31H c ATOM 3670 CG PRO 118 0.030 41.917 41.436 1.00112.56 L31H c ATOM 3671 C PRO 118 -0.236 43.959 43.974 1.00104.68 L31H c ATOM 3672 O PRO 118 -1.468 43.915 43.878 1.00103.62 L31H 0 ATOM 3673 N SER 119 0.429 45.015 44.434 1.00 98.81 L31H N ATOM 3674 CA SER 119 -0.215 46.302 44.650 1.00 92.70 L31H c ATOM 3675 CB SER 119 0.456 47.045 45.805 1.00 93.69 L31H c ATOM 3676 OG SER 119 1.866 47.017 45.677 1.00 95.23 L31H 0 ATOM 3677 C SER 119 -0.112 47.119 43.373 1.00 87.43 L31H c ATOM 3678 O SER 119 0.908 47.093 42.684 1.00 85.84 L31H 0 ATOM 3679 N VAL 120 -1.180 47.835 43.053 1.00 82.08 L31H N ATOM 3680 CA VAL 120 -1.258 48.520 41.780 1.00 78.07 L31H c ATOM 3681 CB VAL 120 -2.216 47.795 40.833 1.00 78.62 L31H c ATOM 3682 CGI VAL 120 -2.413 48.604 39.569 1.00 79.64 L31H c ATOM 3683 CG2 VAL 120 -1.661 46.424 40.502 1.00 79.29 L31H c ATOM 3684 C VAL 120 -1.725 49.949 41.944 1.00 75.01 L31H c ATOM 3685 O VAL 120 -2.768 50.201 42.530 1.00 73.87 L31H 0 ATOM 3686 N THR 121 -0.943 50.888 41.432 1.00 72.79 L31H N ATOM 3687 CA THR 121 -1.383 52.276 41.371 1.00 71.71 L31H c ATOM 3688 CB THR 121 -0.371 53.227 42.045 1.00 69.80 L31H c ATOM 3689 OG1 THR 121 -0.160 52.821 43.403 1.00 67.98 L31H 0 ATOM 3690 CG2 THR 121 -0.900 54.647 42.039 1.00 69.16 L31H c ATOM 3691 C THR 121 -1.543 52.676 39.909 1.00 71.78 L31H c ATOM 3692 O THR 121 -0.764 52.242 39.054 1.00 72.43 L31H 0 ATOM 3693 N LEU 122 -2.558 53.487 39.621 1.00 70.64 L31H N ATOM 3694 CA LEU 122 -2.806 53.917 38.252 1.00 70.47 L31H c ATOM 3695 CB LEU 122 -4.121 53.331 37.737 1.00 69.96 L31H c ATOM 3696 CG LEU 122 -4.416 53.622 36.263 1.00 69.35 L31H c ATOM 3697 CDl LEU 122 -3.214 53.213 35.412 1.00 68.20 L31H c ATOM 3698 CD2 LEU 122 -5.663 52.865 35.823 1.00 69.21 L31H c ATOM 3699 C LEU 122 -2.848 55.432 38.124 1.00 70.57 L31H c ATOM 3700 O LEU 122 -3.630 56.098 38.805 1.00 71.23 L31H 0 ATOM 3701 N PHE 123 -2.008 55.967 37.239 1.00 69.59 L31H N ATOM 3702 CA PHE 123 -1.916 57.410 37.026 1.00 67.96 L31H c ATOM 3703 CB PHE 123 -0.460 57.865 37.114 1.00 68.86 L31H c ATOM 3704 CG PHE 123 0.025 58.076 38.516 1.00 70.50 L31H c ATOM 3705 CDl PHE 123 0.808 57.124 39.144 1.00 71.72 L31H c ATOM 3706 CD2 PHE 123 -0.301 59.230 39.206 1.00 71.39 L31H c ATOM 3707 CEl PHE 123 1.256 57.318 40.431 1.00 72.59 L31H c ATOM 3708 CE2 PHE 123 0.145 59.432 40.495 1.00 71.92 L31H c ATOM 3709 CZ PHE 123 0.924 58.475 41.107 1.00 73.15 L31H c ATOM 3710 C PHE 123 -2.499 57.859 35.690 1.00 66.49 L31H c ATOM 3711 O PHE 123 -2.185 57.293 34.636 1.00 66.68 L31H 0 ATOM 3712 N PRO 124 -3.360 58.890 35.728 1.00 64.71 L31H N ATOM 3713 CD PRO 124 -3.896 59.403 '36.999 1.00 64.64 L31H c ATOM 3714 CA PRO 124 -3.870 59.650 34.579 1.00 62.32 L31H' c ATOM 3715 CB PRO 124 -4.992 60.483 35.175 1.00 64.01 L31H c ATOM 3716 CG PRO 124 -4.579 60.680 36.592 1.00 64.63 L31H c ATOM 3717 C PRO 124 -2.792 60.544 33.954 1.00 62.33 L31H c ATOM 3718 O PRO 124 -1.774 60.847 34.587 1.00 61.20 L31H 0 ATOM 3719 N PRO 125 -3.002 60.978 32.700 1.00 62.33 . L31H N ATOM 3720 CD PRO 125 -3.860 60.367 31.677 1.00 62.42 L31H c ATOM 3721 CA PRO 125 -2.120 61.991 32.117 1.00 60.75 L31H c ATOM 3722 CB PRO 125 -2.604 62.094 30.672 1.00 61.44 L31H c 369 WO 2009/026558 PCT/US2008/074097 ATOM 3723 CG PRO 125 -3.179 60 ATOM 3724 C PRO 125 -2.189 63 ATOM 3725 O PRO 125 -3.210 63 ATOM 3726 N SER 126 -1.085 64 ATOM 3727 CA SER 126 -1.027 65 ATOM 3728 CB SER 126 0.402 65 ATOM 3729 OG SER 126 1.278 65 ATOM 3730 C SER 126 -1.509 66 ATOM 3731 O SER 126 -1.473 66 ATOM 3732 N SER 127 -1.959 67 ATOM 3733 CA SER 127 -2.261 68 ATOM 3734 CB SER 127 -2.431 69 ATOM 3735 OG SER 127 -2.162 71 ATOM 3736 C SER 127 -1.102 68 ATOM 3737 O SER 127 -1.295 69 ATOM 3738 N GLU 128 0.106 68 ATOM 3739 CA GLU 128 1.282 69 ATOM 3740 CB GLU 128 2.533 69 ATOM 3741 CG GLU 128 2.688 70 ATOM 3742 CD GLU 128 4 . 104 70 ATOM 3743 OE1 GLU 128 4.807 70 ATOM 3744 OE2 GLU 128 4.510 71 ATOM 3745 C GLU 128 1.417 68 ATOM 3746 0 GLU 128 1.695 68 ATOM 3747 N GLU 129 1.220 67 ATOM 3748 CA GLU 129 1.441 66 ATOM 3749 CB GLU 129 1 . 426 64 ATOM 3750 CG GLU 129 2.033 63 ATOM 3751 CD GLU 129 1.519 62 ATOM 3752 OE1 GLU 129 2.071 61 ATOM 3753 OE2 GLU 129 0.560 62 ATOM 3754 C GLU 129 0.363 66 ATOM 3755 0 GLU 129 0.588 66 ATOM 3756 N LEU 130 -0.819 66 ATOM 3757 CA LEU 130 -1.917 66 ATOM 3758 CB LEU 130 -3.198 67 ATOM 3759 CG LEU 130 -4.161 65 ATOM 3760 CDl LEU 130 -3.374 64 ATOM 3761 CD2 LEU 130 -4.999 65 ATOM 3762 C LEU 130 -1.578 68 ATOM 3763 O LEU 130 -1.741 68 ATOM 3764 N GLN 131 -1.082 69 ATOM 3765 CA GLN 131 -0.650 70 ATOM 3766 CB GLN 131 -0.101 71 ATOM 3767 CG GLN 131 -1 . 142 72 ATOM 3768 CD GLN 131 -1.880 73 ATOM 3769 OE1 GLN 131 -3.018 73 ATOM 3770 NE2 GLN 131 -1.237 73 ATOM 3771 C GLN 131 0.412 70 ATOM 3772 0 GLN 131 0.656 70 ATOM 3773 N ALA 132 1.063 68 ATOM 3774 CA ALA 132 2.122 68 ATOM 3775 CB ALA 132 3.210 67 ATOM 3776 C ALA 132 1.517 67 ATOM 3777 0 ALA 132 2.218 67 ATOM 3778 N ASN 133 0.199 67 ATOM 3779 CA ASN 133 -0.592 66 ATOM 3780 CB ASN 133 -0.380 67 ATOM 3781 CG ASN 133 -1.567 67 ATOM 3782 OD1 ASN 133 -2.663 67 ATOM 3783 ND2 ASN 133 -1.345 66 ATOM 3784 C ASN 133 -0.235 65 ATOM 3785 O ASN 133 -0.227 64 ATOM 3786 N LYS 134 0.070 64 ATOM 3787 CA LYS 134 0.210 63 ATOM 3788 CB LYS 134 1.67 6 63 ATOM 3789 CG LYS 134 2.559 63 ATOM 3790 CD LYS 134 2.539 62 ATOM 3791 CE LYS 134 3.597 62 ATOM 3792 NZ LYS 134 4.983 62 ATOM 3793 C LYS 134 -0.595 63 ATOM 3794 0 LYS 134 -1.126 64 ATOM 3795 N ALA 135 -0.696 61 ATOM 3796 CA ALA 135 -1.287 61 ATOM 3797 CB ALA 135 -2.810 61 ATOM 3798 C ALA 135 -0.749 59 30.395 1.00 62.48 L31H c 32.854 1.00 60.75 L31H c 33.447 1.00 59.69 L31H 0 32.819 1.00 60.32 L31H N 33.416 1.00 58.57 L31H c 33.827 1.00 58.32 L31H c 32.719 1.00 57.04 L31H 0 32.436 1.00 57.83 L31H c 31.223 1.00 56.21 L31H 0 32.981 1.00 58.56 L31H N 32.165 1.00 59.40 L31H c 33.049 1.00 60.04 L31H c 32.312 1.00 61.03 L31H 0 31.207 1.00 59.25 L31H c 30.009 1.00 59.39 L31H 0 31.748 1.00 58.37 L31H N 30.976 1.00 57.49 L31H c 31.830 1.00 58.17 L31H c 32.877 1.00 58.94 L31H c 32.938 1.00 60.68 L31H c 31.902 1.00 61.85 L31H 0 34.016 1.00 60.55 L31H 0 29.728 1.00 55.84 L31H c 28.652 1.00 53.53 L31H 0 29.883 1.00 55.94 L31H N 28.796 1.00 55.91 L31H c 29.316 1.00 57.14 L31H c 28.336 1.00 59.19 L31H c 28.538 1.00 60.92 L31H c 27.906 1.00 60.62 L31H 0 29.328 1.00 61.87 L31H 0 27.747 1.00 55.89 L31H c 26.556 1.00 54.96 L31H 0 28.203 1.00 56.93 L31H N 27.304 1.00 57.51 L31H c 28.112 1.00 57.09 L31H c 28.097 1.00 58.06 L31H c 27.940 1.00 56.91 L31H c 29.366 1.00 57.58 L31H c 26.464 1.00 57.33 L31H c 25.251 1.00 58.08 L31H 0 27 . 111 1.00 57.04 L31H N 26.402 1.00 56.50 L31H c 27.389 1.00 56.13 L31H c 27.972 1.00 59.45 L31H c 26.905 1.00 61.61 L31H c 27.114 1.00 61.71 L31H 0 25.746 1.00 60.83 L31H N 25.340 1.00 57.13 L31H c 24.457 1.00 58.38 L31H 0 25.431 1.00 56.27 L31H N 24.493 1.00 54.83 L31H c 25.199 1.00 53.35 L31H c 23.380 1.00 54.99 L31H c 22.484 1.00 53.23 L31H 0 23.465 1.00 56.66 L31H N 22.499 1.00 58.35 L31H c 21.083 1.00 61.86 L31H c 20.149 1.00 63.84 L31H c 20.322 1.00 64.92 L31H 0 19.148 1.00 63.87 L31H N 22.562 1.00 58.50 L31H c 21.542 1.00 58.17 L31H 0 23.772 1.00 57.34 L31H N 24.045 1.00 55.52 L31H c .24.266 1.00 54.57 L31H c 23.065 1.00 53.32 L31H c 22.131 1.00 53.44 L31H’ c 21.049 1.00 52.60 L31H c 21.589 1.00 51.62 L31H N 25.284 1.00 55.69 L31H c 25.987 1.00 5 6.06 L31H 0 25.545 1.00 55.25 . L31H N 26.793 1.00 55.37 L31H c 26.681 1.00 53.00 ' L31H c 27.120 1.00 55.35 L31H c 370 WO 2009/026558 PCT/US2008/074097 ATOM 3799 0 ALA 135 -0.805 ATOM 3800 N THR 136 -0.202 ATOM 3801 CA THR 136 0.250 ATOM 3802 CB THR 136 1.772 ATOM 3803 OG1 THR 136 2.306 ATOM 3804 CG2 THR 136 2.223 ATOM 3805 C THR 136 -0.323 ATOM 3806 O THR 136 -0.081 ATOM 3807 N LEU 137 -1.091 ATOM 3808 CA LEU 137 -1.559 ATOM 3809 CB LEU 137 -2.723 ATOM 3810 CG LEU 137 -3.954 ATOM 3811 CDl LEU 137 -5.070 ATOM 3812 CD2 LEU 137 -4.420 ATOM 3813 C LEU 137 -0.418 ATOM 3814 O LEU 137 0.310 ATOM 3815 N VAL 138 -0.258 ATOM 3816 CA VAL 138 0.802 ATOM 3817 CB VAL 138 1.685 ATOM 3818 CGI VAL 138 2.717 ATOM 3819 CG2 VAL 138 2.366 ATOM 3820 C VAL 138 0.203 ATOM 3821 O VAL 138 -0.596 ATOM 3822 N CYS 139 0.577 ATOM 3823 CA CYS 139 0.107 ATOM 3824 C CYS 139 1.281 ATOM 3825 0 CYS 139 2.050 ATOM 3826 CB CYS 139 -0.727 ATOM 3827 SG CYS 139 -1.495 ATOM 3828 N LEU 140 1.411 ATOM 3829 CA LEU 140 2.547 ATOM 3830 CB LEU 140 3.230 ATOM 3831 CG LEU 140 3.587 ATOM 3832 CDl LEU 140 3.474 ATOM 3833 CD2 LEU 140 4.975 ATOM 3834 C LEU 140 2.139 ATOM 3835 O LEU 140 1 . 163 ATOM 3836 N ILE 141 2.895 ATOM 3837 CA ILE 141 2.601 ATOM 3838 CB ILE 141 2.208 ATOM 3839 CG2 ILE 141 2.084 ATOM 3840 CGI ILE 141 0.905 ATOM 3841 CDl ILE 141 1 . 111 ATOM 3842 C ILE 141 3.813 ATOM 3843 0 ILE 141 4.911 ATOM 3844 N SER 142 3.614 ATOM 3845 CA SER 142 4.703 ATOM 3846 CB SER 142 5.371 ATOM 3847 OG SER 142 4.482 ATOM 3848 C SER 142 4.237 ATOM 3849 O SER 142 3.041 ATOM 3850 N ASP 143 5.205 ATOM 3851 CA ASP 143 4.990 ATOM 3852 CB ASP 143 4.247 ATOM 3853 CG ASP 143 5.084 ATOM 3854 OD1 ASP 143 6.124 ATOM 3855 OD2 ASP 143 4.703 ATOM 3856 C ASP 143 4.222 ATOM 3857 O ASP 143 3.249 ATOM 3858 N PHE 144 4.654 ATOM 3859 CA PHE 144 4.002 ATOM 3860 CB PHE 144 3.227 ATOM 3861 CG PHE 144 4 . 030 ATOM 3862 CDl PHE 144 4.561 ATOM 3863 CD2 PHE 144 4.236 ATOM 3864 CEl PHE 144 5.282 ATOM 3865 CE2 PHE 144 4 . 956 ATOM 3866 CZ PHE 144 5.479 ATOM 3867 C PHE 144 4.974 ATOM 3868 O PHE 144 6.103 ATOM 3869 N TYR 145 4.523 ATOM 3870 CA TYR 145 5.322 ATOM 3871 CB TYR 145 6.216 ATOM 3872 CG TYR 145 7.203 ATOM 3873 CDl TYR 145 7.035 ATOM 3874 CEl TYR 145 7.939 26.292 1.00 56.00 L31H 0 28.319 1.00 54.87 L31H N 28.754 1.00 54.77 L31H C 28.819 1.00 53.90 L31H c 27.506 1.00 55.20 L31H 0 29.318 1.00 53.01 L31H c 30.095 1.00 55.19 L31H c 31.121 1.00 55.30 L31H 0 30.063 1.00 56.06 L31H N 31.267 1.00 57.51 L31H c 30.931 1.00 58.17 L31H c 30.301 1.00 60.61 L31H c 30.171 1.00 60.26 L31H c 31.159 1.00 60.91 L31H c 31.885 1.00 58.44 L31H c 31.193 1.00 58.78 L31H 0 33.195 1.00 59.31 L31H N 33.890 1.00 60.22 L31H c 34.681 1.00 58.67 L31H c 35.481 1.00 57.67 L31H c 33.724 1.00 59.34 L31H c 34.841 1.00 62.22 L31H c 35.705 1.00 62.49 L31H 0 34.674 1.00 64.39 L31H N 35.574 1.00 66.45 L31H c 36.234 1.00 63.76 L31H c 35.569 1.00 63.60 L31H 0 34.808 1.00 72.30 L31H c 35.852 1.00 80.69 L31H s 37.543 1.00 61.42 L31H N 38.267 1.00 61.83 L31H c 39.082 1.00 59.77 L31H c 38.205 1.00 57.02 L31H c 38.989 1.00 56.73 L31H c 37.659 1.00 58.13 L31H c 39.174 1.00 62.96 L31H c 39.926 1.00 61.87 L31H 0 39.080 1.00 64.43 L31H N 39.812 1.00 65.71 L31H c 38.839 1.00 65.35 L31H c 39.581 1.00 65.06 L31H c 38.129 1.00 65.30 L31H c 36.776 1.00 65.52 L31H c 40.629 1.00 67.11 L31H c 40.094 1.00 66.16 L31H 0 41.926 1.00 68.80 L31H N 42.774 1.00 69.99 L31H c 43.465 1.00 69.56 L31H c 44.364 1.00 69.04 L31H 0 43.824 1.00 72.02 L31H c 44.099 1.00 70.57 L31H 0 44.395 1.00 75.76 L31H N 45.561 1.00 79.15 L31H c 46.652 1.00 79.95 L31H c 47.236 1.00 81.27 L31H c 46.640 1.00 83.43 L31H 0 48.296 1.00 82.20 L31H 0 45.217 1.00 81.34 L31H c 45.886 1.00 81.70 L31H 0 44.169 1.00 84 . 09 L31H N 43.793 1.00 88.16 L31H c 42.485 1.00 8 6.52 L31H c 41.371 1.00 84.52 L31H c 40.376 1.00 83.55 L31H c 41.305 1.00 83.02 L31H c 39.338 1.00 81.29 L31H c 40.269 1.00 81.03 L31H c 39.285 1.00 80.66 L31H c 43.670 1.00 91.37 L31H c 43.200 1.00 92.48 L31H 0 44.109 1.00 93.82 L31H N 44.038 1.00 94.58 L31H c 45.271 1.00 95.09 . L31H c 45.180 1.00 95.11 L31H c 45.932 1.00 95.46 L31H c 45.850 1.00 95.67 L31H c 371 WO 2009/026558 PCT/US2008/074097 ATOM 3875 CD2 TYR 145 8.306 35 ATOM 3876 CE2 TYR 145 9.215 34 ATOM 3877 CZ TYR 145 9.027 33 ATOM 3878 OH TYR 145 9.933 32 ATOM 3879 C TYR 145 4.411 35 ATOM 3880 O TYR 145 3.405 35 ATOM 3881 N PRO 146 4.754 34 ATOM 3882 CD PRO 146 3.974 33 ATOM 3883 CA PRO 146 5.945 34 ATOM 3884 CB PRO 146 5.996 33 ATOM 3885 CG PRO 146 4.586 32 ATOM 3886 C PRO 146 5.880 35 ATOM 3887 O PRO 146 4.796 36 ATOM 3888 N GLY 147 7.048 36 ATOM 3889 CA GLY 147 7.104 37 ATOM 3890 C GLY 147 6.669 36 ATOM 3891 0 GLY 147 7.498 36 ATOM 3892 N ALA 148 5.358 36 ATOM 3893 CA ALA 148 4.796 36 ATOM 3894 CB ALA 148 4.810 35 ATOM 3895 C ALA 148 3.375 37 ATOM 3896 0 ALA 148 2.477 36 ATOM 3897 N VAL 149 3.183 38 ATOM 3898 CA VAL 149 1.890 38 ATOM 3899 CB VAL 149 1.857 40 ATOM 3900 CGI VAL 149 1.858 39 ATOM 3901 CG2 VAL 149 3.069 40 ATOM 3902 C VAL 149 1.609 39 ATOM 3903 O VAL 149 2.528 39 ATOM 3904 N THR 150 0.332 39 ATOM 3905 CA THR 150 -0.069 39 ATOM 3906 CB THR 150 -0.798 38 ATOM 3907 OG1 THR 150 0.127 37 ATOM 3908 CG2 THR 150 -1.410 38 ATOM 3909 C THR 150 -1.005 40 ATOM 3910 O THR 150 -1.935 40 ATOM 3911 N VAL 151 -0.758 41 ATOM 3912 CA VAL 151 -1.558 42 ATOM 3913 CB VAL 151 -0.663 44 ATOM 3914 CGI VAL 151 -1.530 45 ATOM 3915 CG2 VAL 151 0.305 44 ATOM 3916 C VAL 151 -2.544 43 ATOM 3917 O VAL 151 -2.207 42 ATOM 3918 N ALA 152 -3.763 43 ATOM 3919 CA ALA 152 -4.775 43 ATOM 3920 CB ALA 152 -5.788 42 ATOM 3921 C ALA 152 -5.466 45 ATOM 3922 0 ALA 152 -6.002 45 ATOM 3923 N TRP 153 -5.452 45 ATOM 3924 CA TRP 153 -6.007 47 ATOM 3925 CB TRP 153 -5.149 48 ATOM 3926 CG TRP 153 -3.833 48 ATOM 3927 CD2 TRP 153 -3.550 49 ATOM 3928 CE2 TRP 153 -2.188 49 ATOM 3929 CE3 TRP 153 -4.315 50 ATOM 3930 CDl TRP 153 -2.665 47 ATOM 3931 NEl TRP 153 -1.672 48 ATOM 3932 CZ2 TRP 153 -1.576 50 ATOM 3933 CZ3 TRP 153 -3.709 51 ATOM 3934 CH2 TRP 153 -2.349 51 ATOM 3935 C TRP 153 -7.444 47 ATOM 3936 O TRP 153 -7.772 46 ATOM 3937 N LYS 154 -8.301 48 ATOM 3938 CA LYS 154 -9.645 48 ATOM 3939 CB LYS 154 -10.688 47 ATOM 3940 CG LYS 154 -10.824 46 ATOM 3941 CD LYS 154 -10.929 45 ATOM 3942 CE LYS 154 -10.925 44 ATOM 3943 NZ LYS 154 -9.774 43 ATOM 3944 C LYS 154 -9.791 49 ATOM 3945 0 LYS 154 -9.726 50 ATOM 3946 N ALA 155 -9.987 50 ATOM 3947 CA ALA 155 -10.381 51 ATOM 3948 CB ALA 155 -10.121 51 ATOM 3949 C ALA 155 -11.865 51 ATOM 3950 0 ALA 155 -12.712 50 44.336 1.00 95.57 L31H c 44 .245 1.00 95.35 L31H c 45.007 1.00 95.54 L31H c 44.935 1.00 93.89 L31H 0 43.947 1.00 96.10 L31H c 44.649 1.00 95.23 L31H .0 43.072 1.00 98.97 L31H N 42.816 1.00102.65 L31H c 42.217 1.00100.63 L31H c 41.552 1.00103.16 L31H c 41.560 1.00103.82 L31H c 41.196 1.00101.63 L31H c 40.814 1.00101.06 L31H 0 40.764 1.00103.99 L31H N 39.837 1.00106.69 L31H c 38.428 1.00107.75 L31H c 37.535 1.00109.16 L31H 0 38.231 1.00106.88 L31H N 36.918 1.00106.36 L31H c 36.644 1.00106.24 L31H c 36.844 1.00106.36 L31H c 37.521 1.00105.85 L31H 0 36.014 1.00107.52 L31H N 35.871 1.00108.34 L31H c 36.625 1.00108.35 L31H c 38.121 1.00108.86 L31H c 36.237 1.00108.49 L31H c 34.405 1.00108.11 L31H c 33.591 1.00108.80 L31H 0 34.075 1.00107.28 L31H N 32.733 1.00106.06 L31H c 32. Oil 1.00105.51 L31H c 31.725 1.00104.72 L31H 0 30.715 1.00104.90 L31H c 32.824 1.00105.63 L31H c 33.628 1.00106.26 L31H 0 31.995 1.00104.86 L31H N 32.022 1.00103.61 L31H c 31.995 1.00103.81 L31H c 32.047 1.00103.60 L31H c 33.166 1.00102.99 L31H c 30.861 1.00101.69 L31H c 29.721 1.00101.44 L31H 0 31.166 1.00 99.44 L31H N 30.147 1.00 97.98 L31H c 30.161 1.00 96.47 L31H c 30.423 1.00 97.32 L31H c 31.511 1.00 98.16 L31H 0 29.436 1.00 95.82 L31H N 29.607 1.00 94.83 L31H c 28.857 1.00 89.61 L31H c 29.516 1.00 83.09 L31H c 30.356 1.00 80.15 L31H c 30.724 1.00 78.88 L31H c 30.832 1.00 78.10 L31H c 29.413 1.00 81.18 L31H c 30.136 1.00 78.50 L31H N 31.544 1.00 78.36 L31H c 31.645 1.00 78.62 L31H c 31.994 1.00 79.04 L31H c 29.102 1.00 97.21 L31H c 28.054 1.00 97.31 L31H 0 29.846 1.00100.61 L31H N 29.366 1.00104.68 L31H c 30.422 1.00104.13 L31H c 30.667 1.00104.81 L31H c 29.358 1.00106.43 L31H c 29.604 1.00108.33 L31H c 30.447 1.00112.27 L31H N 29.011 1.00108.13 L31H c 29.883 1.00108.54 L31H 0 27.723 1.00112.59 L31H N 27.258 1.00115.22 . L31H c 25.761 1.00118.02 L31H c 27.555 1.00116.52 ' L31H c 26.879 1.00115.14 L31H 0 372 WO 2009/026558 PCT/US2008/074097
ATOM 3951 N ASP 156 -12.170 52.324 28.575 1.00118.91 L31H N ATOM 3952 CA ASP 156 -13.519 52.392 29.120 1.00122.96 L31H C ATOM 3953 CB ASP 156 -14.509 52.810 28.028 1.00123.77 L31H C ATOM 3954 CG ASP 156 -15.840 53.254 28.589 1.00125.04 L31H c ATOM 3955 OD1 ASP 156 -16.106 54.475 28.587 1.00126.49 L31H 0 ATOM 3956 OD2 ASP 156 -16.619 52.382 29.031 1.00126.62 L31H 0 ATOM 3957 C ASP 156 -13.885 51.016 29.676 1.00125.66 L31H c ATOM 3958 O ASP 156 -13.474 50.653 30.779 1.00124.90 L31H 0 ATOM 3959 N SER 157 -14.649 50.251 28.905 1.00129.31 L31H N ATOM 3960 CA SER 157 -14.951 48.869 29.257 1.00133.75 L31H c ATOM 3961 CB SER 157 -16.420 48.739 29.660 1.00133.49 L31H c ATOM 3962 OG SER 157 -16.729 49.610 30.736 1.00132.03 L31H 0 ATOM 3963 C SER 157 -14.651 47.984 28.055 1.00136.62 L31H c ATOM 3964 O SER 157 -14.649 46.755 28.146 1.00137.92 L31H 0 ATOM 3965 N SER 158 -14.401 48.632 26.923 1.00138.76 L31H N ATOM 3966 CA SER 158 -13.950 47.944 25.725 1.00139.39 L31H c ATOM 3967 CB SER 158 -14.216 48.808 24.492 1.00138.66 L31H c ATOM 3968 OG SER 158 -15.557 49.263 24.468 1.00135.17 L31H 0 ATOM 3969 C SER 158 -12.456 47.666 25.845 1.00140.86 L31H c ATOM 3970 O SER 158 -11.651 48.583 26.018 1.00142.39 L31H 0 ATOM 3971 N PRO 159 -12.071 46.386 25.760 1.00141.72 L31H N ATOM 3972 CD PRO 159 -13.033 45.270 25.740 1.00142.52 L31H c ATOM 3973 CA PRO 159 -10.681 45.914 25.858 1.00142.97 L31H c ATOM 3974 CB PRO 159 -10.818 44.391 25.810 1.00142.77 L31H c ATOM 3975 CG PRO 159 -12.225 44.122 2 6.2 62 1.00142.30 L31H c ATOM 3976 C PRO 159 -9.746 46.433 24.755 1.00144.51 L31H c ATOM 3977 O PRO 159 -9.762 45.930 23.629 1.00144.32 L31H 0 ATOM 3978 N VAL 160 -8.920 47.423 25.088 1.00145.75 L31H N ATOM 3979 CA VAL 160 -7.951 47.968 24.140 1.00146.54 L31H c ATOM 3980 CB VAL 160 -7.373 49.294 24.640 1.00145.44 L31H c ATOM 3981 CGI VAL 160 -6.897 49.139 26.068 1.00144.76 L31H c ATOM 3982 CG2 VAL 160 -6.214 49.715 23.754 1.00144.65 L31H c ATOM 3983 C VAL 160 -6.786 47.017 23.892 1.00147.40 L31H c ATOM 3984 O VAL 160 -6.278 46.393 24.820 1.00149.15 L31H 0 ATOM 3985 N LYS 161 -6.360 46.921 22.637 1.00147.17 L31H N ATOM 3986 CA LYS 161 -5.296 45.995 22.257 1.00146.00 L31H c ATOM 3987 CB LYS 161 -5.794 45.039 21.166 1.00149.06 L31H c ATOM 3988 CG LYS 161 -7.090 44.313 21.506 1.00152.58 L31H c ATOM 3989 CD LYS 161 -6.931 43.408 22.719 1.00155.68 L31H c ATOM 3990 CE LYS 161 -8.256 42.765 23.106 1.00157.97 L31H c ATOM 3991 NZ LYS 161 -8.862 42.009 21.976 1.00159.35 L31H N ATOM 3992 C LYS 161 -4.035 46.712 21.766 1.00143.65 L31H c ATOM 3993 0 LYS 161 -2.954 46.121 21.722 1.00142.97 L31H 0 ATOM 3994 N ALA 162 -4.175 47.981 21.391 1.00141.12 L31H N ATOM 3995 CA ALA 162 -3.054 48.748 20.855 1.00137.51 L31H c ATOM 3996 CB ALA 162 -3.354 49.183 19.427 1.00139.76 L31H c ATOM 3997 C ALA 162 -2.743 49.966 21.716 1.00134 .24 L31H c ATOM 3998 0 ALA 162 -3.619 50.502 22.395 1.00132.85 L31H 0 ATOM 3999 N GLY 163 -1.489 50.399 21.680 1.00130.13 L31H N ATOM 4000 CA GLY 163 -1.082 51.547 22.469 1.00125.56 L31H c ATOM 4001 C GLY 163 -0.547 51.148 23.829 1.00122.13 L31H c ATOM 4002 0 GLY 163 -0.385 51.983 24.719 1.00122.41 L31H 0 ATOM 4003 N VAL 164 -0.274 49.859 23.989 1.00117.65 L31H N ATOM 4004 CA VAL 164 0.178 49.329 25.264 1.00112.18 L31H c ATOM 4005 CB VAL 164 -0.770 48.246 25.771 1.00111.56 L31H c ATOM 4006 CGI VAL 164 -0.274 47.711 27.098 1.00110.84 L31H c ATOM 4007 CG2 VAL 164 -2.169 48.805 25.897 1.00110.72 L31H c ATOM 4008 C VAL 164 1.563 48.721 25.145 1.00108.74 L31H c ATOM 4009 O VAL 164 1.923 48.178 24.104 1.00109.80 L31H 0 ATOM 4010 N GLU 165 2.340 48.810 26.214 1.00103.31 L31H N ATOM 4011 CA GLU 165 3.605 48.099 26.271 1.00 97.93 L31H c ATOM 4012 CB GLU 165 4.683 48.891 25.534 1.00 99.42 L31H c ATOM 4013 CG GLU 165 5.841 48.038 25.045 1.00102.44 L31H c ATOM 4014 CD GLU 165 6.165 48.284 23.583 1.00104.36 L31H c ATOM 4015 OE1 GLU 165 6.303 47.296 22.829 1.00105.42 L31H 0 ATOM 4016 OE2 GLU 165 6.281 49.467 23.191 1.00105.49 L31H 0 ATOM 4017 C GLU 165 4.004 47.874 27.725 1.00 93.34 L31H c ATOM 4018 0 GLU 165 4 .181 48.826 28.484 1.00 92.89 L31IT 0 ATOM 4019 N THR 166 4 . 132 46.610 28.113 1.00 87.51 L31H N ATOM 4020 CA THR 166 4.417 46.263 29.498 1.00 82.22 L31H c ATOM 4021 CB THR 166 3.504 45.138 29.970 1.00 79.71 L31H c ATOM 4022 OG1 THR 166 2.136 45.535 29.821 1.00 77.59 L31H 0 ATOM 4 02 3 CG2 THR 166 3.784 44.814 31.415 1.00 78.67 . L31H c ATOM 4024 C THR 166 5.8 62 45.805 29.647 1.00 81.16 L31H c ATOM 4 02 5 O THR 166 6.469 45.332 28.687 1.00 81.15 ' L31H 0 ATOM 4 02 6 N THR 167 6.425 45.953 30.842 1.00 79.71 L31H N 373 WO 2009/026558 PCT/US2008/074097
ATOM 4027 CA THR 167 7.755 45.411 31.101 1.00 78.78 L31H c ATOM 4028 CB THR 167 8.555 46.266 32.125 1.00 77.41 L31H c ATOM 4029 OG1 THR 167 7.949 46.166 33.418 1.00 75.88 L31H 0 ATOM 4030 CG2 THR 167 8.588 47.723 31.701 1.00 75.26 L31H c ATOM 4031 C THR 167 7.640 43.990 31.650 1.00 79.22 L31H c ATOM 4032 O THR 167 6.599 43.588 32.174 1.00 79.15 L31H _0. ATOM 4033 N THR 168 8.714 43.226 31.515 1.00 79.89 L31H N ATOM 4034 CA THR 168 8.823 41.965 32.220 1.00 80.51 L31H c ATOM 4035 CB THR 168 9.904 41.072 31.594 1.00 80.02 L31H c ATOM 4036 OG1 THR 168 11.170 41.744 31.649 1.00 80.02 L31H 0 ATOM 4037 CG2 THR 168 9.553 40.758 30.139 1.00 78.70 L31H c ATOM 4038 C THR 168 9.194 42.275 33.664 1.00 81.33 L31H c ATOM 4039 O THR 168 10.021 43.149 33.937 1.00 80.31 L31H 0 ATOM 4040 N PRO 169 8.570 41.565 34.609 1.00 82.60 L31H N ATOM 4041 CD PRO 169 7.606 40.479 34.373 1.00 80.47 L31H c ATOM 4042 CA PRO 169 8.725 41.854 36.035 1.00 85.29 L31H c ATOM 4043 CB PRO 169 7.885 40.775 36.706 1.00 82.01 L31H c ATOM 4044 CG PRO 169 6.876 40.399 35.673 1.00 79.24 L31H c ATOM 4045 C PRO 169 10.179 41.824 36.483 1.00 89.48 L31H c ATOM 4046 O PRO 169 11.051 41.286 35.797 1.00 91.81 L31H 0 ATOM 4047 N SER 170 10.437 42.412 37.642 1.00 92.27 L31H N ATOM 4048 CA SER 170 11.800 42.582 38.105 1.00 94.31 L31H c ATOM 4049 CB SER 170 12.258 44.010 37.807 1.00 94.07 L31H c ATOM 4050 OG SER 170 13.452 44.326 38.498 1.00 89.69 L31H 0 ATOM 4051 C SER 170 11.886 42.300 39.596 1.00 96.61 L31H c ATOM 4052 O SER 170 10.964 42.609 40.347 1.00 97.99 L31H 0 ATOM 4053 N LYS 171 12.996 41.707 40.020 1.00 98.61 L31H N ATOM 4054 CA LYS 171 13.235 41.485 41.439 1.00 99.91 L31H c ATOM 4055 CB LYS 171 14.609 40.856 41.664 1.00100.64 L31H c ATOM 4056 CG LYS 171 14.768 39.457 41.092 1.00103.49 L31H c ATOM 4057 CD LYS 171 14.183 38.400 42.018 1.00108.13 L31H c ATOM 4058 CE LYS 171 14.654 37.002 41.624 1.00111.94 L31H c ATOM 4059 NZ LYS 171 14.016 35.924 42.438 1.00117.51 L31H N ATOM 4060 C LYS 171 13.173 42.814 42.164 1.00 99.93 L31H c ATOM 4061 0 LYS 171 13.773 43.791 41.727 1.00 99.84 L31H 0 ATOM 4 0 62 N GLN 172 12.443 42.848 43.271 1.00100.47 L31H N ATOM 4063 CA GLN 172 12.382 44.039 44 .101 1.00101.48 L31H c ATOM 4064 CB GLN 172 11.002 44.178 44.740 1.00 98.99 L31H c ATOM 4065 CG GLN 172 9.949 44.798 43.840 1.00 94.44 L31H c ATOM 4066 CD GLN 172 8.802 45.394 44.630 1.00 91.26 L31H c ATOM 4067 OE1 GLN 172 7.771 44.757 44.825 1.00 89.71 L31H 0 ATOM 4068 NE2 GLN 172 8.980 46.626 45.093 1.00 89.08 L31H N ATOM 4069 C GLN 172 13.436 43.996 45.196 1.00103.90 L31H c ATOM 4070 0 GLN 172 13.942 42.926 45.546 1.00104.53 L31H 0 ATOM 4071 N SER 173 13.763 45.167 45.735 1.00106.09 L31H N ATOM 4072 CA SER 173 14.639 45.244 46.892 1.00107.30 L31H c ATOM 4073 CB SER 173 14.693 46.685 47.431 1.00108.22 L31H c ATOM 4074 OG SER 173 13.400 47.231 47.635 1.00109.67 L31H 0 ATOM 4075 C SER 173 14.121 44.284 47.960 1.00107.59 L31H c ATOM 4076 O SER 173 14.899 43.592 48.609 1.00107.41 L31H 0 ATOM 4077 N ASN 174 12.802 44.221 48.118 1.00108.22 L31H N ATOM 4078 CA ASN 174 12.195 43.317 49.091 1.00109.03 L31H c ATOM 4079 CB ASN 174 10.791 43.792 49.460 1.00111.08 L31H c ATOM 4080 CG ASN 174 9.730 43.232 48.535 1.00113.10 L31H c ATOM 4081 OD1 ASN 174 9.974 43.021 47.348 1.00114.08 L31H 0 ATOM 4082 ND2 ASN 174 8.542 42.986 49.077 1.00114.85 L31H N ATOM 4083 C ASN 174 12.115 41.888 48.559 1.00108.23 L31H c ATOM 4084 0 ASN 174 11.580 41.004 49.227 1.00108.50 L31H 0 ATOM 4085 N ASN 175 12.624 41.672 47.350 1.00106.34 L31H N ATOM 4086 CA ASN 175 12.779 40.328 46.804 1.00103.04 L31H c ATOM 4087 CB ASN 175 13.367 39.407 47.868 1.00105.63 L31H c ATOM 4088 CG ASN 175 13.858 38.101 47.294 1.00108.23 L31H c ATOM 4089 OD1 ASN 175 13.064 37.240 46.912 1.00110.12 L31H 0 ATOM 4090 ND2 ASN 175 15.175 37.942 47.226 1.00108.79 L31H N ATOM 4091 C ASN 175 11.488 39.719 46.243 1.00 98.67 L31H c ATOM 4 0 92 0 ASN 175 11.485 38.590 ,45.754 1.00 98.94 L31H 0 ATOM 4093 N LYS 176 10.391 40.467 46.316 1.00 92.52 L31H N ATOM 4094 CA LYS 176 9.232 40.193 45.467 1.00 84.85 L31H' c ATOM 4095 CB LYS 176 7.957 40.777 46.076 1.00 82.79 L31H c ATOM 4096 CG LYS 176 7.607 40.260 47.446 1.00 78.63 L31H c ATOM 4097 CD LYS 176 6.213 40.708 47.808 1.00 76.31 L31H c ATOM 4098 CE LYS 176 5.944 40.605 49.289 1.00 74.93 L31H c ATOM 4099 NZ LYS 176 4.626 41.208 49.610 1.00 73.02 . L31H N ATOM 4100 C LYS 176 9.475 40.837 44.101 1.00 81.53 L31H c ATOM 4101 0 LYS 176 10.603 41.215 43.777 1.00 79.55 ' L31H 0 ATOM 4102 N TYR 177 8.422 40.980 43.303 1.00 78.56 L31H N 374 WO 2009/026558 PCT/US2008/074097 ATOM 4103 CA TYR 177 8.594 41 ATOM 4104 CB TYR 177 8.269 40 ATOM 4105 CG TYR 177 9.271 39 ATOM 4106 CDl TYR 177 10.276 39 ATOM 4107 CEl TYR 177 11.193 38 ATOM 4108 CD2 TYR 177 9.216 38 ATOM 4109 CE2 TYR 177 10.126 37 ATOM 4110 CZ TYR 177 11.110 37 ATOM 4111 OH TYR 177 12.005 36 ATOM 4112 C TYR 177 7.812 42 ATOM 4113 O TYR 177 6.801 43 ATOM 4114 N ALA 178 8.318 43 ATOM 4115 CA ALA 178 7.723 44 ATOM 4116 CB ALA 178 8.625 46 ATOM 4117 C ALA 178 7.592 44 ATOM 4118 O ALA 178 8.361 44 ATOM 4119 N ALA 179 6.62 6 45 ATOM 4120 CA ALA 179 6.476 45 ATOM 4121 CB ALA 179 5.974 44 ATOM 4122 C ALA 179 5.532 46 ATOM 4123 O ALA 179 4.528 47 ATOM 4124 N SER 180 5.854 47 ATOM 4125 CA SER 180 5.019 48 ATOM 4126 CB SER 180 5.809 49 ATOM 4127 OG SER 180 7.114 49 ATOM 4128 C SER 180 4.470 48 ATOM 4129 O SER 180 5.167 47 ATOM 4130 N SER 181 3.216 48 ATOM 4131 CA SER 181 2.627 48 ATOM 4132 CB SER 181 1 . 489 47 ATOM 4133 OG SER 181 1.028 47 ATOM 4134 C SER 181 2.091 50 ATOM 4135 O SER 181 1.392 50 ATOM 4136 N TYR 182 2.415 50 ATOM 4137 CA TYR 182 1.992 52 ATOM 4138 CB TYR 182 3.190 52 ATOM 4139 CG TYR 182 4.257 53 ATOM 4140 CDl TYR 182 5.161 52 ATOM 4141 CEl TYR 182 6.159 52 ATOM 4142 CD2 TYR 182 4.377 54 ATOM 4143 CE2 TYR 182 5.369 54 ATOM 4144 CZ TYR 182 6.264 53 ATOM 4145 OH TYR 182 7.264 53 ATOM 4146 C TYR 182 0.971 51 ATOM 4147 O TYR 182 1.008 51 ATOM 4148 N LEU 183 0.077 52 ATOM 4149 CA LEU 183 -0.935 53 ATOM 4150 CB LEU 183 -2.328 52 ATOM 4151 CG LEU 183 -3.392 52 ATOM 4152 CDl LEU 183 -2.992 52 ATOM 4153 CD2 LEU 183 -4.749 52 ATOM 4154 C LEU 183 -0.930 54 ATOM 4155 O LEU 183 -1.397 55 ATOM 4156 N SER 184 -0.439 54 ATOM 4157 CA SER 184 -0.326 55 ATOM 4158 CB SER 184 0.806 55 ATOM 4159 OG SER 184 2.085 55' ATOM 4160 C SER 184 -1.611 55 ATOM 4161 O SER 184 -2.030 55 ATOM 4162 N LEU 185 -2 .217 57 ATOM 4163 CA LEU 185 -3.396 57 ATOM 4164 CB LEU 185 -4.493 57 ATOM 4165 CG LEU 185 -5.146 56 ATOM 4166 CDl LEU 185 -6.109 57 ATOM 4167 CD2 LEU 185 -5.871 55 ATOM 4168 C LEU 185 -3.103 58 ATOM 4169 O LEU 185 -1.968 59 ATOM 4170 N THR 186 -4.149 59 ATOM 4171 CA THR 186 -4.165 60 ATOM 4172 CB THR 186 -4.752 60 ATOM 4173 OG1 THR 186 -6.127 60 ATOM 4174 CG2 THR 186 -3.981 60 ATOM 4175 C THR 186 -5.093 61 ATOM 4176 O THR 186 -6.005 61 ATOM 4177 N PRO 187 -4.882 62 ATOM 4178 CD PRO 187 -3.868 63
41.979 1.00 75.70 L31H c 40.916 1.00 75.16 L31H c 40.898 1.00 76.26 L31H c 39.948 1.00 75.58 L31H c 39.940 1.00 76.47 L31H c 41.843 1.00 76.97 L31H c 41.839 1.00 76.87 L31H "c 40.888 1.00 76.76 L31H c 40.877 1.00 79.13 L31H 0 41.716 1.00 73.16 L31H c 42.357 1.00 73.48 L31H 0 40.762 1.00 69.40 L31H N 40.352 1.00 65.29 L31H c 40.787 1.00 64.49 L31H c 38.833 1.00 62.74 L31H c 38.156 1.00 62.95 L31H 0 38.303 1.00 59.52 L31H N 36.858 1.00 57.65 L31H C 36.267 1.00 57.21 L31H C 36.473 1.00 56.23 L31H C 37.144 1.00 56.72 L31H 0 35.384 1.00 53.90 L31H N 34.912 1.00 53.09 L31H C 34.967 1.00 51.19 L31H C 34.444 1.00 48.03 L31H O 33.501 1.00 53.56 L31H C 32.629 1.00 52.95 L31H O 33.288 1.00 53.75 L31H N 31.956 1.00 5 6.72 L31H C 31.910 1.00 58.34 L31H C 30.587 1.00 61.46 L31H O 31.607 1.00 58.40 L31H C 32.417 1.00 58.88 L31H O 30.410 1.00 59.24 L31H N 29.994 1.00 60.58 L31H C 29.526 1.00 59.97 L31H C 30.567 1.00 61.07 L31H C 30.852 1.00 61.25 L31H C 31.783 1.00 63.96 L31H C 31.243 1.00 62.41 L31H C 32.177 1.00 64.17 L31H C 32.449 1.00 65.02 L31H C 33.386 1.00 64.46 L31H 0 28.863 1.00 61.39 L31H c 28.025 1.00 61.61 L31H 0 28.831 1.00 61.88 L31H N 27.777 1.00 63.70 L31H C 28.354 1.00 62.49 L31H C 27.265 1.00 61.82 L31H C 26.097 1.00 60.30 L31H C 27.815 1.00 63.19 L31H C 27.044 1.00 65.27 L31H c 27.587 1.00 66.49 L31H 0 25.805 1.00 66.26 L31H N 25.029 1.00 65.98 L31H C 23.999 1.00 64.96 L31H C 24.613 1.00 60.60 L31H O 24.299 1.00 66.76 L31H C 23.379 1.00 67.45 L31H O 24.705 1.00 67.44 L31H N 24.035 1.00 66.92 L31H C 25.054 1.00 65.96 L31H C 25.720 1.00 65.79 L31H C 26.794 1.00 65.42 L31H C 24.673 1.00 66.19 L31H C 2 3.2 62 1.00 67.86 L31H C '23.227 1.00 66.43 L31H O 22.637 1.00 69.39 L31H- N 22.143 1.00 70.50 L31H C 20.739 1.00 71.20 L31H C 20.780 1.00 73.03 L31H O 19.792 1.00 70.92 L31H C 23.071 1.00 72 .25 , L31H C 23.648 1.00 71.28 L31H O 23.227 1.00 74.63 L31H N 22.607 1.00 75.83 L31H C 375 WO 2009/026558 PCT/US2008/074097 ATOM 4179 CA PRO 187 -5.702 63.639 24.193 1.00 77.83 L31H c ATOM 4180 CB PRO 187 -5.257 65.091 24.016 1.00 76.66 L31H c ATOM 4181 CG PRO 187 -3.865 64.986 23.509 1.00 75.65 L31H c ATOM 4182 C PRO 187 -7.183 63.447 23.912 1.00 81.70 L31H c ATOM 4183 O PRO 187 -7.983 63.246 24.828 1.00 82.51 L31H 0 ATOM 4184 N GLU 188 -7.546 63.487 22.638 1.00 86.40 L31H N ATOM 4185 CA GLU 188 -8.949 63.405 22.266 1.00 90.69 L31H c ATOM 4186 CB GLU 188 -9.095 63.677 20.764 1.00 93.16 L31H c ATOM 4187 CG GLU 188 -8.586 65.065 20.335 1.00 96.35 L31H c ATOM 4188 CD GLU 188 -7.112 65.069 19.929 1.00 98.21 L31H c ATOM 4189 OE1 GLU 188 -6.420 66.079 20.197 1.00 98.38 L31H 0 ATOM 4190 OE2 GLU 188 -6.648 64.066 19.337 1.00 99.43 L31H 0 ATOM 4191 C GLU 188 -9.540 62.037 22.646 1.00 91.37 L31H c ATOM 4192 0 GLU 188 -10.648 61.957 23.185 1.00 91.61 L31H 0 ATOM 4193 N GLN 189 -8.790 60.969 22.385 1.00 91.22 L31H N ATOM 4194 CA GLN 189 -9.160 59.642 22.872 1.00 90.89 L31H c ATOM 4195 CB GLN 189 -8.070 58.625 22.520 1.00 90.99 L31H c ATOM 4196 CG GLN 189 -8.070 58.177 21.077 1.00 92.41 L31H c ATOM 4197 CD GLN 189 -7.153 56.987 20.842 1.00 94.60 L31H c ATOM 4198 OE1 GLN 189 -5.963 57.035 21.157 1.00 96.03 L31H 0 ATOM 4199 NE2 GLN 189 -7.706 55.910 20.285 1.00 95.79 L31H N ATOM 4200 C GLN 189 -9.364 59.655 24.390 1.00 91.43 L31H c ATOM 4201 0 GLN 189 -10.352 59.129 24.900 1.00 90.47 L31H 0 ATOM 4202 N TRP 190 -8.419 60.263 25.101 1.00 92.68 L31H N ATOM 4203 CA TRP 190 -8.422 60.283 26.559 1.00 93.50 L31H c ATOM 4204 CB TRP 190 -7.126 60.914 27.068 1.00 89.68 L31H c ATOM 4205 CG TRP 190 -7.192 61.346 28.504 1.00 84.95 L31H c ATOM 4206 CD2 TRP 190 -7.416 60.504 29.642 1.00 81.90 L31H c ATOM 4207 CE2 TRP 190 -7.386 61.329 30.781 1.00 80.42 L31H c ATOM 4208 CE3 TRP 190 -7.637 59.132 29.806 1.00 79.74 L31H c ATOM 4209 CDl TRP 190 -7.042 62.613 28.988 1.00 82.64 L31H c ATOM 4210 NEl TRP 190 -7.157 62.611 30.355 1.00 81.46 L31H N ATOM 4211 CZ2 TRP 190 -7.570 60.826 32.068 1.00 78.89 L31H c ATOM 4212 CZ3 TRP 190 -7.818 58.637 31.081 1.00 77.91 L31H c ATOM 4213 CH2 TRP 190 -7.783 59.482 32.195 1.00 78.15 L31H c ATOM 4214 C TRP 190 -9.610 61.045 27.135 1.00 96.42 L31H c ATOM 4215 O TRP 190 -10.117 60.709 28.210 1.00 97.82 L31H 0 ATOM 4216 N LYS 191 -10.047 62.077 26.422 1.00 98.25 L31H N ATOM 4217 CA LYS 191 -11.203 62.852 26.846 1.00100.49 L31H c ATOM 4218 CB LYS 191 -11.041 64.311 26.415 1.00101.18 L31H c ATOM 4219 CG LYS 191 -9.788 64.978 26.969 1.00102.90 L31H c ATOM 4220 CD LYS 191 -9.867 66.503 26.892 1.00106.93 L31H c ATOM 4221 CE LYS 191 -9.818 67.013 25.448 1.00110.65 L31H c ATOM 4222 NZ LYS 191 -8.442 67.022 24.860 1.00114.77 L31H N ATOM 4223 C LYS 191 -12.477 62.266 26.249 1.00102.09 L31H c ATOM 4224 0 LYS 191 -13.582 62.683 26.591 1.00101.51 L31H 0 ATOM 4225 N SER 192 -12.306 61.287 25.363 1.00104.72 L31H N ATOM 4226 CA SER 192 -13.417 60.682 24.629 1.00106.72 L31H c ATOM 4227 CB SER 192 -12.921 60.124 23.295 1.00106.20 L31H c ATOM 4228 OG SER 192 -13.778 59.094 22.834 1.00104.28 L31H 0 ATOM 4229 C SER 192 -14.151 59.571 25.381 1.00108.14 L31H c ATOM 4230 O SER 192 -15.380 59.490 25.333 1.00109.03 L31H 0 ATOM 4231 N HIS 193 -13.398 58.708 26.057 1.00109.30 L31H N ATOM 4232 CA HIS 193 -13.983 57.583 26.780 1.00111.11 L31H c ATOM 4233 CB HIS 193 -12.986 56.425 26.830 1.00111.11 L31H c ATOM 4234 CG HIS 193 -12.560 55.939 25.476 1.00111.14 L31H c ATOM 4235 CD2 HIS 193 -12.706 54.734 24.873 1.00111.10 L31H c ATOM 4236 NDl HIS 193 -11.882 56.736 24.578 1.00111.45 L31H N ATOM 4237 CEl HIS 193 -11.629 56.044 23.480 1.00111.53 L31H c ATOM 4238 NE2 HIS 193 -12.118 54.826 23.634 1.00111.26 L31H N ATOM 4239 C HIS 193 -14.397 57.990 28.195 1.00113.91 L31H C ATOM 4240 0 HIS 193 -14.072 59.088 28.655 1.00111.98 L31H 0 ATOM 4241 N ARG 194 -15.127 57.112 28.878 1.00118.43 L31H N ATOM 4242 CA ARG 194 -15.711 57.466 30.168 1.00123.44 L31H C ATOM 4243 CB ARG 194 -16.983 56.645 30.416 1.00125.26 L31H c ATOM 4244 CG ARG 194 -18.237 57.237 29.774 1.00128.96 L31H c ATOM 4245 CD ARG 194 -18.480 58.659 30.274 1.00132.25 L31H c ATOM 4246 NE ARG 194 -19.711 59.247 29.752 1.00136.13 L31H' N ATOM 4247 CZ ARG 194 -20.074 60.510 29.952 1.00138.35 L31H c ATOM 4248 NHl ARG 194 -21.209 60.967 29.442 1.00140.09 L31H N ATOM 4249 NH2 ARG 194 -19.300 61.319 30.662 1.00140.23 L31H N ATOM 4250 C ARG 194 -14.728 57.273 31.315 1.00124.67 L31H C ATOM 4251 O ARG 194 -14.760 58.008 32.304 1.00126.55 . L31H 0 ATOM 4252 N SER 195 -13.850 56.287 31.169 1.00124.75 L31H N ATOM 4253 CA SER 195 -12.792 56.039 32.144 1.00123.68 L31H C ATOM 4254 CB SER 195 -13.382 55.629 33.485 1.00124.49 L31H c 376 WO 2009/026558 PCT/US2008/074097 ATOM 4255 OG SER 195 -13.668 54 ATOM 4256 C SER 195 -11.930 54 ATOM 4257 O SER 195 -12.385 54 ATOM 4258 N TYR 196 -10.690 54 ATOM 4259 CA TYR 196 -9.808 53 ATOM 4260 CB TYR 196 -8.525 54 ATOM 4261 CG TYR 196 -8.693 54 ATOM 4262 CDl TYR 196 -8.219 53 ATOM 4263 CEl TYR 196 -8.356 54 ATOM 4264 CD2 TYR 196 -9.316 55 ATOM 4265 CE2 TYR 196 -9.457 56 ATOM 4266 CZ TYR 196 -8.974 55 ATOM 4267 OH TYR 196 -9.100 56 ATOM 4268 C TYR 196 -9.463 52 ATOM 4269 O TYR 196 -9.385 53 ATOM 4270 N SER 197 -9.265 51 ATOM 4271 CA SER 197 -8.875 50 ATOM 4272 CB SER 197 -10.025 49 ATOM 4273 OG SER 197 -11.131 50 ATOM 4274 C SER 197 -7.650 49 ATOM 4275 O SER 197 -7.510 49 ATOM 4276 N CYS 198 -6.763 49 ATOM 4277 CA CYS 198 -5.640 48 ATOM 4278 C CYS 198 -5.983 47 ATOM 4279 0 CYS 198 -6.588 47 ATOM 4280 CB CYS 198 -4.387 49 ATOM 4281 SG CYS 198 -2.880 48 ATOM 4282 N GLN 199 -5.613 46 ATOM 4283 CA GLN 199 -5.964 45 ATOM 4284 CB GLN 199 -7.214 44 ATOM 4285 CG GLN 199 -8.459 45 ATOM 4286 CD GLN 199 -9.671 44 ATOM 4287 OEl GLN 199 -9.569 43 ATOM 4288 NE2 GLN 199 -10.831 45 ATOM 4289 C GLN 199 -4.852 44 ATOM 4290 0 GLN 199 -4.604 43 ATOM 4291 N VAL 200 -4.197 43 ATOM 4292 CA VAL 200 -3.076 42 ATOM 4293 CB VAL 200 -1.931 43 ATOM 4294 CGI VAL 200 -0.764 42 ATOM 4295 CG2 VAL 200 -1.484 44 ATOM 4296 C VAL 200 -3.496 41 ATOM 4297 O VAL 200 -4.264 41 ATOM 4298 N THR 201 -2.984 40 ATOM 4299 CA THR 201 -3.321 39 ATOM 4300 CB THR 201 -3.668 38 ATOM 4301 OG1 THR 201 -4.591 39 ATOM 4302 CG2 THR 201 -4.292 36 ATOM 4303 C THR 201 -2.121 38 ATOM 4304 O THR 201 -1.079 38 ATOM 4305 N HIS 202 -2.265 38 ATOM 4306 CA HIS 202 -1.243 37 ATOM 4307 CB HIS 2 02 -0.565 38 ATOM 4308 CG HIS 202 0.532 37 ATOM 4309 CD2 HIS 202 1.730 37 ATOM 4310 NDl HIS 202 0.460 37 ATOM 4311 CEl HIS 202 1.566 36 ATOM 4312 NE2 HIS 202 2.353 36 ATOM 4313 C HIS 202 -1.856 36 ATOM 4314 0 HIS 202 -2.775 36 ATOM 4315 N GLU 203 -1.337 34 ATOM 4316 CA GLU 203 -1.795 33 ATOM 4317 CB GLU 203 -1.393 33 ATOM 4318 CG GLU 203 0.065 33 ATOM 4319 CD GLU 203 0.423 31 ATOM 4320 OEl GLU 203 0.839 31 ATOM 4321 OE2 GLU 203 0.288 31 ATOM 4322 C GLU 203 -3.302 33 ATOM 4323 0 GLU 203 -3.943 32 ATOM 4324 N GLY 203 -3.866 33 ATOM 4325 CA GLY 203 -5.292 33 ATOM 4326 C GLY 203 -6.158 34 ATOM 4327 0 GLY 203 -7.383 34 ATOM 4328 N SER 205 -5.522 35 ATOM 4329 CA SER 205 -6.219 36 ATOM 4330 CB SER 205 -5.801 37 33.477 1.00123.08 L31H 0 31.638 1.00122.61 L31H c 30.847 1.00121.79 L31H 0 32.105 1.00122.31 L31H N 31.740 1.00122.26 L31H c 31.096 1.00126.23 L31H c 29.663 1.00130.75 L31H c 28.596 1.00132.15 L31H c 27.290 1.00134.17 L31H c 29.378 1.00132.83 L31H c 28.073 1.00134.67 L31H c 27.036 1.00134.93 L31H c 25.742 1.00136.58 L31H 0 32.957 1.00119.64 L31H c 34.073 1.00119.26 L31H 0 32.735 1.00116.33 L31H N 33.812 1.00112.39 L31H c 34.160 1.00112.14 L31H c 34.647 1.00111.27 L31H 0 33.461 1.00109.10 L31H c 32.337 1.00110.35 L31H 0 34.437 1.00103.72 L31H N 34.309 1.00 98.46 L31H c 35.017 1.00 98.24 L31H c 36.093 1.00 96.63 L31H 0 34.923 1.00 94.19 L31H c 34.620 1.00 88.73 L31H s 34.412 1.00 98.30 L31H N 34.964 1.00 98.37 L31H c 34.279 1.00 97.13 L31H c 34.584 1.00 95.47 L31H c 33.914 1.00 93.77 L31H c 33.165 1.00 91.94 L31H 0 34.176 1.00 93.03 L31H N 34.845 1.00 99.27 L31H c 33.766 1.00 99.69 L31H 0 35.967 1.00 99.34 L31H N 35.983 1.00 99.87 L31H c 36.881 1.00101.07 L31H c 36.866 1.00100.65 L31H c 36.398 1.00101.41 L31H c 36.467 1.00 99.94 L31H c 37.418 1.00 98.21 L31H 0 35.798 1.00101.27 L31H N 36.125 1.00103.26 L31H c 34.848 1.00103.65 L31H c 34.060 1.00105.27 L31H 0 35.195 1.00104.43 L31H c 36.808 1.00105.17 L31H c 36.185 1.00104.71 L31H 0 38.094 1.00107.14 L31H N 38.819 1.00109.43 L31H c 39.877 1.00107.76 L31H c 40.622 1.00105.81 L31H c 40.206 1.00104.55 L31H c 41.970 1.00104.95 L31H N 42.352 1.00104.13 L31H c 41.300 1.00103.58 L31H N 39.500 1.00112.26 L31H C 40.307 1.00112.96 L31H 0 39.172 1.00115.35 L31H N 39.780 1.00117.88 L31H C 41.258 1.00119.01 L31H c 41.501 1.00120.93 L31H c 40.997 1.00122.12 L31H c 41.814 1.00122.96 L31H 0 39.780 1.00122.34 L31H 0 39.658 1.00118.66 L31H c 40.561 1.00119.67 L31H 0 38.543 1.00118.23 L31H N 38.312 1.00116.73 L31H c 39.031 1.00116.04 L31H c 38.938 1.00115.24 . L31H 0 39.755 1.00116.14 L31H N 40.372 1.00116.01 ' L31H c 41.837 1.00115.22 L31H c 377 WO 2009/026558 PCT/US2008/074097 ATOM 4331 OG SER 205 -6.212 35 ATOM 4332 C SER 205 -5.890 38 ATOM 4333 O SER 205 -4.725 38 ATOM 4334 N THR 206 -6.920 38 ATOM 4335 CA THR 206 -6.726 40 ATOM 4336 CB THR 206 -7.560 40 ATOM 4337 OG1 THR 206 -7.060 39 ATOM 4338 CG2 THR 206 -7.481 41 ATOM 4339 C THR 206 -7.062 41 ATOM 4340 O THR 206 -8.218 41 ATOM 4341 N VAL 207 -6.031 42 ATOM 4342 CA VAL 207 -6.202 43 ATOM 4343 CB VAL 207 -4.883 43 ATOM 4344 CGI VAL 207 -5.067 45 ATOM 4345 CG2 VAL 207 -4.455 43 ATOM 4346 C VAL 207 -6.606 44 ATOM 4347 O VAL 207 -6.032 44 ATOM 4348 N GLU 208 -7.595 45 ATOM 4349 CA GLU 208 -8.014 46 ATOM 4350 CB GLU 208 -9.452 46 ATOM 4351 CG GLU 208 -9.922 47 ATOM 4352 CD GLU 208 -11.408 47 ATOM 4353 OE1 GLU 208 -12.221 46 ATOM 4354 OE2 GLU 208 -11.758 48 ATOM 4355 C GLU 208 -7.915 47 ATOM 4356 O GLU 208 -8.078 47 ATOM 4357 N LYS 209 -7.632 48 ATOM 4358 CA LYS 209 -7.599 50 ATOM 4359 CB LYS 209 -6.167 50 ATOM 4360 CG LYS 209 -5.551 49 ATOM 4361 CD LYS 209 -5.467 50 ATOM 4362 CE LYS 209 -5.392 49 ATOM 4363 NZ LYS 209 -4.863 50 ATOM 4364 C LYS 209 -8.099 51 ATOM 4365 0 LYS 209 -7.729 50 ATOM 4366 N THR 210 -8.935 52 ATOM 4367 CA THR 210 -9.552 52 ATOM 4368 CB THR 210 -11.077 52 ATOM 4369 OG1 THR 210 -11.391 51 ATOM 4370 CG2 THR 210 -11.706 53 ATOM 4371 C THR 210 -9.263 54 ATOM 4372 O THR 210 -9.142 54 ATOM 4373 N VAL 211 -9.161 55 ATOM 4374 CA VAL 211 -9.075 56 ATOM 4375 CB VAL 211 -7.650 57 ATOM 4376 CGI VAL 211 -6.654 56 ATOM 4377 CG2 VAL 211 -7.220 56 ATOM 4378 C VAL 211 -10.099 57 ATOM 4379 O VAL 211 -10.532 56 ATOM 4380 N ALA 212 -10.489 58 ATOM 4381 CA ALA 212 -11.443 59 ATOM 4382 CB ALA 212 -12.842 59 ATOM 4383 C ALA 212 -11.085 60 ATOM 4384 0 ALA 212 -10.995 61 ATOM 4385 N PRO 213 -10.905 61 ATOM 4386 CD PRO 213 -11.212 60 ATOM 4387 CA PRO 213 -10.408 62 ATOM 4388 CB PRO 213 -10.372 62 ATOM 4389 CG PRO 213 -11.269 61 ATOM 4390 C PRO 213 -11.198 63 ATOM 4391 O PRO 213 -10.971 64 ATOM 4392 N THR 214 -12.116 63 ATOM 4393 CA THR 214 -12.907 64 ATOM 4394 CB THR 214 -14.039 63 ATOM 4395 OG1 THR 214 -14.770 62 ATOM 4396 CG2 THR 214 -15.005 65 ATOM 4397 C THR 214 -12.003 65 ATOM 4398 O THR 214 -11.989 66 ATOM 4399 OXT THR 214 -11.314 64 TER 4400 THR 214 ATOM 4401 CB GLU 1 36.818 24 ATOM 4402 CG GLU 1 36.442 25 ATOM 4403 CD GLU 1 35.215 25 ATOM 4404 OE1 GLU 1 35.228 26 ATOM 4405 OE2 GLU 1 34.237 25 ATOM 4406 C GLU 1 36.959 23 42.612 1.00112.64 L31H 0 39.623 1.00115.80 L31H c 39.347 1.00116.83 L31H 0 39.299 1.00114.25 L31H N 38.598 1.00111.42 L31H c 37.306 1.00109.53 L31H c 36.364 1.00105.70 L31H 0 36.694 1.00107.19 L31H c 39.447 1.00110.26 L31H c 39.801 1.00110.98 L31H 0 39.765 1.00108.60 L31H N 40.402 1.00107.27 L31H c 41.054 1.00106.79 L31H c 41.615 1.00106.40 L31H c 42.157 1.00105.72 L31H c 39.331 1.00106.10 L31H c 38.242 1.00105.64 L31H 0 39.638 1.00105.37 L31H N 38.721 1.00104.39 L31H c 38.250 1.00104.64 L31H c 37.182 1.00106.41 L31H c 37.281 1.00107.65 L31H c 36.646 1.00108.81 L31H 0 37.990 1.00107.97 L31H 0 39.397 1.00103.40 L31H c 40.611 1.00103.44 L31H 0 38.599 1.00102.70 L31H N 39.064 1.00102.80 L31H c 39.443 1.00101.95 L31H c 40.587 1.00 99.94 L31H c 41.876 1.00 98.45 L31H c 43.096 1.00 98.07 L31H c 44.300 1.00 97.51 L31H N 37.932 1.00103.44 L31H c 36.776 1.00103.27 L31H 0 38.258 1.00104.82 L31H N 37.234 1.00106.53 L31H c 37.218 1.00104.13 L31H c 36.967 1.00101.83 L31H 0 36.143 1.00102.17 L31H c 37.411 1.00108.67 L31H c 38.535 1.00110.86 L31H 0 36.295 1.00109.56 L31H N 36.314 1.00109.07 L31H c 35.925 1.00108.56 L31H c 37.022 1.00106.89 L31H c 34.614 1.00107.30 L31H c 35.360 1.00109.17 L31H c 34.393 1.00108.84 L31H 0 35.639 1.00110.64 L31H N 34.786 1.00113.75 L31H c 35.359 1.00114.93 L31H c 34.611 1.00115.04 L31H c 35.583 1.00114.62 L31H 0 33.353 1.00115.69 L31H N 32.179 1.00111.97 L31H c 32.964 1.00117.21 L31H c 31.434 1.00113.00 L31H c 31.055 1.00111.14 L31H c 33.459 1.00119.54 L31H c 32.998 1.00121.28 L31H 0 34.395 1.00120.41 L31H N 34.933 1.00120.39 L31H c 35.857 1.00121.60 L31H c 35.184 1.00119.92 L31H 0 36.207 1.00119.36 L31H c 35.725 1.00119.41 L31H c 35.410 1.00121.23 L31R 0 36.649 1.00120.59 L31H L31H 0 27.876 1.00 91.51 H31H c 27.850 1.00 97.41 H31H c 28.707 1.00100.73 . H31H c 29.392 1.00102.86 H31H 0 28.693 1.00102.54 H31H 0 25.393 1.00 84.82 H31H c 378 WO 2009/026558 PCT/US2008/074097 ATOM 4407 0 GLU 1 37.515 24 ATOM 4408 N GLU 1 38.978 24 ATOM 4409 CA GLU 1 37.693 23 ATOM 4410 N VAL 2 35.705 23 ATOM 4411 CA VAL 2 34.873 23 ATOM 4412 CB VAL 2 33.865 22 ATOM 4413 CGI VAL 2 33.140 22 ATOM 4414 CG2 VAL 2 34.575 21 ATOM 4415 C VAL 2 34.112 24 ATOM 4416 O VAL 2 33.272 25 ATOM 4417 N GLN 3 34.401 25 ATOM 4418 CA GLN 3 33.936 27 ATOM 4419 CB GLN 3 35.091 28 ATOM 4420 CG GLN 3 34.683 29 ATOM 4421 CD GLN 3 35.868 30 ATOM 4422 OE1 GLN 3 35.795 31 ATOM 4423 NE2 GLN 3 36.980 29 ATOM 4424 C GLN 3 33.375 27 ATOM 4425 0 GLN 3 33.905 27 ATOM 4426 N LEU 4 32.297 28 ATOM 4427 CA LEU 4 31.736 29 ATOM 4428 CB LEU 4 30.289 28 ATOM 4429 CG LEU 4 30.063 27 ATOM 4430 CD1 LEU 4 28.572 27 ATOM 4431 CD2 LEU 4 30.716 27 ATOM 4432 C LEU 4 31.768 30 ATOM 4433 O LEU 4 31.480 31 ATOM 4434 N VAL 5 32.112 31 ATOM 4435 CA VAL 5 32.099 33 ATOM 4436 CB VAL 5 33.505 33 ATOM 4437 CGI VAL 5 33.387 35 ATOM 4438 CG2 VAL 5 34.141 32 ATOM 4439 C VAL 5 31.563 33 ATOM 4440 O VAL 5 32.284 34 ATOM 4441 N GLU 6 30.311 34 ATOM 4442 CA GLU 6 29.732 35 ATOM 4443 CB GLU 6 28.226 34 ATOM 4444 CG GLU 6 27.495 34 ATOM 4445 CD GLU 6 27.518 33 ATOM 4446 OE1 GLU 6 28.549 33 ATOM 4447 OE2 GLU 6 26.500 32 ATOM 4448 C GLU 6 29.998 36 ATOM 4449 0 GLU 6 30.002 37 ATOM 4450 N SER 7 30.225 37 ATOM 4451 CA SER 7 30.437 38 ATOM 4452 CB SER 7 31.906 39 ATOM 4453 OG SER 7 32.269 38 ATOM 4454 C SER 7 29.589 39 ATOM 4455 O SER 7 28.690 38 ATOM 4456 N GLY 8 29.876 40 ATOM 4457 CA GLY 8 29.352 41 ATOM 4458 C GLY 8 28.048 42 ATOM 4459 0 GLY 8 27.650 43 ATOM 4460 N GLY 9 27.384 41 ATOM 4461 CA GLY 9 26.120 42 ATOM 4 4 62 C GLY 9 26.265 44 ATOM 4463 0 GLY 9 27.372 4 4' ATOM 4464 N GLY 10 25.145 44 ATOM 4465 CA GLY 10 25.175 46 ATOM 4466 C GLY 10 23.875 46 ATOM 4467 0 GLY 10 22.830 46 ATOM 4468 N LEU 11 23.948 48 ATOM 4469 CA LEU 11 22.814 49 ATOM 4470 CB LEU 11 22.908 50 ATOM 4471 CG LEU 11 21.886 51 ATOM 4472 CD1 LEU 11 20.477 51 ATOM 4473 CD2 LEU 11 22.372 52 ATOM 4474 C LEU 11 22.830 49 ATOM 4475 O LEU 11 23.904 49 ATOM 4476 N VAL 12 21.640 49 ATOM 4477 CA VAL 12 21.489 49 ATOM 4478 CB VAL 12 21.935 48 ATOM 4479 CGI VAL 12 21.083 47 ATOM 4480 CG2 VAL 12 23.416 48 ATOM 4481 C VAL 12 20.056 49 ATOM 4482 O VAL 12 19.106 49
24.446 1.00 85.09 H31H 0 26.678 1.00 88.13 H31H N 26.704 1.00 87.70 H31H C 25.343 1.00 80.58 H31H N 24.168 1.00 75.75 H31H C 24.026 1.00 74.92 H31H C 22.704 1.00 73.70 H31H C 24.147 1.00 74.46 H31H C 24.255 1.00 72.89 H31H C 25.136 1.00 71.91 H31H O 23.327 1.00 68.98 H31H N 23.439 1.00 63.56 H31H C 23.915 1.00 64.18 H31H C 24.562 1.00 64.34 H31H C 25.193 1.00 64 .70 H31H C 25.602 1.00 64.94 H31H O 25.276 1.00 64.00 H31H N 22.131 1.00 59.78 H31H C 21.051 1.00 59.58 H31H O 22.244 1.00 55.16 H31H N 21.122 1.00 51.64 H31H C 20.884 1.00 48.66 H31H C 20.293 1.00 46.75 H31H C 20.180 1.00 47.44 H31H C 18.927 1.00 45.40 H31H C 21.485 1.00 51.24 H31H C 22.627 1.00 51.53 H31H O 20.543 1.00 51.07 H31H N 20.843 1.00 52.18 H31H C 21.180 1.00 50.09 H31H C 21.543 1.00 49.53 H31H C 22.322 1.00 49.00 H31H C 19.713 1.00 53.87 H31H C 18.766 1.00 55.08 H31H O 19.819 1.00 54.66 H31H N 18.770 1.00 56.37 H31H C 18.665 1.00 54.99 H31H C 19.987 1.00 54.97 H31H C 20.770 1.00 55.38 H31H C 21.431 1.00 53.88 H31H O 20.723 1.00 53.41 H31H O 19.010 1.00 57.61 H31H C 20.156 1.00 59.58 H31H O 17.926 1.00 57.59 H31H N 18.006 1.00 56.93 H31H C 17.764 1.00 55.14 H31H C 16.441 1.00 54.54 H31H O 16.969 1.00 57.75 H31H C 16.347 1.00 58.75 H31H O 16.792 1.00 57.04 H31H N 15.643 1.00 57.05 H31H C 15.900 1.00 57.40 H31H C 15.110 1.00 57.11 H31H O 17.002 1.00 57.05 H31H N 17.332 1.00 57.07 H31H C 17.523 1.00 57.42 H31H C 17.456 1.00 57.35 H31H O 17.757 1.00 57.20 H31H N 17.926 1.00 57.17 H31H C 17.566 1.00 58.48 H31H C 17.363 1.00 57.46 H31H O 17.494 1.00 59.75 H31H N 17.119 1.00 59.30 H31H C 17.860 1.00 61.04 H31H C 17.591 1.00 63.37 H31H C 18.065 1.00 60.92 H31H C 18.308 1.00 63.68 H31H C 15.606 1.00 59.16 H31H C 14.995 1.00 58.55 H31H O 15.013 1.00 57.89 H31H N 13.560 1.00 57.68 H31H C 12.891 1.00 58.73 H31H C 11.667 1.00 57.50 . H31H C 12.488 1.00 58.66 H31H C 13.134 1.00 57.57 H31H C 13.624 1.00 57.48 H31H O 379 WO 2009/026558 PCT/US2008/074097 ATOM 4483 N LYS 13 19.905 50 ATOM 4484 CA LYS 13 18.583 51 ATOM 4485 CB LYS 13 18.701 52 ATOM 4486 CG LYS 13 19.294 53 ATOM 4487 CD LYS 13 19.230 55 ATOM 4488 CE LYS 13 17.828 55 ATOM 4489 NZ LYS 13 16.837 54 ATOM 4490 C LYS 13 17.846 50 ATOM 4491 0 LYS 13 18.456 49 ATOM 4 4 92 N PRO 14 16.513 50 ATOM 4493 CD PRO 14 15.629 51 ATOM 4494 CA PRO 14 15.756 49 ATOM 4495 CB PRO 14 14.315 49 ATOM 4496 CG PRO 14 14.283 50 ATOM 4497 C PRO 14 16.245 49 ATOM 4498 O PRO 14 16.571 50 ATOM 4499 N GLY 15 16.293 48 ATOM 4500 CA GLY 15 16.747 48 ATOM 4501 C GLY 15 18.237 48 ATOM 4502 0 GLY 15 18.736 47 ATOM 4503 N GLY 16 18.959 48 ATOM 4504 CA GLY 16 20.401 48 ATOM 4505 C GLY 16 20.827 46 ATOM 4506 0 GLY 16 20.030 45 ATOM 4507 N SER 17 22.088 46 ATOM 4508 CA SER 17 22.700 45 ATOM 4509 CB SER 17 23.081 45 ATOM 4510 OG SER 17 21.949 45 ATOM 4511 C SER 17 23.919 44 ATOM 4512 O SER 17 25.036 45 ATOM 4513 N LEU 18 23.694 44 ATOM 4514 CA LEU 18 24.773 43 ATOM 4515 CB LEU 18 24.274 43 ATOM 4516 CG LEU 18 25.328 43 ATOM 4517 CDl LEU 18 26.373 44 ATOM 4518 CD2 LEU 18 24.658 43 ATOM 4519 C LEU 18 25.255 42 ATOM 4520 O LEU 18 24.562 41 ATOM 4521 N ARG 19 26.440 41 ATOM 4522 CA ARG 19 26.975 40 ATOM 4523 CB ARG 19 27.973 40 ATOM 4524 CG ARG 19 28.777 39 ATOM 4525 CD ARG 19 29.711 39 ATOM 4526 NE ARG 19 30.114 38 ATOM 4527 CZ ARG 19 31.321 37 ATOM 4528 NHl ARG 19 31.630 36 ATOM 4529 NH2 ARG 19 32.217 38 ATOM 4530 C ARG 19 27.646 39 ATOM 4531 O ARG 19 28.622 40 ATOM 4532 N LEU 20 27.141 38 ATOM 4533 CA LEU 20 27.496 38 ATOM 4534 CB LEU 20 26.259 37 ATOM 4535 CG LEU 20 25.242 38 ATOM 4536 CDl LEU 20 24.000 37 ATOM 4537 CD2 LEU 20 25.945 39 ATOM 4538 C LEU 20 28.553 36 ATOM 4539 O LEU 20 28.522 36 ATOM 4540 N SER 21 29.489 36 ATOM 4541 CA SER 21 30.476 35 ATOM 4542 CB SER 21 31.877 36 ATOM 4543 OG SER 21 32.052 37 ATOM 4544 C SER 21 30.361 35 ATOM 4545 O SER 21 29.816 35 ATOM 4546 N CYS 22 30.872 33 ATOM 4547 CA CYS 22 30.833 32 ATOM 4548 C CYS 22 32.020 32 ATOM 4549 0 CYS 22 32.082 31 ATOM 4550 CB CYS 22 29.529 32 ATOM 4551 SG CYS 22 29.593 30 ATOM 4552 N ALA 23 32.962 32 ATOM 4553 CA ALA 23 34.255 31 ATOM 4554 CB ALA 23 35.374 32 ATOM 4555 C ALA 23 34.367 30 ATOM 4556 O ALA 23 34.373 30 ATOM 4557 N ALA 24 34.473 29 ATOM 4558 CA ALA 24 34.486 27 12 . .212 1 . 00 56 . 16 H31H N 11. .835 1 .00 54 .93 H31H C 11. .111 1. . 00 57 .48 H31H C 11. .951 1 .00 58 .72 H31H c 11, .220 0 . 50 60. . 60 H31H c 11. .249 1 .00 61 .98 H31H c 10 . .504 1 . 00 65 .29 H31H N 10 .938 1 . 00 52 .27 H31H c 10 .276 1 .00 51 .72 H31H 0 10 . .888 1 . 00 51 . 07 H31H N 11. .701 1. . 00 50 .36 H31H c 9, .981 1 . 00 51 .56 H31H c 10 . .136 1 . 00 49 .93 H31H c 11, .491 1 . 00 50 .40 H31H c 8 .52 6 1 . 00 52 .20 H31H c 8 . .016 1 . 00 51 .66 H31H 0 7 , . 871 1 . 00 53 . 10 H31H N 6. .493 1 . 00 53 . 00 H31H c 6. .398 1 . 00 54 . 02 H31H c 5, . 368 1 .00 55. .51 H31H 0 7 . .477 1 .00 53 .44 H31H N 7 , .455 1 .00 52 .71 H31H c 7 . .437 1 . 00 53 .74 H31H c 7 , . 131 1. .00 53 .76 H31H 0 7 .781 1. . 00 53 .93 H31H N 7 . .494 1 .00 52 .93 H31H c 6, . 008 1. .00 51. .53 H31H c 5. . 180 1. .00 49 .99 H31H 0 8 . .363 1. .00 53. .75 H31H c 8 , . 051 1. .00 54 . .05 H31H 0 9, . 451 1. .00 54 . .07 H31H N 10 . .346 1. .00 52 , . 61 H31H c 11. .799 1. .00 53 . .51 H31H c 12 , . 864 1. .00 55. .27 H31H c 12 , . 903 1. .00 54 .03 H31H c 14 , .229 1. . 00 53. .34 H31H c 9, . 977 1. .00 50 . .58 H31H c 9, .269 1. .00 50 , .59 H31H 0 10 , .447 1, . 00 47 , . 55 H31H N 10 , . 144 1, . 00 45 , .24 H31H c 8 . .998 1, . 00 44 , .78 H31H c 8 , .827 1, . 00 46, . 47 H31H c 7 , . 655 1, . 00 46, .31 H31H c 7 , . 109 1. .00 47 , .93 H31H N 7 , .278 1 , . 00 50 . .43 H31H c 6. .743 1 . .00 48 . .32 H31H N 7 , .992 1 , . 00 50 , .58 H31H N 11. .312 1. . 00 43 . .40 H31H C 11. .881 1. .00 43 , .30 H31H 0 11. .630 1. .00 41 . .57 H31H N 12 . .866 1. , 00 40 . .63 H31H C 13. ,482 1. .00 38 . .45 H31H c 13. .92 5 1. .00 37 . .41 H31H c 14 . .531 1. , 00 35. .80 H31H c 14 . .911 1. , 00 34 . .57 H31H c 12 . .664 1. .00 40 . .56 H31H c 11. .696 1. , 00 41. .52 H31H 0 13 . .597 1. , 00 42 . .24 H31H N 13. .614 1. .00 44 . .84 H31H c 13 . , 484 1. , 00 45 . .20 H31H c 12 . .210 1. . 00 45 . .61 H31H 0 14 . .913 1. .00 46. , 37 H31H c 15. .897 1. , 00 48 . .51 H31H 0 14 . , 902 1. , 00 45 . ,31 H31H N 16. .053 1. , 00 45 . , 48 H31H c 15 . .972 1. , 00 45 . .47 H31H c 15. . 081 1. .00 45 . .24 H31H 0 16. , 053 1. , 00 46. .72 H 3 1H' c 16. .967 1. .00 52 . , 03 H31H s 16. .903 1. . 00 45 . .04 H31H N 16. .821 1. .00 45 . ,19 H31H c 17 . .065 1. .00 43 . ,20 H31H c 17 . .806 1. .00 45. .82 . H31H c 19. .023 1. .00 47 . .17 H31H 0 17 . 272 1. .00 44 . .91 H31H N 18 . .098 1. .00 44 . .44 H31H c 380 WO 2009/026558 PCT/US2008/074097 ATOM 4559 CB ALA 24 33.590 26 ATOM 4560 C ALA 24 35.881 27 ATOM 4561 O ALA 24 36.701 27 ATOM 4562 N SER 25 36.137 26 ATOM 4563 CA SER 25 37.454 26 ATOM 4564 CB SER 25 38.327 27 ATOM 4565 OG SER 25 37.541 28 ATOM 4566 C SER 25 37.366 24 ATOM 4567 O SER 25 36.397 24 ATOM 4568 N GLY 26 38.384 24 ATOM 4569 CA GLY 26 38.428 23 ATOM 4570 C GLY 26 37.508 21 ATOM 4571 0 GLY 26 37.004 21 ATOM 4572 N PHE 27 37.280 21 ATOM 4573 CA PHE 27 36.499 20 ATOM 4574 CB PHE 27 35.074 20 ATOM 4575 CG PHE 27 34.256 21 ATOM 4576 CDl PHE 27 34.255 23 ATOM 4577 CD2 PHE 27 33.405 21 ATOM 4578 CEl PHE 27 33.402 23 ATOM 4579 CE2 PHE 27 32.553 22 ATOM 4580 CZ PHE 27 32.549 23 ATOM 4581 C PHE 27 36.495 20 ATOM 4582 O PHE 27 36.708 21 ATOM 4583 N THR 28 36.266 19 ATOM 4584 CA THR 28 36.311 19 ATOM 4585 CB THR 28 36.369 17 ATOM 4586 OG1 THR 28 35.447 17 ATOM 4587 CG2 THR 28 37.764 17 ATOM 4588 C THR 28 35.125 19 ATOM 4589 O THR 28 34.120 19 ATOM 4590 N PHE 29 35.271 21 ATOM 4591 CA PHE 29 34.258 22 ATOM 4592 CB PHE 29 34.820 23 ATOM 4593 CG PHE 29 33.869 24 ATOM 4594 CDl PHE 29 32.871 25 ATOM 4595 CD2 PHE 29 34.033 24 ATOM 4596 CEl PHE 29 32.055 26 ATOM 4597 CE2 PHE 29 33.229 25 ATOM 4598 CZ PHE 29 32.238 26 ATOM 4599 C PHE 29 33.802 21 ATOM 4600 O PHE 29 32.664 21 ATOM 4601 N SER 30 34.689 20 ATOM 4602 CA SER 30 34.351 20 ATOM 4603 CB SER 30 35.615 20 ATOM 4604 OG SER 30 36.576 21 ATOM 4605 C SER 30 33.495 19 ATOM 4606 O SER 30 33.013 18 ATOM 4607 N SER 31 33.285 18 ATOM 4608 CA SER 31 32.404 17 ATOM 4609 CB SER 31 33.079 16 ATOM 4610 OG SER 31 34.428 16 ATOM 4611 C SER 31 31.043 17 ATOM 4612 O SER 31 30.155 17 ATOM 4613 N TYR 32 30.863 19 ATOM 4614 CA TYR 32 29.593 19 ATOM 4615 CB TYR 32 29.824 20 ATOM 4616 CG TYR 32 30.191 19 ATOM 4617 CDl TYR 32 31.384 18 ATOM 4618 CEl TYR 32 31.691 17 ATOM 4619 CD2 TYR 32 29.313 19 ATOM 4620 CE2 TYR 32 29.614 18 ATOM 4 621 CZ TYR 32 30.809 17 ATOM 4622 OH TYR 32 31.143 16 ATOM 4623 C TYR 32 28.758 20 ATOM 4624 O TYR 32 29.277 21 ATOM 4625 N SER 33 27.449 20 ATOM 4 62 6 CA SER 33 26.532 21 ATOM 4627 CB SER 33 25.173 20 ATOM 4628 OG SER 33 25.209 19 ATOM 4629 C SER 33 26.390 22 ATOM 4630 O SER 33 26.681 22 ATOM 4631 N MET 34 25.939 23 ATOM 4632 CA MET 34 25.839 24 ATOM 4633 CB MET 34 26.990 25 ATOM 4634 CG MET 34 28.361 25
17.502 1.00 45.51 H31H c 18.230 1.00 44.69 H31H c 17.323 1.00 44.96 H31H 0 19.362 1.00 44.80 H31H N 19.654 1.00 44.29 H31H C 20.285 1.00 44.22 H31H C 20.983 1.00 44.39 H31H O 20.580 1.00 44.72 H31H C 21.322 1.00 44.63 H31H O 20.526 1.00 44.89 H31H N 21.430 1.00 44.97 H31H C 21.024 1.00 44.73 H31H C 21.872 1.00 45.24 H31H O 19.725 1.00 44.04 H31H N 19.220 1.00 42.33 H31H C 19.739 1.00 39.84 H31H C 19.078 1.00 38.30 H31H C 19.549 1.00 38.44 H31H C 18.038 1.00 39.02 H31H C 18.999 1.00 38.76 H31H C 17.484 1.00 39.23 H31H C 17.968 1.00 38.31 H31H C 17.697 1.00 42.00 H31H C 17.042 1.00 44.48 H31H O 17.131 1.00 39.42 H31H N 15.692 1.00 40.18 H31H C 15.307 1.00 40.22 H31H C 16.120 1.00 4 3.67 H31H O 15.536 1.00 39.15 H31H C 15.010 1.00 40.83 H31H C 14.642 1.00 41.68 H31H O 14.844 1.00 39.15 H31H N 14.237 1.00 36.37 H31H C 14.064 1.00 34.08 H31H C 13.420 1.00 32.57 H31H C 14.161 1.00 32 .26 H31H C 12.098 1.00 31.00 H31H C 13.595 1.00 33.72 H31H C 11.523 1.00 30.04 H31H C 12.269 1.00 32.68 H31H C 12.891 1.00 35.94 H31H c 12.489 1.00 37.05 H31H 0 12.185 1.00 34.97 H31H N 10.866 1.00 37.04 H31H C 10.079 1.00 38.55 H31H C 10.284 1.00 45.91 H31H O 10.995 1.00 38.11 H31H C 10.000 1.00 40.04 H31H O 12.226 1.00 37.14 H31H N 12.449 1.00 37.25 H31H C 13.379 1.00 39.60 H31H C 12.995 1.00 41.49 H31H O 13.021 1.00 36.03 H31H C 13.164 1.00 36.13 H31H O 13.350 1.00 34.15 H31H N 13.924 1.00 33.10 H31H C 15.257 1.00 32.49 H31H C 16.369 1.00 33.31 H31H C 16.336 1.00 32.16 H31H C 17.293 1.00 34.34 H31H C 17.410 1.00 32.93 H31H C 18.379 1.00 33.46 H31H C 18.315 1.00 33.85 H31H C 19.278 1.00 35.15 H31H 0 12.999 1.00 32.60 H31H c 12.172 1.00 35.97 H31H 0 13.124 1.00 30.53 H31H N 12.463 1.00 28.81 H31R C 12.302 1.00 25.79 H31H C 11.302 1.00 22.79 H31H O 13.335 1.00 29.79 H31H C 14.530 1.00 29.74 H31H 0 12.745 1.00 30.43 . H31H N 13.483 1.00 31.05 H31H C 13.106 1.00 31.89 H31H C 13.325 1.00 32 .27 H31H C 381 WO 2009/026558 PCT/US2008/074097 ATOM 4635 SD MET 34 28.799 25 ATOM 4636 CE MET 34 28.136 26 ATOM 4637 C MET 34 24.519 25 ATOM 4638 0 MET 34 23.991 25 ATOM 4639 N ASN 35 23.981 26 ATOM 4640 CA ASN 35 22.678 26 ATOM 4641 CB ASN 35 21.686 26 ATOM 4642 CG ASN 35 21.946 24 ATOM 4643 OD1 ASN 35 21.254 23 ATOM 4644 ND2 ASN 35 22.961 24 ATOM 4645 C ASN 35 22.822 28 ATOM 4646 0 ASN 35 23.693 28 ATOM 4647 N TRP 36 21.990 29 ATOM 4648 CA TRP 36 21.827 30 ATOM 4649 CB TRP 36 21.871 31 ATOM 4650 CG TRP 36 23.227 31 ATOM 4651 CD2 TRP 36 24.252 32 ATOM 4652 CE2 TRP 36 25.363 32 ATOM 4653 CE3 TRP 36 24.341 33 ATOM 4654 CDl TRP 36 23.743 31 ATOM 4655 NEl TRP 36 25.020 32 ATOM 4656 CZ2 TRP 36 26.556 33 ATOM 4657 CZ3 TRP 36 25.526 33 ATOM 4658 CH2 TRP 36 26.618 33 ATOM 4659 C TRP 36 20.472 30 ATOM 4660 O TRP 36 19.465 30 ATOM 4661 N VAL 37 20.455 30 ATOM 4662 CA VAL 37 19.212 30 ATOM 4663 CB VAL 37 19.034 29 ATOM 4664 CGI VAL 37 17.703 29 ATOM 4665 CG2 VAL 37 19.123 28 ATOM 4666 C VAL 37 19.187 32 ATOM 4667 O VAL 37 20.165 32 ATOM 4668 N ARG 38 18.057 32 ATOM 4669 CA ARG 38 17.945 34 ATOM 4670 CB ARG 38 17.639 35 ATOM 4671 CG ARG 38 16.240 35 ATOM 4672 CD ARG 38 16.041 36 ATOM 4673 NE ARG 38 14.706 36 ATOM 4674 CZ ARG 38 14.329 36 ATOM 4675 NHl ARG 38 15.190 37 ATOM 4676 NH2 ARG 38 13.101 36 ATOM 4677 C ARG 38 16.868 34 ATOM 4678 O ARG 38 15.848 33 ATOM 4679 N GLN 39 17.106 35 ATOM 4680 CA GLN 39 16.211 35 ATOM 4681 CB GLN 39 16.793 34 ATOM 4682 CG GLN 39 15.815 34 ATOM 4683 CD GLN 39 16.497 33 ATOM 4684 OE1 GLN 39 17.640 34 ATOM 4685 NE2 GLN 39 15.813 33 ATOM 4686 C GLN 39 16.018 37 ATOM 4687 0 GLN 39 16.893 37 ATOM 4688 N ALA 40 14.870 37 ATOM 4689 CA ALA 40 14.456 38 ATOM 4690 CB ALA 40 13.087 39 ATOM 4691 C ALA 40 14.403 38 ATOM 4692 O ALA 40 14.006 38 ATOM 4693 N PRO 41 14.790 40 ATOM 4694 CD PRO 41 15.211 41 ATOM 4695 CA PRO 41 14.848 40 ATOM 4696 CB PRO 41 15.227 41 ATOM 4697 CG PRO 41 15.917 42 ATOM 4698 C PRO 41 13.519 39 ATOM 4699 O PRO 41 12.459 40 ATOM 4700 N GLY 42 13.580 39 ATOM 4701 CA GLY 42 12.365 38 ATOM 4702 C GLY 42 11.418 37 ATOM 4703 0 GLY 42 10.220 37 ATOM 4704 N LYS 43 11.950 37 ATOM 4705 CA LYS 43 11.163 36 ATOM 4706 CB LYS 43 11.258 37 ATOM 4707 CG LYS 43 10.223 38 ATOM 4708 CD LYS 43 8.805 37 ATOM 4709 CE LYS 43 7.809 38 ATOM 4710 NZ LYS 43 7.763 39
15.077 1.00 32.96 H31H s 15.651 1.00 34.63 H31H c 13.235 1.00 31.84 H31H c 12.120 1.00 30.49 H31H 0 14.300 1.00 34.23 H31H N 14.254 1.00 35.04 H31H c 15.069 1.00 33.61 H31H c 14.982 1.00 30.94 H31H c 14.272 1.00 30.44 H31H 0 15.704 1.00 30.36 H31H N 14.851 1.00 36.26 H31H c 15.703 1.00 38.02 H31H 0 14.380 1.00 35.97 H31H N 15.043 1.00 35.60 H31H c 14.046 1.00 33.77 H31H c 13.556 1.00 34.67 H31H c 14.265 1.00 34.96 H31H c 13.398 1.00 35.76 H31H c 15.543 1.00 36.02 H31H c 12.329 1.00 35.15 H31H c 12.225 1.00 34.37 H31H N 13.768 1.00 34.70 H31H c 15.914 1.00 37.06 H31H c 15.024 1.00 36.44 H31H c 15.698 1.00 38.32 H31H c 15.043 1.00 38.04 H31H 0 16.993 1.00 40.27 H31H N 17.730 1.00 43.42 H31H c 18.807 1.00 42.89 H31H c 19.523 1.00 39.41 H31H c 18.170 1.00 41.48 H31H c 18.416 1.00 46.02 H31H c 19.056 1.00 44.43 H31H 0 18.291 1.00 48.68 H31H N 18.807 1.00 52.25 H31H c 17.668 1.00 51.00 H31H c 17.069 1.00 47.89 H31H c 15.962 1.00 46.37 H31H c 15.372 1.00 45.46 H31H N 14.337 1.00 43.87 H31H c 13.791 1.00 43.17 H31H N 13.840 1.00 40.65 H31H N 19.872 1.00 56.24 H31H C 19.829 1.00 54.41 H31H 0 20.811 1.00 62.26 H31H N 21.936 1.00 68.98 H31H C 23.175 1.00 65.66 H31H c 24.288 1.00 61.47 H31H c 25.467 1.00 59.61 H31H c 25.768 1.00 58.86 H31H 0 26.139 1.00 59.10 H31H N 22.206 1.00 75.28 H31H c 22.776 1.00 76.14 H31H 0 21.798 1.00 82.49 H31H N 22.195 1.00 88.68 H31H c 21.614 1.00 86.83 H31H c 23.722 1.00 93.41 H31H c 24.383 1.00 96.08 H31H 0 24.304 1.00 96.76 H31H N 23.659 1.00 99.21 H31H c 25.769 1.00 98.49 H31H c 26.015 1.00 99.06 H31H c 24.767 1.00 99.43 H31H c 26.427 1.00 99.33 H31H c 26.032 1.00 98.92 H31H 0 27.423 1.00100.58 H31H N 28.062 1.00101.63 H31H c 27.102 1.00101.74 H 3 1H' c 27.354 1.00103.13 H31H 0 25.994 1.00100.03 H31H N 25.059 1.00 97.53 H31H c 23.644 1.00100.83 H31H c 23.322 1.00105.01 . H31H c 23.437 1.00110.42 H31H c 22.588 1.00115.16 ' H31H c 22.929 1.00120.90 H31H N 382 WO 2009/026558 PCT/US2008/074097 ATOM 4711 c LYS 43 11.645 35 ATOM 4712 0 LYS 43 12.586 34 ATOM 4713 N GLY 44 10.994 34 ATOM 4714 CA GLY 44 11.399 32 ATOM 4715 C GLY 44 12.655 32 ATOM 4716 0 GLY 44 13.386 33 ATOM 4717 N LEU 45 12.909 31 ATOM 4718 CA LEU 45 13.967 31 ATOM 4719 CB LEU 45 14.739 29 ATOM 4720 CG LEU 45 15.730 30 ATOM 4721 CD1 LEU 45 16.271 28 ATOM 4722 CD2 LEU 45 16.872 30 ATOM 4723 C LEU 45 13.368 30 ATOM 4724 O LEU 45 12.401 30 ATOM 4725 N GLU 46 13.936 31 ATOM 4726 CA GLU 46 13.544 31 ATOM 4727 CB GLU 46 12.874 32 ATOM 4728 CG GLU 46 12.279 31 ATOM 4729 CD GLU 46 11.623 33 ATOM 4730 OE1 GLU 46 10.599 32 ATOM 4731 OE2 GLU 46 12.126 34 ATOM 4732 C GLU 46 14.739 30 ATOM 4733 O GLU 46 15.717 31 ATOM 4734 N TRP 47 14.653 29 ATOM 4735 CA TRP 47 15.666 28 ATOM 4736 CB TRP 47 15.390 27 ATOM 4737 CG TRP 47 16.115 27 ATOM 4738 CD2 TRP 47 15.560 26 ATOM 4739 CE2 TRP 47 16.639 26 ATOM 4740 CE3 TRP 47 14.260 26 ATOM 4741 CD1 TRP 47 17.458 26 ATOM 4742 NEl TRP 47 17.785 26 ATOM 4743 CZ2 TRP 47 16.462 26 ATOM 4744 CZ3 TRP 47 14.084 26 ATOM 4745 CH2 TRP 47 15.183 26 ATOM 4746 C TRP 47 15.659 29 ATOM 4747 O TRP 47 14.613 29 ATOM 4748 N VAL 48 16.830 30 ATOM 4749 CA VAL 48 16.926 31 ATOM 4750 CB VAL 48 17.852 32 ATOM 4751 CGI VAL 48 18.160 32 ATOM 4752 CG2 VAL 48 17.191 33 ATOM 4753 C VAL 48 17.407 30 ATOM 4754 O VAL 48 16.730 30 ATOM 4755 N SER 49 18.580 29 ATOM 4756 CA SER 49 19.169 29 ATOM 4757 CB SER 49 19.985 30 ATOM 4758 OG SER 49 20.437 29 ATOM 4759 C SER 49 20.060 27 ATOM 4760 O SER 49 20.574 27 ATOM 4761 N SER 50 20.229 26 ATOM 4 7 62 CA SER 50 21.244 25 ATOM 4763 CB SER 50 20.598 24 ATOM 4764 OG SER 50 20.026 24 ATOM 4765 C SER 50 22.101 25 ATOM 4766 O SER 50 21.675 25 ATOM 4767 N ILE 51 23.306 25 ATOM 4768 CA ILE 51 24.194 24 ATOM 4769 CB ILE 51 25.101 25 ATOM 4770 CG2 ILE 51 25.868 26 ATOM 4771 CGI ILE 51 26.066 25 ATOM 4772 CD1 ILE 51 26.529 26 ATOM 4773 C ILE 51 25.045 23 ATOM 4774 0 ILE 51 25.720 23 ATOM 4775 N SER 52 25.010 22 ATOM 4776 CA SER 52 25.716 21 ATOM 4777 CB SER 52 25.185 20 ATOM 4778 OG SER 52 25.317 20 ATOM 4779 C SER 52 27.203 21 ATOM 4780 O SER 52 27.659 22 ATOM 4781 N SER 53 27.962 20 ATOM 4782 CA SER 53 29.414 20 ATOM 4783 CB SER 53 30.061 19 ATOM 4784 OG SER 53 29.791 18 ATOM 4785 C SER 53 29.998 20 ATOM 4786 O SER 53 30.897 21 25.049 1.00 93.32 H31H c 25.759 1.00 92.70 H31H 0 24.240 1.00 88.87 H31H N 24.125 1.00 82.75 H31H c 23.294 1.00 77.82 H31H c 23.025 1.00 77.56 H31H _0 22.900 1.00 73.49 H31H N 21.945 1.00 67.33 H31H c 22.413 1.00 65.36 H31H c 23.567 1.00 62.88 H31H c 23.952 1.00 63.05 H31H c 23.158 1.00 62.71 H31H c 20.566 1.00 65.07 H31H c 20.440 1.00 63.83 H31H 0 19.536 1.00 62.28 H31H N 18.170 1.00 59.26 H31H c 17.522 1.00 59.59 H31H c 16.166 1.00 64.07 H31H c 15.462 1.00 66.06 H31H c 14.777 1.00 67.56 H31H 0 15.581 1.00 65.32 H31H 0 17.325 1.00 56.58 H31H c 17.160 1.00 56.38 H31H 0 16.801 1.00 52.74 H31H N 15.893 1.00 47.43 H31H c 15.559 1.00 45.19 H31H c 14.328 1.00 40.33 H31H c 13.019 1.00 38.45 H31H c 12.141 1.00 37.27 H31H c 12.503 1.00 36.40 H31H c 14.197 1.00 39.72 H31H c 12.888 1.00 39.52 H31H N 10.775 1.00 34.81 H31H c 11.148 1.00 35.90 H31H c 10.296 1.00 34.98 H31H c 14.601 1.00 45.07 H31H c 13.970 1.00 43.66 H31H 0 14.200 1.00 43.15 H31H N 13.025 1.00 41.49 H31H c 13.274 1.00 42.05 H31H c 11.963 1.00 4 0.58 H31H c 14.232 1.00 42.96 H31H c 11.770 1.00 39.83 H31H c 10.736 1.00 37.72 H31H 0 11.864 1.00 37.12 H31H N 10.722 1.00 35.46 H31H c 9.893 1.00 33.71 H31H c 8.701 1.00 37.92 H31H 0 11.173 1.00 34.93 H31H c 12.291 1.00 34.06 H31H 0 10.313 1.00 33.84 H31H N 10.552 1.00 31.90 H31H c 10.919 1.00 32.87 H31H c 12.211 1.00 36.99 H31H 0 9.318 1.00 29.80 H31H c 8.208 1.00 30.95 H31H 0 9.516 1.00 27.14 H31H N 8.410 1.00 24.85 H31H c 8.040 1.00 24.72 H31H c 9.254 1.00 24.95 H31H c 6.92 9 1.00 27.20 H31H c 6.101 1.00 28.08 H31H c 8.817 1.00 25.34 H31H c 9.851 1.00 24.66 H31H 0 8.033 1.00 25.68 H31H N 8.435 1.00 24.38 H31H c 7.683 1.00 22.57 H31H c 6.272 1.00 22.51 H31H 0 8.193 1.00 25.36 H31H c 7.547 1.00 27.15 H31H 0 8.691 1.00 26.78 H31H N 8.715 1.00 27.05 H31H c 9.317 1.00 30.95 . H31H c 8.553 1.00 33.86 H31H 0 7.339 1.00 24.84 H31H c 7.200 1.00 23.50 H31H 0 383 WO 2009/026558 PCT/US2008/074097 ATOM 4787 N SER 54 29.475 20 ATOM 4788 CA SER 54 29.955 20 ATOM 4789 CB SER 54 30.116 19 ATOM 4790 OG SER 54 28.858 18 ATOM 4791 C SER 54 29.070 21 ATOM 4792 O SER 54 29.316 21 ATOM 4793 N SER 55 28.054 21 ATOM 4794 CA SER 55 27.186 22 ATOM 4795 CB SER 55 28.004 24 ATOM 4796 OG SER 55 28.836 24 ATOM 4797 C SER 55 26.310 22 ATOM 4798 O SER 55 26.060 22 ATOM 4799 N SER 56 25.843 21 ATOM 4800 CA SER 56 25.012 20 ATOM 4801 CB SER 56 25.446 18 ATOM 4802 OG SER 56 26.824 18 ATOM 4803 C SER 56 23.594 20 ATOM 4804 O SER 56 22.655 20 ATOM 4805 N TYR 57 23.460 21 ATOM 4806 CA TYR 57 22.165 21 ATOM 4807 CB TYR 57 22.027 20 ATOM 4808 CG TYR 57 21.899 18 ATOM 4809 CDl TYR 57 22.920 18 ATOM 4810 CEl TYR 57 22.790 16 ATOM 4811 CD2 TYR 57 20.733 18 ATOM 4812 CE2 TYR 57 20.596 16 ATOM 4813 CZ TYR 57 21.632 16 ATOM 4814 OH TYR 57 21.526 14 ATOM 4815 C TYR 57 22.116 22 ATOM 4816 O TYR 57 22.869 23 ATOM 4817 N ILE 58 21.247 23 ATOM 4818 CA ILE 58 21.036 24 ATOM 4819 CB ILE 58 21.641 25 ATOM 4820 CG2 ILE 58 21.097 27 ATOM 4821 CGI ILE 58 23.157 25 ATOM 4822 CDl ILE 58 23.842 26 ATOM 4823 C ILE 58 19.554 25 ATOM 4824 0 ILE 58 18.759 24 ATOM 4825 N SER 59 19.186 25 ATOM 4826 CA SER 59 17.811 25 ATOM 4827 CB SER 59 17.191 24 ATOM 4828 OG SER 59 17.150 23 ATOM 4829 C SER 59 17.739 27 ATOM 4830 O SER 59 18.696 27 ATOM 4831 N TYR 60 16.568 27 ATOM 4832 CA TYR 60 16.235 29 ATOM 4833 CB TYR 60 16.383 30 ATOM 4834 CG TYR 60 17.790 30 ATOM 4835 CDl TYR 60 18.719 31 ATOM 4836 CEl TYR 60 19.980 31 ATOM 4837 CD2 TYR 60 18.165 29 ATOM 4838 CE2 TYR 60 19.415 30 ATOM 4839 CZ TYR 60 20.331 30 ATOM 4840 OH TYR 60 21.583 31 ATOM 4841 C TYR 60 14.798 29 ATOM 4842 O TYR 60 13.929 28 ATOM 4843 N ALA 61 14.551 2 9' ATOM 4844 CA ALA 61 13.187 30 ATOM 4845 CB ALA 61 13.214 30 ATOM 4846 C ALA 61 12.468 30 ATOM 4847 0 ALA 61 13.079 31 ATOM 4848 N ASP 62 11.175 30 ATOM 4849 CA ASP 62 10.362 31 ATOM 4850 CB ASP 62 8.874 31 ATOM 4851 CG ASP 62 8.480 29 ATOM 4852 OD1 ASP 62 7.576 29 ATOM 4853 OD2 ASP 62 9.062 29 ATOM 4854 C ASP 62 10.488 32 ATOM 4855 O ASP 62 10.516 33 ATOM 4856 N SER 63 10.573 33 ATOM 4857 CA SER 63 10.617 34 ATOM 4858 CB SER 63 10.284 35 ATOM 4859 OG SER 63 11.163 34 ATOM 4860 C SER 63 11.946 35 ATOM 4861 O SER 63 12.054 36 ATOM 4 8 62 N VAL 64 12.964 34
6.323 1.00 24.23 H31H N 4.967 1.00 24.68 H31H C 4.223 1.00 23.52 H31H C 3.938 1.00 27.63 H31H 0 4 . 146 1.00 26.14 H31H c 2.945 1.00 25.03 H31H 0 4.780 1.00 26.34 H31H N 4 . 126 1.00 27.36 H31H c 3.500 1.00 24.26 H31H c 4 . 449 1.00 27.22 H31H 0 3.025 1.00 30.48 H31H c 2.026 1.00 31.05 H31H 0 3.196 1.00 33.26 H31H N 2.180 1.00 34.73 H31H c 2.021 1.00 35.72 H31H c 2.313 1.00 39.26 H31H 0 2.688 1.00 34.95 H31H c 2.043 1.00 35.68 H31H 0 3.882 1.00 34.46 H31H N 4.499 1.00 34.44 H31H c 5.740 1.00 33.79 H31H c 5.474 1.00 35.21 H31H c 5.831 1.00 35.98 H31H c 5.671 1.00 35.95 H31H c 4.931 1.00 33.79 H31H c 4.765 1.00 33.48 H31H c 5.146 1.00 34.19 H31H c 5.059 1.00 34.50 H31H 0 4.927 1.00 34.00 H31H c 5.808 1.00 37.57 H31H 0 4.319 1.00 32.02 H31H N 4.811 1.00 30.95 H31H c 3.851 1.00 28.79 H31H c 4 .152 1.00 29.09 H31H c 3.993 1.00 28.87 H31H c 3.009 1.00 26.40 H31H c 5 . Oil 1.00 31.64 H31H c 4.087 1.00 32.16 H31H 0 6.233 1.00 31.86 H31H N 6.528 1.00 32.29 H31H c 7.576 1.00 32.65 H31H c 7.139 1.00 36.33 H31H 0 7.063 1.00 31.69 H31H c 7.661 1.00 30.20 H31H 0 6.874 1.00 30.90 H31H N 7.495 1.00 32.01 H31H c 6.473 1.00 28.90 H31H c 5.922 1.00 25.82 H31H c 6.586 1.00 24.60 H31H c 6.059 1.00 25.44 H31H c 4.713 1.00 21.26 H31H c 4 .176 1.00 23.84 H31H c 4.846 1.00 27.34 H31H c 4.295 1.00 24.44 H31H 0 8.034 1.00 34.54 H31H c 7.482 1.00 34.40 H31H 0 9.118 1.00 37.78 H31H N 9.576 1.00 40.86 H31H c 10.946 1.00 42.20 H31H c 8.573 1.00 42.66 H31H c 8.009 1.00 40.39 H31H 0 8.357 1.00 46.05 H31H N 7.409 1.00 49.44 H31H c 7.494 1.00 52.61 H31H c 6.482 1.00 5 6.56 H31H c 6.791 1.00 58.22 H31H 0 5.376 1.00 58.42 H31H 0 7.609 1.00 49.31 H31H c 6.641 1.00 48.62 H31H 0 8.859 1.00 49.39 H31H N 9.152 1.00 49.60 H31H c 10.625 1.00 51.26 H31H c 11.473 1.00 52.27 . H31H 0 8.810 1.00 49.28 H31H c 8.864 1.00 49.16 H31H 0 8.477 1.00 49.23 H31H N 384 WO 2009/026558 PCT/US2008/074097 ATOM 4863 CA VAL 64 14.203 35 ATOM 4864 CB VAL 64 15.410 34 ATOM 4865 CGI VAL 64 15.263 35 ATOM 4866 CG2 VAL 64 15.542 33 ATOM 4867 C VAL 64 14.482 34 ATOM 4868 O VAL 64 15.322 35 ATOM 4869 N LYS 65 13.784 33 ATOM 4870 CA LYS 65 14.060 33 ATOM 4871 CB LYS 65 13.015 32 ATOM 4872 CG LYS 65 13.477 31 ATOM 4873 CD LYS 65 12.342 30 ATOM 4874 CE LYS 65 11.667 29 ATOM 4875 NZ LYS 65 12.525 28 ATOM 4876 C LYS 65 14.034 34 ATOM 4877 0 LYS 65 13.028 35 ATOM 4878 N GLY 66 15.156 34 ATOM 4879 CA GLY 66 15.207 35 ATOM 4880 C GLY 66 16.102 36 ATOM 4881 0 GLY 66 16.658 37 ATOM 4882 N ARG 67 16.255 37 ATOM 4883 CA ARG 67 16.979 38 ATOM 4884 CB ARG 67 16.146 38 ATOM 4885 CG ARG 67 15.156 39 ATOM 4886 CD ARG 67 13.700 39 ATOM 4887 NE ARG 67 13.499 39 ATOM 4888 CZ ARG 67 13.916 39 ATOM 4889 NHl ARG 67 14.590 41 ATOM 4890 NH2 ARG 67 13.622 39 ATOM 4891 C ARG 67 18.326 37 ATOM 4892 O ARG 67 19.294 38 ATOM 4893 N PHE 68 18.391 36 ATOM 4894 CA PHE 68 19.646 36 ATOM 4895 CB PHE 68 19.390 35 ATOM 4896 CG PHE 68 18.923 36 ATOM 4897 CD1 PHE 68 18.783 36 ATOM 4898 CD2 PHE 68 18.633 38 ATOM 4899 CEl PHE 68 18.361 37 ATOM 4900 CE2 PHE 68 18.207 38 ATOM 4901 CZ PHE 68 18.073 38 ATOM 4902 C PHE 68 20.393 35 ATOM 4903 O PHE 68 19.790 34 ATOM 4904 N THR 69 21.712 35 ATOM 4905 CA THR 69 22.451 34 ATOM 4906 CB THR 69 23.226 34 ATOM 4907 OG1 THR 69 22.324 35 ATOM 4908 CG2 THR 69 23.843 33 ATOM 4909 C THR 69 23.404 33 ATOM 4910 O THR 69 24.206 34 ATOM 4911 N ILE 70 23.287 32 ATOM 4912 CA ILE 70 24.162 31 ATOM 4913 CB ILE 70 23.375 30 ATOM 4914 CG2 ILE 70 22.789 29 ATOM 4915 CGI ILE 70 24.263 29 ATOM 4916 CD1 ILE 70 23.492 28 ATOM 4917 C ILE 70 25.327 31 ATOM 4918 0 ILE 70 25.172 30 ATOM 4919 N SER 71 26.499 30 ATOM 4920 CA SER 71 27.667 30 ATOM 4921 CB SER 71 28.220 31 ATOM 4922 OG SER 71 28.839 32 ATOM 4923 C SER 71 28.734 30 ATOM 4924 O SER 71 28.878 30 ATOM 4925 N ARG 72 29.490 29 ATOM 4926 CA ARG 72 30.624 28 ATOM 4927 CB ARG 72 30.459 27 ATOM 4928 CG ARG 72 29.515 26 ATOM 4929 CD ARG 72 30.152 25 ATOM 4930 NE ARG 72 30.836 24 ATOM 4931 CZ ARG 72 30.230 24 ATOM 4932 NHl ARG 72 28.920 23 ATOM 4933 NH2 ARG 72 30.934 23 ATOM 4934 C ARG 72 31.939 28 ATOM 4935 O ARG 72 31.957 28 ATOM 4936 N ASP 73 33.037 28 ATOM 4937 CA ASP 73 34.380 28 ATOM 4938 CB ASP 73 35.056 30 7.978 1.00 48.95 H31H c 8.851 1.00 47.82 H31H c 10.224 1.00 46.76 H31H c 8.924 1.00 49.37 H31H c 6.569 1.00 49.25 H31H c 5.881 1.00 4 9.52 H31H 0 6.136 1.00 49.86 H31H N 4.826 1.00 52.89 H31H c 4.467 1.00 55.35 H31H c 3.436 1.00 60.33 H31H c 3.010 1.00 66.57 H31H c 4 .212 1.00 71.34 H31H c 4.925 1.00 7 9.97 H31H N 3.822 1.00 52.76 H31H c 3.675 1.00 54.46 H31H 0 3.153 1.00 52.42 H31H N 2.158 1.00 49.76 H31H c 2.565 1.00 50.14 H31H c 1.717 1.00 50.75 H31H 0 3.866 1.00 49.59 H31H N 4.368 1.00 47.70 H31H c 5.429 1.00 48.66 H31H c 4.890 1.00 47.79 H31H c 5.337 1.00 49.90 H31H c 6.738 1.00 49.54 H31H N 7.808 1.00 48.90 H31H c 7.674 1.00 46.55 H31H N 9.019 1.00 47.78 H31H N 4.969 1.00 46.20 H31H C 4.863 1.00 46.99 H31H 0 5.630 1.00 44.42 H31H N 6.2 62 1.00 43.90 H31H C 7.658 1.00 46.31 H31H c 8.655 1.00 48.27 H31H c 9.991 1.00 48.40 H31H c 8.265 1.00 49.75 H31H c 10.925 1.00 50.45 H31H c 9.193 1.00 49.99 H31H c 10.525 1.00 50.51 H31H c 5.434 1.00 41.81 H31H c 4.782 1.00 42.54 H31H 0 5.453 1.00 39.78 H31H N 4.884 1.00 37.73 H31H c 3.637 1.00 37.83 H31H c 2.707 1.00 40.88 H31H 0 2.980 1.00 36.18 H31H c 5.902 1.00 36.00 H31H c 6.497 1.00 34.40 H31H 0 6.107 1.00 33.23 H31H N 7.015 1.00 32.07 H31H c 7.735 1.00 31.36 H31H c 6.722 1.00 28.51 H31H c 8.739 1.00 28.22 H31H c 9.500 1.00 26.73 H31H c 6.221 1.00 33.56 H31H c 5.052 1.00 32.66 H31H 0 6.845 1.00 34.11 H31H N 6.196 1.00 35.09 H31H c 5.130 1.00 34.90 H31H c 5.718 1.00 38.50 H31H 0 7.225 1.00 35.70 H31H c 8.167 1.00 37.92 H31H 0 7.053 1.00 36.94 H31H N 7.931 1.00 37.72 H31H c 8.667 1.00 36.35 H31H c 7.986 1.00 33.89 H31H c 7.804 1.00 31.35 H31H c 9.002 1.00 30.33 H31H· N 10.015 1.00 31.11 H31H c 9.976 1.00 32.29 H31H N 11.055 1.00 30.74 H31H N 7.165 1.00 38.69 H31H C 5.944 1.00 35.95 . H31H 0 7.906 1.00 42.23 H31H N 7.344 1.00 44.50 ' H31H C 7.307 1.00 4 6.65 H31H c 385 WO 2009/026558 PCT/US2008/074097 ATOM 4939 CG ASP 73 36.385 30 ATOM 4940 OD1 ASP 73 36.846 29 ATOM 4941 OD2 ASP 73 36.969 31 ATOM 4942 C ASP 73 35.206 27 ATOM 4943 O ASP 73 35.841 28 ATOM 4944 N ASN 74 35.206 26 ATOM 4945 CA ASN 74 35.841 25 ATOM 4946 CB ASN 74 35.761 24 ATOM 4947 CG ASN 74 34.398 23 ATOM 4948 OD1 ASN 74 33.479 24 ATOM 4949 ND2 ASN 74 34.254 22 ATOM 4950 C ASN 74 37.297 25 ATOM 4951 0 ASN 74 37.777 25 ATOM 4952 N ALA 75 37.998 26 ATOM 4953 CA ALA 75 39.411 26 ATOM 4954 CB ALA 75 39.864 27 ATOM 4955 C ALA 75 39.617 27 ATOM 4956 O ALA 75 40.545 27 ATOM 4957 N LYS 76 38.725 28 ATOM 4958 CA LYS 76 38.763 29 ATOM 4959 CB LYS 76 38.127 30 ATOM 4960 CG LYS 76 38.887 31 ATOM 4961 CD LYS 76 38.191 32 ATOM 4962 CE LYS 76 39.084 33 ATOM 4963 NZ LYS 76 38.491 35 ATOM 4964 C LYS 76 38.034 29 ATOM 4965 0 LYS 76 38.020 29 ATOM 4966 N ASN 77 37.410 27 ATOM 4967 CA ASN 77 36.691 27 ATOM 4968 CB ASN 77 37.656 27 ATOM 4969 CG ASN 77 38.109 26 ATOM 4970 OD1 ASN 77 37.684 25 ATOM 4971 ND2 ASN 77 38.980 25 ATOM 4972 C ASN 77 35.637 28 ATOM 4973 0 ASN 77 35.521 29 ATOM 4974 N SER 78 34.873 29 ATOM 4975 CA SER 78 33.932 30 ATOM 4976 CB SER 78 34.564 31 ATOM 4977 OG SER 78 35.815 31 ATOM 4978 C SER 78 32.589 30 ATOM 4979 O SER 78 32.450 29 ATOM 4980 N LEU 79 31.601 30 ATOM 4981 CA LEU 79 30.232 30 ATOM 4982 CB LEU 79 29.313 30 ATOM 4983 CG LEU 79 27.843 30 ATOM 4984 CDl LEU 79 27.708 29 ATOM 4985 CD2 LEU 79 27.043 29 ATOM 4986 C LEU 79 29.840 32 ATOM 4987 O LEU 79 30.407 33 ATOM 4988 N TYR 80 28.884 32 ATOM 4989 CA TYR 80 28.496 33 ATOM 4990 CB TYR 80 29.241 34 ATOM 4991 CG TYR 80 30.730 34 ATOM 4992 CDl TYR 80 31.421 33 ATOM 4993 CEl TYR 80 32.800 33 ATOM 4994 CD2 TYR 80 31.455 34 ATOM 4995 CE2 TYR 80 32.837 34' ATOM 4996 CZ TYR 80 33.501 33 ATOM 4997 OH TYR 80 34.860 33 ATOM 4998 C TYR 80 27.033 33 ATOM 4999 O TYR 80 26.479 32 ATOM 5000 N LEU 81 26.424 34 ATOM 5001 CA LEU 81 25.080 35 ATOM 5002 CB LEU 81 24.131 35 ATOM 5003 CG LEU 81 22.641 35 ATOM 5004 CDl LEU 81 22.202 34 ATOM 5005 CD2 LEU 81 21.868 35 ATOM 5006 C LEU 81 25.048 36 ATOM 5007 O LEU 81 25.212 37 ATOM 5008 N GLN 82 24.850 36 ATOM 5009 CA GLN 82 24.705 37 ATOM 5010 CB GLN 82 24.978 37 ATOM 5011 CG GLN 82 26.194 38 ATOM 5012 CD GLN 82 26.244 39 ATOM 5013 OEl GLN 82 27.320 40 ATOM 5014 NE2 GLN 82 25.068 40
6.577 1.00 50.59 H31H c 6.248 1.00 53.52 H31H 0 6.323 1.00 53.00 H31H 0 8.219 1.00 45.16 H31H c 9.180 1.00 44.90 H31H 0 7.887 1.00 46.03 H31H N 8.742 1.00 45.42 H31H c 8.108 1.00 43.35 H31H c 8.208 1.00 40.70 H31H c 8.738 1.00 38.41 H31H 0 7.696 1.00 42.55 H31H N 8.995 1.00 45.96 H31H c 10.126 1.00 47.31 H31H 0 7.92 5 1.00 44.61 H31H N 8.003 1.00 43.81 H31H c 6.693 1.00 41.11 H31H c 9.138 1.00 45.05 H31H c 9.941 1.00 45.68 H31H 0 9.194 1.00 46.12 H31H N 10.189 1.00 4 6.69 H31H c 9.62 6 1.00 48.88 H31H c 8.494 1.00 49.92 H31H c 8.107 1.00 51.68 H31H c 7.272 1.00 52.61 H31H c 7.225 1.00 5 6.36 H31H N 11.470 1.00 46.37 H31H c 12.432 1.00 48.52 H31H 0 11.488 1.00 44 .21 H31H N 12.685 1.00 41.76 H31H c 13.870 1.00 41.56 H31H c 14.116 1.00 41.99 H31H c 15.078 1.00 45.05 H31H 0 13.255 1.00 41.31 H31H N 13.034 1.00 40.31 H31H c 14.187 1.00 39.76 H31H 0 12.056 1.00 38.73 H31H N 12.348 1.00 38.78 H31H c 12.031 1.00 37.52 H31H c 12.700 1.00 40.76 H31H 0 11.655 1.00 39.34 H31H c 10.632 1.00 38.37 H31H 0 12.249 1.00 38.57 H31H N 11.759 1.00 38.65 H31H c 12.811 1.00 37.25 H31H c 12.420 1.00 36.78 H31H c 11.119 1.00 34.19 H31H c 13.547 1.00 37.12 H31H c 11.517 1.00 39.27 H31H c 12.136 1.00 40.45 H31H 0 10.620 1.00 38.92 H31H N 10.241 1.00 37.79 H31H c 8.993 1.00 36.09 H31H c 9.073 1.00 36.73 H31H c 8.289 1.00 37.10 H31H c 8.391 1.00 37.42 H31H c 9.957 1.00 36.52 H31H c 10.065 1.00 37.01 H31H c 9.285 1.00 36.52 H31H c 9.429 1.00 36.87 H31H 0 9.919 1.00 37.36 H31H c 9.415 1.00 38.45 H31H 0 10.191 1.00 36.86 H31H N 9.731 1.00 38.28 H31H c 10.923 1.00 38.22 H31H c 10.624 1.00 42.17 H31H c 9.801 1.00 42.79 H31H c 11.946 1.00 42.84 H31H c 9.066 1.00 39.75 Η31» c 9.734 1.00 40.10 H31H 0 7.751 1.00 40.37 H31H N 7.061 1.00 41.87 H31H c 5.569 1.00 42.62 H31H c 5.084 1.00 42.97 . H31H c 5.634 1.00 43.64 H31H c 5.913 1.00 38.06 H31H 0 5.794 1.00 44.28 H31H N 386 WO 2009/026558 PCT/US2008/074097 ATOM 5015 c GLN 82 23.291 38 ATOM 5016 0 GLN 82 22.388 37 ATOM 5017 N MET 83 23.083 39 ATOM 5018 CA MET 83 21.722 39 ATOM 5019 CB MET 83 21.500 40 ATOM 5020 CG MET 83 21.310 39 ATOM 5021 SD MET 83 21.149 39 ATOM 5022 CE MET 83 22.766 40 ATOM 5023 C MET 83 21.410 41 ATOM 5024 0 MET 83 22.081 42 ATOM 5025 N ASN 84 20.389 41 ATOM 5026 CA ASN 84 20.077 42 ATOM 5027 CB ASN 84 20.227 41 ATOM 5028 CG ASN 84 21.666 41 ATOM 5029 OD1 ASN 84 22.441 42 ATOM 5030 ND2 ASN 84 22.045 40 ATOM 5031 C ASN 84 18.653 42 ATOM 5032 O ASN 84 17.833 41 ATOM 5033 N SER 85 18.356 43 ATOM 5034 CA SER 85 16.991 44 ATOM 5035 CB SER 85 16.067 43 ATOM 5036 OG SER 85 16.474 43 ATOM 5037 C SER 85 16.488 44 ATOM 5038 O SER 85 15.347 43 ATOM 5039 N LEU 86 17.336 44 ATOM 5040 CA LEU 86 16.960 44 ATOM 5041 CB LEU 86 18.081 44 ATOM 5042 CG LEU 86 19.154 43 ATOM 5043 CDl LEU 86 20.334 44 ATOM 5044 CD2 LEU 86 18.526 42 ATOM 5045 C LEU 86 15.629 45 ATOM 5046 O LEU 86 15.174 45 ATOM 5047 N ARG 87 14.987 44 ATOM 5048 CA ARG 87 13.719 45 ATOM 5049 CB ARG 87 12.580 44 ATOM 5050 CG ARG 87 12.534 43 ATOM 5051 CD ARG 87 11.671 42 ATOM 5052 NE ARG 87 11.220 42 ATOM 5053 CZ ARG 87 10.722 41 ATOM 5054 NHl ARG 87 10.333 41 ATOM 5055 NH2 ARG 87 10.621 40 ATOM 5056 C ARG 87 13.795 45 ATOM 5057 O ARG 87 14.652 44 ATOM 5058 N ALA 88 12.911 45 ATOM 5059 CA ALA 88 12.838 46 ATOM 5060 CB ALA 88 11.691 46 ATOM 5061 C ALA 88 12.626 44 ATOM 5062 0 ALA 88 13.061 44 ATOM 5063 N GLU 89 11.979 43 ATOM 5064 CA GLU 89 11.535 42 ATOM 5065 CB GLU 89 10.529 41 ATOM 5066 CG GLU 89 9.345 42 ATOM 5067 CD GLU 89 9.752 44 ATOM 5068 OE1 GLU 89 9.627 45 ATOM 5069 OE2 GLU 89 10.198 44 ATOM 5070 C GLU 89 12.706 41 ATOM 5071 0 GLU 89 12.559 40 ATOM 5072 N ASP 90 13.871 41 ATOM 5073 CA ASP 90 15.043 41 ATOM 5074 CB ASP 90 15.880 41 ATOM 5075 CG ASP 90 15.065 40 ATOM 5076 OD1 ASP 90 14.182 39 ATOM 5077 OD2 ASP 90 15.326 41 ATOM 5078 C ASP 90 15.904 41 ATOM 5079 O ASP 90 17.039 41 ATOM 5080 N THR 91 15.397 42 ATOM 5081 CA THR 91 16.217 42 ATOM 5082 CB THR 91 15.783 44 ATOM 5083 OG1 THR 91 15.867 45 ATOM 5084 CG2 THR 91 16.703 44 ATOM 5085 C THR 91 16.113 41 ATOM 5086 O THR 91 15.016 41 ATOM 5087 N ALA 92 17.256 41 ATOM 5088 CA ALA 92 17.306 39 ATOM 5089 CB ALA 92 16.595 38 ATOM 5090 C ALA 92 18.752 39 7.219 1.00 42.93 H31H c 6.666 1.00 45.25 H31H 0 7.958 1.00 44.37 H31H N 8.172 1.00 46.84 H31H c 9.651 1.00 48.94 H31H c 10.530 1.00 51.24 H31H c 12.271 1.00 54.99 H31H s 12.592 1.00 4 9.92 H31H c 7.330 1.00 46.55 H31H c 7.434 1.00 47.66 H31H 0 6.494 1.00 45.09 H31H N 5.558 1.00 44.96 H31H c 4 . 119 1.00 4 6.67 H31H c 3.722 1.00 49.33 H31H c 3.639 1.00 50.57 H31H 0 3.475 1.00 50.44 H31H N 5.790 1.00 44.59 H31H c 6.257 1.00 42.65 H31H 0 5.443 1.00 44.77 H31H N 5.525 1.00 45.45 H31H c 4.595 1.00 42.38 H31H c 3.259 1.00 40.36 H31H 0 6.935 1.00 47.12 H31H c 7.151 1.00 47.21 H31H 0 7.896 1.00 47.75 H31H N 9.266 1.00 51.11 H31H c 10.184 1.00 47.93 H31H c 10.351 1.00 45.15 H31H c 11.166 1.00 43.75 H31H c 11.017 1.00 41.27 H31H c 9.578 1.00 55.36 H31H c 8.854 1.00 55.80 H31H 0 10.639 1.00 59.60 H31H N 11.079 1.00 63.34 H31H c 10.673 1.00 63.61 H31H c 9.202 1.00 66.77 H31H c 9.001 1.00 71.73 H31H c 7.620 1.00 76.44 H31H N 7.134 1.00 78.44 H31H c 5.866 1.00 79.88 H31H N 7.910 1.00 77.64 H31H N 12.603 1.00 66.43 H31H C 13.222 1.00 66.59 H31H 0 13.210 1.00 69.22 H31H N 14.669 1.00 70.35 H31H C 15.101 1.00 71.65 H31H c 15.208 1.00 71.16 H31H c 16.317 1.00 70.52 H31H 0 14.386 1.00 70.86 H31H N 14.767 1.00 70.01 H31H c 13.743 1.00 72.23 H31H c 13.487 1.00 79.51 H31H c 13.250 1.00 83.99 H31H c 14.191 1.00 86.96 H31H 0 12.127 1.00 8 6.67 H31H 0 14.859 1.00 66.80 H31H c 15.325 1.00 68.37 H31H 0 14.404 1.00 61.86 H31H N 14.496 1.00 58.04 H31H c 13.207 1.00 56.31 H31H c 11.949 1.00 54.61 H31H c 11.952 1.00 53.40 H31H 0 10.948 1.00 52.88 H31H 0 15.675 1.00 56.02 H31H c 15.808 1.00 56.72 H31H 0 16.540 1.00 54.77 H31H N 17.693 1.00 53.43 H31H c 18.353 1.00 53.62 H31H c 17.400 1.00 52.95 H31H 0 19.531 1.00 52.72 H31H c 18.712 1.00 51.54 H31H c 19.023 1.00 52.16 H31H 0 19.218 1.00 48.98 . H31H N 20.096 1.00 48.01 H31H c 19.447 1.00 48.07 ' H31H c 20.385 1.00 47.42 H31H c 387 WO 2009/026558 PCT/US2008/074097 o 2 CJ CJ CJ CJ CJ o 2 CJ CJ CJ CJ CJ CJ CJ CJ o CJ o 2 CJ CJ CJ CJ CJ CJ CJ CJ CJ O 2 CJ CJ O CJ CO 2 CJ CJ CJ O 2 CJ CJ CJ CJ 2 CJ 2 2 CJ O 2 CJ CJ CJ O O CJ O 2 CJ CJ CJ CJ CJ CJ CJ CJ O CJ O 2 CJ CJ 2 X X X X X X 2 X X X X X X X X X 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 t—1 !—1 t—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 !—1 o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o X X X X X X X X X X X X X X X X X 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 t—ιο'0^'τοο<Ν'7’0'0'<νο cTtnoO'O'TnOTt—iOlOt 00'<7''0'0<7>'<7''CNOOO ocoojroror^LO'T’Coo
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T, T, T, T, T, T, T, T, T, T, a T, T, T, T, T, o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O O O O O O O O o o o O o o o o o o o o o o o o o o o o H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H Fh H Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh Fh < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < WO 2009/026558 PCT/US2008/074097 ATOM 5243 c ALA 109 21.616 19 ATOM 5244 0 ALA 109 22.711 18 ATOM 5245 N PHE 110 21.379 20 ATOM 5246 CA PHE 110 22.445 21 ATOM 5247 CB PHE 110 21.872 22 ATOM 5248 CG PHE 110 20.961 23 ATOM 5249 CD1 PHE 110 20.489 24 ATOM 5250 CD2 PHE 110 20.560 22 ATOM 5251 CEl PHE 110 19.638 24 ATOM 5252 CE2 PHE 110 19.703 22 ATOM 5253 CZ PHE 110 19.246 23 ATOM 5254 C PHE 110 23.181 21 ATOM 5255 O PHE 110 22.827 22 ATOM 5256 N ASP 111 24.204 20 ATOM 5257 CA ASP 111 24.739 20 ATOM 5258 CB ASP 111 25.618 19 ATOM 5259 CG ASP 111 26.789 19 ATOM 5260 OD1 ASP 111 26.798 20 ATOM 5261 OD2 ASP 111 27.708 18 ATOM 52 62 C ASP 111 25.501 21 ATOM 5263 O ASP 111 25.620 21 ATOM 5264 N VAL 112 26.017 22 ATOM 5265 CA VAL 112 26.888 23 ATOM 52 66 CB VAL 112 28.369 23 ATOM 5267 CGI VAL 112 29.266 24 ATOM 5268 CG2 VAL 112 28.709 21 ATOM 5269 C VAL 112 26.526 24 ATOM 5270 O VAL 112 26.478 25 ATOM 5271 N TRP 113 26.275 25 ATOM 5272 CA TRP 113 25.983 27 ATOM 5273 CB TRP 113 24.672 27 ATOM 5274 CG TRP 113 23.485 26 ATOM 5275 CD2 TRP 113 22.154 27 ATOM 5276 CE2 TRP 113 21.323 26 ATOM 5277 CE3 TRP 113 21.588 28 ATOM 5278 CD1 TRP 113 23.414 25 ATOM 5279 NEl TRP 113 22.112 25 ATOM 5280 CZ2 TRP 113 19.955 26 ATOM 5281 CZ3 TRP 113 20.224 28 ATOM 5282 CH2 TRP 113 19.424 27 ATOM 5283 C TRP 113 27.071 28 ATOM 52 8 4 O TRP 113 27.778 28 ATOM 5285 N GLY 114 27.193 29 ATOM 5286 CA GLY 114 27.996 30 ATOM 5287 C GLY 114 27.275 31 ATOM 5288 0 GLY 114 26.102 31 ATOM 5289 N GLN 115 27.973 32 ATOM 5290 CA GLN 115 27.459 33 ATOM 5291 CB GLN 115 28.611 34 ATOM 5292 CG GLN 115 29.457 33 ATOM 5293 CD GLN 115 28.620 32 ATOM 5294 OE1 GLN 115 28.448 33 ATOM 5295 NE2 GLN 115 28.086 31 ATOM 5296 C GLN 115 26.337 34 ATOM 5297 0 GLN 115 25.461 34 ATOM 5298 N GLY 116 26.374 34 ATOM 5299 CA GLY 116 25.326 35 ATOM 5300 C GLY 116 25.876 36 ATOM 5301 0 GLY 116 26.974 37 ATOM 5302 N THR 117 25.110 37 ATOM 5303 CA THR 117 25.468 38 ATOM 5304 CB THR 117 26.301 38 ATOM 5305 OG1 THR 117 27.299 39 ATOM 5306 CG2 THR 117 25.410 38 ATOM 5307 C THR 117 24.165 39 ATOM 5308 O THR 117 23.145 39 ATOM 5309 N MET 118 24.188 40 ATOM 5310 CA MET 118 22.944 41 ATOM 5311 CB MET 118 22.865 42 ATOM 5312 CG MET 118 21.515 43 ATOM 5313 SD MET 118 20.114 42 ATOM 5314 CE MET 118 18.732 43 ATOM 5315 C MET 118 22.777 42 ATOM 5316 0 MET 118 23.583 43 ATOM 5317 N VAL 119 21.724 42 ATOM 5318 CA VAL 119 21.431 42 20.382 1.00 35.45 H31H c 20.079 1.00 37.43 H31H 0 20.479 1.00 34.40 H31H N 20.407 1.00 35.00 H31H c 20.195 1.00 34.51 H31H c 18.997 1.00 33.42 H31H c 18.619 1.00 33.80 H31H c 18.266 1.00 34.66 H31H c 17.544 1.00 33.62 H31H c 17.186 1.00 34.07 H31H c 16.831 1.00 33.99 H31H c 21.742 1.00 35.07 H31H c 22.665 1.00 3 6.68 H31H 0 21.863 1.00 34.77 H31H N 23.185 1.00 37.29 H31H c 23.190 1.00 36.40 H31H c 22.221 1.00 35.66 H31H c 21.339 1.00 34.96 H31H 0 22.349 1.00 37.27 H31H 0 23.790 1.00 38.76 H31H c 25.006 1.00 40.16 H31H 0 22.963 1.00 40.27 H31H N 23.473 1.00 41.93 H31H c 23.147 1.00 43.13 H31H c 23.943 1.00 40.95 H31H c 23.435 1.00 4 0.65 H31H c 22.843 1.00 43.13 H31H c 21.616 1.00 44.68 H31H 0 23.668 1.00 43.43 H31H N 23.149 1.00 43.70 H31H c 23.712 1.00 40.08 H31H c 23.464 1.00 37.13 H31H c 23.183 1.00 34.61 H31H c 23.184 1.00 34.01 H31H c 22.936 1.00 34.32 H31H c 23.604 1.00 35.50 H31H c 23.444 1.00 35.84 H31H N 22.946 1.00 36.16 H31H c 22.699 1.00 36.33 H31H c 22.706 1.00 35.59 H31H c 23.429 1.00 45.51 H31H c 24.446 1.00 44.71 H31H 0 22.519 1.00 46.53 H31H N 22.795 1.00 49.42 H31H c 23.754 1.00 52.13 H31H c 24.058 1.00 51.42 H31H 0 24.221 1.00 56.29 H31H N 25.260 1.00 59.63 H31H c 25.840 1.00 63.79 H31H c 26.847 1.00 71.42 H31H c 27.993 1.00 76.37 H31H c 29.022 1.00 79.37 H31H 0 27.818 1.00 80.03 H31H N 24.820 1.00 58.74 H31H c 25.610 1.00 57.37 H31H 0 23.559 1.00 58.43 H31H N 23.019 1.00 58.13 H31H c 22.544 1.00 59.56 H31H c 22.938 1.00 59.14 H31H 0 21.690 1.00 60.54 H31H N 21.226 1.00 59.73 H31H c 19.926 1.00 60.22 H31H c 19.943 1.00 60.73 H31H 0 18.710 1.00 59.64 H31H c 20.975 1.00 58.58 H31H c .20.634 1.00 55.70 H31H 0 21.175 1.00 58.61 H31H N 21.156 1.00 58.29 H31H c 22.377 1.00 55.41 H31H c 22.541 1.00 54.00 H31H c 22.578 1.00 54.63 H31H s 21.995 1.00 51.15 H31H c 19.867 1.00 59.12 . H31H c 19.538 1.00 58.18 H31H 0 19.129 1.00 61.17 ' H31H N 17.907 1.00 63.75 H31H c 390 WO 2009/026558 PCT/US2008/074097 ATOM 5319 CB VAL 119 21.186 41 ATOM 5320 CGI VAL 119 20.577 42 ATOM 5321 CG2 VAL 119 22.502 41 ATOM 5322 C VAL 119 20.191 43 ATOM 5323 O VAL 119 19.113 43 ATOM 5324 N THR 120 20.360 45 ATOM 5325 CA THR 120 19.261 45 ATOM 5326 CB THR 120 19.589 47 ATOM 5327 OG1 THR 120 20.422 46 ATOM 5328 CG2 THR 120 18.298 47 ATOM 5329 C THR 120 19.009 46 ATOM 5330 O THR 120 19.924 47 ATOM 5331 N VAL 121 17.767 46 ATOM 5332 CA VAL 121 17.370 47 ATOM 5333 CB VAL 121 16.748 46 ATOM 5334 CGI VAL 121 16.259 47 ATOM 5335 CG2 VAL 121 17.771 45 ATOM 5336 C VAL 121 16.368 48 ATOM 5337 O VAL 121 15.201 48 ATOM 5338 N SER 122 16.837 49 ATOM 5339 CA SER 122 15.948 50 ATOM 5340 CB SER 122 15.411 51 ATOM 5341 OG SER 122 14.609 52 ATOM 5342 C SER 122 16.563 52 ATOM 5343 O SER 122 17.785 52 ATOM 5344 N SER 123 15.672 53 ATOM 5345 CA SER 123 16.044 54 ATOM 5346 CB SER 123 14.839 55 ATOM 5347 OG SER 123 13.660 54 ATOM 5348 C SER 123 16.526 55 ATOM 5349 O SER 123 17.133 56 ATOM 5350 N ALA 124 16.262 54 ATOM 5351 CA ALA 124 16.615 55 ATOM 5352 CB ALA 124 16.471 54 ATOM 5353 C ALA 124 18.016 56 ATOM 5354 0 ALA 124 18.869 55 ATOM 5355 N SER 125 18.243 57 ATOM 5356 CA SER 125 19.499 57 ATOM 5357 CB SER 125 19.631 58 ATOM 5358 OG SER 125 20.889 59 ATOM 5359 C SER 125 19.496 58 ATOM 5360 O SER 125 18.436 59 ATOM 5361 N THR 126 20.683 59 ATOM 5362 CA THR 126 20.843 59 ATOM 5363 CB THR 126 22.361 60 ATOM 5364 OG1 THR 126 22.496 60 ATOM 5365 CG2 THR 126 22.968 60 ATOM 5366 C THR 126 19.973 61 ATOM 5367 O THR 126 20.164 62 ATOM 5368 N LYS 127 19.026 60 ATOM 5369 CA LYS 127 17.996 61 ATOM 5370 CB LYS 127 16.834 61 ATOM 5371 CG LYS 127 15.469 61 ATOM 5372 CD LYS 127 14.393 61 ATOM 5373 CE LYS 127 13.002 62 ATOM 5374 NZ LYS 127 12.866 63 ATOM 5375 C LYS 127 17.441 61 ATOM 5376 O LYS 127 17.107 60 ATOM 5377 N GLY 128 17.321 63 ATOM 5378 CA GLY 128 16.933 63 ATOM 5379 C GLY 128 15.431 63 ATOM 5380 0 GLY 128 14.664 63 ATOM 5381 N PRO 129 14.978 62 ATOM 5382 CD PRO 129 15.828 62 ATOM 5383 CA PRO 129 13.566 62 ATOM 5384 CB PRO 129 13.636 61 ATOM 5385 CG PRO 129 14.824 62 ATOM 5386 C PRO 129 12.685 63 ATOM 5387 O PRO 129 13.155 65 ATOM 5388 N SER 130 11.401 63 ATOM 5389 CA SER 130 10.380 64 ATOM 5390 CB SER 130 9.172 64 ATOM 5391 OG SER 130 9.521 64 ATOM 5392 C SER 130 9.944 64 ATOM 5393 O SER 130 9.720 63 ATOM 5394 N VAL 131 9.812 65
16.730 1.00 62.58 H31H c 15.548 1.00 61.18 H31H c 16.309 1.00 61.02 H31H c 18.145 1.00 66.03 H31H c 18.410 1.00 67.24 H31H 0 18.061 1.00 67.50 H31H N 18.247 1.00 66.26 H31H c 19.299 1.00 65.93 H31H c 20.329 1.00 64.19 H31H 0 19.908 1.00 62.66 H31H c 16.942 1.00 65.33 H31H c 16.373 1.00 64.94 H31H 0 16.478 1.00 64.42 H31H N 15.282 1.00 64.31 H31H C 14.242 1.00 64.18 H31H C 13.018 1.00 63.06 H31H C 13.839 1.00 62.69 H31H C 15.641 1.00 65.00 H31H c 15.953 1.00 64.07 H31H 0 15.610 1.00 65.59 H31H N 15.712 1.00 66.99 H31H C 17.134 1.00 67.36 H31H C 17.233 1.00 67.09 H31H O 15.284 1.00 67.53 H31H C 15.235 1.00 66.70 H31H O 14.992 1.00 67.46 H31H N 14.568 1.00 65.91 H31H C 13.898 1.00 65.83 H31H C 14.237 1.00 63.82 H31H O 15.741 1.00 64.19 H31H C 15.543 1.00 64.69 H31H O 16.959 1.00 62.50 H31H N 18.163 1.00 61.24 H31H C 19.382 1.00 61.18 H31H C 18.124 1.00 61.63 H31H C 17.355 1.00 62.06 H31H O 18.970 1.00 61.89 H31H N 18.985 1.00 61.67 H31H C 17.687 1.00 63.06 H31H C 17.586 1.00 65.82 H31H O 20.208 1.00 60.83 H31H C 20.668 1.00 60.45 H31H O 20.725 1.00 59.55 H31H N 22.055 1.00 58.53 H31H C 22.324 1.00 59.12 H31H C 23.539 1.00 57.87 H31H O 21.156 1.00 57.69 H31H C 22.314 1.00 57.27 H31H C 21.693 1.00 58.39 H31H O 23.247 1.00 54.41 H31H N 23.478 1.00 50.77 H31H C 22.505 1.00 49.90 H31H C 23.161 1.00 48.86 H31H C 22.117 1.00 49.04 H31H C 22.731 1.00 49.43 H31H C 23.602 1.00 48.62 H31H N 24.908 1.00 48.34 H31H C 25.480 1.00 48.08 H31H O 25.464 1.00 45.40 H31H N 26.858 1.00 41.87 H31H C 27.066 1.00 40.01 H31H C 26.124 1.00 38.07 H31H 0 28.296 1.00 40.21 H31H N 29.492 1.00 40.34 H31H c 28.617 1.00 3 9.64 H31H c .2 9.967 1.00 38.84 H31H c 30.603 1.00 39.50 H31H c 28.677 1.00 39.72 H31H c 28.963 1.00 38.60 H31H 0 28.397 1.00 40.04 H31H N 28.806 1.00 39.31 H31H C 27.857 1.00 39.01 H31H C 26.520 1.00 40.33 . H31H O 30.190 1.00 38.84 H31H C 30.395 1.00 39.02 H31H 0 31.133 1.00 38.94 H31H N 391 WO 2009/026558 PCT/US2008/074097 ATOM 5395 CA VAL 131 9.342 64 ATOM 5396 CB VAL 131 10.370 65 ATOM 5397 CGI VAL 131 10.159 64 ATOM 5398 CG2 VAL 131 11.776 65 ATOM 5399 C VAL 131 8.010 65 ATOM 5400 O VAL 131 7.889 66 ATOM 5401 N PHE 132 6.997 64 ATOM 5402 CA PHE 132 5.727 65 ATOM 5403 CB PHE 132 4.625 64 ATOM 5404 CG PHE 132 4 . 873 65 ATOM 5405 CDl PHE 132 4.524 66 ATOM 5406 CD2 PHE 132 5.457 64 ATOM 5407 CEl PHE 132 4.752 66 ATOM 5408 CE2 PHE 132 5.687 64 ATOM 5409 CZ PHE 132 5.332 65 ATOM 5410 C PHE 132 5.468 64 ATOM 5411 O PHE 132 5.802 63 ATOM 5412 N PRO 133 4 . 874 65 ATOM 5413 CD PRO 133 4 . 401 67 ATOM 5414 CA PRO 133 4.565 65 ATOM 5415 CB PRO 133 4.235 66 ATOM 5416 CG PRO 133 3.636 67 ATOM 5417 C PRO 133 3.374 64 ATOM 5418 O PRO 133 2.421 64 ATOM 5419 N LEU 134 3.430 63 ATOM 5420 CA LEU 134 2.235 62 ATOM 5421 CB LEU 134 2.554 61 ATOM 5422 CG LEU 134 3.341 60 ATOM 5423 CDl LEU 134 3.959 59 ATOM 5424 CD2 LEU 134 2.424 60 ATOM 5425 C LEU 134 1.798 62 ATOM 5426 O LEU 134 2.431 62 ATOM 5427 N ALA 135 0.726 63 ATOM 5428 CA ALA 135 0.2 92 64 ATOM 5429 CB ALA 135 -0.610 65 ATOM 5430 C ALA 135 -0.436 63 ATOM 5431 0 ALA 135 -0.947 62 ATOM 5432 N PRO 136 -0.488 63 ATOM 5433 CD PRO 136 0.300 64 ATOM 5434 CA PRO 136 -1.275 62 ATOM 5435 CB PRO 136 -0.755 63 ATOM 5436 CG PRO 136 -0.256 64 ATOM 5437 C PRO 136 -2.775 63 ATOM 5438 O PRO 136 -3.215 64 ATOM 5439 N SER 137 -3.552 62 ATOM 5440 CA SER 137 -5.003 62 ATOM 5441 CB SER 137 -5.583 60 ATOM 5442 OG SER 137 -5.241 60 ATOM 5443 C SER 137 -5.682 62 ATOM 5444 O SER 137 -5.100 63 ATOM 5445 N GLY 144 -3.876 56 ATOM 5446 CA GLY 144 -3.690 57 ATOM 5447 C GLY 144 -2.769 58 ATOM 5448 0 GLY 144 -2.568 59 ATOM 5449 N THR 145 -2.202 57 ATOM 5450 CA THR 145 -1.246 58 ATOM 5451 CB THR 145 0 . 194 58 ATOM 5452 OG1 THR 145 0.388 56 ATOM 5453 CG2 THR 145 0.460 58 ATOM 5454 C THR 145 -1.490 58 ATOM 5455 O THR 145 -2.372 57 ATOM 5456 N ALA 146 -0.708 59 ATOM 5457 CA ALA 146 -0.910 59 ATOM 5458 CB ALA 146 -1.355 61 ATOM 5459 C ALA 146 0.359 59 ATOM 5460 0 ALA 146 1.468 59 ATOM 5461 N ALA 147 0.187 58 ATOM 5462 CA ALA 147 1.320 58 ATOM 5463 CB ALA 147 1 . 154 57 ATOM 5464 C ALA 147 1 . 447 59 ATOM 5465 0 ALA 147 0.531 59 ATOM 5466 N LEU 148 2.587 60 ATOM 5467 CA LEU 148 2.890 60 ATOM 5468 CB LEU 148 3.086 62 ATOM 5469 CG LEU 148 4.068 62 ATOM 5470 CDl LEU 148 5.140 63 32.462 1.00 37.98 H31H c 33.533 1.00 38.94 H31H c 34.794 1.00 37.15 H31H c 32.982 1.00 37.53 H31H c 32.798 1.00 39.20 H31H c 32.855 1.00 39.59 H31H 0 33.036 1.00 40.76 H31H N 33.454 1.00 41.89 H31H c 32.531 1.00 45.07 H31H c 31.086 1.00 47.51 H31H c 30.556 1.00 45.96 H31H c 30.255 1.00 47.99 H31H c 29.224 1.00 47.37 H31H c 28.921 1.00 49.35 H31H c 28.405 1.00 48.08 H31H c 34.867 1.00 42.41 H31H c 35.239 1.00 40.02 H31H 0 35.681 1.00 44.73 H31H N 35.358 1.00 4 2.60 H31H c 37.059 1.00 45.76 H31H c 37.709 1.00 44.76 H31H c 36.595 1.00 41.73 H31H c 37.062 1.00 47.64 H31H c 36.325 1.00 49.24 H31H 0 37.880 1.00 48.88 H31H N 38.190 1.00 50.70 H31H c 38.207 1.00 50.15 H31H c 36.999 1.00 49.91 H31H c 37.321 1.00 48.75 H31H c 35.788 1.00 49.17 H31H c 39.575 1.00 52.49 H31H c 40.567 1.00 53.95 H31H 0 39.639 1.00 54.85 H31H N 40.892 1.00 57.86 H31H c 40.606 1.00 54.42 H31H c 41.784 1.00 60.60 H31H c 41.318 1.00 60.28 H31H 0 43.088 1.00 64.55 H31H N 43.725 1.00 67.29 H31H c 44.067 1.00 69.15 H31H c 45.409 1.00 69.65 H31H c 45.123 1.00 68.88 H31H c 43.917 1.00 72.89 H31H c 43.691 1.00 73.33 H31H 0 44.058 1.00 77.84 H31H N 43.878 1.00 82.41 H31H c 43.864 1.00 82.42 H31H c 45.050 1.00 83.20 H31H 0 44.973 1.00 84.96 H31H c 46.028 1.00 87.33 H31H 0 54.474 1.00 84.33 H31H N 55.159 1.00 83.90 H31H c 54.437 1.00 82.39 H31H c 54.882 1.00 82.07 H31H 0 53.316 1.00 80.81 H31H N 52.603 1.00 79.74 H31H c 52.897 1.00 81.45 H31H c 52.413 1.00 82.63 H31H 0 54.389 1.00 81.35 H31H c 51.093 1.00 78.23 H31H c 50.607 1.00 76.79 H31H 0 50.357 1.00 76.75 H31H N 48.922 1.00 74.80 H31H c 48.617 1.00 74.54 H31H c 48.151 1.00 72.36 H31H c 48.662 1.00 72.82 H31H 0 46.917 1.00 68.95 H31H N 4 6.0 62 1.00 64.43 H31H' c 45.501 1.00 65.16 H31H c 44.921 1.00 61.83 H31H c 44.116 1.00 61.04 H31H 0 44.851 1.00 58.23 H31H N 43.689 1.00 55.96 . H31H c 44.072 1.00 55.54 H31H c 45.194 1.00 54.79 ' H31H c 44.718 1.00 57.06 H31H c 392 WO 2009/026558 PCT/US2008/074097
ATOM 5471 CD2 LEU 148 3.289 63.337 46.346 1.00 54.72 H31H c ATOM 5472 C LEU 148 4 . 149 60.448 43.063 1.00 54.70 H31H c ATOM 5473 O LEU 148 4 . 822 59.596 43.633 1.00 54.10 H31H 0 ATOM 5474 N GLY 149 4.462 60.946 41.879 1.00 53.02 H31H N ATOM 5475 CA GLY 149 5.675 60.521 41.221 1.00 51.68 H31H c ATOM 5476 C GLY 149 5.905 61.418 40.034 1.00 49.79 H31H c ATOM 5477 0 GLY 149 5.166 62.368 39.832 1.00 50.10 H31H 0 ATOM 5478 N CYS 150 6.927 61.131 39.246 1.00 48.52 H31H N ATOM 5479 CA CYS 150 7.064 61.821 37.986 1.00 47.23 H31H c ATOM 5480 C CYS 150 7.447 60.877 36.839 1.00 43.82 H31H c ATOM 5481 0 CYS 150 8.290 60.002 36.996 1.00 43.71 H31H 0 ATOM 5482 CB CYS 150 8.048 62.988 38.150 1.00 49.36 H31H c ATOM 5483 SG CYS 150 9.812 62.571 38.243 1.00 56.29 H31H s ATOM 5484 N LEU 151 6.772 61.050 35.701 1.00 41.91 H31H N ATOM 5485 CA LEU 151 6.853 60.144 34.545 1.00 40.54 H31H c ATOM 5486 CB LEU 151 5.505 60.099 33.823 1.00 40.30 H31H c ATOM 5487 CG LEU 151 5.616 59.625 32.371 1.00 40.58 H31H c ATOM 5488 CDl LEU 151 6.148 58.202 32.343 1.00 42.03 H31H c ATOM 5489 CD2 LEU 151 4.256 59.696 31.685 1.00 40.84 H31H c ATOM 5490 C LEU 151 7.924 60.558 33.533 1.00 40.01 H31H c ATOM 5491 O LEU 151 7.765 61.548 32.833 1.00 39.20 H31H 0 ATOM 5492 N VAL 152 9.000 59.789 33.444 1.00 40.24 H31H N ATOM 5493 CA VAL 152 10.169 60.190 32.664 1.00 41.29 H31H c ATOM 5494 CB VAL 152 11.463 59.823 33.443 1.00 40.87 H31H c ATOM 5495 CGI VAL 152 12.663 60.541 32.856 1.00 41.31 H31H c ATOM 5496 CG2 VAL 152 11.292 60.147 34.921 1.00 38.03 H31H c ATOM 5497 C VAL 152 10.164 59.463 31.312 1.00 42.74 H31H c ATOM 5498 O VAL 152 10.623 58.321 31.225 1.00 45.26 H31H 0 ATOM 5499 N LYS 153 9.654 60.098 30.257 1.00 43.18 H31H N ATOM 5500 CA LYS 153 9.476 59.375 28.991 1.00 45.09 H31H c ATOM 5501 CB LYS 153 8.035 59.501 28.491 1.00 44.98 H31H c ATOM 5502 CG LYS 153 7.594 60.909 28.168 1.00 46.95 H31H c ATOM 5503 CD LYS 153 6.077 60.974 27.919 1.00 49.28 H31H c ATOM 5504 CE LYS 153 5.711 60.748 26.441 1.00 49.98 H31H c ATOM 5505 NZ LYS 153 4.315 61.196 26.093 1.00 48.65 H31H N ATOM 5506 C LYS 153 10.425 59.736 27.848 1.00 45.72 H31H c ATOM 5507 0 LYS 153 11.028 60.813 27.822 1.00 46.61 H31H 0 ATOM 5508 N ASP 154 10.568 58.798 26.920 1.00 45.12 H31H N ATOM 5509 CA ASP 154 11.169 59.055 25.618 1.00 45.38 H31H c ATOM 5510 CB ASP 154 10.349 60.101 24.882 1.00 44.90 H31H c ATOM 5511 CG ASP 154 8.960 59.602 24.521 1.00 48.08 H31H c ATOM 5512 OD1 ASP 154 8.805 58.376 24.299 1.00 49.40 H31H 0 ATOM 5513 OD2 ASP 154 8.019 60.434 24.455 1.00 51.13 H31H 0 ATOM 5514 C ASP 154 12.639 59.453 25.601 1.00 45.46 H31H c ATOM 5515 O ASP 154 13.013 60.401 24.932 1.00 44.22 H31H 0 ATOM 5516 N TYR 155 13.476 58.712 26.318 1.00 47.16 H31H N ATOM 5517 CA TYR 155 14.921 58.918 26.259 1.00 49.79 H31H c ATOM 5518 CB TYR 155 15.467 59.204 27.659 1.00 51.22 H31H c ATOM 5519 CG TYR 155 15.315 58.042 28.623 1.00 54.62 H31H c ATOM 5520 CDl TYR 155 16.430 57.412 29.156 1.00 55.10 H31H c ATOM 5521 CEl TYR 155 16.294 56.327 30.002 1.00 57.77 H31H c ATOM 5522 CD2 TYR 155 14.055 57.556 28.970 1.00 54.59 H31H c ATOM 5523 CE2 TYR 155 13.909 56.479 29.811 1.00 55.80 H31H c ATOM 5524 CZ TYR 155 15.031 55.860 30.325 1.00 57.60 H31H c ATOM 5525 OH TYR 155 14.905 54.749 31.139 1.00 59.92 H31H 0 ATOM 5526 C TYR 155 15.669 57.716 25.654 1.00 50.37 H31H c ATOM 5527 O TYR 155 15.057 56.698 25.296 1.00 48.82 H31H 0 ATOM 5528 N PHE 156 16.991 57.866 25.549 1.00 49.83 H31H N ATOM 5529 CA PHE 156 17.889 56.872 24.984 1.00 50.40 H31H c ATOM 5530 CB PHE 156 17.494 56.525 23.545 1.00 51.14 H31H c ATOM 5531 CG PHE 156 18.311 55.411 22.949 1.00 52.08 H31H c ATOM 5532 CDl PHE 156 19.596 55.651 22.470 1.00 53.14 H31H c ATOM 5533 CD2 PHE 156 17.818 54.112 22.922 1.00 52.74 H31H c ATOM 5534 CEl PHE 156 20.379 54.618 21.982 1.00 54.59 H31H c ATOM 5535 CE2 PHE 156 18.592 53.068 22.437 1.00 54.30 H31H c ATOM 5536 CZ PHE 156 19.875 53.317 .21.966 1.00 54.91 H31H c ATOM 5537 C PHE 156 19.306 57.436 24.975 1.00 52.12 H31H c ATOM 5538 O PHE 156 19.518 58.620 24.715 1.00 51.42 H 3 1H 0 ATOM 5539 N PRO 157 20.303 56.586 25.246 1.00 52.79 H31H N ATOM 5540 CD PRO 157 21.723 56.973 25.178 1.00 55.23 H31H c ATOM 5541 CA PRO 157 20.151 55.191 25.668 1.00 56.36 H31H c ATOM 5542 CB PRO 157 21.487 54.576 25.285 1.00 54.78 H31H c ATOM 5543 CG PRO 157 22.456 55.688 25.531 1.00 54.58 . H31H c ATOM 5544 C PRO 157 19.921 55.158 27.179 1.00 58.64 H31H c ATOM 5545 O PRO 157 19.828 56.220 27.807 1.00 60.21 H31H 0 ATOM 5546 N GLU 158 19.850 53.960 27.761 1.00 59.18 H31H N 393 WO 2009/026558 PCT/US2008/074097 ATOM 5547 CA GLU 158 19.939 53 ATOM 5548 CB GLU 158 19.800 52 ATOM 5549 CG GLU 158 18.442 51 ATOM 5550 CD GLU 158 17.480 51 ATOM 5551 OE1 GLU 158 17.604 53 ATOM 5552 OE2 GLU 158 16.611 51 ATOM 5553 C GLU 158 21.266 54 ATOM 5554 0 GLU 158 22.245 54 ATOM 5555 N PRO 159 21.315 54 ATOM 5556 CD PRO 159 22.618 54 ATOM 5557 CA PRO 159 20.205 54 ATOM 5558 CB PRO 159 20.813 54 ATOM 5559 CG PRO 159 22.263 54 ATOM 5560 C PRO 159 19.769 56 ATOM 5561 O PRO 159 20.471 57 ATOM 5562 N VAL 160 18.630 56 ATOM 5563 CA VAL 160 18.411 57 ATOM 5564 CB VAL 160 16.999 58 ATOM 5565 CGI VAL 160 16.883 58 ATOM 5566 CG2 VAL 160 15.970 57 ATOM 5567 C VAL 160 18.552 57 ATOM 5568 O VAL 160 18.305 56 ATOM 5569 N THR 161 18.933 58 ATOM 5570 CA THR 161 18.797 58 ATOM 5571 CB THR 161 20.164 58 ATOM 5572 OG1 THR 161 20.751 59 ATOM 5573 CG2 THR 161 21.073 57 ATOM 5574 C THR 161 17.836 59 ATOM 5575 O THR 161 17.912 60 ATOM 5576 N VAL 162 16.900 58 ATOM 5577 CA VAL 162 15.885 59 ATOM 5578 CB VAL 162 14.470 59 ATOM 5579 CGI VAL 162 13.426 60 ATOM 5580 CG2 VAL 162 14.253 58 ATOM 5581 C VAL 162 16.123 59 ATOM 5582 O VAL 162 16.495 58 ATOM 5583 N SER 163 15.909 61 ATOM 5584 CA SER 163 16.055 61 ATOM 5585 CB SER 163 17.421 62 ATOM 5586 OG SER 163 17.530 62 ATOM 5587 C SER 163 14.966 62 ATOM 5588 O SER 163 14.323 63 ATOM 5589 N TRP 164 14.754 62 ATOM 5590 CA TRP 164 13.855 63 ATOM 5591 CB TRP 164 12.660 62 ATOM 5592 CG TRP 164 11.840 61 ATOM 5593 CD2 TRP 164 10.677 62 ATOM 5594 CE2 TRP 164 10.229 61 ATOM 5595 CE3 TRP 164 9.969 63 ATOM 5596 CDl TRP 164 12.045 60 ATOM 5597 NEl TRP 164 11.082 60 ATOM 5598 CZ2 TRP 164 9.103 61 ATOM 5599 CZ3 TRP 164 8.855 63 ATOM 5600 CH2 TRP 164 8.432 62 ATOM 5601 C TRP 164 14.559 64 ATOM 5602 O TRP 164 15.408 63 ATOM 5603 N ASN 165 14.211 65 ATOM 5604 CA ASN 165 14.805 66 ATOM 5605 CB ASN 165 14.254 66 ATOM 5606 CG ASN 165 12.780 66 ATOM 5607 OD1 ASN 165 12.330 67 ATOM 5608 ND2 ASN 165 12.016 65 ATOM 5609 C ASN 165 16.320 66 ATOM 5610 O ASN 165 16.996 66 ATOM 5611 N SER 166 16.848 65 ATOM 5612 CA SER 166 18.277 66 ATOM 5613 CB SER 166 18.802 67 ATOM 5614 OG SER 166 18.185 68 ATOM 5615 C SER 166 19.030 64 ATOM 5616 O SER 166 20.245 65 ATOM 5617 N GLY 167 18.301 63 ATOM 5618 CA GLY 167 18.929 62 ATOM 5619 C GLY 167 18.292 62 ATOM 5620 0 GLY 167 18.144 61 ATOM 5621 N ALA 168 17.896 63 ATOM 5622 CA ALA 168 17.324 63 29.217 1.00 60.12 H31H c 29.593 1.00 60.44 H31H c 29.306 1.00 61.07 H31H c 30.436 1.00 61.97 H31H c 31.095 1.00 62.07 H31H 0 30.668 1.00 61.87 H31H 0 29.781 1.00 59.69 H31H c 29.057 1.00 60.37 H31H 0 31.091 1.00 58.97 H31H N 31.768 1.00 59.60 H31H c 32.051 1.00 58.30 H31H c 33.319 1.00 60.20 H31H c 33.248 1.00 60.02 H31H c 32.257 1.00 5 6.56 H31H c 31.838 1.00 55.30 H31H 0 32.913 1.00 55.04 H31H N 33.649 1.00 54.39 H31H c 33.447 1.00 55.26 H31H c 32.090 1.00 58.59 H31H c 33.612 1.00 55.92 H31H c 35.131 1.00 53.67 H31H c 35.607 1.00 53.08 H31H 0 35.878 1.00 50.80 H31H N 37.305 1.00 49.44 H31H c 37.983 1.00 49.51 H31H c 37.771 1.00 50.02 H31H 0 37.382 1.00 50.69 H31H c 37.839 1.00 49.75 H31H c 37.492 1.00 49.46 H31H 0 38.662 1.00 4 9.63 H31H N 39.218 1.00 48.46 H31H c 39.007 1.00 50.10 H31H c 39.528 1.00 51.21 H31H c 37.527 1.00 49.13 H31H c 40.707 1.00 46.96 H31H c 41.399 1.00 44.46 H31H 0 41.196 1.00 47.63 H31H N 42.619 1.00 47.37 H31H c 42.892 1.00 45.40 H31H c 44.262 1.00 47.31 H31H 0 43.125 1.00 46.40 H31H c 42.339 1.00 47.13 H31H 0 44.435 1.00 44.44 H31H N 45.007 1.00 42.49 H31H c 45.676 1.00 36.70 H31H c 44.694 1.00 34 .26 H31H c 43.979 1.00 34.05 H31H c 43.192 1.00 34.15 H31H c 43.925 1.00 32.87 H31H c 44.315 1.00 33.54 H31H c 43.416 1.00 30.36 H31H N 42.362 1.00 33.86 H31H c 43.102 1.00 32.86 H31H c 42.331 1.00 34.03 H31H c 45.981 1.00 43.04 H31H c 46.783 1.00 41.69 H31H 0 45.882 1.00 44.35 H31H N 46.735 1.00 43.74 H31H c 48.145 1.00 45.04 H31H c 48.205 1.00 4 6.52 H31H c 47.603 1.00 49.82 H31H 0 48.920 1.00 45.08 H31H N 46.728 1.00 43.80 H31H c 47.687 1.00 43.40 H31H 0 45.632 1.00 43.57 H31H N 45.387 1.00 44.05 H31H c 45.778 1.00 44.33 H31H c 44.978 1.00 48.35 H31H' 0 46.164 1.00 42.94 H31H c 46.326 1.00 41.74 H31H 0 46.655 1.00 42.43 H31H N 47.418 1.00 41.74 H31H c 48.772 1.00 42.53 . H31H c 49.209 1.00 43.39 H31H 0 49.436 1.00 42.33 H31H N 50.778 1.00 40.60 H31H c 394 WO 2009/026558 PCT/US2008/074097 ATOM 5623 CB ALA 168 17.054 ATOM 5624 C ALA 168 16.061 ATOM 5625 O ALA 168 15.870 ATOM 5626 N LEU 169 15.204 ATOM 5627 CA LEU 169 13.955 ATOM 5628 CB LEU 169 12.848 ATOM 5629 CG LEU 169 11.506 ATOM 5630 CDl LEU 169 11.201 ATOM 5631 CD2 LEU 169 10.372 ATOM 5632 C LEU 169 14.109 ATOM 5633 O LEU 169 13.874 ATOM 5634 N THR 170 14.479 ATOM 5635 CA THR 170 14.772 ATOM 5636 CB THR 170 16.187 ATOM 5637 OG1 THR 170 16.368 ATOM 5638 CG2 THR 170 17.262 ATOM 5639 C THR 170 13.731 ATOM 5640 O THR 170 13.345 ATOM 5641 N SER 171 13.250 ATOM 5642 CA SER 171 12.273 ATOM 5643 CB SER 171 11.928 ATOM 5644 OG SER 171 11.290 ATOM 5645 C SER 171 11.005 ATOM 5646 O SER 171 10.606 ATOM 5647 N GLY 172 10.370 ATOM 5648 CA GLY 172 9.101 ATOM 5649 C GLY 172 9.206 ATOM 5650 0 GLY 172 8.187 ATOM 5651 N VAL 173 10.430 ATOM 5652 CA VAL 173 10.683 ATOM 5653 CB VAL 173 11.999 ATOM 5654 CGI VAL 173 12.280 ATOM 5655 CG2 VAL 173 11.933 ATOM 5656 C VAL 173 10.837 ATOM 5657 O VAL 173 11.828 ATOM 5658 N HIS 174 9.899 ATOM 5659 CA HIS 174 10.185 ATOM 5660 CB HIS 174 9.160 ATOM 5661 CG HIS 174 9.618 ATOM 5662 CD2 HIS 174 10.847 ATOM 5663 NDl HIS 174 8.755 ATOM 5664 CEl HIS 174 9.432 ATOM 5665 NE2 HIS 174 10.702 ATOM 5666 C HIS 174 10.243 ATOM 5667 0 HIS 174 9.222 ATOM 5668 N THR 175 11.450 ATOM 5669 CA THR 175 11.689 ATOM 5670 CB THR 175 13.096 ATOM 5671 OG1 THR 175 13.205 ATOM 5672 CG2 THR 175 13.383 ATOM 5673 C THR 175 11.608 ATOM 5674 O THR 175 12.380 ATOM 5675 N PHE 176 10.686 ATOM 5676 CA PHE 176 10.489 ATOM 5677 CB PHE 176 9.036 ATOM 5678 CG PHE 176 8.102 ATOM 5679 CDl PHE 176 7.654 ATOM 5680 CD2 PHE 176 7.647 ATOM 5681 CEl PHE 176 6.771 ATOM 5682 CE2 PHE 176 6.7 62 ATOM 5683 CZ PHE 176 6.325 ATOM 5684 C PHE 176 11.364 ATOM 5685 O PHE 176 11.760 ATOM 5686 N PRO 177 11.688 ATOM 5687 CD PRO 177 11.330 ATOM 5688 CA PRO 177 12.573 ATOM 5689 CB PRO 177 12.832 ATOM 5690 CG PRO 177 12.471 ATOM 5691 C PRO 177 11.898 ATOM 5692 O PRO 177 10.692 ATOM 5693 N ALA 178 12.681 ATOM 5694 CA ALA 178 12.133 ATOM 5695 CB ALA 178 13.218 ATOM 5696 C ALA 178 11.530 ATOM 5697 O ALA 178 11.955 ATOM 5698 N VAL 179 10.538
51.346 1.00 39.45 H31H c 50.846 1.00 39.62 H31H c 51.809 1.00 39.68 H31H 0 49.830 1.00 39.52 H31H N 49.897 1.00 40.32 H31H c 49.076 1.00 38.82 H31H c 49.118 1.00 38.57 H31H c 50.544 1.00 36.39 H31H c 48.547 1.00 38.11 H31H c 49.437 1.00 42.25 H31H c 48.268 1.00 41.44 H31H 0 50.363 1.00 44.70 H31H N 49.961 1.00 4 6.53 H31H c 50.439 1.00 45.23 H31H c 51.831 1.00 46.22 H31H 0 4 9.62 5 1.00 45.00 H31H c 50.373 1.00 47.49 H31H c 49.568 1.00 49.33 H31H 0 51.604 1.00 48.12 H31H N 52.035 1.00 49.02 H31H c 53.502 1.00 50.34 H31H c 53.670 1.00 49.96 H31H 0 51.206 1.00 48.93 H31H c 50.859 1.00 50.01 H31H 0 50.887 1.00 48.36 H31H N 50.184 1.00 46.99 H31H c 48.687 1.00 45.95 H31H c 48.015 1.00 46.41 H31H 0 48.168 1.00 45.18 H31H N 46.748 1.00 44.79 H31H c 46.546 1.00 43.99 H31H c 45.068 1.00 43.36 H31H c 47.224 1.00 45.03 H31H c 45.970 1.00 46.04 H31H c 46.157 1.00 46.61 H31H 0 45.091 1.00 48.02 H31H N 44.167 1.00 50.67 H31H c 44.299 1.00 56.04 H31H c 43.707 1.00 64.33 H31H c 43.652 1.00 67.01 H31H c 43.097 1.00 67.38 H31H N 42.694 1.00 67.43 H31H c 43.019 1.00 68.12 H31H N 42.715 1.00 48.63 H31H C 42.110 1.00 48.68 H31H 0 42.167 1.00 46.86 H31H N 40.747 1.00 45.90 H31H C 40.559 1.00 45.07 H31H c 41.317 1.00 42.71 H31H 0 39.077 1.00 44.22 H31H c 39.946 1.00 45.53 H31H c 40.193 1.00 44.10 H31H 0 38.991 1.00 45.00 H31H N 38.236 1.00 47.18 H31H c 37.827 1.00 46.51 H31H c 38.986 1.00 48.17 H31H c 39.694 1.00 45.97 H31H c 39.353 1.00 47.11 H31H c 40.738 1.00 45.93 H31H c 40.400 1.00 46.13 H31H c 41.090 1.00 46.30 H31H c 36.999 1.00 48.64 H31H c 36.394 1.00 48.01 H31H 0 36.613 1.00 48.62 H31H N 37.338 1.00 50.33 H31H c .35.474 1.00 49.81 H31H c 35.590 1.00 49.25 H31H c 37.005 1.00 49.07 H31M- c 34.157 1.00 48.15 H31H c 33.977 1.00 44.95 H31H 0 33.250 1.00 47.67 H31H N 32.055 1.00 49.62 H31H c 31.354 1.00 50.13 . H31H c 31.087 1.00 50.13 H31H c 31.023 1.00 50.26 H31H 0 30.325 1.00 50.60 H31H N 395 WO 2009/026558 PCT/US2008/074097 ATOM 5699 CA VAL 179 10.123 49 ATOM 5700 CB VAL 179 8.585 49 ATOM 5701 CGI VAL 179 8.075 51 ATOM 5702 CG2 VAL 179 8.204 48 ATOM 5703 C VAL 179 10.760 50 ATOM 5704 O VAL 179 11.205 51 ATOM 5705 N LEU 180 10.824 49 ATOM 5706 CA LEU 180 11.157 50 ATOM 5707 CB LEU 180 12.042 48 ATOM 5708 CG LEU 180 13.014 49 ATOM 5709 CDl LEU 180 13.527 50 ATOM 5710 CD2 LEU 180 14.172 48 ATOM 5711 C LEU 180 9.829 50 ATOM 5712 O LEU 180 9.032 49 ATOM 5713 N GLN 181 9.576 51 ATOM 5714 CA GLN 181 8.376 51 ATOM 5715 CB GLN 181 7.882 52 ATOM 5716 CG GLN 181 7.427 53 ATOM 5717 CD GLN 181 7.670 54 ATOM 5718 OE1 GLN 181 6.731 55 ATOM 5719 NE2 GLN 181 8.933 55 ATOM 5720 C GLN 181 8.741 51 ATOM 5721 0 GLN 181 9.930 50 ATOM 5722 N SER 182 7.723 50 ATOM 5723 CA SER 182 7.937 50 ATOM 5724 CB SER 182 6.599 50 ATOM 5725 OG SER 182 5.733 49 ATOM 5726 C SER 182 8.853 51 ATOM 5727 O SER 182 9.297 51 ATOM 5728 N SER 183 9.131 52 ATOM 5729 CA SER 183 9.965 53 ATOM 5730 CB SER 183 9.624 54 ATOM 5731 OG SER 183 10.483 55 ATOM 5732 C SER 183 11.445 53 ATOM 5733 O SER 183 12.305 53 ATOM 5734 N GLY 184 11.747 52 ATOM 5735 CA GLY 184 13.137 52 ATOM 5736 C GLY 184 13.634 53 ATOM 5737 0 GLY 184 14.828 53 ATOM 5738 N LEU 185 12.703 54 ATOM 5739 CA LEU 185 12.987 55 ATOM 5740 CB LEU 185 12.357 56 ATOM 5741 CG LEU 185 12.913 57 ATOM 5742 CDl LEU 185 12.278 58 ATOM 5743 CD2 LEU 185 14.431 57 ATOM 5744 C LEU 185 12.398 54 ATOM 5745 O LEU 185 11.390 53 ATOM 5746 N TYR 186 13.030 54 ATOM 5747 CA TYR 186 12.629 54 ATOM 5748 CB TYR 186 13.853 54 ATOM 5749 CG TYR 186 14.782 53 ATOM 5750 CDl TYR 186 14.423 51 ATOM 5751 CEl TYR 186 15.281 50 ATOM 5752 CD2 TYR 186 16.023 53 ATOM 5753 CE2 TYR 186 16.885 52 ATOM 5754 CZ TYR 186 16.509 50. ATOM 5755 OH TYR 186 17.366 50 ATOM 5756 C TYR 186 11.663 55 ATOM 5757 O TYR 186 11.697 56 ATOM 5758 N SER 187 10.798 54 ATOM 5759 CA SER 187 10.108 55 ATOM 5760 CB SER 187 8.619 55 ATOM 5761 OG SER 187 8.416 56 ATOM 5762 C SER 187 10.278 54 ATOM 5763 O SER 187 10.304 53 ATOM 5764 N LEU 188 10.408 55 ATOM 5765 CA LEU 188 10.223 54 ATOM 5766 CB LEU 188 11.572 54 ATOM 5767 CG LEU 188 12.446 55 ATOM 5768 CDl LEU 188 11.988 55 ATOM 5769 CD2 LEU 188 13.876 55 ATOM 5770 C LEU 188 9.549 55 ATOM 5771 O LEU 188 9.594 57 ATOM 5772 N SER 189 8.920 55 ATOM 5773 CA SER 189 8.382 56 ATOM 5774 CB SER 189 6.857 56 29.181 1.00 52.63 H31H c 29.017 1.00 49.49 H31H c 28.523 1.00 47.79 H31H c 28.057 1.00 48.76 H31H c 27.890 1.00 57.03 H31H c 27.820 1.00 55.93 H31H p 26.880 1.00 61.40 H31H N 25.528 1.00 63.99 H31H c 24.878 1.00 61.84 H31H c 23.813 1.00 60.90 H31H c 24.190 1.00 58.46 H31H c 23.684 1.00 60.70 H31H c 24.788 1.00 67.05 H31H c 24.813 1.00 68.83 H31H 0 24.158 1.00 69.86 H31H N 23.341 1.00 71.70 H31H c 23.384 1.00 74.68 H31H c 24.772 1.00 79.74 H31H c 25.014 1.00 83.20 H31H c 25.273 1.00 85.51 H31H 0 24.938 1.00 84 .18 H31H N 21.912 1.00 72.09 H31H c 21.574 1.00 70.09 H31H 0 21.080 1.00 72.37 H31H N 19.694 1.00 72.49 H31H c 18.967 1.00 71.69 H31H c 19.639 1.00 72.82 H31H 0 18.976 1.00 72.06 H31H c 17.855 1.00 73.81 H31H 0 19.640 1.00 69.30 H31H N 19.076 1.00 67.21 H31H c 19.735 1.00 69.40 H31H c 19.280 1.00 71.75 H31H 0 19.269 1.00 65.60 H31H c 18.552 1.00 64.41 H31H 0 20.245 1.00 64.00 H31H N 20.626 1.00 62.60 H31H c 21.562 1.00 61.18 H31H c 21.850 1.00 60.60 H31H 0 22.030 1.00 59.98 H31H N 23.079 1.00 59.22 H31H c 22.744 1.00 59.91 H31H c 21.502 1.00 59.10 H31H c 21.353 1.00 57.09 H31H c 21.621 1.00 57.14 H31H c 24.372 1.00 58.54 H31H c 24.343 1.00 58.03 H31H 0 25.495 1.00 56.77 H31H N 26.792 1.00 54.56 H31H c 27.678 1.00 53.50 H31H c 27.218 1.00 53.54 H31H c 27.341 1.00 53.96 H31H c 26.928 1.00 53.54 H31H c 26.673 1.00 52.95 H31H c 26.259 1.00 55.74 H31H c 26.386 1.00 54.83 H31H c 25.944 1.00 54.90 H31H 0 27.526 1.00 53.17 H31H c 27.374 1.00 55.58 H31H 0 28.331 1.00 50.88 H31H N 29.376 1.00 49.39 H31H c 29.057 1.00 48.12 H31H c 27.956 1.00 49.32 H31H 0 30.699 1.00 48.74 H31H c 30.741 1.00 49.37 H31H 0 31.779 1.00 46.61 H31H N 33.099 1.00 45.05 H31H c 33.708 1.00 41.87 H 3 1H c 34.348 1.00 41.43 H31H c 35.773 1.00 41.51 H31H c 34.363 1.00 40.21 H31H c 33.943 1.00 44.78 H31H c 33.599 1.00 44.93 . H31H 0 35.038 1.00 44.18 H31H N 35.993 1.00 43.74 H31H c 35.905 1.00 42.81 H31H c 396 WO 2009/026558 PCT/US2008/074097 ATOM 5775 OG SER 189 6.384 55 ATOM 5776 C SER 189 8.835 56 ATOM 5777 O SER 189 9.054 54 ATOM 5778 N SER 190 8.986 57 ATOM 5779 CA SER 190 9.349 57 ATOM 5780 CB SER 190 10.651 57 ATOM 5781 OG SER 190 10.959 57 ATOM 5782 C SER 190 8.228 57 ATOM 5783 O SER 190 7.793 58 ATOM 5784 N VAL 191 7.749 56 ATOM 5785 CA VAL 191 6.716 57 ATOM 5786 CB VAL 191 5.628 56 ATOM 5787 CGI VAL 191 4.361 56 ATOM 5788 CG2 VAL 191 5.378 55 ATOM 5789 C VAL 191 7.344 57 ATOM 5790 O VAL 191 8.455 56 ATOM 5791 N VAL 192 6.625 57 ATOM 5792 CA VAL 192 7.071 58 ATOM 5793 CB VAL 192 7.993 59 ATOM 5794 CGI VAL 192 7.188 60 ATOM 5795 CG2 VAL 192 8.716 59 ATOM 5796 C VAL 192 5.833 58 ATOM 5797 O VAL 192 4 . 869 58 ATOM 5798 N THR 193 5.845 57 ATOM 5799 CA THR 193 4.707 57 ATOM 5800 CB THR 193 4.442 56 ATOM 5801 OG1 THR 193 4.299 55 ATOM 5802 CG2 THR 193 3.174 56 ATOM 5803 C THR 193 4.949 58 ATOM 5804 O THR 193 6.014 58 ATOM 5805 N VAL 194 3.951 59 ATOM 5806 CA VAL 194 4 . 007 60 ATOM 5807 CB VAL 194 4 . 182 62 ATOM 5808 CGI VAL 194 5.482 62 ATOM 5809 CG2 VAL 194 3.001 62 ATOM 5810 C VAL 194 2.705 60 ATOM 5811 O VAL 194 1.692 60 ATOM 5812 N PRO 195 2.721 61 ATOM 5813 CD PRO 195 3.960 61 ATOM 5814 CA PRO 195 1.521 61 ATOM 5815 CB PRO 195 2.088 62 ATOM 5816 CG PRO 195 3.473 62 ATOM 5817 C PRO 195 0.575 62 ATOM 5818 O PRO 195 1.016 63 ATOM 5819 N SER 196 -0.725 62 ATOM 5820 CA SER 196 -1.705 63 ATOM 5821 CB SER 196 -3.117 62 ATOM 5822 OG SER 196 -3.210 61 ATOM 5823 C SER 196 -1.607 64 ATOM 5824 O SER 196 -1.704 65 ATOM 5825 N SER 197 -1.403 64 ATOM 5826 CA SER 197 -1.411 65 ATOM 5827 CB SER 197 -1.255 65 ATOM 5828 OG SER 197 -0.156 64 ATOM 5829 C SER 197 -0.329 66 ATOM 5830 O SER 197 -0.543 68 ATOM 5831 N SER 198 0.835 66 ATOM 5832 CA SER 198 1.959 67 ATOM 5833 CB SER 198 3.295 66 ATOM 5834 OG SER 198 3.418 65 ATOM 5835 C SER 198 1.855 67 ATOM 5836 O SER 198 2.640 68 ATOM 5837 N LEU 199 0.875 67 ATOM 5838 CA LEU 199 0.587 68 ATOM 5839 CB LEU 199 -0.469 67 ATOM 5840 CG LEU 199 -0.068 65 ATOM 5841 CDl LEU 199 -1.221 65 ATOM 5842 CD2 LEU 199 1. 127 65 ATOM 5843 C LEU 199 0.077 69 ATOM 5844 O LEU 199 -0.534 69 ATOM 5845 N GLY 200 0.331 70 ATOM 5846 CA GLY 200 -0.025 71 ATOM 5847 C GLY 200 1. 110 72 ATOM 5848 0 GLY 200 1.260 73 ATOM 5849 N THR 201 1.922 71 ATOM 5850 CA THR 201 2.984 72 35.391 1.00 40.88 H31H 0 37.416 1.00 44 . 62 H31H c 37.758 1.00 44 . 06 H31H 0 38.235 1.00 45.13 H31H N 39.637 1.00 47.28 H31H c 39.910 1.00 47.70 H31H c 41.291 1.00 51.62 H31H 0 40.559 1.00 48.63 H31H c 40.449 1.00 49.40 H31H 0 41.460 1.00 48.61 H31H N 42.404 1.00 48.08 H31H c 42.579 1.00 48.63 H31H c 43.120 1.00 49.16 H31H c 41.276 1.00 50.66 H31H c 43.770 1.00 48.14 H31H c 44.032 1.00 48.84 H31H 0 44.649 1.00 47.74 H31H N 46.020 1.00 49.09 H31H c 46.168 1.00 47.37 H31H c 46.033 1.00 49.41 H31H c 47.494 1.00 48.43 H31H c 46.893 1.00 51.29 H31H c 46.491 1.00 52.06 H31H 0 48.076 1.00 53.99 H31H N 48.978 1.00 55.72 H31H c 49.712 1.00 54 . 82 H31H c 48.762 1.00 52.78 H31H 0 50.529 1.00 53.19 H31H c 50.024 1.00 57.60 H31H c 50.638 1.00 60.19 H31H 0 50.223 1.00 59.12 H31H N 51.244 1.00 59.31 H31H c 50.614 1.00 57.34 H31H c 49.839 1.00 56.49 H31H c 49.714 1.00 53.69 H31H c 52.041 1.00 61.25 H31H c 51.604 1.00 61.92 H31H 0 53.222 1.00 62.39 H31H N 53.933 1.00 60.34 H31H c 53.980 1.00 63.17 H31H c 55.197 1.00 59.42 H31H c 55.326 1.00 58.40 H31H c 53.182 1.00 64.78 H31H c 52.486 1.00 65.00 H31H 0 53.297 1.00 65.72 H31H N 52.714 1.00 66.61 H31H c 52.895 1.00 65.85 H31H c 52.356 1.00 61.78 H31H 0 53.393 1.00 67.65 H31H c 52.746 1.00 68.06 H31H 0 54.704 1.00 69.10 H31H N 55.516 1.00 69.65 H31H c 56.990 1.00 69.31 H31H c 57.169 1.00 68.21 H31H 0 55.130 1.00 70.07 H31H c 55.225 1.00 70.52 H31H 0 54.712 1.00 69.45 H31H N 54.405 1.00 68.99 H31H c 54.588 1.00 70.62 H31H c 53.730 1.00 73.17 H31H 0 52.996 1.00 68.67 H31H c 52.610 1.00 66.31 H31H 0 52.233 1.00 69.05 H31H N 50.938 1.00 70.87 H31H c 50.205 1.00 68.03 H31H c 49.805 1.00 66.69 H31H c 49.119 1.00 65.13 H31H c 48.884 1.00 66.64 H31R c 51.171 1.00 74.01 H31H c 52.202 1.00 75.02 H31H 0 50.224 1.00 76.20 H31H N 50.442 1.00 79.03 H31H c 51.069 1.00 81.18 . H31H c 50.805 1.00 82.30 H31H 0 51.889 1.00 82.71 H31H N 52.591 1.00 83.47 H31H c 397 WO 2009/026558 PCT/US2008/074097
ATOM 5851 CB THR 201 2.869 72.334 54.093 1.00 82.12 H31H c ATOM 5852 OG1 THR 201 2.774 70.932 54.358 1.00 82.06 H31H 0 ATOM 5853 CG2 THR 201 1.643 73.031 54.632 1.00 80.62 H31H c ATOM 5854 C THR 201 4.377 72.143 52.142 1.00 84.13 H31H c ATOM 5855 O THR 201 5.191 72.988 51.766 1.00 86.17 H31H 0 ATOM 5856 N GLN 202 4.653 70.846 52.189 1.00 83.67 H31H N ATOM 5857 CA GLN 202 5.949 70.339 51.760 1.00 81.24 H31H C ATOM 5858 CB GLN 202 6.141 68.902 52.250 1.00 84.61 H31H C ATOM 5859 CG GLN 202 6.355 68.812 53.740 1.00 89.81 H31H C ATOM 5860 CD GLN 202 7.301 69.881 54.232 1.00 93.21 H31H C ATOM 5861 OE1 GLN 202 6.995 70.603 55.178 1.00 95.82 H31H 0 ATOM 5862 NE2 GLN 202 8.458 69.997 53.586 1.00 96.62 H31H N ATOM 5863 C GLN 202 6.013 70.393 50.246 1.00 76.65 H31H C ATOM 5864 0 GLN 202 4.997 70.253 49.575 1.00 75.95 H31H O ATOM 5865 N THR 203 7.199 70.607 49.699 1.00 72.04 H31H N ATOM 5866 CA THR 203 7.326 70.634 48.253 1.00 67.97 H31H C ATOM 5867 CB THR 203 7.958 71.961 47.791 1.00 68.16 H31H C ATOM 5868 OG1 THR 203 9.304 72.037 48.263 1.00 69.55 H31H O ATOM 5869 CG2 THR 203 7.170 73.149 48.352 1.00 66.96 H31H C ATOM 5870 C THR 203 8.145 69.439 47.737 1.00 64.26 H31H C ATOM 5871 O THR 203 9.212 69.119 48.262 1.00 63.14 H31H O ATOM 5872 N TYR 204 7.623 68.769 46.713 1.00 60.03 H31H N ATOM 5873 CA TYR 204 8.261 67.567 46.183 1.00 56.87 H31H C ATOM 5874 CB TYR 204 7.262 66.406 46.201 1.00 56.87 H31H C ATOM 5875 CG TYR 204 6.884 66.022 47.605 1.00 58.37 H31H C ATOM 5876 CDl TYR 204 5.636 66.324 48.121 1.00 59.73 H31H C ATOM 5877 CEl TYR 204 5.318 66.035 49.436 1.00 60.84 H31H C ATOM 5878 CD2 TYR 204 7.805 65.414 48.440 1.00 60.23 H31H C ATOM 5879 CE2 TYR 204 7.500 65.119 49.749 1.00 60.88 H31H C ATOM 5880 CZ TYR 204 6.257 65.432 50.245 1.00 61.19 H31H C ATOM 5881 OH TYR 204 5.964 65.141 51.558 1.00 60.98 H31H O ATOM 5882 C TYR 204 8.844 67.751 44.774 1.00 54.04 H31H C ATOM 5883 O TYR 204 8.117 67.841 43.784 1.00 52.97 H31H 0 ATOM 5884 N ILE 205 10.167 67.806 44.693 1.00 50.55 H31H N ATOM 5885 CA ILE 205 10.831 67.982 43.415 1.00 48.02 H31H C ATOM 5886 CB ILE 205 11.880 69.126 43.485 1.00 4 3.92 H31H C ATOM 5887 CG2 ILE 205 12.670 69.191 42.178 1.00 39.57 H31H C ATOM 5888 CGI ILE 205 11.171 70.449 43.801 1.00 40.24 H31H C ATOM 5889 CDl ILE 205 12.090 71.615 44.002 1.00 36.63 H31H C ATOM 5890 C ILE 205 11.511 66.685 43.017 1.00 48.10 H31H C ATOM 5891 0 ILE 205 12.252 66.096 43.801 1.00 49.28 H31H 0 ATOM 5892 N CYS 206 11.256 66.234 41.801 1.00 47.41 H31H N ATOM 5893 CA CYS 206 11.926 65.042 41.313 1.00 47.33 H31H C ATOM 5894 C CYS 206 13.021 65.467 40.346 1.00 46.16 H31H C ATOM 5895 0 CYS 206 12.751 66.190 39.395 1.00 46.16 H31H O ATOM 5896 CB CYS 206 10.905 64.116 40.637 1.00 48.70 H31H C ATOM 5897 SG CYS 206 10.705 64.310 38.841 1.00 49.42 H31H S ATOM 5898 N ASN 207 14.259 65.046 40.608 1.00 46.09 H31H N ATOM 5899 CA ASN 207 15.400 65.405 39.758 1.00 45.79 H31H C ATOM 5900 CB ASN 207 16.598 65.771 40.618 1.00 47.44 H31H C ATOM 5901 CG ASN 207 16.194 66.274 41.978 1.00 49.48 H31H C ATOM 5902 OD1 ASN 207 15.873 65.481 42.884 1.00 49.54 H31H O ATOM 5903 ND2 ASN 207 16.199 67.597 42.140 1.00 48.35 H31H N ATOM 5904 C ASN 207 15.794 64.256 38.841 1.00 45.19 H31H C ATOM 5905 O ASN 207 15.981 63.126 39.292 1.00 45.98 H31H O ATOM 5906 N VAL 208 15.920 64.545 37.552 1.00 44.59 H31H N ATOM 5907 CA VAL 208 16.179 63.499 36.579 1.00 44.44 H31H C ATOM 5908 CB VAL 208 15.061 63.395 35.565 1.00 42.93 H31H C ATOM 5909 CGI VAL 208 15.378 62.291 34.596 1.00 42.05 H31H C ATOM 5910 CG2 VAL 208 13.733 63.145 36.275 1.00 42.37 H31H C ATOM 5911 C VAL 208 17.477 63.703 35.824 1.00 46.24 H31H C ATOM 5912 O VAL 208 17.649 64.664 35.076 1.00 46.31 H31H O ATOM 5913 N ASN 209 18.398 62.774 36.027 1.00 49.74 H31H N ATOM 5914 CA ASN 209 19.695 62.842 35.389 1.00 51.57 H31H C ATOM 5915 CB ASN 209 20.775 62.534 36.408 1.00 53.49 H31H C ATOM 5916 CG ASN 209 21.866 63.555 36.397 1.00 58.10 H31H C ATOM 5917 OD1 ASN 209 22.623 63.663 35.425 1.00 61.93 H31H O ATOM 5918 ND2 ASN 209 21.961 64.331 37.476 1.00 60.31 H31H' N ATOM 5919 C ASN 209 19.758 61.854 34.233 1.00 53.30 H31H C ATOM 5920 O ASN 209 19.119 60.794 34.266 1.00 52.74 H31H O ATOM 5921 N HIS 210 20.521 62.213 33.208 1.00 55.96 H31H N ATOM 5922 CA HIS 210 20.682 61.371 32.027 1.00 60.39 H31H C ATOM 5923 CB HIS 210 19.506 61.586 31.075 1.00 57.95 . H31H C ATOM 5924 CG HIS 210 19.554 60.737 29.841 1.00 57.46 H31H C ATOM 5925 CD2 HIS 210 18.962 59.554 29.550 1.00 56.95 H31H C ATOM 5926 NDl HIS 210 20.240 61. 111 28.705 1.00 56.62 H31H N 398 WO 2009/026558 PCT/US2008/074097 ATOM 5927 CEl HIS 210 20.064 60.196 27.768 1.00 56.04 H31H c ATOM 5928 NE2 HIS 210 19.293 59.241 28.255 1.00 56.13 H31H N ATOM 5929 C HIS 210 21.989 61.732 31.332 1.00 64.05 H31H C ATOM 5930 0 HIS 210 21.999 62.563 30.423 1.00 66.26 H31H 0 ATOM 5931 N LYS 211 23.088 61.105 31.759 1.00 67.42 H31H N ATOM 5932 CA LYS 211 24.422 61.500 31.308 1.00 71.12 H31H C ATOM 5933 CB LYS 211 25.493 60.800 32.148 1.00 73.47 H31H c ATOM 5934 CG LYS 211 25.650 61.391 33.537 1.00 78.05 H31H c ATOM 5935 CD LYS 211 26.676 60.635 34.371 1.00 83.09 H31H c ATOM 5936 CE LYS 211 26.518 60.963 35.851 1.00 87.25 H31H c ATOM 5937 NZ LYS 211 25.078 60.948 36.299 1.00 92.55 H31H N ATOM 5938 C LYS 211 24.717 61.288 29.821 1.00 71.44 H31H c ATOM 5939 0 LYS 211 25.602 61.954 29.265 1.00 70.88 H31H 0 ATOM 5940 N PRO 212 23.988 60.363 29.161 1.00 70.66 H31H N ATOM 5941 CD PRO 212 23.075 59.370 29.752 1.00 68.67 H31H c ATOM 5942 CA PRO 212 24.151 60.136 27.723 1.00 70.83 H31H c ATOM 5943 CB PRO 212 23.177 59.003 27.425 1.00 68.87 H31H c ATOM 5944 CG PRO 212 23.014 58.308 28.708 1.00 67.41 H31H c ATOM 5945 C PRO 212 23.856 61.369 26.881 1.00 71.39 H31H c ATOM 5946 O PRO 212 24.549 61.634 25.897 1.00 73.26 H31H 0 ATOM 5947 N SER 213 22.831 62.124 27.268 1.00 69.78 H31H N ATOM 5948 CA SER 213 22.506 63.363 26.573 1.00 67.25 H31H c ATOM 5949 CB SER 213 20.998 63.448 26.316 1.00 68.21 H31H c ATOM 5950 OG SER 213 20.260 63.475 27.523 1.00 69.83 H31H 0 ATOM 5951 C SER 213 22.976 64.603 27.333 1.00 64.95 H31H c ATOM 5952 O SER 213 22.739 65.733 26.895 1.00 64.30 H31H 0 ATOM 5953 N ASN 214 23.651 64.380 28.458 1.00 63.80 H31H N ATOM 5954 CA ASN 214 23.966 65.445 29.405 1.00 62.78 H31H c ATOM 5955 CB ASN 214 25.135 66.282 28.898 1.00 64.09 H31H c ATOM 5956 CG ASN 214 26.432 65.517 28.892 1.00 66.41 H31H c ATOM 5957 OD1 ASN 214 26.678 64.705 28.003 1.00 68.49 H31H 0 ATOM 5958 ND2 ASN 214 27.276 65.771 29.886 1.00 68.13 H31H N ATOM 5959 C ASN 214 22.752 66.338 29.632 1.00 60.83 H31H c ATOM 5960 O ASN 214 22.733 67.513 29.258 1.00 59.28 H31H 0 ATOM 5961 N THR 215 21.732 65.767 30.257 1.00 58.26 H31H N ATOM 5962 CA THR 215 20.473 66.471 30.437 1.00 55.62 H31H c ATOM 5963 CB THR 215 19.412 65.954 29.444 1.00 52.20 H31H c ATOM 5964 OG1 THR 215 19.909 66.088 28.112 1.00 47.16 H31H 0 ATOM 5965 CG2 THR 215 18.137 66.741 29.585 1.00 49.57 H31H c ATOM 5966 C THR 215 19.937 66.288 31.855 1.00 54.60 H31H c ATOM 5967 O THR 215 19.390 65.228 32.174 1.00 57.16 H31H 0 ATOM 5968 N LYS 216 20.069 67.298 32.710 1.00 51.53 H31H N ATOM 5969 CA LYS 216 19.366 67.224 33.976 1.00 49.41 H31H c ATOM 5970 CB LYS 216 20.251 67.745 35.109 1.00 47.56 H31H c ATOM 5971 CG LYS 216 19.748 67.34 6 36.505 1.00 51.25 H31H c ATOM 5972 CD LYS 216 20.613 67.953 37.610 1.00 56.11 H31H c ATOM 5973 CE LYS 216 19.792 68.452 38.809 1.00 59.03 H31H c ATOM 5974 NZ LYS 216 19.922 69.939 39.020 1.00 66.78 H31H N ATOM 5975 C LYS 216 18.032 67.994 33.913 1.00 4 7.52 H31H c ATOM 5976 0 LYS 216 17.947 69.086 33.343 1.00 47.37 H31H 0 ATOM 5977 N VAL 217 16.986 67.399 34.475 1.00 45.17 H31H N ATOM 5978 CA VAL 217 15.675 68.029 34.495 1.00 45.48 H31H c ATOM 5979 CB VAL 217 14.705 67.359 33.504 1.00 42.90 H31H c ATOM 5980 CGI VAL 217 13.382 68.094 33.502 1.00 43.01 H31H c ATOM 5981 CG2 VAL 217 15.291 67.349 32.12 6 1.00 42.04 H31H c ATOM 5982 C VAL 217 15.033 67.935 35.874 1.00 45.53 H31H c ATOM 5983 O VAL 217 14.689 66.837 36.325 1.00 44.46 H31H 0 ATOM 5984 N ASP 218 14.844 69.085 36.522 1.00 45.13 H31H N ATOM 5985 CA ASP 218 14.068 69.157 37.765 1.00 44.22 H31H c ATOM 5986 CB ASP 218 14.646 70.233 38.697 1.00 45.01 H31H c ATOM 5987 CG ASP 218 16.039 69.896 39.177 1.00 46.69 H31H c ATOM 5988 OD1 ASP 218 16.230 68.770 39.690 1.00 48.07 H31H 0 ATOM 5989 OD2 ASP 218 16.942 70.752 39.040 1.00 47.24 H31H 0 ATOM 5990 C ASP 218 12.609 69.485 37.468 1.00 41.82 H31H c ATOM 5991 O ASP 218 12.325 70.438 36.759 1.00 41.41 H31H 0 ATOM 5992 N LYS 219 11.688 68.690 .38.000 1.00 41.58 H31H N ATOM 5993 CA LYS 219 10.261 69.006 37.898 1.00 43.18 H31H c ATOM 5994 CB LYS 219 9.546 68.005 36.983 1.00 42.71 H31H c ATOM 5995 CG LYS 219 8.209 68.494 36.454 1.00 42.46 H31H c ATOM 5996 CD LYS 219 8.401 69.794 35.667 1.00 46.00 H31H c ATOM 5997 CE LYS 219 7.112 70.264 34.971 1.00 46.61 H31H c ATOM 5998 NZ LYS 219 7.108 69.969 33.497 1.00 46.37 H31H N ATOM 5999 C LYS 219 9.612 68.982 39.279 1.00 44.12 . H31H c ATOM 6000 0 LYS 219 9.785 68.027 40.035 1.00 43.32 H31H 0 ATOM 6001 N LYS 220 8.879 70.037 39.616 1.00 46.31 ' H31H N ATOM 6002 CA LYS 220 8.173 70.073 40.887 1.00 51.36 H31H c 399 WO 2009/026558 PCT/US2008/074097 ATOM 6003 CB LYS 220 8.004 71.512 41.356 1.00 51.83 H31H c ATOM 6004 CG LYS 220 7.136 71.684 42.587 1.00 53.30 H31H c ATOM 6005 CD LYS 220 7.297 73.099 43.134 1.00 55.65 H31H c ATOM 6006 CE LYS 220 6.414 73.349 44.343 1.00 58.38 H31H c ATOM 6007 NZ LYS 220 6.792 74.612 45.042 1.00 61.74 H31H N ATOM 6008 C LYS 220 6.810 69.413 40.731 1.00 55.52 H31H c ATOM 6009 0 LYS 220 6.127 69.592 39.727 1.00 56.17 H31H 0 ATOM 6010 N VAL 221 6.425 68.622 41.717 1.00 59.39 H31H N ATOM 6011 CA VAL 221 5.191 67.885 41.62 0 1.00 63.66 H31H c ATOM 6012 CB VAL 221 5.439 66.388 41.823 1.00 64.08 H31H c ATOM 6013 CGI VAL 221 4.117 65.618 41.778 1.00 62.71 H31H c ATOM 6014 CG2 VAL 221 6.391 65.892 40.743 1.00 61.51 H31H c ATOM 6015 C VAL 221 4.234 68.410 42.661 1.00 67.49 H31H c ATOM 6016 O VAL 221 4.508 68.365 43.852 1.00 67.95 H31H 0 ATOM 6017 N GLU 222 3.118 68.942 42.182 1.00 72.52 H31H N ATOM 6018 CA GLU 222 2.115 69.555 43.032 1.00 77.04 H31H c ATOM 6019 CB GLU 222 1.951 71.041 42.689 1.00 79.41 H31H c ATOM 6020 CG GLU 222 3.071 71.952 43.174 1.00 87.22 H31H c ATOM 6021 CD GLU 222 2.790 73.425 42.900 1.00 91.43 H31H c ATOM 6022 OE1 GLU 222 3.133 74.277 43.750 1.00 95.60 H31H 0 ATOM 6023 OE2 GLU 222 2.224 73.730 41.829 1.00 95.74 H31H 0 ATOM 6024 C GLU 222 0.793 68.843 42.802 1.00 79.22 H31H c ATOM 6025 0 GLU 222 0.551 68.271 41.737 1.00 78.25 H31H 0 ATOM 6026 N PRO 223 -0.084 68.879 43.803 1.00 81.42 H31H N ATOM 6027 CD PRO 223 0.214 69.436 45.129 1.00 83.23 H31H c ATOM 6028 CA PRO 223 -1.433 68.318 43.734 1.00 83.45 H31H c ATOM 6029 CB PRO 223 -2.002 68.595 45.121 1.00 84.78 H31H c ATOM 6030 CG PRO 223 -0.805 68.783 45.992 1.00 85.56 H31H c ATOM 6031 C PRO 223 -2.261 68.981 42.635 1.00 84.25 H31H c ATOM 6032 O PRO 223 -1.940 70.080 42.185 1.00 82.72 H31H 0 ATOM 6033 N LYS 224 -3.332 68.310 42.221 1.00 85.68 H31H N ATOM 6034 CA LYS 224 -4.128 68.730 41.069 1.00 87.49 H31H c ATOM 6035 CB LYS 224 -4.799 67.507 40.432 1.00 87.94 H31H c ATOM 6036 CG LYS 224 -4.095 66.198 40.749 1.00 88.70 H31H c ATOM 6037 CD LYS 224 -4.345 65.129 39.692 1.00 90.62 H31H c ATOM 6038 CE LYS 224 -3.572 63.850 40.031 1.00 92.06 H31H c ATOM 6039 NZ LYS 224 -3.487 62.866 38.912 1.00 92.45 H31H N ATOM 6040 C LYS 224 -5.191 69.764 41.441 1.00 88.37 H31H c ATOM 6041 0 LYS 224 -6.384 69.388 41.475 1.00 89.80 H31H 0 ATOM 6042 OXT LYS 224 -4.825 70.932 41.701 1.00 89.87 H31H 0 TER 6043 LYS 224 H31H ATOM 6044 CB SER 2 63.863 32.817 2.917 1.00 52.61 L21B c ATOM 6045 OG SER 2 65.036 32.750 2.112 1.00 56.46 L21B 0 ATOM 6046 C SER 2 63.296 30.542 1.965 1.00 51.89 L21B c ATOM 6047 O SER 2 62.911 29.519 2.538 1.00 49.06 L21B 0 ATOM 6048 N SER 2 61.635 31.805 3.365 1.00 50.71 L21B N ATOM 6049 CA SER 2 62.738 31.922 2.361 1.00 50.89 L21B c ATOM 6050 N ALA 3 64.199 30.533 0.985 1.00 56.94 L21B N ATOM 6051 CA ALA 3 64.675 29.305 0.362 1.00 57.67 L21B C ATOM 6052 CB ALA 3 65.526 29.649 -0.843 1.00 55.59 L21B c ATOM 6053 C ALA 3 65.454 28.390 1.309 1.00 57.11 L21B c ATOM 6054 O ALA 3 65.912 28.813 2.368 1.00 57.76 L21B 0 ATOM 6055 N LEU 4 65.585 27.125 0.922 1.00 51.91 L21B N ATOM 605 6 CA LEU 4 66.411 26.170 1.654 1.00 50.60 L21B c ATOM 6057 CB LEU 4 65.999 24.735 1.303 1.00 49.68 L21B c ATOM 6058 CG LEU 4 64.497 24.436 1.262 1.00 46.57 L21B c ATOM 6059 CDl LEU 4 64.270 22.951 1.014 1.00 42.80 L21B c ATOM 6060 CD2 LEU 4 63.852 24.877 2.561 1.00 45.01 L21B c ATOM 6061 C LEU 4 67.880 26.383 1.282 1.00 51.12 L21B c ATOM 6062 O LEU 4 68.178 26.834 0.185 1.00 51.19 L21B 0 ATOM 6063 N THR 5 68.791 26.045 2.191 1.00 53.04 L21B N ATOM 6064 CA THR 5 70.207 26.318 1.999 1.00 54.33 L21B c ATOM 6065 CB THR 5 70.858 26.820 3.300 1.00 55.17 L21B c ATOM 6066 OG1 THR 5 70.095 27.914 3.834 1.00 56.53 L21B 0 ATOM 6067 CG2 THR 5 72.293 27.267 3.037 1.00 54.92 L21B c ATOM 6068 C THR 5 70.958 25.072 . 1.561 1.00 55.20 L21B c ATOM 6069 O THR 5 71.0 62 24.107 2.315 1.00 53.92 L21B 0 ATOM 6070 N GLN 6 71.480 25.103 0.339 1.00 57.74 L21B' N ATOM 6071 CA GLN 6 72.399 24.075 -0.142 1.00 60.09 L21B c ATOM 6072 CB GLN 6 71.997 23.595 -1.536 1.00 58.92 L21B c ATOM 6073 CG GLN 6 70.627 22.949 -1.646 1.00 57.25 L21B c ATOM 6074 CD GLN 6 70.367 22.370 -3.041 1.00 56.07 L21B c ATOM 6075 OE1 GLN 6 69.373 22.697 -3.688 1.00 55.90 . L21B 0 ATOM 6076 NE2 GLN 6 71.266 21.508 -3.503 1.00 51.99 L21B N ATOM 6077 C GLN 6 73.798 24.676 -0.220 1.00 62.99 L21B c ATOM 6078 0 GLN 6 73.962 25.893 -0.141 1.00 63.57 L21B 0 400 WO 2009/026558 PCT/US2008/074097
ATOM 6079 N PRO 7 74.827 23.831 -0.364 1.00 65.06 L21B N ATOM 6080 CD PRO 7 74.858 22.407 0.006 1.00 66.69 L21B C ATOM 6081 CA PRO 7 76.150 24.319 -0.761 1.00 66.63 L21B C ATOM 6082 CB PRO 7 77.052 23.094 -0.600 1.00 67.18 L21B c ATOM 6083 CG PRO 7 76.305 22.179 0.307 1.00 68.34 L21B c ATOM 6084 C PRO 7 76.081 24.772 -2.212 1.00 66.86 L21B c ATOM 6085 O PRO 7 75.360 24.179 -3.001 1.00 67.36 L21B 0 ATOM 6086 N ALA 8 76.824 25.810 -2.575 1.00 67.52 L21B N ATOM 6087 CA ALA 8 76.860 26.225 -3.971 1.00 68.06 L21B c ATOM 6088 CB ALA 8 77.642 27.526 -4.121 1.00 70.77 L21B c ATOM 6089 C ALA 8 77.482 25.126 -4.831 1.00 68.63 L21B c ATOM 6090 0 ALA 8 77.122 24.967 -5.993 1.00 67.08 L21B 0 ATOM 6091 N SER 9 78.413 24.364 -4.265 1.00 69.56 L21B N ATOM 6092 CA SER 9 78.988 23.232 -4.990 1.00 71.04 L21B c ATOM 6093 CB SER 9 80.051 23.718 -5.979 1.00 71.64 L21B c ATOM 6094 OG SER 9 81.060 24.455 -5.315 1.00 75.30 L21B 0 ATOM 6095 C SER 9 79.587 22.153 -4.083 1.00 69.92 L21B c ATOM 6096 O SER 9 79.840 22.389 -2.902 1.00 69.61 L21B 0 ATOM 6097 N VAL 10 79.771 20.963 -4.651 1.00 68.05 L21B N ATOM 6098 CA VAL 10 80.487 19.867 -4.009 1.00 67.25 L21B c ATOM 6099 CB VAL 10 79.553 18.805 -3.398 1.00 68.41 L21B c ATOM 6100 CGI VAL 10 78.759 19.393 -2.259 1.00 69.36 L21B c ATOM 6101 CG2 VAL 10 78.639 18.242 -4.478 1.00 68.43 L21B c ATOM 6102 C VAL 10 81.273 19.173 -5.093 1.00 66.54 L21B c ATOM 6103 O VAL 10 80.874 19.177 -6.262 1.00 67.05 L21B 0 ATOM 6104 N SER 11 82.383 18.560 -4.701 1.00 65.07 L21B N ATOM 6105 CA SER 11 83.317 18.029 -5.670 1.00 63.23 L21B c ATOM 6106 CB SER 11 84.572 18.897 -5.687 1.00 61.31 L21B c ATOM 6107 OG SER 11 85.258 18.728 -6.908 1.00 63.07 L21B 0 ATOM 6108 C SER 11 83.683 16.584 -5.352 1.00 62.63 L21B c ATOM 6109 O SER 11 83.759 16.194 -4.184 1.00 62.08 L21B 0 ATOM 6110 N GLY 12 83.911 15.794 -6.397 1.00 61.55 L21B N ATOM 6111 CA GLY 12 84.362 14.427 -6.206 1.00 59.55 L21B c ATOM 6112 C GLY 12 84.904 13.767 -7.463 1.00 59.44 L21B c ATOM 6113 0 GLY 12 84.533 14.127 -8.585 1.00 57.13 L21B 0 ATOM 6114 N SER 13 85.784 12.787 -7.256 1.00 60.89 L21B N ATOM 6115 CA SER 13 86.412 12.017 -8.334 1.00 61.13 L21B c ATOM 6116 CB SER 13 87.909 11.855 -8.050 1.00 61.04 L21B c ATOM 6117 OG SER 13 88.515 11. Oil -9.010 1.00 60.21 L21B 0 ATOM 6118 C SER 13 85.759 10.646 -8.439 1.00 59.77 L21B c ATOM 6119 O SER 13 85.223 10.145 -7.463 1.00 59.25 L21B 0 ATOM 6120 N PRO 14 85.809 10.014 -9.621 1.00 59.99 L21B N ATOM 6121 CD PRO 14 86.598 10.379 -10.812 1.00 59.07 L21B c ATOM 6122 CA PRO 14 85.040 8.776 -9.823 1.00 62.35 L21B c ATOM 6123 CB PRO 14 85.579 8.235 -11.148 1.00 60.39 L21B c ATOM 6124 CG PRO 14 86.045 9.474 -11.883 1.00 59.18 L21B c ATOM 6125 C PRO 14 85.163 7.759 -8.676 1.00 64.90 L21B c ATOM 6126 O PRO 14 86.192 7.676 -8.010 1.00 65.34 L21B 0 ATOM 6127 N GLY 15 84.098 7.001 -8.434 1.00 67.76 L21B N ATOM 6128 CA GLY 15 84.110 6.056 -7.336 1.00 71.41 L21B c ATOM 6129 C GLY 15 84.108 6.707 -5.963 1.00 75.03 L21B c ATOM 6130 0 GLY 15 84.199 6.020 -4.950 1.00 74.91 L21B 0 ATOM 6131 N GLN 16 84.006 8.029 -5.908 1.00 79.31 L21B N ATOM 6132 CA GLN 16 83.878 8.712 -4.623 1.00 83.11 L21B c ATOM 6133 CB GLN 16 84.415 10.143 -4.714 1.00 85.50 L21B c ATOM 6134 CG GLN 16 85.929 10.243 -4.740 1.00 90.35 L21B c ATOM 6135 CD GLN 16 86.419 11.683 -4.710 1.00 92.66 L21B c ATOM 6136 OE1 GLN 16 87.482 12.005 -5.256 1.00 92.77 L21B 0 ATOM 6137 NE2 GLN 16 85.644 12.560 -4.069 1.00 93.76 L21B N ATOM 6138 C GLN 16 82.428 8.746 -4.145 1.00 83.84 L21B c ATOM 6139 0 GLN 16 81.498 8.490 -4.919 1.00 84.75 L21B 0 ATOM 6140 N SER 17 82.246 9.056 -2.864 1.00 83.83 L21B N ATOM 6141 CA SER 17 80.913 9.239 -2.294 1.00 84.75 L21B c ATOM 6142 CB SER 17 80.603 8.125 -1.279 1.00 86.49 L21B c ATOM 6143 OG SER 17 80.314 6.891 -1.922 1.00 89.21 L21B 0 ATOM 6144 C SER 17 80.758 10.607 -1.620 1.00 83.88 L21B c ATOM 6145 O SER 17 81.204 10.812 -0.490 1.00 82.32 L21B 0 ATOM 6146 N ILE 18 80.116 11.539 -2.318 1.00 83.58 L21B’ N ATOM 6147 CA ILE 18 79.808 12.850 -1.751 1.00 83.01 L21B c ATOM 6148 CB ILE 18 79.972 13.974 -2.794 1.00 82.86 L21B c ATOM 6149 CG2 ILE 18 81.394 14.495 -2.776 1.00 80.11 L21B c ATOM 6150 CGI ILE 18 79.581 13.462 -4.182 1.00 85.84 L21B c ATOM 6151 CDl ILE 18 78.174 12.921 -4.275 1.00 90.99 . L21B c ATOM 6152 C ILE 18 78.394 12.925 -1.211 1.00 81.22 L21B c ATOM 6153 0 ILE 18 77.562 12.068 -1.492 1.00 83.09 L21B 0 ATOM 6154 N THR 19 78.117 13.960 -0.433 1.00 77.37 L21B N 401 WO 2009/026558 PCT/US2008/074097 ATOM 6155 CA THR 19 76.739 14 ATOM 6156 CB THR 19 76.344 13 ATOM 6157 OG1 THR 19 76.707 14 ATOM 6158 CG2 THR 19 77.049 12 ATOM 6159 C THR 19 76.458 15 ATOM 6160 O THR 19 77.370 16 ATOM 6161 N ILE 20 75.178 16 ATOM 6162 CA ILE 20 74.737 17 ATOM 6163 CB ILE 20 74.059 17 ATOM 6164 CG2 ILE 20 73.641 19 ATOM 6165 CGI ILE 20 75.028 17 ATOM 6166 CD1 ILE 20 74.481 17 ATOM 6167 C ILE 20 73.773 17 ATOM 6168 0 ILE 20 72.859 17 ATOM 6169 N SER 21 73.988 19 ATOM 6170 CA SER 21 73.178 19 ATOM 6171 CB SER 21 74.038 20 ATOM 6172 OG SER 21 73.230 21 ATOM 6173 C SER 21 71.953 20 ATOM 6174 O SER 21 71.994 21 ATOM 6175 N CYS 22 70.868 20 ATOM 6176 CA CYS 22 69.663 20 ATOM 6177 C CYS 22 69.109 21 ATOM 6178 0 CYS 22 68.334 20 ATOM 6179 CB CYS 22 68.629 20 ATOM 6180 SG CYS 22 67.077 20 ATOM 6181 N THR 23 69.495 22 ATOM 6182 CA THR 23 69.051 22 ATOM 6183 CB THR 23 70.205 23 ATOM 6184 OG1 THR 23 70.577 24 ATOM 6185 CG2 THR 23 71.409 22 ATOM 6186 C THR 23 67.903 23 ATOM 6187 O THR 23 68.068 25 ATOM 6188 N GLY 24 66.737 23 ATOM 6189 CA GLY 24 65.554 24 ATOM 6190 C GLY 24 65.173 24 ATOM 6191 0 GLY 24 66.042 24 ATOM 6192 N THR 25 63.878 24 ATOM 6193 CA THR 25 63.429 25 ATOM 6194 CB THR 25 62.866 26 ATOM 6195 OG1 THR 25 61.621 26 ATOM 6196 CG2 THR 25 63.846 27 ATOM 6197 C THR 25 62.372 24 ATOM 6198 O THR 25 62.153 23 ATOM 6199 N SER 26 61.735 24 ATOM 6200 CA SER 26 60.632 23 ATOM 6201 CB SER 26 60.383 24 ATOM 6202 OG SER 26 60.268 25 ATOM 6203 C SER 26 59.375 24 ATOM 6204 O SER 26 58.300 23 ATOM 6205 N SER 27 59.520 24 ATOM 6206 CA SER 27 58.409 24 ATOM 6207 CB SER 27 58.176 26 ATOM 6208 OG SER 27 58.262 27 ATOM 6209 C SER 27 58.730 24 ATOM 6210 O SER 27 57.837 23 ATOM 6211 N ASP 28 60.019 23 ATOM 6212 CA ASP 28 60.507 23 ATOM 6213 CB ASP 28 61.825 24 ATOM 6214 CG ASP 28 61.718 25 ATOM 6215 OD1 ASP 28 62.749 26 ATOM 6216 OD2 ASP 28 60.603 26 ATOM 6217 C ASP 28 60.724 21 ATOM 6218 O ASP 28 59.811 21 ATOM 6219 N VAL 29 61.938 21 ATOM 6220 CA VAL 29 62.221 20 ATOM 6221 CB VAL 29 63.636 19 ATOM 6222 CGI VAL 29 63.907 20 ATOM 6223 CG2 VAL 29 64.651 20 ATOM 6224 C VAL 29 62.108 19 ATOM 6225 O VAL 29 62.414 18 ATOM 6226 N GLY 30 61.671 20 ATOM 6227 CA GLY 30 61.450 20 ATOM 6228 C GLY 30 60.199 19 ATOM 6229 0 GLY 30 60.273 18 ATOM 6230 N GLY 31 59.047 20
-0 , . 115 1. .00 73 .65 L21B c 1, .250 1, . 00 72 .21 L21B c 2 . .277 1, . 00 70 .39 L21B 0 1. .488 1, . 00 70 .27 L21B c -0 . . 134 1. .00 71 .42 L21B c -0 . .039 1, . 00 71 . 11 L21B 0 -0 , .261 1, . 00 69 .05 L21B N -0 , .418 1, . 00 65 .68 L21B c -1. .789 1, . 00 61 .69 L21B c -1, .966 1, . 00 61 . 81 L21B c -2 . .906 1, . 00 58 . 15 L21B c -4 , .286 1, . 00 54 .31 L21B c 0 . .700 1. .00 65 .38 L21B c 1. .041 1. .00 65 . 12 L21B 0 1, .270 1 . .00 66 .68 L21B N 2 . .381 1. .00 67 .79 L21B c 3. .303 1, . 00 68 . 52 L21B c 4 , . 187 1 , . 00 70 .90 L21B 0 1. .930 1 . .00 67 .36 L21B c 0 . .932 1. .00 66 .91 L21B 0 2 , .689 1 . .00 67 . 57 L21B N 2 , . 452 1 . .00 68 .05 L21B c 3, .798 1 , . 00 69 . 14 L21B c 4 . .402 1 , . 00 69 . 10 L21B 0 1, .732 1. .00 67 .60 L21B c 1, .216 1 , . 00 65 . 97 L21B s 4 , .290 1 , .00 72 .15 L21B N 5, . 628 1 , .00 76 .33 L21B c 6, .473 1 , .00 75 .55 L21B c 5, . 972 1 . .00 78 .73 L21B 0 6, .407 1 . .00 75 . 50 L21B c 5, . 615 1 . .00 78 .37 L21B c 5. .217 1 . .00 79 .56 L21B 0 6, . 059 1. .00 79 .38 L21B N 6, . 057 1. .00 80 .39 L21B c 7. .472 1. .00 81 .41 L21B c 8 , .306 1. .00 81, .58 L21B 0 7 , .757 1. .00 83 .11 L21B N 9, . 085 1. .00 85 .45 L21B c 9, . 071 1. .00 86, .14 L21B c 8 . .360 1. . 00 87 , .19 L21B 0 8 , .388 1. .00 86 .73 L21B c 9, .692 1. , 00 86 .38 L21B c 9, .217 1. ,00 85 .39 L21B 0 10 , .757 1. .00 87 .61 L21B N 11 , .394 1. . 00 89, .14 L21B c 12 , .781 1. . 00 87 , .79 L21B c 12 . .708 1. .00 85 .49 L21B 0 10, .538 1. .00 91. .27 L21B c 10 , .923 1. .00 92 , . 38 L21B 0 9, .374 1. .00 93. .31 L21B N 8 . .452 1. ,00 94 . .36 L21B c 8, . 174 1. .00 94 , .15 L21B c 9, .369 1. ,00 91. .23 L21B 0 7, .148 1. ,00 95. .59 L21B c 6. .376 1. .00 97 . .39 L21B 0 6, .913 1. .00 96. .07 L21B N 5. . 637 1 . .00 96, . 19 L21B c 5. .270 1. , 00 98. . 10 L21B c 5. .281 1 . , 00 99, .61 L21B c 5. .067 1 . ,00 97. .89 L21B 0 5. .502 1. . 00103, . 08 L21B 0 5, .704 1 . , 00 96. .20 L21B c 5. .451 1 . , 00 94 , . 14 L21B 0 6. .046 1 . ,00 97 . . 12 L21B N 6. .218 1. .00 99. .22 L21B c 5. ,739 1. . 00 98 , .78 L21B c 4 . .416 1. .00 98 . .60 L21B c 6. .771 1. .00 98 , .58 L21B c 7 . ,695 1. .00100, .89 L21B c 8 . . 110 1 . ,00102, .16 L21B 0 8 . , 481 1. 00102. .57 L21B N 9. ,899 1 . .00105, .19 . L21B c 10. , 159 1. .00106, .33 L21B c 10. .716 1. .00106, .20 L21B 0 9. .764 1. 00106. .57 L21B N 402 WO 2009/026558 PCT/US2008/074097 ATOM 6231 CA GLY 31 57.841 19 ATOM 6232 C GLY 31 57 .-715 18 ATOM 6233 0 GLY 31 58.503 19 ATOM 6234 N TYR 32 56.739 17 ATOM 6235 CA TYR 32 56.571 17 ATOM 6236 CB TYR 32 56.262 18 ATOM 6237 CG TYR 32 55.157 19 ATOM 6238 CDl TYR 32 55.442 20 ATOM 6239 CEl TYR 32 54.436 21 ATOM 6240 CD2 TYR 32 53.832 18 ATOM 62 41 CE2 TYR 32 52.819 19 ATOM 6242 CZ TYR 32 53.127 21 ATOM 6243 OH TYR 32 52.120 21 ATOM 6244 C TYR 32 57.824 16 ATOM 6245 O TYR 32 58.878 17 ATOM 6246 N ASN 33 57.707 15 ATOM 6247 CA ASN 33 58.799 14 ATOM 6248 CB ASN 33 58.848 13 ATOM 6249 CG ASN 33 59.306 13 ATOM 6250 OD1 ASN 33 60.493 13 ATOM 6251 ND2 ASN 33 58.367 13 ATOM 6252 C ASN 33 58.608 14 ATOM 6253 0 ASN 33 58.512 13 ATOM 6254 N SER 34 58.548 15 ATOM 6255 CA SER 34 58.362 15 ATOM 6256 CB SER 34 56.946 15 ATOM 6257 OG SER 34 55.978 14 ATOM 6258 C SER 34 59.392 16 ATOM 6259 O SER 34 59.077 17 ATOM 6260 N VAL 35 60.626 15 ATOM 6261 CA VAL 35 61.709 16 ATOM 62 62 CB VAL 35 62.984 16 ATOM 6263 CGI VAL 35 64.129 16 ATOM 6264 CG2 VAL 35 62.715 17 ATOM 62 65 C VAL 35 62.066 15 ATOM 6266 O VAL 35 62.069 14 ATOM 62 67 N SER 36 62.367 16 ATOM 6268 CA SER 36 62.736 15 ATOM 6269 CB SER 36 61.610 15 ATOM 6270 OG SER 36 60.416 15 ATOM 6271 C SER 36 64.048 16 ATOM 6272 O SER 36 64.421 17 ATOM 6273 N TRP 37 64.747 15 ATOM 6274 CA TRP 37 65.956 15 ATOM 6275 CB TRP 37 67.188 14 ATOM 6276 CG TRP 37 67.512 15 ATOM 6277 CD2 TRP 37 68.289 16 ATOM 6278 CE2 TRP 37 68.218 16 ATOM 6279 CE3 TRP 37 69.031 17 ATOM 6280 CDl TRP 37 67.032 14 ATOM 6281 NEl TRP 37 67.446 14 ATOM 6282 CZ2 TRP 37 68.860 16 ATOM 6283 CZ3 TRP 37 69.671 18 ATOM 6284 CH2 TRP 37 69.578 18 ATOM 6285 C TRP 37 65.789 15 ATOM 6286 O TRP 37 65.254 14 ATOM 6287 N TYR 38 66.232 16 ATOM 6288 CA TYR 38 66.171 16 ATOM 6289 CB TYR 38 65.166 17 ATOM 6290 CG TYR 38 63.817 17 ATOM 6291 CDl TYR 38 63.592 18 ATOM 62 92 CEl TYR 38 62.358 18 ATOM 6293 CD2 TYR 38 62.769 16 ATOM 6294 CE2 TYR 38 61.528 16 ATOM 6295 CZ TYR 38 61.335 17 ATOM 6296 OH TYR 38 60.110 17 ATOM 6297 C TYR 38 67.538 16 ATOM 6298 O TYR 38 68.369 17 ATOM 6299 N GLN 39 67.756 16 ATOM 6300 CA GLN 39 69.051 16 ATOM 6301 CB GLN 39 69.563 14 ATOM 6302 CG GLN 39 70.923 14 ATOM 6303 CD GLN 39 71.010 13 ATOM 6304 OE1 GLN 39 70.373 13 ATOM 6305 NE2 GLN 39 71.803 12 ATOM 6306 C GLN 39 68.918 16 9.704 1.00108.37 L21B c 8.308 1.00110.31 L21B c 7.432 1.00110.17 L21B 0 8.088 1.00113.44 L21B N 6.789 1.00116.17 L21B c 5.701 1.00116.41 L21B c 6.065 1.00116.91 L21B c 6.478 1.00116.46 L21B c 6.863 1.00116.02 L21B c 6.040 1.00117.30 L21B c 6.423 1.00116.92 L21B c 6.836 1.00116.30 L21B c 7.244 1.00115.72 L21B 0 6.393 1.00116.81 L21B c 6.156 1.00119.69 L21B 0 6.314 1.00115.62 L21B N 5.812 1.00113.19 L21B c 6.566 1.00117.95 L21B c 8.009 1.00119.92 L21B c 8.310 1.00121.58 L21B 0 8.904 1.00121.03 L21B N 4.323 1.00109.46 L21B c 3.852 1.00106.99 L21B 0 3.591 1.00106.79 L21B N 2.152 1.00104.32 L21B c 1.803 1.00106.50 L21B c 2.390 1.00111.24 L21B 0 1.439 1.00100.10 L21B c 0.958 1.00 99.91 L21B 0 1.385 1.00 94.55 L21B N 0.646 1.00 89.79 L21B c 1.524 1.00 92.16 L21B c 0.699 1.00 93.68 L21B c 2.701 1.00 92.64 L21B c -0.616 1.00 84.92 L21B c -0.616 1.00 83.72 L21B 0 -1.694 1.00 79.11 L21B N -2.953 1.00 72.73 L21B c -3.973 1.00 73.26 L21B c -3.537 1.00 71.59 L21B 0 -3.514 1.00 67.49 L21B c -3.221 1.00 67.42 L21B 0 -4.311 1.00 59.72 L21B N -4.991 1.00 53.82 L21B c -4.533 1.00 52.55 L21B c -3.075 1.00 51.75 L21B c -2.492 1.00 51.86 L21B c -1.089 1.00 51.73 L21B c -3.017 1.00 51.67 L21B c -2.033 1.00 50.94 L21B c -0.838 1.00 50.27 L21B N -0.201 1.00 52.65 L21B c -2.131 1.00 52.41 L21B c -0.739 1.00 52.64 L21B c -6.500 1.00 50.21 L21B c -7.016 1.00 48.35 L21B 0 -7.216 1.00 46.26 L21B N -8.663 1.00 44.46 L21B c -9.204 1.00 43.15 L21B c -8.542 1.00 43.72 L21B c -7.300 1.00 43.01 L21B c -6.671 1.00 43.19 L21B c -9.139 1.00 43.98 L21B c -8.514 1.00 45.21 L21B c -7.284 1.00 44.43 L21B c -6.672 1.00 46.77 L21B 0 -9.283 1.00 43.39 L21B c -8.765 1.00 41.69 L21B 0 -10.415 1.00 42.45 L21B N -11.045 1.00 44.62 L21B c -11.147 1.00 43.52 L21B c -11.736 1.00 43.60 L21B c -12.675 1.00 43.02 . L21B c -13.729 1.00 44.47 L21B 0 -12.305 1.00 44.49 ' L21B N -12.420 1.00 45.66 L21B c 403 WO 2009/026558 PCT/US2008/074097 ATOM 6307 0 GLN 39 68.207 16 ATOM 6308 N GLN 40 69.595 18 ATOM 6309 CA GLN 40 69.399 18 ATOM 6310 CB GLN 40 68.899 20 ATOM 6311 CG GLN 40 68.128 20 ATOM 6312 CD GLN 40 67.849 22 ATOM 6313 OE1 GLN 40 68.289 22 ATOM 6314 NE2 GLN 40 67.110 22 ATOM 6315 C GLN 40 70.700 18 ATOM 6316 0 GLN 40 71.663 19 ATOM 6317 N HIS 41 70.723 18 ATOM 6318 CA HIS 41 71.838 18 ATOM 6319 CB HIS 41 71.747 16 ATOM 6320 CG HIS 41 72.508 15 ATOM 6321 CD2 HIS 41 73.110 14 ATOM 6322 NDl HIS 41 72.715 15 ATOM 6323 CEl HIS 41 73.412 14 ATOM 6324 NE2 HIS 41 73.664 13 ATOM 6325 C HIS 41 71.762 19 ATOM 6326 0 HIS 41 70.686 19 ATOM 6327 N PRO 42 72.910 20 ATOM 6328 CD PRO 42 74.271 19 ATOM 6329 CA PRO 42 72.911 21 ATOM 6330 CB PRO 42 74.385 21 ATOM 6331 CG PRO 42 75.127 20 ATOM 6332 C PRO 42 72.039 21 ATOM 6333 O PRO 42 72.244 20 ATOM 6334 N GLY 43 71.056 22 ATOM 6335 CA GLY 43 70.264 22 ATOM 6336 C GLY 43 69.196 21 ATOM 6337 0 GLY 43 68.511 21 ATOM 6338 N LYS 44 69.050 20 ATOM 6339 CA LYS 44 67.954 19 ATOM 6340 CB LYS 44 68.496 18 ATOM 6341 CG LYS 44 68.098 17 ATOM 6342 CD LYS 44 69.236 17 ATOM 6343 CE LYS 44 70.137 16 ATOM 6344 NZ LYS 44 69.357 14 ATOM 6345 C LYS 44 66.993 20 ATOM 6346 0 LYS 44 67.323 20 ATOM 6347 N ALA 45 65.807 19 ATOM 6348 CA ALA 45 64.799 19 ATOM 6349 CB ALA 45 63.420 19 ATOM 6350 C ALA 45 65.016 18 ATOM 6351 0 ALA 45 65.471 17 ATOM 6352 N PRO 46 64.699 19 ATOM 6353 CD PRO 46 64.061 20 ATOM 6354 CA PRO 46 64.986 18 ATOM 6355 CB PRO 46 64.389 19 ATOM 6356 CG PRO 46 64.330 20 ATOM 6357 C PRO 46 64.345 17 ATOM 6358 O PRO 46 63.377 16 ATOM 6359 N LYS 47 64.882 16 ATOM 6360 CA LYS 47 64.447 14 ATOM 6361 CB LYS 47 65.377 13 ATOM 6362 CG LYS 47 64.962 12. ATOM 6363 CD LYS 47 66.095 11 ATOM 6364 CE LYS 47 65.859 10 ATOM 63 65 NZ LYS 47 66.936 9 ATOM 6366 C LYS 47 64.482 14 ATOM 6367 0 LYS 47 65.471 14 ATOM 6368 N LEU 48 63.415 13 ATOM 6369 CA LEU 48 63.282 13 ATOM 6370 CB LEU 48 61.821 13 ATOM 6371 CG LEU 48 61.539 12 ATOM 6372 CDl LEU 48 61.520 13 ATOM 6373 CD2 LEU 48 60.213 11 ATOM 6374 C LEU 48 64.121 12 ATOM 6375 O LEU 48 64.150 11 ATOM 6376 N MET 49 64.778 12 ATOM 6377 CA MET 49 65.732 11 ATOM 6378 CB MET 49 67.106 11 ATOM 6379 CG MET 49 68.147 11 ATOM 6380 SD MET 49 67.781 11 ATOM 6381 CE MET 49 69.100 10 ATOM 6382 C MET 49 65.324 10 -13.288 1.00 46.08 L21B 0 -12.624 1.00 47.83 L21B N -13.863 1.00 51.69 L21B C -13.548 1.00 47.93 L21B c -14.645 1.00 40.63 L21B c -14.288 1.00 40.95 L21B c -13.245 1.00 38.49 L21B 0 -15.147 1.00 40.56 L21B N -14.648 1.00 56.56 L21B c -14.257 1.00 56.79 L21B 0 -15.751 1.00 63.38 L21B N -16.682 1.00 70.76 L21B c -17.723 1.00 7 6.62 L21B c -17.354 1.00 84 .15 L21B c -18.126 1.00 87.55 L21B c -16.047 1.00 85.99 L21B N -16.031 1.00 8 9.12 L21B c -17.279 1.00 90.00 L21B N -17.386 1.00 72.18 L21B C -17.756 1.00 72.48 L21B 0 -17.602 1.00 74.10 L21B N -17.437 1.00 75.72 L21B C -18.160 1.00 74.30 L21B c -18.467 1.00 75.42 L21B c -17.534 1.00 76.94 L21B c -19.413 1.00 73.03 L21B c -20.374 1.00 73.33 L21B 0 -19.391 1.00 70.77 L21B N -20.580 1.00 69.10 L21B c -20.847 1.00 68.64 L21B c -21.877 1.00 68.71 L21B 0 -19.924 1.00 66.15 L21B N -19.990 1.00 62.25 L21B c -19.887 1.00 63.41 L21B c -21.052 1.00 63.60 L21B c -22.039 1.00 64.54 L21B c -21.614 1.00 66.95 L21B c -21.329 1.00 67.67 L21B N -18.841 1.00 59.21 L21B c -17.943 1.00 60.37 L21B 0 -18.873 1.00 53.31 L21B N -17.849 1.00 47.57 L21B c -18.421 1.00 4 6.62 L21B c -16.653 1.00 44.16 L21B c -16.813 1.00 45.35 L21B 0 -15.436 1.00 40.96 L21B N -15.160 1.00 39.13 L21B c -14.194 1.00 39.73 L21B c -13.109 1.00 37.66 L21B c -13.706 1.00 37.73 L21B c -14.197 1.00 39.44 L21B c -14.928 1.00 39.36 L21B 0 -13.364 1.00 38.72 L21B N -13.300 1.00 38.21 L21B c -14 .145 1.00 38.85 L21B c -14.275 1.00 40.70 L21B c -13.885 1.00 41.88 L21B c -14.427 1.00 41.50 L21B c -13.966 1.00 43.50 L21B N -11.854 1.00 38.19 L21B c -11.163 1.00 39.09 L21B 0 -11.402 1.00 38.85 L21B N -9.998 1.00 38.42 L21B c -9.662 1.00 36.60 L21B c -8.241 1.00 34.74 L21B c .-7.240 1.00 32.22 L21B c -8.233 1.00 30.83 L21B c -9.609 1.00 42.07 L21B c -10.323 1.00 39.62 L21B 0 -8.448 1.00 46.56 L21B N -7.926 1.00 49.08 L21B c -7.794 1.00 47.33 L21B c -8.707 1.00 46.66 . L21B c -10.453 1.00 49.31 L21B s -11.241 1.00 43.99 L21B c -6.567 1.00 52.99 L21B c 404 WO 2009/026558 PCT/US2008/074097 ATOM 6383 0 MET 49 65.582 9 ATOM 6384 N ILE 50 64.698 11 ATOM 6385 CA ILE 50 64 .297 11 ATOM 6386 CB ILE 50 65.429 11 ATOM 6387 CG2 ILE 50 64.975 11 ATOM 6388 CGI ILE 50 66.674 10 ATOM 6389 CDl ILE 50 66.568 9 ATOM 6390 C ILE 50 63.024 11 ATOM 6391 0 ILE 50 62.874 13 ATOM 6392 N TYR 51 62.108 11 ATOM 6393 CA TYR 51 60.957 11 ATOM 6394 CB TYR 51 59.684 11 ATOM 6395 CG TYR 51 59.343 10 ATOM 6396 CDl TYR 51 58.614 9 ATOM 6397 CEl TYR 51 58.273 8 ATOM 6398 CD2 TYR 51 59.723 9 ATOM 6399 CE2 TYR 51 59.388 8 ATOM 6400 CZ TYR 51 58.664 7 ATOM 6401 OH TYR 51 58.334 6 ATOM 6402 C TYR 51 60.751 11 ATOM 6403 O TYR 51 61.310 10 ATOM 6404 N GLU 52 59.942 11 ATOM 6405 CA GLU 52 59.763 11 ATOM 6406 CB GLU 52 58.756 10 ATOM 6407 CG GLU 52 57.474 10 ATOM 6408 CD GLU 52 56.273 9 ATOM 6409 OE1 GLU 52 55.551 9 ATOM 6410 OE2 GLU 52 56.043 9 ATOM 6411 C GLU 52 61.119 11 ATOM 6412 0 GLU 52 61.477 10 ATOM 6413 N VAL 53 61.856 12 ATOM 6414 CA VAL 53 63.236 12 ATOM 6415 CB VAL 53 63.293 11 ATOM 6416 CGI VAL 53 62.286 12 ATOM 6417 CG2 VAL 53 63.040 10 ATOM 6418 C VAL 53 64.137 11 ATOM 6419 O VAL 53 65.296 11 ATOM 6420 N SER 54 63.623 9 ATOM 6421 CA SER 54 64.491 8 ATOM 6422 CB SER 54 64.597 7 ATOM 6423 OG SER 54 63.409 7 ATOM 6424 C SER 54 64.110 7 ATOM 6425 O SER 54 64.851 6 ATOM 6426 N ASN 55 62.975 8 ATOM 6427 CA ASN 55 62.484 7 ATOM 6428 CB ASN 55 60.962 7 ATOM 6429 CG ASN 55 60.417 6 ATOM 6430 OD1 ASN 55 60.253 6 ATOM 6431 ND2 ASN 55 60.143 4 ATOM 6432 C ASN 55 62.974 7 ATOM 6433 0 ASN 55 63.184 8 ATOM 6434 N ARG 56 63.143 6 ATOM 6435 CA ARG 56 63.667 6 ATOM 6436 CB ARG 56 64.995 5 ATOM 6437 CG ARG 56 65.465 5 ATOM 6438 CD ARG 56 66.854 4 ATOM 6439 NE ARG 56 66.905 3 ATOM 6440 CZ ARG 56 67.379 3 ATOM 6441 NHl ARG 56 67.382 2 ATOM 6442 NH2 ARG 56 67.846 4 ATOM 6443 C ARG 56 62.700 5 ATOM 6444 O ARG 56 62.260 4 ATOM 6445 N PRO 57 62.361 6 ATOM 6446 CD PRO 57 62.335 8 ATOM 6447 CA PRO 57 61.659 6 ATOM 6448 CB PRO 57 61.704 7 ATOM 6449 CG PRO 57 62.227 8 ATOM 6450 C PRO 57 62.341 4 ATOM 6451 O PRO 57 63.301 4 ATOM 6452 N SER 58 61.840 4 ATOM 6453 CA SER 58 62.325 3 ATOM 6454 CB SER 58 61.282 2 ATOM 6455 OG SER 58 60.341 1 ATOM 6456 C SER 58 63.660 3 ATOM 6457 O SER 58 64.612 2 ATOM 6458 N GLY 59 63.733 4
-6.269 1.00 56.08 L21B 0 -5.740 1.00 57.38 L21B N -4.386 1.00 62.77 L21B C -3.365 1.00 61.84 L21B c -1.946 1.00 59.34 L21B c -3.701 1.00 62.37 L21B c -3.330 1.00 62.87 L21B c -3.937 1.00 67.31 L21B c -4.172 1.00 67.56 L21B 0 -3.297 1.00 72.88 L21B N -2.655 1.00 77.81 L21B c -3.470 1.00 80.69 L21B c -3.728 1.00 85.48 L21B c -2.805 1.00 86.81 L21B c -3.059 1.00 91.20 L21B c -4.913 1.00 87.17 L21B c -5.175 1.00 91.86 L21B c -4.249 1.00 93.04 L21B c -4.525 1.00 98.22 L21B 0 -1.254 1.00 78.65 L21B c -0.891 1.00 80.21 L21B 0 -0.470 1.00 79.50 L21B N 0.928 1.00 80.88 L21B c 1.052 1.00 84.81 L21B c 0.252 1.00 91.28 L21B c 0.749 1.00 94.35 L21B c -0.097 1.00 96.91 L21B 0 1.978 1.00 97.80 L21B 0 1.496 1.00 79.08 L21B c 1.495 1.00 78.80 L21B 0 1.967 1.00 77.54 L21B N 2.446 1.00 75.58 L21B c 3.981 1.00 7 6.57 L21B c 4.630 1.00 7 6.93 L21B c 4.380 1.00 78.24 L21B c 1.839 1.00 72.99 L21B c 1.555 1.00 72.93 L21B 0 1.638 1.00 70.73 L21B N 1.383 1.00 69.14 L21B c 2.641 1.00 67.96 L21B c 2.862 1.00 66.01 L21B 0 0.205 1.00 68.64 L21B c -0.132 1.00 68.13 L21B 0 -0.430 1.00 68.81 L21B N -1.435 1.00 70.32 L21B c -1.418 1.00 68.63 L21B c -0.273 1.00 66.99 L21B c 0.840 1.00 65.31 L21B 0 -0.536 1.00 67.92 L21B N -2.850 1.00 72.09 L21B c -3.242 1.00 72.67 L21B 0 -3.614 1.00 74.41 L21B N -4.969 1.00 78.24 L21B c -5.070 1.00 78.52 L21B c -6.488 1.00 79.19 L21B c -6.501 1.00 81.29 L21B c -5.831 1.00 85.09 L21B N -4.602 1.00 87.03 L21B c -4.078 1.00 89.77 L21B N -3.897 1.00 87.54 L21B N -6.025 1.00 78.99 L21B C -5.958 1.00 81.35 L21B 0 -7.022 1.00 78.11 L21B N -6.931 1.00 74.41 L21B C -8.222 1.00 80.05 L21B c -9.177 1.00 75.32 L21B c -8.372 1.00 7 3.32 L21B c -8.834 1.00 82.95 L21B c -8.279 1.00 85.80 L21B 0 -9.980 1.00 84.28 L21B N -10.595 1.00 85.65 L21B c -11.564 1.00 86.16 L21B c -10.881 1.00 86.06 . L21B 0 -11.323 1.00 86.71 L21B c -11.028 1.00 87.93 L21B 0 -12.272 1.00 87.65 L21B N 405 WO 2009/026558 PCT/US2008/074097 ATOM 6459 CA GLY 59 64.947 4 ATOM 6460 C GLY 59 66.181 4 ATOM 6461 0 GLY 59 67.286 4 ATOM 64 62 N VAL 60 66.002 5 ATOM 6463 CA VAL 60 67.131 6 ATOM 6464 CB VAL 60 66.649 6 ATOM 6465 CGI VAL 60 67.830 7 ATOM 6466 CG2 VAL 60 65.926 8 ATOM 6467 C VAL 60 67.965 4 ATOM 6468 O VAL 60 67.431 3 ATOM 6469 N SER 61 69.279 5 ATOM 6470 CA SER 61 70.220 3 ATOM 6471 CB SER 61 71.616 4 ATOM 6472 OG SER 61 72.558 3 ATOM 6473 C SER 61 70.284 3 ATOM 6474 O SER 61 69.902 4 ATOM 6475 N ASN 62 70.762 2 ATOM 6476 CA ASN 62 70.855 2 ATOM 6477 CB ASN 62 71.117 1 ATOM 6478 CG ASN 62 71.867 0 ATOM 6479 OD1 ASN 62 72.751 -0 ATOM 6480 ND2 ASN 62 71.504 0 ATOM 6481 C ASN 62 71.936 3 ATOM 6482 0 ASN 62 72.013 3 ATOM 6483 N ARG 63 72.756 4 ATOM 6484 CA ARG 63 73.833 4 ATOM 6485 CB ARG 63 74.654 5 ATOM 6486 CG ARG 63 75.721 4 ATOM 6487 CD ARG 63 76.425 5 ATOM 6488 NE ARG 63 75.705 4 ATOM 6489 CZ ARG 63 76.177 4 ATOM 6490 NHl ARG 63 77.379 5 ATOM 6491 NH2 ARG 63 75.449 4 ATOM 6492 C ARG 63 73.279 6 ATOM 6493 O ARG 63 73.897 6 ATOM 6494 N PHE 64 72.112 6 ATOM 6495 CA PHE 64 71.492 7 ATOM 6496 CB PHE 64 70.617 8 ATOM 6497 CG PHE 64 71.371 9 ATOM 6498 CDl PHE 64 72.315 10 ATOM 6499 CD2 PHE 64 71.116 8 ATOM 6500 CEl PHE 64 72.995 10 ATOM 6501 CE2 PHE 64 71.791 9 ATOM 6502 CZ PHE 64 72.731 10 ATOM 6503 C PHE 64 70.643 7 ATOM 6504 O PHE 64 69.857 6 ATOM 6505 N SER 65 70.805 8 ATOM 6506 CA SER 65 70.039 7 ATOM 6507 CB SER 65 70.851 6 ATOM 6508 OG SER 65 72.221 7 ATOM 6509 C SER 65 69.646 9 ATOM 6510 O SER 65 70.332 10 ATOM 6511 N GLY 66 68.541 9 ATOM 6512 CA GLY 66 68.127 10 ATOM 6513 C GLY 66 68.129 10 ATOM 6514 0 GLY 66 68.074 8 ATOM 6515 N SER 67 68.187 11 ATOM 6516 CA SER 67 68.061 11 ATOM 6517 CB SER 67 69.374 10 ATOM 6518 OG SER 67 69.386 11 ATOM 6519 C SER 67 67.682 12 ATOM 6520 O SER 67 67.820 13 ATOM 6521 N LYS 68 67.202 12 ATOM 6522 CA LYS 68 66.874 13 ATOM 6523 CB LYS 68 65.350 13 ATOM 6524 CG LYS 68 64.889 15 ATOM 6525 CD LYS 68 63.737 15 ATOM 652 6 CE LYS 68 62.378 15 ATOM 6527 NZ LYS 68 62.140 16 ATOM 6528 C LYS 68 67.435 13 ATOM 6529 0 LYS 68 68.008 12 ATOM 6530 N SER 69 67.283 14 , ATOM 6531 CA SER 69 67.631 15 ATOM 6532 CB SER 69 69.064 14 ATOM 6533 OG SER 69 69.420 14 ATOM 6534 C SER 69 67.504 16 -13.056 1.00 87.89 L21B c -12.229 1.00 88.35 L21B c -12.552 1.00 88.22 L21B 0 -11.156 1.00 89.24 L21B N -10.355 1.00 90.52 L21B c -9.176 1.00 90.94 L21B c. -8.309 1.00 90.92 L21B c -9.698 1.00 89.49 L21B c -9.820 1.00 90.98 L21B c -9.263 1.00 90.77 L21B 0 -10.000 1.00 92.18 L21B N -9.562 1.00 93.58 L21B c -10.126 1.00 93.45 L21B c -9.762 1.00 93.35 L21B 0 -8.038 1.00 94.34 L21B c -7.332 1.00 93.56 L21B 0 -7.535 1.00 95.84 L21B N -6.098 1.00 96.77 L21B c -5.795 1.00 97.06 L21B c -6.920 1.00 97.69 L21B c -6.662 1.00 94.14 L21B 0 -8.167 1.00 99.77 L21B N -5.465 1.00 96.37 L21B c -4.238 1.00 97.21 L21B 0 -6.313 1.00 94.95 L21B N -5.862 1.00 92.26 L21B c -7.056 1.00 96.28 L21B c -7.538 1.00102.27 L21B c -8.780 1.00109.64 L21B c -10.006 1.00117.20 L21B N -11.237 1.00120.97 L21B c -11.416 1.00123.18 L21B N -12.290 1.00122.26 L21B N -5.107 1.00 88.51 L21B C -4 . 162 1.00 87.03 L21B 0 -5.533 1.00 84.21 L21B N -4.926 1.00 79.46 L21B C -5.947 1.00 77.20 L21B c -7.139 1.00 73.89 L21B c -6.997 1.00 71.50 L21B c -8.409 1.00 73.34 L21B c -8.099 1.00 69.83 L21B c -9.520 1.00 71.53 L21B c -9.363 1.00 70.20 L21B c -3.734 1.00 77.58 L21B c -3.817 1.00 77.96 L21B 0 -2.629 1.00 75.04 L21B N -1.413 1.00 74.86 L21B c -0.459 1.00 74.40 L21B c -0.478 1.00 74.90 L21B 0 -0.702 1.00 7 5.62 L21B c -0.808 1.00 75.41 L21B 0 0.030 1.00 76.47 L21B N 0.745 1.00 77.49 L21B c 2.243 1.00 79.01 L21B c 2.718 1.00 79.00 L21B 0 2.985 1.00 81.38 L21B N 4.432 1.00 84 .01 L21B c 5.067 1.00 8 3.67 L21B c 6.454 1.00 79.98 L21B 0 4.981 1.00 8 6.52 L21B c 4.296 1.00 88.88 L21B 0 6.219 1.00 87.89 L21B N 6.879 1.00 89.48 L21B c 6.906 1.00 90.65 L21B c , 7.302 1.00 91.64 L21B c 8.302 1.00 93.17 L21B c 7.615 1.00 94.61 L2 IB c 6.858 1.00 96.05 L21B N 8.309 1.00 90.68 L21B c 8.748 1.00 90.52 L21B 0 9.017 1.00 92.64 L21B N 10.434 1.00 94.30 . L21B c 10.685 1.00 94.54 L21B c 12.050 1.00 94.63 L21B 0 10.853 1.00 94.68 L21B c 406 WO 2009/026558 PCT/US2008/074097 ATOM 6535 0 SER 69 67.8 67 17 ATOM 6536 N GLY 70 66.988 16 ATOM 6537 CA GLY 70 66.749 18 ATOM 6538 C GLY 70 66.095 18 ATOM 6539 0 GLY 70 65.264 18 ATOM 6540 N ASN 71 66.476 20 ATOM 6541 CA ASN 71 65.925 20 ATOM 6542 CB ASN 71 65.702 22 ATOM 6543 CG ASN 71 64.724 22 ATOM 6544 OD1 ASN 71 64.501 21 ATOM 6545 ND2 ASN 71 64.131 23 ATOM 6546 C ASN 71 66.828 20 ATOM 6547 0 ASN 71 66.873 21 ATOM 6548 N THR 72 67.541 19 ATOM 6549 CA THR 72 68.445 19 ATOM 6550 CB THR 72 69.884 20 ATOM 6551 OG1 THR 72 70.792 19 ATOM 6552 CG2 THR 72 70.291 19 ATOM 6553 C THR 72 68.495 18 ATOM 6554 O THR 72 69.052 17 ATOM 6555 N ALA 73 67.919 18 ATOM 6556 CA ALA 73 67.911 16 ATOM 6557 CB ALA 73 66.668 16 ATOM 6558 C ALA 73 69.151 16 ATOM 6559 0 ALA 73 69.801 17 ATOM 6560 N SER 74 69.482 15 ATOM 6561 CA SER 74 70.686 15 ATOM 6562 CB SER 74 71.920 15 ATOM 6563 OG SER 74 71.556 15 ATOM 6564 C SER 74 70.648 14 ATOM 6565 O SER 74 70.224 13 ATOM 6566 N LEU 75 71.100 14 ATOM 6567 CA LEU 75 71.247 13 ATOM 6568 CB LEU 75 70.961 14 ATOM 6569 CG LEU 75 71.478 13 ATOM 6570 CD1 LEU 75 70.723 12 ATOM 6571 CD2 LEU 75 71.333 14 ATOM 6572 C LEU 75 72.683 13 ATOM 6573 O LEU 75 73.597 13 ATOM 6574 N THR 76 72.887 11 ATOM 6575 CA THR 76 74.217 11 ATOM 6576 CB THR 76 74.689 10 ATOM 6577 OG1 THR 76 75.672 9 ATOM 6578 CG2 THR 76 73.520 9 ATOM 6579 C THR 76 74.301 10 ATOM 6580 O THR 76 73.356 9 ATOM 6581 N ILE 77 75.441 10 ATOM 6582 CA ILE 77 75.659 9 ATOM 6583 CB ILE 77 75.768 10 ATOM 6584 CG2 ILE 77 75.926 9 ATOM 6585 CGI ILE 77 74.542 11 ATOM 6586 CDl ILE 77 74.658 12 ATOM 6587 C ILE 77 76.966 8 ATOM 6588 0 ILE 77 78.022 9 ATOM 6589 N SER 78 76.900 7 ATOM 6590 CA SER 78 78.101 6 ATOM 6591 CB SER 78 77.860 5 ATOM 6592 OG SER 78 76.778 4 ATOM 6593 C SER 78 78.479 6 ATOM 6594 O SER 78 77.635 6 ATOM 6595 N GLY 79 79.750 6 ATOM 6596 CA GLY 79 80.152 5 ATOM 6597 C GLY 79 80.059 6 ATOM 6598 0 GLY 79 79.582 6 ATOM 6599 N LEU 80 80.529 7 ATOM 6600 CA LEU 80 80.457 8 ATOM 6601 CB LEU 80 81.414 10 ATOM 6602 CG LEU 80 80.769 11 ATOM 6603 CDl LEU 80 81.385 11 ATOM 6604 CD2 LEU 80 80.951 12 ATOM 6605 C LEU 80 80.799 8 ATOM 6606 O LEU 80 81.746 7 ATOM 6607 N GLN 81 80.033 8 ATOM 6608 CA GLN 81 80.361 8 ATOM 6609 CB GLN 81 79.558 7 ATOM 6610 CG GLN 81 80.408 6
10.099 1.00 95.48 L21B 0 12.053 1.00 93.84 L21B N 12.471 1.00 93.22 L21B C 11.338 1.00 93.55 L21B C 10.616 1.00 92.49 L21B O 11.166 1.00 94.45 L21B . N 10.089 1.00 94.23 L21B C 10.571 1.00 95.39 L21B C 11.730 1.00 98.12 L21B c 12.438 1.00 98.62 L21B 0 11.930 1.00 98.55 L21B N 8.863 1.00 92.16 L21B C 8.119 1.00 94.10 L21B O 8.648 1.00 87.06 L21B N 7.510 1.00 82.06 L21B C 7.900 1.00 82 .77 L21B C 6.860 1.00 80.39 L21B 0 9.213 1.00 83.47 L21B c 6.865 1.00 78.60 L21B c 7.418 1.00 77.66 L21B 0 5.673 1.00 75.24 L21B N 4.915 1.00 72.01 L21B C 4 . 045 1.00 72.86 L21B C 4 . 048 1.00 69.53 L21B C 3.812 1.00 70.14 L21B O 3.566 1.00 65.99 L21B N 2.761 1.00 62.02 L21B C 3.670 1.00 62.25 L21B C 5.022 1.00 60.36 L21B O 1.802 1.00 59.13 L21B C 2.153 1.00 57.73 L21B O 0.580 1.00 56.92 L21B N -0.405 1.00 56.96 L21B C -1.813 1.00 53.44 L21B C -3.055 1.00 49.90 L21B C -3.242 1.00 47.92 L21B C -4.283 1.00 47.50 L21B C -0.319 1.00 59.01 L21B C -0.273 1.00 58.67 L21B O -0.286 1.00 61.56 L21B N -0.522 1.00 63.56 L21B C 0.679 1.00 63.91 L21B C 0.239 1.00 62.00 L21B O 1.317 1.00 65.76 L21B C -1.806 1.00 63.85 L21B C -2.181 1.00 64.85 L21B O -2.481 1.00 64.17 L21B N -3.700 1.00 65.28 L21B C -4.929 1.00 66.15 L21B C -6.193 1.00 65.87 L21B C -5.005 1.00 66.23 L21B C -6.022 1.00 63.85 L21B C -3.595 1.00 66.96 L21B C -3.335 1.00 66.30 L21B O -3.804 1.00 68.95 L21B N -3.865 1.00 71.17 L21B C -3.129 1.00 72.64 L21B C -3.723 1.00 77.40 L21B O -5.313 1.00 71.61 L21B C -6.209 1.00 72.46 L21B O -5.544 1.00 71.26 L21B N -6.849 1.00 72.39 L21B C -7.983 1.00 73.11 L21B C -9.076 1.00 73.09 L21B 0 -7.729 1.00 73.02 L21B N ,-8.701 1.00 75.02 L21B C -8.289 1.00 73.44 L21B C -7.849 1.00 73.15 L21B C -6.549 1.00 72.79 L21B C -8.949 1.00 73.15 L21B C -10.109 1.00 76.64 L21B C -10.294 1.00 77.62 L21B O -11.101 1.00 78.31 . L21B N -12.499 1.00 80.13 L21B C -13.027 1.00 81.09 L21B C -13.313 1.00 86.00 L21B C 407 WO 2009/026558 PCT/US2008/074097 ATOM 6611 CD GLN 81 81.532 6 ATOM 6612 OE1 GLN 81 81.628 5 ATOM 6613 NE2 GLN 81 82.384 7 ATOM 6614 C GLN 81 80.158 9 ATOM 6615 0 GLN 81 79.674 10 ATOM 6616 N ALA 82 80.532 9 ATOM 6617 CA ALA 82 80.618 10 ATOM 6618 CB ALA 82 81.479 10 ATOM 6619 C ALA 82 79.252 11 ATOM 6620 0 ALA 82 79.142 12 ATOM 6621 N GLU 83 78.215 10 ATOM 6622 CA GLU 83 76.853 10 ATOM 6623 CB GLU 83 76.027 9 ATOM 6624 CG GLU 83 76.485 8 ATOM 662 5 CD GLU 83 76.352 9 ATOM 6626 OE1 GLU 83 75.306 10 ATOM 6627 OE2 GLU 83 77.297 9 ATOM 6628 C GLU 83 76.203 11 ATOM 6629 0 GLU 83 75.026 11 ATOM 6630 N ASP 84 76.970 11 ATOM 6631 CA ASP 84 76.427 12 ATOM 6632 CB ASP 84 76.985 11 ATOM 6633 CG ASP 84 76.359 10 ATOM 6634 OD1 ASP 84 75.368 9 ATOM 6635 OD2 ASP 84 76.854 9 ATOM 6636 C ASP 84 76.709 13 ATOM 6637 O ASP 84 76.047 14 ATOM 6638 N GLU 85 77.696 14 ATOM 6639 CA GLU 85 78.000 15 ATOM 6640 CB GLU 85 79.103 15 ATOM 6641 CG GLU 85 79.936 17 ATOM 6642 CD GLU 85 81.225 17 ATOM 6643 OE1 GLU 85 81.886 18 ATOM 6644 OE2 GLU 85 81.579 16 ATOM 6645 C GLU 85 76.707 16 ATOM 6646 0 GLU 85 76.233 16 ATOM 6647 N ALA 86 76.126 17 ATOM 6648 CA ALA 86 74.894 17 ATOM 6649 CB ALA 86 73.738 16 ATOM 6650 C ALA 86 74.588 18 ATOM 6651 0 ALA 86 75.329 18 ATOM 6652 N ASP 87 73.488 19 ATOM 6653 CA ASP 87 72.981 20 ATOM 6654 CB ASP 87 72.359 21 ATOM 6655 CG ASP 87 73.392 22 ATOM 6656 OD1 ASP 87 74.611 22 ATOM 6657 OD2 ASP 87 72.965 23 ATOM 6658 C ASP 87 71.925 19 ATOM 6659 O ASP 87 71.115 18 ATOM 6660 N TYR 88 71.928 19 ATOM 6661 CA TYR 88 70.998 19 ATOM 6662 CB TYR 88 71.738 18 ATOM 6663 CG TYR 88 72.244 17 ATOM 6664 CDl TYR 88 73.344 17 ATOM 6665 CEl TYR 88 73.805 16 ATOM 6666 CD2 TYR 88 71.618 15 ATOM 6667 CE2 TYR 88 72.075 14 ATOM 6668 CZ TYR 88 73.169 14 ATOM 6669 OH TYR 88 73.645 13 ATOM 6670 C TYR 88 70.236 20 ATOM 6671 O TYR 88 70.823 21 ATOM 6672 N TYR 89 68.916 20 ATOM 6673 CA TYR 89 68.089 20 ATOM 6674 CB TYR 89 67.103 21 ATOM 6675 CG TYR 89 67.755 22 ATOM 6676 CDl TYR 89 68.093 22 ATOM 6677 CEl TYR 89 68.727 22 ATOM 6678 CD2 TYR 89 68.058 23 ATOM 6679 CE2 TYR 89 68.694 24 ATOM 6680 CZ TYR 89 69.031 24 ATOM 6681 OH TYR 89 69.699 24 ATOM 6682 C TYR 89 67.315 20 ATOM 6683 O TYR 89 66.771 19 ATOM 6684 N CYS 90 67.265 20 ATOM 6685 CA CYS 90 66.297 19 ATOM 6686 C CYS 90 65.021 20
-14.348 1.00 87.47 L21B c -15.344 1.00 88.68 L21B 0 -14.105 1.00 87.99 L21B N -13.425 1.00 80.81 L21B C -13.011 1.00 80.44 L21B O -14.688 1.00 83.61 L21B . N. -15.648 1.00 85.92 L21B C -16.830 1.00 87.14 L21B C -16.143 1.00 87.29 L21B C -16.800 1.00 87.53 L21B O -15.836 1.00 88.20 L21B N -16.168 1.00 88.75 L21B C -16.581 1.00 93.51 L21B C -17.876 1.00101.49 L21B C -19.106 1.00105.65 L21B C -19.249 1.00108.12 L21B O -19.929 1.00108.37 L21B O -14.967 1.00 87.10 L21B C -15.004 1.00 85.86 L21B O -13.899 1.00 85.49 L21B N -12.677 1.00 85.32 L21B C -11.457 1.00 85.04 L21B C -11.263 1.00 85.56 L21B C -11.971 1.00 84.97 L21B O -10.409 1.00 84.74 L21B O -12.553 1.00 84.15 L21B C -11.789 1.00 86.30 L21B O -13.299 1.00 81.29 L21B N -13.284 1.00 77.09 L21B C -14.298 1.00 80.08 L21B C -13.971 1.00 82.41 L21B C -14.784 1.00 85.05 L21B C -14.775 1.00 87.67 L21B O -15.433 1.00 86.35 L21B O -13.663 1.00 72.73 L21B C -14.795 1.00 72.00 L21B O -12.700 1.00 67.45 L21B N -12.930 1.00 62.87 L21B C -13.092 1.00 61.14 L21B C -11.803 1.00 60.31 L21B C -10.823 1.00 59.84 L21B O -11.953 1.00 56.64 L21B N -10.892 1.00 51.63 L21B C -11.495 1.00 51.56 L21B C -11.931 1.00 49.78 L21B C -11.745 1.00 4 6.62 L21B O -12.464 1.00 49.17 L21B O -10.067 1.00 48.54 L21B C -10.616 1.00 47.22 L21B O -8.756 1.00 44.85 L21B N -7.863 1.00 43.21 L21B C -7.004 1.00 41.53 L21B C -7.777 1.00 41.60 L21B C -8.624 1.00 42.48 L21B C -9.349 1.00 41.25 L21B C -7.674 1.00 39.77 L21B C -8.396 1.00 41.08 L21B C -9.228 1.00 40.42 L21B C -9.924 1.00 41.65 L21B 0 -6.945 1.00 42.70 L21B c -6.237 1.00 43.49 L21B 0 -6.943 1.00 43.07 L21B N -6.095 1.00 41.89 L21B C -6.955 1.00 37.85 L21B C -8.038 1.00 31.95 L21B C ,-9.269 1.00 29.53 L21B C -10.259 1.00 28.25 L21B c -7.820 1.00 30.26 L21B c -8.808 1.00 27.69 L21B c -10.026 1.00 27.67 L21B c -11.002 1.00 21.69 L21B 0 -5.112 1.00 42.66 L21B c -5.481 1.00 44.45 • L21B 0 -3.861 1.00 44.04 L21B N -2.964 1.00 49.10 ' L21B C -2.907 1.00 50.09 L21B C 408 WO 2009/026558 PCT/US2008/074097 ATOM 6687 0 CYS 90 65.039 21 ATOM 6688 CB CYS 90 66.890 19 ATOM 6689 SG CYS 90 67.391 21 ATOM 6690 N ASN 91 63.905 20 ATOM 6691 CA ASN 91 62.625 20 ATOM 6692 CB ASN 91 61.774 20 ATOM 6693 CG ASN 91 60.330 20 ATOM 6694 OD1 ASN 91 59.971 19 ATOM 6695 ND2 ASN 91 59.476 21 ATOM 6696 C ASN 91 61.984 20 ATOM 6697 0 ASN 91 62.323 19 ATOM 6698 N SER 92 61.085 21 ATOM 6699 CA SER 92 60.248 20 ATOM 6700 CB SER 92 60.893 20 ATOM 6701 OG SER 92 59.963 20 ATOM 6702 C SER 92 58.869 21 ATOM 6703 O SER 92 58.706 22 ATOM 6704 N TYR 93 57.876 20 ATOM 6705 CA TYR 93 56.552 20 ATOM 6706 CB TYR 93 55.628 19 ATOM 6707 CG TYR 93 55.188 18 ATOM 6708 CDl TYR 93 55.740 18 ATOM 6709 CEl TYR 93 55.373 17 ATOM 6710 CD2 TYR 93 54.243 17 ATOM 6711 CE2 TYR 93 53.871 16 ATOM 6712 CZ TYR 93 54.443 16 ATOM 6713 OH TYR 93 54.110 15 ATOM 6714 C TYR 93 56.733 22 ATOM 6715 O TYR 93 57.557 21 ATOM 6716 N THR 94 55.951 23 ATOM 6717 CA THR 94 55.672 23 ATOM 6718 CB THR 94 56.079 25 ATOM 6719 OG1 THR 94 55.926 26 ATOM 6720 CG2 THR 94 55.212 26 ATOM 6721 C THR 94 54.178 23 ATOM 6722 O THR 94 53.428 23 ATOM 6723 N SER 95 53.754 24 ATOM 6724 CA SER 95 52.365 24 ATOM 6725 CB SER 95 52.192 25 ATOM 6726 OG SER 95 53.426 25 ATOM 6727 C SER 95 51.402 24 ATOM 6728 O SER 95 50.291 24 ATOM 6729 N THR 96 51.847 25 ATOM 6730 CA THR 96 51.009 26 ATOM 6731 CB THR 96 50.750 27 ATOM 6732 OG1 THR 96 51.992 28 ATOM 6733 CG2 THR 96 49.805 27 ATOM 6734 C THR 96 51.567 26 ATOM 6735 O THR 96 50.810 26 ATOM 6736 N SER 97 52.878 25 ATOM 6737 CA SER 97 53.459 25 ATOM 6738 CB SER 97 53.716 27 ATOM 6739 OG SER 97 54.028 28 ATOM 6740 C SER 97 54.739 24 ATOM 6741 O SER 97 54.927 23 ATOM 6742 N MET 98 55.605 25 ATOM 6743 CA MET 98 56.908 24 ATOM 6744 CB MET 98 57.126 24 ATOM 6745 CG MET 98 55.993 23 ATOM 6746 SD MET 98 55.659 21 ATOM 6747 CE MET 98 56.438 20 ATOM 6748 C MET 98 58.031 25 ATOM 6749 0 MET 98 57.833 26 ATOM 6750 N VAL 99 59.201 25 ATOM 6751 CA VAL 99 60.453 25 ATOM 6752 CB VAL 99 60.916 26 ATOM 6753 CGI VAL 99 60.298 27 ATOM 6754 CG2 VAL 99 60.547 25 ATOM 6755 C VAL 99 61.569 24 ATOM 6756 O VAL 99 61.746 23 ATOM 6757 N PHE 100 62.325 25 ATOM 6758 CA PHE 100 63.500 24 ATOM 6759 CB PHE 100 63.664 24 ATOM 6760 CG PHE 100 62.723 24 ATOM 6761 CDl PHE 100 61.481 24 ATOM 6762 CD2 PHE 100 63.107 22 -3.019 1.00 4 7.52 L21B 0 -1.568 1.00 53.04 L21B c -0.757 1.00 61.42 L21B s -2.734 1.00 51.79 L21B N -2.62 0 1.00 53.65 L21B c -3.834 1.00 55.81 L21B c -3.495 1.00 59.21 L21B c -2.820 1.00 62.36 L21B 0 -3.967 1.00 60.75 L21B N -1.307 1.00 52.94 L21B c -0.777 1.00 52.18 L21B 0 -0.765 1.00 52.71 L21B N 0.347 1.00 51.08 L21B c 1.680 1.00 50.00 L21B c 2.715 1.00 46.75 L21B 0 0.347 1.00 51.25 L21B c 0.053 1.00 50.09 L21B 0 0.699 1.00 52.79 L21B N 1.003 1.00 54.65 L21B c 1.579 1.00 50.92 L21B c 0.616 1.00 48.58 L21B c -0.647 1.00 47.35 L21B c -1.513 1.00 48.50 L21B c 0.995 1.00 4 6.57 L21B c 0.143 1.00 46.50 L21B c -1.115 1.00 48.92 L21B c -1.982 1.00 50.22 L21B 0 2.068 1.00 57.60 L21B c 2.959 1.00 57.59 L21B 0 1.991 1.00 62.04 L21B N 3.183 1.00 64.72 L21B c 2.997 1.00 62.42 L21B c 4.243 1.00 64.29 L21B 0 1.955 1.00 59.60 L21B c 3.512 1.00 65.94 L21B c 2.854 1.00 69.06 L21B 0 4.538 1.00 65.95 L21B N 4.967 1.00 64.79 L21B c 6.120 1.00 66.94 L21B c 6.818 1.00 69.87 L21B 0 3.830 1.00 63.59 L21B c 3.763 1.00 61.36 L21B 0 2.932 1.00 63.25 L21B N 1.860 1.00 63.14 L21B c 2.070 1.00 61.83 L21B c 2.345 1.00 62.39 L21B 0 3.225 1.00 61.90 L21B c 0.442 1.00 64.18 L21B c -0.525 1.00 65.09 L21B 0 0.301 1.00 64.48 L21B N -1.034 1.00 64.51 L21B c -1.627 1.00 63.56 L21B c -0.603 1.00 61.46 L21B 0 -1.078 1.00 64.82 L21B c -0.270 1.00 66.42 L21B 0 -2.041 1.00 64.07 L21B N -2.149 1.00 62.18 L21B c -3.574 1.00 63.88 L21B c -4.104 1.00 67.65 L21B c -3.078 1.00 72.81 L21B s -4.065 1.00 73.59 L21B c -1.802 1.00 59.11 L21B c -1.831 1.00 60.23 L21B 0 -1.459 1.00 55.44 L21B N -1.572 1.00 51.98 L21B c -0.239 1.00 52.88 L21B c -0.041 1.00 54.75 L21B c 0.903 1.00 55.69 L2 IB c -2.041 1.00 49.13 L21B c -1.539 1.00 47.82 L21B 0 -3.013 1.00 4 6.97 L21B N -3.481 1.00 44.40 L21B c -4.981 1.00 42.82 . L21B c -5.813 1.00 41.24 L21B c -6.164 1.00 40.72 ' L21B c -6.298 1.00 40.13 L21B c 409 WO 2009/026558 PCT/US2008/074097 ATOM 6763 CEl PHE 100 60.632 23 ATOM 6764 CE2 PHE 100 62.2 69 22 ATOM 6765 CZ PHE 100 61.027 22 ATOM 6766 C PHE 100 64.705 25 ATOM 67 67 O PHE 100 64.636 26 ATOM 6768 N GLY 101 65.808 24 ATOM 6769 CA GLY 101 67.050 24 ATOM 6770 C GLY 101 67.713 25 ATOM 6771 0 GLY 101 67.280 25 ATOM 6772 N GLY 102 68.764 26 ATOM 6773 CA GLY 102 69.452 27 ATOM 6774 C GLY 102 70.110 26 ATOM 6775 0 GLY 102 70.423 27 ATOM 6776 N GLY 103 70.305 25 ATOM 6777 CA GLY 103 70.929 24 ATOM 6778 C GLY 103 72.381 24 ATOM 6779 0 GLY 103 73.019 24 ATOM 6780 N THR 104 72.898 22 ATOM 6781 CA THR 104 74.308 22 ATOM 6782 CB THR 104 74.541 21 ATOM 6783 OG1 THR 104 74.064 22 ATOM 6784 CG2 THR 104 76.018 21 ATOM 6785 C THR 104 74.850 22 ATOM 6786 O THR 104 74.168 21 ATOM 6787 N LYS 105 76.074 22 ATOM 6788 CA LYS 105 76.745 22 ATOM 6789 CB LYS 105 77.629 23 ATOM 6790 CG LYS 105 77.714 23 ATOM 6791 CD LYS 105 78.692 22 ATOM 6792 CE LYS 105 79.046 22 ATOM 6793 NZ LYS 105 80.160 22 ATOM 6794 C LYS 105 77.602 20 ATOM 6795 O LYS 105 78.315 20 ATOM 6796 N LEU 106 77.534 19 ATOM 6797 CA LEU 106 78.335 18 ATOM 6798 CB LEU 106 77.446 17 ATOM 6799 CG LEU 106 78.153 16 ATOM 6800 CD1 LEU 106 78.509 15 ATOM 6801 CD2 LEU 106 77.252 15 ATOM 6802 C LEU 106 79.392 18 ATOM 6803 O LEU 106 79.095 18 ATOM 6804 N THR 107 80.628 18 ATOM 6805 CA THR 107 81.684 18 ATOM 6806 CB THR 107 82.803 19 ATOM 6807 OG1 THR 107 82.220 20 ATOM 6808 CG2 THR 107 83.692 19 ATOM 6809 C THR 107 82.272 16 ATOM 6810 O THR 107 82.644 16 ATOM 6811 N VAL 108 82.349 15 ATOM 6812 CA VAL 108 83.153 14 ATOM 6813 CB VAL 108 82.594 13 ATOM 6814 CGI VAL 108 83.486 12 ATOM 6815 CG2 VAL 108 81.188 13 ATOM 6816 C VAL 108 84.553 15 ATOM 6817 O VAL 108 84.814 15 ATOM 6818 N LEU 109 85.443 15 ATOM 6819 CA LEU 109 86.805 15 ATOM 6820 CB LEU 109 87.622 15 ATOM 6821 CG LEU 109 87.127 16 ATOM 6822 CD1 LEU 109 87.677 16 ATOM 6823 CD2 LEU 109 87.544 17 ATOM 6824 C LEU 109 87.518 14 ATOM 6825 O LEU 109 87.811 13 ATOM 6826 N GLY 110 87.792 15 ATOM 6827 CA GLY 110 88.496 15 ATOM 6828 C GLY 110 89.870 15 ATOM 6829 0 GLY 110 90.465 15 ATOM 6830 N GLN 111 90.362 16 ATOM 6831 CA GLN 111 91.662 17 ATOM 6832 CB GLN 111 91.706 18 ATOM 6833 CG GLN 111 90.660 19 ATOM 6834 CD GLN 111 91.022 20 ATOM 6835 OE1 GLN 111 91.918 21 ATOM 6836 NE2 GLN 111 90.332 20 ATOM 6837 C GLN 111 91.887 17 ATOM 6838 0 GLN 111 91.014 17
-6.996 1.00 38.77 L21B c -7.129 1.00 39.31 L21B c -7.482 1.00 40.01 L21B c -2.749 1.00 4 3.67 L21B c -2.138 1.00 42.08 L21B 0 -2.794 1.00 44.87 L21B N -2.278 1.00 44.48 L21B C -3.385 1.00 44.11 L21B C -4.550 1.00 42.11 L21B O -3.021 1.00 43.78 L21B N -3.973 1.00 42.09 L21B C -5.064 1.00 41.93 L21B C -6.133 1.00 39.38 L21B O -4.792 1.00 43.18 L21B N -5.760 1.00 44.49 L21B C -5.405 1.00 46.09 L21B C -4.735 1.00 45.13 L21B O -5.839 1.00 47.33 L21B N -5.691 1.00 49.35 L21B C -4.622 1.00 46.64 L21B C -3.353 1.00 43.30 L21B O -4.491 1.00 43.32 L21B C -7.026 1.00 52.94 L21B C -7.752 1.00 53.31 L21B O -7.342 1.00 55.91 L21B N -8.566 1.00 59.05 L21B C -9.068 1.00 61.76 L21B C -10.584 1.00 65.69 L21B C -11.214 1.00 68.17 L21B C -12.635 1.00 70.95 L21B C -13.244 1.00 73.15 L21B N -8.252 1.00 59.65 L21B C -7.252 1.00 60.37 L21B O -9.095 1.00 60.39 L21B N -8.898 1.00 61.91 L21B C -8.881 1.00 62.09 L21B C -8.764 1.00 60.56 L21B C -7.314 1.00 60.55 L21B C -9.277 1.00 60.14 L21B C -9.977 1.00 64.04 L21B C -11.170 1.00 63.86 L21B O -9.559 1.00 65.89 L21B N -10.521 1.00 67.61 L21B C -10.378 1.00 67.75 L21B C -10.228 1.00 68.92 L21B O -11.613 1.00 67.06 L21B C -10.316 1.00 68.99 L21B C -9.200 1.00 68.71 L21B O -11.400 1.00 70.46 L21B N -11.425 1.00 72.21 L21B C -12.423 1.00 73.56 L21B C -12.449 1.00 74.74 L21B C -12.040 1.00 74.55 L21B C -11.880 1.00 72.19 L21B C -13.083 1.00 71.74 L21B O -10.909 1.00 72.49 L21B N -11.160 1.00 72.84 L21B C -9.871 1.00 70.84 L21B C -8.755 1.00 70.37 L21B C -7.441 1.00 69.58 L21B C -9.031 1.00 69.90 L21B C -12.280 1.00 73.49 L21B C -12.154 1.00 74.15 L21B O -13.374 1.00 73.86 L21B N -14.497 1.00 74.58 L21B C -14.688 1.00 74.91 L21B C -15.762 1.00 73.20 L21B O -13.631 1.00 77.03 L2 IB N -13.625 1.00 80.05 L21B C -14.680 1.00 81.49 L21B C -14.485 1.00 82.71 L21B C -15.171 1.00 81.90 L21B C -14.726 1.00 81.02 . L21B O -16.264 1.00 80.18 L21B N -12.238 1.00 80.10 ' L21B C -11.377 1.00 81.14 L21B O 410 WO 2009/026558 PCT/US2008/074097 ATOM 6839 N PRO 112 93.073 18 ATOM 6840 CD PRO 112 94.285 18 ATOM 6841 CA PRO 112 93.327 18 ATOM 6842 CB PRO 112 94.845 18 ATOM 6843 CG PRO 112 95.361 18 ATOM 6844 C PRO 112 92.615 19 ATOM 6845 O PRO 112 92.349 20 ATOM 6846 N LYS 113 92.312 20 ATOM 6847 CA LYS 113 91.651 21 ATOM 6848 CB LYS 113 91.273 21 ATOM 6849 CG LYS 113 90.170 20 ATOM 6850 CD LYS 113 89.612 20 ATOM 6851 CE LYS 113 88.519 19 ATOM 6852 NZ LYS 113 88.060 19 ATOM 6853 C LYS 113 92.570 22 ATOM 6854 0 LYS 113 93.767 22 ATOM 6855 N ALA 114 92.018 23 ATOM 6856 CA ALA 114 92.836 24 ATOM 6857 CB ALA 114 92.869 25 ATOM 6858 C ALA 114 92.280 26 ATOM 6859 0 ALA 114 91.119 26 ATOM 6860 N ALA 115 93.098 26 ATOM 6861 CA ALA 115 92.658 28 ATOM 6862 CB ALA 115 93.698 28 ATOM 6863 C ALA 115 92.432 29 ATOM 6864 0 ALA 115 93.166 29 ATOM 68 65 N PRO 116 91.409 29 ATOM 6866 CD PRO 116 90.642 30 ATOM 6867 CA PRO 116 91.089 30 ATOM 6868 CB PRO 116 89.689 31 ATOM 6869 CG PRO 116 89.720 31 ATOM 6870 C PRO 116 92.103 32 ATOM 6871 O PRO 116 92.627 32 ATOM 6872 N SER 117 92.375 32 ATOM 6873 CA SER 117 93.083 33 ATOM 6874 CB SER 117 93.978 33 ATOM 6875 OG SER 117 94.987 32 ATOM 6876 C SER 117 92.109 35 ATOM 6877 O SER 117 91.326 35 ATOM 6878 N VAL 118 92.163 35 ATOM 6879 CA VAL 118 91.337 37 ATOM 6880 CB VAL 118 90.715 37 ATOM 6881 CGI VAL 118 89.895 38 ATOM 6882 CG2 VAL 118 89.862 36 ATOM 6883 C VAL 118 92.215 38 ATOM 6884 O VAL 118 93.224 38 ATOM 6885 N THR 119 91.846 39 ATOM 6886 CA THR 119 92.433 40 ATOM 6887 CB THR 119 93.380 40 ATOM 6888 OG1 THR 119 92.629 40 ATOM 6889 CG2 THR 119 94.098 39 ATOM 6890 C THR 119 91.335 41 ATOM 6891 O THR 119 90.328 41 ATOM 6892 N LEU 120 91.511 42 ATOM 6893 CA LEU 120 90.407 43 ATOM 6894 CB LEU 120 89.973 43 ATOM 6895 CG LEU 120 89.176 44 ATOM 6896 CDl LEU 120 87.826 44 ATOM 6897 CD2 LEU 120 89.019 44 ATOM 6898 C LEU 120 90.716 44 ATOM 6899 O LEU 120 91.618 45 ATOM 6900 N PHE 121 89.959 45 ATOM 6901 CA PHE 121 90.240 46 ATOM 6902 CB PHE 121 90.054 46 ATOM 6903 CG PHE 121 91.133 45 ATOM 6904 CDl PHE 121 90.885 44 ATOM 6905 CD2 PHE 121 92.403 46 ATOM 6906 CEl PHE 121 91.882 43 ATOM 6907 CE2 PHE 121 93.407 45 ATOM 6908 CZ PHE 121 93.147 44 ATOM 6909 C PHE 121 89.327 47 ATOM 6910 O PHE 121 88.118 47 ATOM 6911 N PRO 122 89.895 48 ATOM 6912 CD PRO 122 91.343 49 ATOM 6913 CA PRO 122 89.118 50 ATOM 6914 CB PRO 122 90.165 51 -11.990 1.00 78.66 L21B N -12.819 1.00 74.89 L21B C -10.625 1.00 76.87 L21B C -10.569 1.00 74.73 L21B c -11.803 1.00 73.97 L21B c -10.358 1.00 75.57 L21B c. -11.285 1.00 76.36 L21B 0 -9.091 1.00 72.84 L21B N -8.695 1.00 70.02 L21B c -7.210 1.00 71.19 L21B c -6.863 1.00 71.89 L21B c -5.473 1.00 72.26 L21B c -5.076 1.00 73.00 L21B c -3.667 1.00 71.49 L21B N -8.943 1.00 68.17 L21B c -8.675 1.00 68.73 L21B 0 -9.449 1.00 65.81 L21B N -9.802 1.00 62.76 L21B c -11.313 1.00 63.57 L21B c -9.159 1.00 60.79 L21B c -9.362 1.00 59.21 L21B 0 -8.381 1.00 57.86 L21B N -7.771 1.00 55.74 L21B c -6.786 1.00 54.06 L21B c -8.879 1.00 54.53 L21B c -9.861 1.00 56.60 L21B 0 -8.739 1.00 52.44 L21B N -7.513 1.00 53.94 L21B c -9.816 1.00 50.36 L21B c -9.447 1.00 52.55 L21B c -7.930 1.00 53.47 L21B c -9.851 1.00 48.65 L21B c -8.803 1.00 47.48 L21B 0 -11.043 1.00 45.92 L21B N -11.154 1.00 43.14 L21B c -12.384 1.00 42.23 L21B c -12.258 1.00 47.57 L21B 0 -11.241 1.00 41.00 L21B c -12.181 1.00 4 0.97 L21B 0 -10.259 1.00 37.34 L21B N -10.274 1.00 36.92 L21B c -8.878 1.00 36.85 L21B c -8.867 1.00 34.92 L21B c -8.495 1.00 38.22 L21B c -10.635 1.00 37.10 L21B c -9.971 1.00 37.46 L21B 0 -11.673 1.00 36.80 L21B N -11.836 1.00 38.29 L21B c -13.072 1.00 40.02 L21B c -14 .249 1.00 42.31 L21B 0 -13.267 1.00 41.99 L21B c -11.949 1.00 36.59 L21B c -12.631 1.00 35.96 L21B 0 -11.262 1.00 34.86 L21B N -11.101 1.00 35.65 L21B c -9.627 1.00 32.38 L21B c -9.256 1.00 32.01 L21B c -9.988 1.00 29.34 L21B c -7.740 1.00 30.16 L21B c -11.595 1.00 34.81 L21B c -11.081 1.00 35.69 L21B 0 -12.580 1.00 35.05 L21B N -13.227 1.00 37.49 L21B c -14.733 1.00 37.01 L21B c -15.418 1.00 39.94 L21B c -15.950 1.00 41.17 L21B c -15.546 1.00 40.30 L21B c -16.601 1.00 41.70 L21B c -16.193 1.00 41.18 L21B c -16.725 1.00 42.12 L21B c -12.727 1.00 37.59 L21B c -12.717 1.00 38.34 L21B 0 -12.320 1.00 33.96 L21B N -12.217 1.00 33.93 L21B c -11.849 1.00 38.29 L21B c -11.187 1.00 35.32 L21B c 411 WO 2009/026558 PCT/US2008/074097 ATOM 6915 CG PRO 122 91.417 50 ATOM 6916 C PRO 122 88.425 50 ATOM 6917 O PRO 122 88.852 50 ATOM 6918 N PRO 123 87.360 51 ATOM 6919 CD PRO 123 86.853 52 ATOM 6920 CA PRO 123 86.729 52 ATOM 6921 CB PRO 123 85.750 53 ATOM 6922 CG PRO 123 85.552 52 ATOM 6923 C PRO 123 87.813 53 ATOM 6924 O PRO 123 88.806 53 ATOM 6925 N SER 124 87.644 53 ATOM 6926 CA SER 124 88.611 54 ATOM 6927 CB SER 124 88.663 53 ATOM 6928 OG SER 124 87.506 54 ATOM 6929 C SER 124 88.267 55 ATOM 6930 O SER 124 87.158 56 ATOM 6931 N SER 125 89.255 56 ATOM 6932 CA SER 125 89.127 57 ATOM 6933 CB SER 125 90.474 58 ATOM 6934 OG SER 125 91.447 57 ATOM 6935 C SER 125 88.062 58 ATOM 6936 O SER 125 87.218 59 ATOM 6937 N GLU 126 88.093 57 ATOM 6938 CA GLU 126 87.157 58 ATOM 6939 CB GLU 126 87.458 57 ATOM 6940 CG GLU 126 88.843 57 ATOM 6941 CD GLU 126 88.903 57 ATOM 6942 OE1 GLU 126 88.015 57 ATOM 6943 OE2 GLU 126 89.822 56 ATOM 6944 C GLU 126 85.734 57 ATOM 6945 0 GLU 126 84.833 58 ATOM 6946 N GLU 127 85.528 56 ATOM 6947 CA GLU 127 84.197 56 ATOM 6948 CB GLU 127 84.213 54 ATOM 6949 CG GLU 127 82.828 54 ATOM 6950 CD GLU 127 82.845 53 ATOM 6951 OE1 GLU 127 81.780 52 ATOM 6952 OE2 GLU 127 83.920 52 ATOM 6953 C GLU 127 83.656 57 ATOM 6954 0 GLU 127 82.534 57 ATOM 6955 N LEU 128 84.447 57 ATOM 6956 CA LEU 128 84.003 58 ATOM 6957 CB LEU 128 85.145 58 ATOM 6958 CG LEU 128 85.440 57 ATOM 6959 CDl LEU 128 8 6.4 92 58 ATOM 6960 CD2 LEU 128 84.160 57 ATOM 6961 C LEU 128 83.461 59 ATOM 6962 O LEU 128 82.445 60 ATOM 6963 N GLN 129 84.124 60 ATOM 6964 CA GLN 129 83.690 61 ATOM 6965 CB GLN 129 84.730 61 ATOM 6966 CG GLN 129 84.757 63 ATOM 6967 CD GLN 129 84.894 64 ATOM 6968 OE1 GLN 129 83.960 64 ATOM 6969 NE2 GLN 129 86.065 63 ATOM 6970 C GLN 129 82.335 61 ATOM 6971 0 GLN 129 81.613 62 ATOM 6972 N ALA 130 81.999 59 ATOM 6973 CA ALA 130 80.723 59 ATOM 6974 CB ALA 130 80.842 58 ATOM 6975 C ALA 130 79.613 59 ATOM 6976 0 ALA 130 78.444 59 ATOM 6977 N ASN 131 79.998 59 ATOM 6978 CA ASN 131 79.057 59 ATOM 6979 CB ASN 131 77.856 60 ATOM 6980 CG ASN 131 77.079 60 ATOM 6981 OD1 ASN 131 77.634 60 ATOM 6982 ND2 ASN 131 75.788 61 ATOM 6983 C ASN 131 78.572 58 ATOM 6984 O ASN 131 77.431 58 ATOM 6985 N LYS 132 79.456 57 ATOM 6986 CA LYS 132 79.241 55 ATOM 6987 CB LYS 132 78.787 55 ATOM 6988 CG LYS 132 77.627 55 ATOM 6989 CD LYS 132 76.291 55 ATOM 6990 CE LYS 132 75.556 54 -11.910 1.00 33.59 L21B c -12.992 1.00 39.54 L21B c -14.136 1.00 39.03 L21B 0 -12.697 1.00 38.00 L21B N -11.371 1.00 42.45 L21B c -13.778 1.00 40.80 L21B ,c. -13.057 1.00 41.73 L21B c -11.698 1.00 44.67 L21B c -14.490 1.00 42.29 L21B c -13.871 1.00 4 0.52 L21B 0 -15.788 1.00 44.28 L21B N -16.506 1.00 47.54 L21B c -17.988 1.00 47.47 L21B c -18.684 1.00 53.94 L21B 0 -16.348 1.00 4 9.32 L21B c -15.948 1.00 4 9.97 L21B 0 -16.636 1.00 50.71 L21B N -16.549 1.00 51.79 L21B c -16.895 1.00 54.13 L21B c -17.108 1.00 58.67 L21B 0 -17.530 1.00 52.33 L21B c -17.197 1.00 53.85 L21B 0 -18.735 1.00 52.90 L21B N -19.780 1.00 53.19 L21B c -21.082 1.00 57.40 L21B c -21.675 1.00 62.62 L21B c -23.100 1.00 66.23 L21B c -23.904 1.00 68.20 L21B 0 -23.414 1.00 68.73 L21B 0 -19.373 1.00 51.91 L21B c -19.467 1.00 50.90 L21B 0 -18.928 1.00 50.99 L21B N -18.523 1.00 49.49 L21B c -18.046 1.00 4 8.63 L21B c -17.767 1.00 4 5.52 L21B c -16.907 1.00 44.98 L21B c -16.353 1.00 42.76 L21B 0 -16.794 1.00 43.35 L21B 0 -17.422 1.00 48.57 L21B c -17.516 1.00 49.29 L21B 0 -16.382 1.00 47.26 L21B N -15.337 1.00 46.49 L21B c -14.377 1.00 44.93 L21B c -13.341 1.00 44.39 L21B c -12.377 1.00 42.24 L21B c -12.588 1.00 43.91 L21B c -15.948 1.00 45.72 L21B c -15.502 1.00 44.90 L21B 0 -16.991 1.00 44.74 L21B N -17.643 1.00 43.60 L21B c -18.673 1.00 44.32 L21B c -18.915 1.00 44.45 L21B c -17.632 1.00 44.59 L21B c -17.184 1.00 46.48 L21B 0 -17.014 1.00 43.44 L21B N -18.318 1.00 43.46 L21B c -18.567 1.00 42.25 L21B 0 -18.612 1.00 43.83 L21B N -19.236 1.00 44.55 L21B c -19.998 1.00 40.95 L21B c -18.190 1.00 45.51 L21B c -18.516 1.00 45.69 L21B 0 -16.932 1.00 46.19 L21B N -15.814 1.00 46.40 L21B c -16.116 1.00 4 6.67 L21B c t14.866 1.00 48.91 L21B c -13.764 1.00 47.77 L21B 0 -15.021 1.00 51.00 L21fi N -15.467 1.00 46.14 L21B c -15.028 1.00 45.59 L21B 0 -15.687 1.00 44.66 L21B N -15.265 1.00 42.08 L21B c -16.450 1.00 40.90 L21B c -17.217 1.00 43.12 L21B c -16.679 1.00 47.00 L21B c -17.718 1.00 51.53 L21B c 412 WO 2009/026558 PCT/US2008/074097 ATOM 6991 NZ LYS 132 75.127 55 .214 -18.892 1.00 53.24 L21B N ATOM 6992 C LYS 132 80.567 55.436 -14.727 1.00 40.86 L21B C ATOM 6993 0 LYS 132 81.625 55.974 -15.036 1.00 39.43 L21B O ATOM 6994 N ALA 133 80.515 54.410 -13.898 1.00 40.80 L21B N ATOM 6995 CA ALA 133 81.742 53.771 -13.469 1.00 40.55 L21B C ATOM 6996 CB ALA 133 82.155 54.284 -12.094 1.00 41.61 L21B C ATOM 6997 C ALA 133 81.503 52.277 -13.436 1.00 39.52 L21B c ATOM 6998 O ALA 133 80.407 51.827 -13.094 1.00 40.03 L21B 0 ATOM 6999 N THR 134 82.517 51.511 -13.816 1.00 37.08 L21B N ATOM 7000 CA THR 134 82.387 50.070 -13.826 1.00 35.24 L21B c ATOM 7001 CB THR 134 82.102 49.568 -15.261 1.00 34.18 L21B c ATOM 7002 OG1 THR 134 81.076 50.373 -15.860 1.00 31.16 L21B 0 ATOM 7003 CG2 THR 134 81.630 48.113 -15.229 1.00 34 .12 L21B c ATOM 7004 C THR 134 83.660 49.413 -13.288 1.00 35.11 L21B c ATOM 7005 O THR 134 84.756 49.639 -13.809 1.00 34 .86 L21B 0 ATOM 7006 N LEU 135 83.527 48.604 -12.240 1.00 35.01 L21B N ATOM 7007 CA LEU 135 84.659 47.785 -11.811 1.00 35.41 L21B c ATOM 7008 CB LEU 135 84.648 47.559 -10.299 1.00 35.87 L21B c ATOM 7009 CG LEU 135 84.344 48.751 -9.393 1.00 35.82 L21B c ATOM 7010 CDl LEU 135 84.432 48.303 -7.946 1.00 37.53 L21B c ATOM 7011 CD2 LEU 135 85.307 49.859 -9.652 1.00 35.35 L21B c ATOM 7012 C LEU 135 84.568 46.451 -12.520 1.00 33.80 L21B c ATOM 7013 O LEU 135 83.529 45.820 -12.520 1.00 35.43 L21B 0 ATOM 7014 N VAL 136 85.659 46.033 -13.136 1.00 33.39 L21B N ATOM 7015 CA VAL 136 85.658 44.817 -13.927 1.00 33.35 L21B c ATOM 7016 CB VAL 136 86.196 45.094 -15.343 1.00 31.20 L21B c ATOM 7017 CGI VAL 136 86.377 43.785 -16.117 1.00 30.64 L21B c ATOM 7018 CG2 VAL 136 85.222 46.009 -16.080 1.00 28.09 L21B c ATOM 7019 C VAL 136 86.492 43.727 -13.262 1.00 33.93 L21B c ATOM 7020 O VAL 136 87.718 43.823 -13.186 1.00 33.89 L21B 0 ATOM 7021 N CYS 137 85.815 42.692 -12.771 1.00 34.36 L21B N ATOM 7022 CA CYS 137 86.505 41.597 -12.113 1.00 36.21 L21B c ATOM 7023 C CYS 137 86.499 40.375 -13.001 1.00 35.27 L21B c ATOM 7024 0 CYS 137 85.460 39.765 -13.199 1.00 34 .76 L21B 0 ATOM 7025 CB CYS 137 85.848 41.264 -10.772 1.00 38.22 L21B c ATOM 7026 SG CYS 137 86.846 40.139 -9.739 1.00 40.11 L21B s ATOM 7027 N LEU 138 87.670 40.029 -13.531 1.00 35.98 L21B N ATOM 7028 CA LEU 138 87.815 38.912 -14.454 1.00 38.04 L21B c ATOM 7029 CB LEU 138 88.747 39.322 -15.594 1.00 37.69 L21B c ATOM 7030 CG LEU 138 88.403 40.638 -16.312 1.00 39.81 L21B c ATOM 7031 CDl LEU 138 89.536 41.044 -17.241 1.00 40.38 L21B c ATOM 7032 CD2 LEU 138 87.129 40.481 -17.103 1.00 39.74 L21B c ATOM 7033 C LEU 138 88.367 37.670 -13.725 1.00 39.64 L21B c ATOM 7034 O LEU 138 89.270 37.784 -12.889 1.00 41.42 L21B 0 ATOM 7035 N ILE 139 87.824 36.490 -14.030 1.00 38.47 L21B N ATOM 7036 CA ILE 139 88.251 35.268 -13.351 1.00 38.43 L21B c ATOM 7037 CB ILE 139 87.150 34.756 -12.429 1.00 37.11 L21B c ATOM 7038 CG2 ILE 139 87.707 33.697 -11.485 1.00 38.23 L21B c ATOM 7039 CGI ILE 139 86.581 35.914 -11.627 1.00 36.92 L21B c ATOM 7040 CDl ILE 139 85.608 35.472 -10.583 1.00 38.37 L21B c ATOM 7041 C ILE 139 88.618 34.150 -14.335 1.00 38.50 L21B c ATOM 7042 0 ILE 139 87.834 33.819 -15.225 1.00 36.72 L21B 0 ATOM 7043 N SER 140 89.803 33.564 -14.172 1.00 39.81 L21B N ATOM 7044 CA SER 140 90.312 32.604 -15.156 1.00 42.70 L21B c ATOM 7045 CB SER 140 91.266 33.292 -16.145 1.00 42.39 L21B c ATOM 7046 OG SER 140 92.065 34.270 -15.498 1.00 4 3.52 L21B 0 ATOM 7047 C SER 140 91.020 31.398 -14.564 1.00 43.55 L21B c ATOM 7048 O SER 140 91.514 31.441 -13.432 1.00 43.83 L21B 0 ATOM 7049 N ASP 141 91.055 30.320 -15.344 1.00 44.57 L21B N ATOM 7050 CA ASP 141 91.910 29.173 -15.060 1.00 46.96 L21B c ATOM 7051 CB ASP 141 93.388 29.589 -15.151 1.00 49.43 L21B c ATOM 7052 CG ASP 141 93.753 30.153 -16.519 1.00 52.67 L21B c ATOM 7053 ODl ASP 141 93.943 31.388 -16.623 1.00 55.09 L21B 0 ATOM 7054 OD2 ASP 141 93.843 29.362 -17.492 1.00 54.16 L21B 0 ATOM 7055 C ASP 141 91.626 28.547 -13.697 1.00 47.35 L21B c ATOM 7056 O ASP 141 92.510 28.431 -12.853 1.00 47.00 L21B 0 ATOM 7057 N PHE 142 90.389 28.134 -13.481 1.00 49.13 L21B N ATOM 7058 CA PHE 142 90.066 27.424 -12.260 1.00 51.26 L21B c ATOM 7059 CB PHE 142 89.306 28.349 -11.315 1.00 50.93 L21B c ATOM 7060 CG PHE 142 88.015 28.882 -11.885 1.00 52.14 L21B c ATOM 7061 CDl PHE 142 86.839 28.146 -11.790 1.00 51.98 L21B c ATOM 7062 CD2 PHE 142 87.960 30.142 -12.457 1.00 51.72 L21B c ATOM 7063 CEl PHE 142 85.641 28.661 -12.245 1.00 49.40 . L21B c ATOM 7064 CE2 PHE 142 86.767 30.658 -12.913 1.00 4 9.64 L21B c ATOM 7065 CZ PHE 142 85.608 29.917 -12.804 1.00 50.17 ' L21B c ATOM 7066 C PHE 142 89.255 26.166 -12.561 1.00 51.68 L21B c 413 WO 2009/026558 PCT/US2008/074097 ATOM 7067 0 PHE 142 88.654 26 ATOM 7068 N TYR 143 89.267 25 ATOM 7069 CA TYR 143 88.530 23 ATOM 7070 CB TYR 143 89.282 23 ATOM 7071 CG TYR 143 88.523 21 ATOM 7072 CDl TYR 143 88.524 20 ATOM 7073 CEl TYR 143 87.865 19 ATOM 7074 CD2 TYR 143 87.844 21 ATOM 7075 CE2 TYR 143 87.185 20 ATOM 7076 CZ TYR 143 87.198 19 ATOM 7077 OH TYR 143 86.534 18 ATOM 7078 C TYR 143 88.382 23 ATOM 7079 O TYR 143 89.303 23 ATOM 7080 N PRO 144 87.206 22 ATOM 7081 CD PRO 144 86.972 22 ATOM 7082 CA PRO 144 86.003 22 ATOM 7083 CB PRO 144 85.062 21 ATOM 7084 CG PRO 144 85.478 21 ATOM 7085 C PRO 144 85.382 24 ATOM 7086 O PRO 144 85.702 25 ATOM 7087 N GLY 145 84.501 24 ATOM 7088 CA GLY 145 83.958 25 ATOM 7089 C GLY 145 82.812 26 ATOM 7090 0 GLY 145 81.719 26 ATOM 7091 N ALA 146 83.062 26 ATOM 7092 CA ALA 146 82.094 26 ATOM 7093 CB ALA 146 81.366 25 ATOM 7094 C ALA 146 82.779 27 ATOM 7095 0 ALA 146 83.631 27 ATOM 7096 N VAL 147 82.417 29 ATOM 7097 CA VAL 147 82.985 30 ATOM 7098 CB VAL 147 83.970 31 ATOM 7099 CGI VAL 147 85.144 30 ATOM 7100 CG2 VAL 147 83.229 31 ATOM 7101 C VAL 147 81.844 31 ATOM 7102 O VAL 147 80.803 31 ATOM 7103 N THR 148 82.033 31 ATOM 7104 CA THR 148 81.051 32 ATOM 7105 CB THR 148 80.323 32 ATOM 7106 OG1 THR 148 80.850 33 ATOM 7107 CG2 THR 148 80.505 30 ATOM 7108 C THR 148 81.807 34 ATOM 7109 O THR 148 82.966 34 ATOM 7110 N VAL 149 81.178 35 ATOM 7111 CA VAL 149 81.858 36 ATOM 7112 CB VAL 149 81.907 37 ATOM 7113 CGI VAL 149 82.473 38 ATOM 7114 CG2 VAL 149 82.767 36 ATOM 7115 C VAL 149 81.145 37 ATOM 7116 O VAL 149 79.944 37 ATOM 7117 N ALA 150 81.886 38 ATOM 7118 CA ALA 150 81.280 39 ATOM 7119 CB ALA 150 81.210 38 ATOM 7120 C ALA 150 82.112 40 ATOM 7121 0 ALA 150 83.349 40 ATOM 7122 N TRP 151 81.430 41 ATOM 7123 CA TRP 151 82.080 42 ATOM 7124 CB TRP 151 81.393 43 ATOM 7125 CG TRP 151 81.582 43 ATOM 7126 CD2 TRP 151 82.611 43 ATOM 7127 CE2 TRP 151 82.391 42 ATOM 7128 CE3 TRP 151 83.694 44 ATOM 7129 CDl TRP 151 80.809 42 ATOM 7130 NEl TRP 151 81.286 42 ATOM 7131 CZ2 TRP 151 83.205 42 ATOM 7132 CZ3 TRP 151 84.503 44 ATOM 7133 CH2 TRP 151 84.257 43 ATOM 7134 C TRP 151 81.997 43 ATOM 7135 O TRP 151 80.964 43 ATOM 7136 N LYS 152 83.092 44 ATOM 7137 CA LYS 152 83.072 45 ATOM 7138 CB LYS 152 84.092 44 ATOM 7139 CG LYS 152 83.871 43 ATOM 7140 CD LYS 152 83.032 43 ATOM 7141 CE LYS 152 82.767 41 ATOM 7142 NZ LYS 152 82.022 41
-13.626 1.00 51.50 L21B 0 -11.625 1.00 52.56 L21B N -11.760 1.00 54.58 L21B C -12.699 1.00 56.96 L21B c -13.117 1.00 59.81 L21B c -12.324 1.00 62.38 L21B c -12.731 1.00 63.84 L21B c -14.327 1.00 60.41 L21B c -14.744 1.00 63.55 L21B c -13.943 1.00 64.86 L21B c -14.356 1.00 65.40 L21B 0 -10.378 1.00 53.01 L21B c -9.569 1.00 53.42 L21B 0 -10.079 1.00 50.74 L21B N -8.767 1.00 49.09 L21B c -10.923 1.00 4 9.32 L21B c -10.164 1.00 47.39 L21B c -8.737 1.00 46.20 L21B c -11.153 1.00 47.94 L21B c -10.440 1.00 46.61 L21B 0 -12.152 1.00 46.23 L21B N -12.578 1.00 42.95 L21B c -11.742 1.00 41.27 L21B c -12.250 1.00 40.44 L21B 0 -10.453 1.00 39.59 L21B N -9.571 1.00 38.70 L21B c -8.763 1.00 31.97 L21B c -8.637 1.00 39.60 L21B c -7.833 1.00 41.88 L21B 0 -8.755 1.00 38.94 L21B N -7.894 1.00 39.15 L21B c -8.630 1.00 40.72 L21B c -9.186 1.00 40.44 L21B c -9.733 1.00 40.31 L21B c -7.439 1.00 38.68 L21B c -8.080 1.00 41.11 L21B 0 -6.335 1.00 36.37 L21B N -5.955 1.00 3 6.67 L21B c -4.659 1.00 35.50 L21B c -3.521 1.00 34.72 L21B 0 -4.467 1.00 37.45 L21B c -5.783 1.00 37.12 L21B c -5.342 1.00 36.84 L21B 0 -6.169 1.00 33.24 L21B N -6.104 1.00 33.40 L21B c -7.485 1.00 31.91 L21B c -7.369 1.00 33.40 L21B c -8.404 1.00 30.80 L21B c -5.121 1.00 34.21 L21B c -4.921 1.00 34.91 L21B 0 -4.487 1.00 33.86 L21B N -3.585 1.00 35.73 L21B c -2.188 1.00 33.79 L21B c -3.597 1.00 39.22 L21B c -3.711 1.00 40.31 L21B 0 -3.487 1.00 40.11 L21B N -3.632 1.00 41.54 L21B c -4.729 1.00 38.77 L21B c -6.112 1.00 3 6.67 L21B c -7.048 1.00 36.37 L21B c -8.219 1.00 34.19 L21B c -7.005 1.00 35.66 L21B c -6.737 1.00 35.59 L21B c -8.006 1.00 35.04 L21B N -9.330 1.00 34.35 L21B c .-8.107 1.00 35.09 L21B c -9.256 1.00 35.84 L21B c -2.316 1.00 44 . 09 L2 IB c -1.644 1.00 45.40 L21B 0 -1.946 1.00 46.45 L21B N -0.811 1.00 48.60 L21B c 0.225 1.00 48.03 L21B c 0.723 1.00 50.00 . L21B c 2.003 1.00 51.32 L21B c 2.424 1.00 52.22 L21B c 1.373 1.00 55.40 L21B N 414 WO 2009/026558 PCT/US2008/074097 ATOM 7143 c LYS 152 83.390 46 ATOM 7144 0 LYS 152 84.217 46 ATOM 7145 N ALA 153 82.701 47 ATOM 7146 CA ALA 153 83.076 48 ATOM 7147 CB ALA 153 81.854 49 ATOM 7148 C ALA 153 83.664 49 ATOM 7149 0 ALA 153 82.970 49 ATOM 7150 N ASP 154 84.950 49 ATOM 7151 CA ASP 154 85.732 49 ATOM 7152 CB ASP 154 85.183 50 ATOM 7153 CG ASP 154 85.664 52 ATOM 7154 OD1 ASP 154 86.880 52 ATOM 7155 OD2 ASP 154 84.842 53 ATOM 7156 C ASP 154 85.659 48 ATOM 7157 O ASP 154 86.161 47 ATOM 7158 N SER 155 85.010 48 ATOM 7159 CA SER 155 84.814 46 ATOM 7160 CB SER 155 85.331 46 ATOM 7161 OG SER 155 86.728 46 ATOM 7162 C SER 155 83.367 46 ATOM 7163 O SER 155 83.069 45 ATOM 7164 N SER 156 82.461 47 ATOM 7165 CA SER 156 81.057 46 ATOM 7166 CB SER 156 80.201 48 ATOM 7167 OG SER 156 80.336 48 ATOM 7168 C SER 156 80.733 46 ATOM 7169 O SER 156 81.328 46 ATOM 7170 N PRO 157 79.792 45 ATOM 7171 CD PRO 157 79.262 44 ATOM 7172 CA PRO 157 79.348 44 ATOM 7173 CB PRO 157 78.687 43 ATOM 7174 CG PRO 157 79.155 43 ATOM 7175 C PRO 157 78.402 45 ATOM 7176 O PRO 157 77.472 45 ATOM 7177 N VAL 158 78.657 45 ATOM 7178 CA VAL 158 77.915 45 ATOM 7179 CB VAL 158 78.700 45 ATOM 7180 CGI VAL 158 77.839 46 ATOM 7181 CG2 VAL 158 79.975 46 ATOM 7182 C VAL 158 76.536 45 ATOM 7183 O VAL 158 76.414 44 ATOM 7184 N LYS 159 75.505 46 ATOM 7185 CA LYS 159 74.113 45 ATOM 7186 CB LYS 159 73.236 46 ATOM 7187 CG LYS 159 73.455 46 ATOM 7188 CD LYS 159 72.644 47 ATOM 7189 CE LYS 159 73.000 46 ATOM 7190 NZ LYS 159 72.140 47 ATOM 7191 C LYS 159 73.462 45 ATOM 7192 0 LYS 159 72.303 45 ATOM 7193 N ALA 160 74.186 46 ATOM 7194 CA ALA 160 73.587 46 ATOM 7195 CB ALA 160 72.592 47 ATOM 7196 C ALA 160 74.622 46 ATOM 7197 0 ALA 160 75.718 47 ATOM 7198 N GLY 161 74.269 4 6 ATOM 7199 CA GLY 161 75.115 46 ATOM 7200 C GLY 161 75.947 45 ATOM 7201 0 GLY 161 76.533 45 ATOM 7202 N VAL 162 75.991 44 ATOM 7203 CA VAL 162 76.766 43 ATOM 7204 CB VAL 162 76.994 42 ATOM 7205 CGI VAL 162 77.924 41 ATOM 7206 CG2 VAL 162 77.563 43 ATOM 7207 C VAL 162 76.066 42 ATOM 7208 O VAL 162 74.848 42 ATOM 7209 N GLU 163 76.852 42 ATOM 7210 CA GLU 163 76.306 41 ATOM 7211 CB GLU 163 75.884 42 ATOM 7212 CG GLU 163 74.748 41 ATOM 7213 CD GLU 163 73.390 41 ATOM 7214 OE1 GLU 163 72.774 41 ATOM 7215 OE2 GLU 163 72.940 43 ATOM 7216 C GLU 163 77.401 40 ATOM 7217 0 GLU 163 78.410 40 ATOM 7218 N THR 164 77.206 38
-1.281 1.00 50.99 L21B c -2.181 1.00 51.75 L21B 0 -0.680 1.00 52.20 L21B N -0.762 1.00 53.01 L21B c -1.069 1.00 53.76 L21B c 0.596 1.00 53.38 L21B c 1.605 1.00 53.17 L21B 0 0.610 1.00 55.41 L21B N 1.840 1.00 56.87 L21B c 2.856 1.00 60.15 L21B c 2.579 1.00 63.17 L21B c 2.319 1.00 66.19 L21B 0 2.609 1.00 63.31 L21B 0 2.398 1.00 56.82 L21B c 1.790 1.00 54.87 L21B 0 3.545 1.00 57.77 L21B N 4 . 112 1.00 58.15 L21B c 5.542 1.00 57.73 L21B c 5.538 1.00 60.83 L21B 0 4.068 1.00 58.08 L21B c 4.217 1.00 59.53 L21B 0 3.858 1.00 58.33 L21B N 3.777 1.00 59.90 L21B c 3.965 1.00 60.53 L21B c 5.283 1.00 59.84 L21B 0 2.445 1.00 60.68 L21B c 1.422 1.00 61.89 L21B 0 2.453 1.00 60.88 L21B N 3.690 1.00 58.20 L21B c 1 .278 1.00 60.26 L21B c 1.886 1.00 58.77 L21B c 3.324 1.00 56.44 L21B c 0.334 1.00 59.58 L21B c 0.763 1.00 57.31 L21B 0 -0.959 1.00 59.32 L21B N -2.002 1.00 59.47 L21B c -3.331 1.00 57.95 L21B c -4.469 1.00 54.31 L21B c -3.213 1.00 53.69 L21B c -2.204 1.00 60.73 L21B c -2.333 1.00 61.06 L21B 0 -2.244 1.00 62.19 L21B N -2.315 1.00 61.60 L21B c -1.341 1.00 63.72 L21B c 0.126 1.00 69.06 L21B c 0.998 1.00 75.91 L21B c 2.478 1.00 82.57 L21B c 3.366 1.00 87.68 L21B N -3.699 1.00 58.86 L21B c -3.847 1.00 57.81 L21B 0 -4.701 1.00 55.78 L21B N -6.008 1.00 52.62 L21B c -5.900 1.00 51.57 L21B c -7.090 1.00 51.55 L21B c -6.803 1.00 52.32 L21B 0 -8.339 1.00 4 9.63 L21B N -9.448 1.00 47.88 L21B c -9.917 1.00 46.51 L21B c -11.000 1.00 47.18 L21B 0 -9.091 1.00 45.68 L21B N -9.420 1.00 46.39 L21B c -8.177 1.00 45.36 L21B c -8.522 1.00 45.18 L21B c -7.048 1.00 43.58 L21B c -10.489 1.00 46.49 L21B c -10.510 1.00 46.00 L21B 0 -11.382 1.00 47.79 L21B N -12.440 1.00 49.24 L21B c -13.625 1.00 52.12 L21B c -14.443 1.00 60.05 L21B c -13.864 1.00 65.24 L21B c -13.209 1.00 67.90 L21B 0 -14.068 1.00 70.08 . L21B 0 -12.865 1.00 46.11 L21B c -13.419 1.00 47.48 L21B 0 -12.599 1.00 41.78 L21B N 415 WO 2009/026558 PCT/US2008/074097 ATOM 7219 CA THR 164 78.282 37 ATOM 7220 CB THR 164 78.531 37 ATOM 7221 OG1 THR 164 78.699 38 ATOM 7222 CG2 THR 164 79.756 36 ATOM 7223 C THR 164 77.871 36 ATOM 7224 O THR 164 76.696 36 ATOM 7225 N THR 165 78.838 36 ATOM 7226 CA THR 165 78.562 35 ATOM 7227 CB THR 165 79.599 35 ATOM 7228 OG1 THR 165 80.880 35 ATOM 7229 CG2 THR 165 79.709 36 ATOM 7230 C THR 165 78.593 33 ATOM 7231 O THR 165 79.114 33 ATOM 7232 N THR 166 78.036 33 ATOM 7233 CA THR 166 78.243 31 ATOM 7234 CB THR 166 77.106 30 ATOM 7235 OG1 THR 166 77.096 30 ATOM 7236 CG2 THR 166 75.787 31 ATOM 7237 C THR 166 79.537 31 ATOM 7238 O THR 166 79.864 31 ATOM 7239 N PRO 167 80.299 30 ATOM 7240 CD PRO 167 80.022 29 ATOM 7241 CA PRO 167 81.614 29 ATOM 7242 CB PRO 167 82.133 28 ATOM 7243 CG PRO 167 81.376 29 ATOM 7244 C PRO 167 81.473 29 ATOM 7245 O PRO 167 80.425 28 ATOM 7246 N SER 168 82.514 29 ATOM 7247 CA SER 168 82.479 28 ATOM 7248 CB SER 168 81.934 29 ATOM 7249 OG SER 168 82.776 30 ATOM 7250 C SER 168 83.860 28 ATOM 7251 O SER 168 84.858 28 ATOM 7252 N LYS 169 83.907 26 ATOM 7253 CA LYS 169 85.169 26 ATOM 7254 CB LYS 169 84.918 24 ATOM 7255 CG LYS 169 84.830 23 ATOM 7256 CD LYS 169 85.821 22 ATOM 7257 CE LYS 169 86.088 21 ATOM 7258 NZ LYS 169 84.856 20 ATOM 7259 C LYS 169 85.955 27 ATOM 7260 O LYS 169 85.383 27 ATOM 7261 N GLN 170 87.269 27 ATOM 7262 CA GLN 170 88.105 28 ATOM 7263 CB GLN 170 89.262 28 ATOM 7264 CG GLN 170 88.852 29 ATOM 7265 CD GLN 170 90.050 29 ATOM 7266 OE1 GLN 170 90.010 30 ATOM 7267 NE2 GLN 170 91.127 30 ATOM 7268 C GLN 170 88.677 27 ATOM 7269 0 GLN 170 87.997 27 ATOM 7270 N SER 171 89.946 27 ATOM 7271 CA SER 171 90.641 26 ATOM 7272 CB SER 171 91.243 27 ATOM 7273 OG SER 171 90.258 27 ATOM 7274 C SER 171 91.744 25 ATOM 7275 O SER 171 92.026 24 ATOM 7276 N ASN 172 92.361 25 ATOM 7277 CA ASN 172 93.171 25 ATOM 7278 CB ASN 172 93.956 26 ATOM 7279 CG ASN 172 93.058 26 ATOM 7280 OD1 ASN 172 92.050 27 ATOM 7281 ND2 ASN 172 93.426 27 ATOM 7282 C ASN 172 92.230 24 ATOM 7283 0 ASN 172 92.64 6 23 ATOM 7284 N ASN 173 90.946 24 ATOM 7285 CA ASN 173 89.937 23 ATOM 7286 CB ASN 173 90.350 22 ATOM 7287 CG ASN 173 89.203 21 ATOM 7288 OD1 ASN 173 89.023 20 ATOM 7289 ND2 ASN 173 88.407 20 ATOM 7290 C ASN 173 89.646 23 ATOM 7291 O ASN 173 88.868 22 ATOM 7292 N LYS 174 90.268 24 ATOM 7293 CA LYS 174 89.852 25 ATOM 7294 CB LYS 174 91.047 25
-12.730 1.00 38.50 L21B c -11.400 1.00 34.50 L21B c -10.346 1.00 30.64 L21B 0 -11.495 1.00 28.00 L21B c -13.756 1.00 38.26 L21B c -13.868 1.00 39.75 L21B ,0 -14.487 1.00 37.96 L21B N -15.483 1.00 37.83 L21B C -16.618 1.00 34.80 L21B C -16.097 1.00 36.93 L21B O -17.215 1.00 31.26 L21B c -14.866 1.00 37.21 L21B c -13.777 1.00 39.28 L21B 0 -15.565 1.00 36.76 L21B N -15.168 1.00 38.24 L21B C -15.660 1.00 34 . 50 L21B C -17.089 1.00 34 .16 L21B O -15.164 1.00 33.33 L21B C -15.827 1.00 37.53 L21B C -16.932 1.00 36.25 L21B O -15.153 1.00 37.69 L21B N -13.837 1.00 37.82 L21B C -15.668 1.00 41.45 L21B C -14.613 1.00 38.56 L21B C -13.368 1.00 37.09 L21B C -17.029 1.00 42.27 L21B C -17.341 1.00 44.62 L21B O -17.845 1.00 43.91 L21B N -19.123 1.00 49.02 L21B C -20.200 1.00 48.31 L21B C -20.353 1.00 51.04 L21B O -19.517 1.00 52.43 L21B C -19.384 1.00 51.73 L21B O -19.981 1.00 56.92 L21B N -20.283 1.00 61.14 L21B C -20.924 1.00 62.84 L21B C -19.932 1.00 66.49 L21B C -20.294 1.00 70.79 L21B C -19.117 1.00 73.34 L21B C -18.570 1.00 78.76 L21B N -21.235 1.00 62.66 L21B C -22.115 1.00 63.23 L21B O -21.053 1.00 64.67 L21B N -21.828 1.00 65.86 L21B C -20.967 1.00 66.96 L21B C -19.725 1.00 68.32 L21B C -18.995 1.00 69.91 L21B C -17.783 1.00 71.16 L21B O -19.734 1.00 71.33 L21B N -23.097 1.00 66.50 L21B C -24.125 1.00 66.61 L21B O -23.009 1.00 66.58 L21B N -24.081 1.00 67.32 L21B C -25.076 1.00 68.07 L21B C -25.985 1.00 70.61 L21B O -23.466 1.00 66.68 L21B C -23.938 1.00 65.89 L21B O -22.408 1.00 65.46 L21B N -21.517 1.00 63.92 L21B C -20.544 1.00 62.95 L21B C -19.652 1.00 62.55 L21B C -20.100 1.00 62.38 L21B O -18.378 1.00 61.56 L21B N -20.754 1.00 63.74 L21B C -19.916 1.00 63.97 L21B O -21.062 1.00 63.55 L21B N -20.518 1.00 62.96 L21B C -20.725 1.00 63.60 L21B C -20.483 1.00 65.50 L21B C -19.366 1.00 67.22 L21B O -21.525 1.00 65.19 L21B N -19.037 1.00 61.57 L21B C -18.415 1.00 60.70 . L21B O -18.474 1.00 58.80 L21B N -17.173 1.00 57.03 ' L21B C -16.436 1.00 56.43 L21B C 416 WO 2009/026558 PCT/US2008/074097 ATOM 7295 CG LYS 174 92.179 24 ATOM 7296 CD LYS 174 93.293 25 ATOM 7297 CE LYS 174 94.474 24 ATOM 7298 NZ LYS 174 95.762 25 ATOM 7299 C LYS 174 88.739 26 ATOM 7300 0 LYS 174 88.342 26 ATOM 7301 N TYR 175 88.227 26 ATOM 7302 CA TYR 175 87.035 27 ATOM 7303 CB TYR 175 85.965 27 ATOM 7304 CG TYR 175 85.217 25 ATOM 7305 CDl TYR 175 84.034 26 ATOM 7306 CEl TYR 175 83.348 24 ATOM 7307 CD2 TYR 175 85.695 24 ATOM 7308 CE2 TYR 175 85.017 23 ATOM 7309 CZ TYR 175 83.845 23 ATOM 7310 OH TYR 175 83.186 22 ATOM 7311 C TYR 175 87.316 29 ATOM 7312 O TYR 175 88.237 29 ATOM 7313 N ALA 176 86.514 30 ATOM 7314 CA ALA 176 86.626 31 ATOM 7315 CB ALA 176 87.113 32 ATOM 7316 C ALA 176 85.264 31 ATOM 7317 0 ALA 176 84.241 31 ATOM 7318 N ALA 177 85.255 33 ATOM 7319 CA ALA 177 84.012 33 ATOM 7320 CB ALA 177 83.549 33 ATOM 7321 C ALA 177 84.303 35 ATOM 7322 0 ALA 177 85.440 35 ATOM 7323 N SER 178 83.296 36 ATOM 7324 CA SER 178 83.560 37 ATOM 7325 CB SER 178 83.893 38 ATOM 7326 OG SER 178 82.756 38 ATOM 7327 C SER 178 82.376 38 ATOM 7328 0 SER 178 81.254 37 ATOM 7329 N SER 179 82.635 39 ATOM 7330 CA SER 179 81.663 39 ATOM 7331 CB SER 179 81.939 39 ATOM 7332 OG SER 179 81.115 40 ATOM 7333 C SER 179 81.785 41 ATOM 7334 0 SER 179 82.882 42 ATOM 7335 N TYR 180 80.670 42 ATOM 7336 CA TYR 180 80.718 43 ATOM 7337 CB TYR 180 80.079 43 ATOM 7338 CG TYR 180 80.858 43 ATOM 7339 CDl TYR 180 80.891 42 ATOM 7340 CEl TYR 180 81.619 41 ATOM 7341 CD2 TYR 180 81.585 44 ATOM 7342 CE2 TYR 180 82.332 43 ATOM 7343 CZ TYR 180 82.341 42 ATOM 7344 OH TYR 180 83.053 41 ATOM 7345 C TYR 180 80.017 44 ATOM 7346 0 TYR 180 78.879 44 ATOM 7347 N LEU 181 80.701 45 ATOM 7348 CA LEU 181 80.075 46 ATOM 7349 CB LEU 181 80.950 46 ATOM 7350 CG LEU 181 80.622 47 ATOM 7351 CDl LEU 181 79.141 47 ATOM 7352 CD2 LEU 181 81.458 47 ATOM 7353 C LEU 181 79.860 47 ATOM 7354 0 LEU 181 80.823 48 ATOM 7355 N SER 182 78.591 48 ATOM 7356 CA SER 182 78.195 49 ATOM 7357 CB SER 182 76.884 49 ATOM 7358 OG SER 182 77.030 48 ATOM 7359 C SER 182 78.001 50 ATOM 7360 0 SER 182 77.212 50 ATOM 7361 N LEU 183 78.717 51 ATOM 7362 CA LEU 183 78.703 52 ATOM 7363 CB LEU 183 80.101 52 ATOM 7364 CG LEU 183 80.297 51 ATOM 7365 CDl LEU 183 81.726 51 ATOM 7366 CD2 LEU 183 79.335 51 ATOM 7367 C LEU 183 78.291 53 ATOM 7368 0 LEU 183 78.384 53 ATOM 7369 N THR 184 77.836 54 ATOM 7370 CA THR 184 77.936 56 -16.202 1.00 54.88 L21B c -15.389 1.00 55.65 L21B c -15.209 1.00 54.27 L21B c -15.121 1.00 55.04 L21B N -17.352 1.00 56.01 L21B c -18.482 1.00 54.56 L21B .0 -16.245 1.00 54.93 L21B N -16.309 1.00 55.31 L21B c -15.319 1.00 57.78 L21B c -15.760 1.00 60.75 L21B c -16.487 1.00 61.53 L21B c -16.896 1.00 63.42 L21B c -15.452 1.00 60.53 L21B c -15.854 1.00 63.85 L21B c -16.578 1.00 63.99 L21B c -16.995 1.00 64.21 L21B 0 -16.058 1.00 53.03 L21B c -15.323 1.00 53.97 L21B 0 -16.686 1.00 48.30 L21B N -16.486 1.00 43.86 L21B c -17.765 1.00 41.69 L21B c -16.087 1.00 41.19 L21B c -16.310 1.00 40.23 L21B 0 -15.480 1.00 37.62 L21B N -15.198 1.00 3 6.67 L21B c -13.807 1.00 36.19 L21B c -15.312 1.00 36.41 L21B c -15.603 1.00 38.70 L21B 0 -15.096 1.00 33.97 L21B N -14.777 1.00 30.19 L21B c -16.039 1.00 29.61 L21B c -16.878 1.00 31.45 L21B 0 -14.076 1.00 29.28 L21B c -14.138 1.00 28.35 L21B 0 -13.420 1.00 28.18 L21B N -12.551 1.00 28.05 L21B c -11.099 1.00 25.74 L21B c -10.164 1.00 25.59 L21B 0 -12.707 1.00 28.42 L21B c -12.632 1.00 30.29 L21B 0 -12.919 1.00 28.81 L21B N -13.137 1.00 29.20 L21B c -14.493 1.00 25.61 L21B c -15.684 1.00 22.04 L21B c -15.973 1.00 21.54 L21B c -17.041 1.00 24.06 L21B c -16.503 1.00 22.08 L21B c -17.586 1.00 23.42 L21B c -17.849 1.00 25.10 L21B c -18.914 1.00 26.40 L21B 0 -12.017 1.00 29.98 L21B c -11.665 1.00 30.59 L21B 0 -11.445 1.00 31.66 L21B N -10.434 1.00 34.40 L21B c -9.178 1.00 35.91 L21B c -8.118 1.00 37.29 L21B c -7.792 1.00 38.10 L21B c -6.874 1.00 35.95 L21B c -11.007 1.00 35.22 L21B c -11.396 1.00 35.53 L21B 0 -11.072 1.00 34.30 L21B N -11.687 1.00 34.46 L21B c -12.448 1.00 33.20 L21B c -13.568 1.00 36.65 L21B 0 -10.620 1.00 35.64 L21B c .-9.687 1.00 37.03 L21B 0 -10.770 1.00 35.80 L21B N -9.796 1.00 36.71 L21B c -9.193 1.00 32.29 L21B c -8.101 1.00 32.15 L21B c -7.616 1.00 31.53 L21B c -6.969 1.00 30.51 L21B c -10.486 1.00 37.88 • L21B c -11.719 1.00 41.35 L21B 0 -9.708 1.00 37.42 L21B N -10.137 1.00 36.46 L21B c 417 WO 2009/026558 PCT/US2008/074097 ATOM 7371 CB THR 184 77.002 57 ATOM 7372 OG1 THR 184 77.609 57 ATOM 7373 CG2 THR 184 75.644 56 ATOM 7374 C THR 184 79.369 56 ATOM 7375 O THR 184 80.027 55 ATOM 7376 N PRO 185 79.867 57 ATOM 7377 CD PRO 185 79.307 58 ATOM 7378 CA PRO 185 81.209 58 ATOM 7379 CB PRO 185 81.441 59 ATOM 7380 CG PRO 185 80.532 58 ATOM 7381 C PRO 185 81.288 58 ATOM 7382 O PRO 185 82.314 58 ATOM 7383 N GLU 186 80.178 59 ATOM 7384 CA GLU 186 80.127 59 ATOM 7385 CB GLU 186 78.767 60 ATOM 7386 CG GLU 186 78.455 61 ATOM 7387 CD GLU 186 78.399 61 ATOM 7388 OE1 GLU 186 78.031 59 ATOM 7389 OE2 GLU 186 78.727 61 ATOM 7390 C GLU 186 80.360 58 ATOM 7391 0 GLU 186 81.019 58 ATOM 7392 N GLN 187 79.830 57 ATOM 7393 CA GLN 187 79.934 56 ATOM 7394 CB GLN 187 78.681 55 ATOM 7395 CG GLN 187 78.234 55 ATOM 7396 CD GLN 187 76.767 54 ATOM 7397 OE1 GLN 187 76.405 53 ATOM 7398 NE2 GLN 187 75.917 55 ATOM 7399 C GLN 187 81.189 55 ATOM 7400 0 GLN 187 81.622 54 ATOM 7401 N TRP 188 81.782 55 ATOM 7402 CA TRP 188 83.108 55 ATOM 7403 CB TRP 188 83.420 55 ATOM 7404 CG TRP 188 84.880 55 ATOM 7405 CD2 TRP 188 85.750 53 ATOM 7406 CE2 TRP 188 87.038 54 ATOM 7407 CE3 TRP 188 85.569 52 ATOM 7408 CDl TRP 188 85.653 56 ATOM 7409 NEl TRP 188 86.950 55 ATOM 7410 CZ2 TRP 188 88.141 53 ATOM 7411 CZ3 TRP 188 86.676 51 ATOM 7412 CH2 TRP 188 87.940 52 ATOM 7413 C TRP 188 84.135 56 ATOM 7414 O TRP 188 85.096 55 ATOM 7415 N LYS 189 83.926 57 ATOM 7416 CA LYS 189 84.898 58 ATOM 7417 CB LYS 189 84.673 59 ATOM 7418 CG LYS 189 85.073 59 ATOM 7419 CD LYS 189 86.572 59 ATOM 7420 CE LYS 189 86.927 59 ATOM 7421 NZ LYS 189 88.402 59 ATOM 7422 C LYS 189 84.818 58 ATOM 7423 0 LYS 189 85.780 58 ATOM 7424 N SER 190 83.671 57 ATOM 7425 CA SER 190 83.425 58 ATOM 7426 CB SER 190 82.007 58 ATOM 7427 OG SER 190 81.100 57 ATOM 7428 C SER 190 83.658 56 ATOM 7429 O SER 190 83.083 56 ATOM 7430 N HIS 191 84.513 56 ATOM 7431 CA HIS 191 85.104 55 ATOM 7432 CB HIS 191 84.467 53 ATOM 7433 CG HIS 191 83.037 53 ATOM 7434 CD2 HIS 191 81.888 53 ATOM 7435 NDl HIS 191 82.669 53 ATOM 7436 CEl HIS 191 81.356 53 ATOM 7437 NE2 HIS 191 80.859 53 ATOM 7438 C HIS 191 86.623 54 ATOM 7439 0 HIS 191 87.143 55 ATOM 7440 N ARG 192 87.334 54 ATOM 7441 CA ARG 192 88.779 54 ATOM 7442 CB ARG 192 89.364 54 ATOM 7443 CG ARG 192 89.706 55 ATOM 7444 CD ARG 192 91.080 56 ATOM 7445 NE ARG 192 91.236 57 ATOM 7446 CZ ARG 192 92.376 58 -9.338 1.00 34.03 L21B c -8.073 1.00 32.25 L21B 0 -9.121 1.00 27.17 L21B c -9.807 1.00 37.89 L21B c -8.984 1.00 38.09 L21B 0 -10.430 1.00 4 0.32 L21B N -11.603 1.00 38.82 L21B c -10.093 1.00 41.63 L21B c -11.113 1.00 37.99 L21B c -12.234 1.00 38.54 L21B c -8.670 1.00 43.60 L21B c -8.008 1.00 43.46 L21B 0 -8.204 1.00 48.02 L21B N -6.887 1.00 53.68 L21B c -6.677 1.00 58.48 L21B c -7.690 1.00 66.64 L21B c -9.148 1.00 70.44 L21B c -9.384 1.00 72.48 L21B 0 -10.057 1.00 73.54 L21B 0 -5.851 1.00 54.01 L21B c -4.841 1.00 55.79 L21B 0 -6.103 1.00 53.63 L21B N -5.109 1.00 51.43 L21B c -5.131 1.00 50.42 L21B c -6.505 1.00 50.59 L21B c -6.554 1.00 50.84 L21B c -7.251 1.00 50.48 L21B 0 -5.821 1.00 49.29 L21B N -5.298 1.00 50.12 L21B c -4.387 1.00 50.30 L21B 0 -6.479 1.00 47.84 L21B N -6.694 1.00 47.52 L21B c -8.187 1.00 42.90 L21B c -8.485 1.00 39.27 L21B c -8.157 1.00 3 6.97 L21B c -8.621 1.00 35.12 L21B c -7.515 1.00 3 6.62 L21B c -9.116 1.00 37.57 L21B c -9.203 1.00 35.22 L21B N -8.467 1.00 35.08 L21B c -7.360 1.00 37.18 L21B c -7.834 1.00 35.01 L21B c -5.962 1.00 50.19 L21B c -5.366 1.00 51.20 L21B 0 -6.004 1.00 50.84 L21B N -5.442 1.00 52.62 L21B c -5.974 1.00 53.78 L21B c -7.425 1.00 58.09 L21B c -7.626 1.00 61.78 L21B c -9.099 1.00 65.61 L21B c -9.287 1.00 73.62 L21B N -3.927 1.00 52.30 L21B c -3.246 1.00 54.71 L21B 0 -3.393 1.00 49.80 L21B N -1.984 1.00 47.44 L21B c -1.772 1.00 45.86 L21B c -2.455 1.00 46.05 L21B 0 -1.150 1.00 46.24 L21B c -0.081 1.00 46.23 L21B 0 -1.633 1.00 45.30 L21B N -0.762 1.00 45.91 L21B c -1.037 1.00 44.94 L21B c -0.602 1.00 44 .01 L21B c -1.241 1.00 42.43 L21B c 0.661 1.00 44.59 L21B N 0.782 1.00 42.41 L21B c -0.357 1.00 40.13 L21B N -0.926 1.00 46.85 L21B C -2.019 1.00 47.33 L21B 0 0.170 1.00 47.92 L21B N 0.102 1.00 49.29 L21B C 1.496 1.00 53.95 L21B c 2.258 1.00 62.03 . L21B c 1.869 1.00 68.57 L21B c 2.178 1.00 76.88 L21B N 2.059 1.00 80.97 L21B c 418 WO 2009/026558 PCT/US2008/074097 ATOM 7447 NHl ARG 192 92.421 59 ATOM 7448 NH2 ARG 192 93.474 57 ATOM 7449 C ARG 192 89.156 53 ATOM 7450 O ARG 192 90.292 53 ATOM 7451 N SER 193 88.222 52 ATOM 7452 CA SER 193 88.496 51 ATOM 7453 CB SER 193 89.566 50 ATOM 7454 OG SER 193 89.199 50 ATOM 7455 C SER 193 87.243 50 ATOM 7456 O SER 193 86.157 50 ATOM 7457 N TYR 194 87.427 49 ATOM 7458 CA TYR 194 86.377 48 ATOM 7459 CB TYR 194 85.754 48 ATOM 7460 CG TYR 194 84.533 49 ATOM 7461 CD1 TYR 194 83.254 49 ATOM 7462 CEl TYR 194 82.127 50 ATOM 7463 CD2 TYR 194 84.656 51 ATOM 7464 CE2 TYR 194 83.526 52 ATOM 7465 CZ TYR 194 82.259 51 ATOM 7466 OH TYR 194 81.124 52 ATOM 7467 C TYR 194 87.121 47 ATOM 7468 O TYR 194 88.316 47 ATOM 7469 N SER 195 86.457 46 ATOM 7470 CA SER 195 87.182 44 ATOM 7471 CB SER 195 87.685 44 ATOM 7472 OG SER 195 88.132 45 ATOM 7473 C SER 195 86.384 43 ATOM 7474 O SER 195 85.171 43 ATOM 7475 N CYS 196 87.077 42 ATOM 7476 CA CYS 196 86.443 41 ATOM 7477 C CYS 196 86.891 40 ATOM 7478 0 CYS 196 88.093 40 ATOM 7479 CB CYS 196 86.881 41 ATOM 7480 SG CYS 196 85.991 40 ATOM 7481 N GLN 197 85.932 39 ATOM 7482 CA GLN 197 86.259 38 ATOM 7483 CB GLN 197 85.733 38 ATOM 7484 CG GLN 197 86.541 39 ATOM 7485 CD GLN 197 85.947 40 ATOM 7486 OE1 GLN 197 84.738 40 ATOM 7487 NE2 GLN 197 86.806 40 ATOM 7488 C GLN 197 85.688 37 ATOM 7489 0 GLN 197 84.475 37 ATOM 7490 N VAL 198 86.565 36 ATOM 7491 CA VAL 198 86.148 35 ATOM 7492 CB VAL 198 86.892 35 ATOM 7493 CGI VAL 198 86.339 34 ATOM 7494 CG2 VAL 198 86.769 36 ATOM 7495 C VAL 198 86.432 34 ATOM 7496 O VAL 198 87.563 33 ATOM 7497 N THR 199 85.411 33 ATOM 7498 CA THR 199 85.579 32 ATOM 7499 CB THR 199 84.428 31 ATOM 7500 OG1 THR 199 84.438 32 ATOM 7501 CG2 THR 199 84.586 30 ATOM 7502 C THR 199 85.602 31 ATOM 7503 O THR 199 84.915 31 ATOM 7504 N HIS 200 86.395 30 ATOM 7505 CA HIS 200 86.419 28 ATOM 7506 CB HIS 200 87.472 29 ATOM 7507 CG HIS 200 87.659 27 ATOM 7508 CD2 HIS 200 86.973 27 ATOM 7509 ND1 HIS 200 88.656 26 ATOM 7510 CEl HIS 200 88.573 25 ATOM 7511 NE2 HIS 200 87.560 26 ATOM 7512 C HIS 200 86.768 27 ATOM 7513 0 HIS 200 87.756 27 ATOM 7514 N GLU 201 85.961 26 ATOM 7515 CA GLU 201 86.200 25 ATOM 7516 CB GLU 201 87.180 24 ATOM 7517 CG GLU 201 86.891 24 ATOM 7518 CD GLU 201 85.769 23 ATOM 7519 OE1 GLU 201 84.840 23 ATOM 7520 OE2 GLU 201 85.820 22 ATOM 7521 C GLU 201 86.793 25 ATOM 7522 0 GLU 201 87.925 25 2.363 1.00 83.55 L21B N 1.640 1.00 83.12 L21B N -0.800 1.00 46.81 L21B C -1.266 1.00 47.72 L21B O -1.037 1.00 42.98 L21B N -1.907 1.00 41.55 L21B C -1.287 1.00 39.74 L21B C 0.018 1.00 40.91 L21B 0 -2.198 1.00 40.51 L21B c -1.774 1.00 40.73 L21B 0 -2.938 1.00 38.90 L21B N -3.338 1.00 35.74 L21B c -4.667 1.00 32.23 L21B c -4.524 1.00 31.63 L21B c -4.528 1.00 28.78 L21B c -4.415 1.00 29.78 L21B c -4.397 1.00 31.17 L21B c -4.283 1.00 32.51 L21B c -4.297 1.00 33.20 L21B c -4.238 1.00 34.06 L21B 0 -3.531 1.00 36.59 L21B c -3.855 1.00 35.94 L21B 0 -3.339 1.00 36.59 L21B N -3.492 1.00 37.13 L21B c -2.135 1.00 36.06 L21B c -1.307 1.00 34.68 L21B 0 -4.162 1.00 37.41 L21B c -3.986 1.00 37.59 L21B 0 -4.933 1.00 37.65 L21B N -5.528 1.00 38.71 L21B c -4.690 1.00 39.42 L21B c -4.532 1.00 40.53 L21B 0 -6.997 1.00 38.27 L21B c -7.892 1.00 40.80 L21B s -4.122 1.00 39.35 L21B N -3.303 1.00 38.91 L21B c -1.876 1.00 38.51 L21B c -1.078 1.00 42.70 L21B c 0.280 1.00 45.03 L21B c 0.416 1.00 47.31 L21B 0 1.296 1.00 44.75 L21B N -3.924 1.00 38.57 L21B c -3.966 1.00 41.15 L21B 0 -4.411 1.00 37.99 L21B N -5.186 1.00 39.54 L21B c -6.527 1.00 36.74 L21B c -7.404 1.00 36.03 L21B c -7.219 1.00 37.28 L21B c -4.434 1.00 41.58 L21B c -4.429 1.00 43.11 L21B 0 -3.798 1.00 43.26 L21B N -3.133 1.00 45.16 L21B c -2.144 1.00 43.09 L21B c -1.072 1.00 42.60 L21B 0 -1.569 1.00 41.46 L21B c -4.175 1.00 45.66 L21B c -5.184 1.00 47.58 L21B 0 -3.921 1.00 47.28 L21B N -4.770 1.00 49.91 L21B c -5.864 1.00 47.40 L21B c -6.713 1.00 44.66 L21B c -7.791 1.00 43.66 L21B c -6.479 1.00 43.35 L21B N -7.379 1.00 44.39 L21B c -8.186 1.00 43.71 L21B N .-3.892 1.00 52.57 L21B C -3.170 1.00 52.42 L21B 0 -3.942 1.00 57.26 L21B N -3.098 1.00 63.32 L21B C -3.776 1.00 66.42 L21B c -5.239 1.00 75.18 L21B c -5.448 1.00 79.87 L21B c -6.242 1.00 82.95 . L21B 0 -4 .818 1.00 82.36 L21B 0 -1.755 1.00 64.56 L21B c -1.431 1.00 64.47 L21B 0 419 WO 2009/026558 PCT/US2008/074097 ATOM 7523 N GLY 201 86.046 26 ATOM 7524 CA GLY 201 86.506 27 ATOM 7525 C GLY 201 87.527 28 ATOM 7526 0 GLY 201 87.648 28 ATOM 7527 N SER 203 88.249 28 ATOM 7528 CA SER 203 89.361 29 ATOM 7529 CB SER 203 90.540 28 ATOM 7530 OG SER 203 90.239 28 ATOM 7531 C SER 203 89.020 30 ATOM 7532 O SER 203 88.819 30 ATOM 7533 N THR 204 88.999 31 ATOM 7534 CA THR 204 88.670 33 ATOM 7535 CB THR 204 87.967 33 ATOM 7536 OG1 THR 204 86.801 33 ATOM 7537 CG2 THR 204 87.560 35 ATOM 7538 C THR 204 89.890 33 ATOM 7539 O THR 204 90.821 34 ATOM 7540 N VAL 205 89.874 34 ATOM 7541 CA VAL 205 90.932 35 ATOM 7542 CB VAL 205 91.390 34 ATOM 7543 CGI VAL 205 92.575 35 ATOM 7544 CG2 VAL 205 91.724 33 ATOM 7545 C VAL 205 90.420 36 ATOM 7546 O VAL 205 89.401 36 ATOM 7547 N GLU 206 91.139 37 ATOM 7548 CA GLU 206 90.673 38 ATOM 7549 CB GLU 206 90.657 39 ATOM 7550 CG GLU 206 90.759 40 ATOM 7551 CD GLU 206 90.102 41 ATOM 7552 OE1 GLU 206 89.339 40 ATOM 7553 OE2 GLU 206 90.339 42 ATOM 7554 C GLU 206 91.495 39 ATOM 7555 0 GLU 206 92.713 39 ATOM 7556 N LYS 207 90.826 40 ATOM 7557 CA LYS 207 91.519 42 ATOM 7558 CB LYS 207 91.554 41 ATOM 7559 CG LYS 207 92.938 41 ATOM 7560 CD LYS 207 93.639 40 ATOM 7561 CE LYS 207 95.108 40 ATOM 7562 NZ LYS 207 95.307 40 ATOM 7563 C LYS 207 90.827 43 ATOM 7564 0 LYS 207 89.633 43 ATOM 7565 N THR 208 91.584 44 ATOM 7566 CA THR 208 91.081 45 ATOM 7567 CB THR 208 91.437 46 ATOM 7568 OG1 THR 208 90.722 45 ATOM 7569 CG2 THR 208 91.091 47 ATOM 7570 C THR 208 91.655 46 ATOM 7571 O THR 208 92.786 46 ATOM 7572 N VAL 209 90.850 47 ATOM 7573 CA VAL 209 91.288 48 ATOM 7574 CB VAL 209 90.703 48 ATOM 7575 CGI VAL 209 91.166 47 ATOM 7576 CG2 VAL 209 89.182 49 ATOM 7577 C VAL 209 90.794 50 ATOM 7578 0 VAL 209 89.876 50 ATOM 7579 N ALA 210 91.411 51 ATOM 7580 CA ALA 210 91.030 52 ATOM 7581 CB ALA 210 92.036 52 ATOM 7582 C ALA 210 90.918 53 ATOM 7583 0 ALA 210 91.609 53 ATOM 7584 N PRO 211 90.039 54 ATOM 7585 CD PRO 211 89.146 54 ATOM 7586 CA PRO 211 89.878 55 ATOM 7587 CB PRO 211 88.663 56 ATOM 7588 CG PRO 211 88.606 56 ATOM 7589 C PRO 211 91.139 56 ATOM 7590 0 PRO 211 91.237 57 ATOM 7591 N THR 212 92.110 56 ATOM 7592 CA THR 212 93.399 56 ATOM 7593 CB THR 212 94.165 56 ATOM 7594 OG1 THR 212 93.322 56 ATOM 7595 CG2 THR 212 95.445 57 ATOM 7596 C THR 212 94.220 56 ATOM 7597 0 THR 212 95.341 56 ATOM 7598 OXT THR 212 93.725 56 -0.988 1.00 66.07 L21B N 0.333 1.00 67.95 L21B C 0.360 1.00 70.16 L21B C 1.373 1.00 71.89 L21B 0 -0.745 1.00 70.44 L21B N -0.812 1.00 69.03 L21B c -1.571 1.00 69.91 L21B c -2.948 1.00 70.63 L21B 0 -1.450 1.00 66.90 L21B c -2.661 1.00 66.99 L21B 0 -0.636 1.00 64 .21 L21B N -1.108 1.00 61.96 L21B c 0.016 1.00 62.44 L21B c 0.457 1.00 61.41 L21B 0 -0.484 1.00 63.92 L21B c -1.604 1.00 59.78 L21B c -0.847 1.00 57.60 L21B 0 -2.874 1.00 57.57 L21B N -3.410 1.00 56.13 L21B c -4.797 1.00 55.74 L21B c -5.245 1.00 55.66 L21B c -4.768 1.00 56.05 L21B c -3.555 1.00 55.70 L21B c -4.202 1.00 57.15 L21B 0 -2.973 1.00 53.18 L21B N -2.912 1.00 50.02 L21B c -1.459 1.00 50.29 L21B c -1.272 1.00 51.53 L21B c 0.009 1.00 52.70 L21B c 0.577 1.00 54.78 L21B 0 0.447 1.00 54.12 L21B 0 -3.743 1.00 48.36 L21B c -3.853 1.00 49.43 L21B 0 -4.325 1.00 46.01 L21B N -5.033 1.00 43.18 L21B c -6.529 1.00 40.80 L21B c -7.081 1.00 37.52 L21B c -6.382 1.00 39.09 L21B c -6.775 1.00 39.83 L21B c -8.260 1.00 39.68 L21B N -4.782 1.00 43.89 L21B c -4.487 1.00 45.18 L21B 0 -4.890 1.00 4 3.72 L21B N -4.527 1.00 43.45 L21B c -3.071 1.00 43.01 L21B c -2.199 1.00 43.45 L21B 0 -2.737 1.00 43.14 L21B c -5.437 1.00 45.05 L21B c -5.903 1.00 4 3.07 L21B 0 -5.696 1.00 47.06 L21B N -6.448 1.00 49.42 L21B c -7.853 1.00 50.14 L21B c -8.573 1.00 47.79 L21B c -7.779 1.00 51.93 L21B c -5.719 1.00 52.56 L21B c -4.906 1.00 51.78 L21B 0 -5.997 1.00 57.14 L21B N -5.343 1.00 60.45 L21B c -4.256 1.00 57.24 L21B c -6.331 1.00 64.66 L21B c -7.352 1.00 61.92 L21B 0 -6.033 1.00 70.80 L21B N -4.868 1.00 73.04 L21B c -6.898 1.00 76.06 L21B c -6.316 1.00 75.09 L21B c -4.918 1.00 75.55 L21B c -6.872 1.00 80.46 L21B c -7.560 1.00 79.95 L21B 0 -6.078 1.00 85.46 L21B N -6.031 1.00 91.28 L21B c -4.734 1.00 93.31 L21B c -3.602 1.00 94.30 L21B 0 -4.596 1.00 94.22 . L21B c -7.260 1.00 92.75 L21B c -7.083 1.00 96.55 L21B 0 -8.390 1.00 95.26 L21B 0 420 WO 2009/026558 PCT/US2008/074097 TER 7599 THR 212 ATOM 7600 CB GLU 1 55.064 6 ATOM 7601 CG GLU 1 55.535 7 ATOM 7602 CD GLU 1 56.988 7 ATOM 7603 OE1 GLU 1 57.708 7 ATOM 7604 OE2 GLU 1 57.407 8 ATOM 7605 C GLU 1 53.453 8 ATOM 7606 0 GLU 1 53.014 9 ATOM 7607 N GLU 1 52.655 6 ATOM 7608 CA GLU 1 53.623 6 ATOM 7609 N VAL 2 53.807 8 ATOM 7610 CA VAL 2 53.524 9 ATOM 7611 CB VAL 2 53.746 10 ATOM 7612 CGI VAL 2 53.593 11 ATOM 7613 CG2 VAL 2 52.763 9 ATOM 7614 C VAL 2 54.417 11 ATOM 7615 O VAL 2 55.621 10 ATOM 7616 N GLN 3 53.806 11 ATOM 7617 CA GLN 3 54.511 12 ATOM 7618 CB GLN 3 54.405 12 ATOM 7619 CG GLN 3 55.250 12 ATOM 7620 CD GLN 3 55.179 11 ATOM 7 621 OE1 GLN 3 55.033 12 ATOM 7622 NE2 GLN 3 55.277 10 ATOM 7623 C GLN 3 53.894 14 ATOM 7624 0 GLN 3 52.7 62 14 ATOM 7 62 5 N LEU 4 54.644 15 ATOM 7 62 6 CA LEU 4 54.177 16 ATOM 7627 CB LEU 4 54.485 17 ATOM 7 62 8 CG LEU 4 53.635 16 ATOM 7 62 9 CDl LEU 4 54.188 16 ATOM 7630 CD2 LEU 4 52.213 17 ATOM 7631 C LEU 4 54.858 17 ATOM 7632 O LEU 4 56.076 17 ATOM 7633 N VAL 5 54.075 18 ATOM 7634 CA VAL 5 54.585 18 ATOM 7635 CB VAL 5 54.087 18 ATOM 7636 CGI VAL 5 54.545 18 ATOM 7637 CG2 VAL 5 54.604 16 ATOM 7638 C VAL 5 54.212 20 ATOM 7639 O VAL 5 53.066 20 ATOM 7640 N GLN 6 55.193 21 ATOM 7641 CA GLN 6 54.936 22 ATOM 7642 CB GLN 6 55.978 23 ATOM 7643 CG GLN 6 56.117 22 ATOM 7644 CD GLN 6 57.118 23 ATOM 7645 OE1 GLN 6 57.615 22 ATOM 7646 NE2 GLN 6 57.419 24 ATOM 7647 C GLN 6 54.900 23 ATOM 7648 0 GLN 6 55.484 22 ATOM 7649 N SER 7 54.205 24 ATOM 7650 CA SER 7 54.059 25 ATOM 7651 CB SER 7 53.273 26 ATOM 7652 OG SER 7 53.846 27 ATOM 7653 C SER 7 55.413 25 ATOM 7654 O SER 7 56.456 25 ATOM 7655 N GLY 8 55.390 26 ATOM 7656 CA GLY 8 56.628 26 ATOM 7657 C GLY 8 57.347 27 ATOM 7658 0 GLY 8 56.899 28 ATOM 7659 N ALA 9 58.481 28 ATOM 7660 CA ALA 9 59.244 29 ATOM 7661 CB ALA 9 60.687 29 ATOM 7662 C ALA 9 58.633 30 ATOM 7663 0 ALA 9 58.185 30 ATOM 7664 N GLU 10 58.612 31 ATOM 7665 CA GLU 10 57.969 33 ATOM 7666 CB GLU 10 56.567 33 ATOM 7667 CG GLU 10 55.579 32 ATOM 7668 CD GLU 10 54.401 31 ATOM 7669 OE1 GLU 10 54.359 32 ATOM 7670 OE2 GLU 10 53.522 31 ATOM 7671 C GLU 10 58.779 34 ATOM 7672 0 GLU 10 59.532 34 ATOM 7673 N VAL 11 58.614 35 ATOM 7674 CA VAL 11 59.360 36 -21.347 1.00 73.12 L21B H21B c -22.516 1.00 78.67 H21B c -22.365 1.00 81.81 H21B c -21.575 1.00 83.96 H21B 0 -23.024 1.00 83.08 H21B .0. -20.546 1.00 66.92 H21B c -21.373 1.00 64.83 H21B 0 -21.940 1.00 69.73 H21B N -20.892 1.00 69.78 H21B c -19.313 1.00 63.58 H21B N -18.788 1.00 61.52 H21B C -17.280 1.00 63.16 H21B c -16.815 1.00 63.16 H21B c -16.571 1.00 63.55 H21B c -19.429 1.00 59.20 H21B c -19.259 1.00 57.87 H21B 0 -20.142 1.00 58.46 H21B N -21. 111 1.00 57.91 H21B c -22.477 1.00 59.52 H21B c -23.581 1.00 64.49 H21B c -24.857 1.00 66.57 H21B c -25.963 1.00 67.65 H21B 0 -24.709 1.00 66.83 H21B N -21.146 1.00 57.21 H21B c -21.599 1.00 57.22 H21B 0 -20.659 1.00 55.99 H21B N -20.595 1.00 54.53 H21B c -19.224 1.00 52.38 H21B c -18.091 1.00 50.58 H21B c -16.749 1.00 49.08 H21B c -18.278 1.00 51.49 H21B c -21.661 1.00 55.60 H21B c -21.806 1.00 56.73 H21B 0 -22.401 1.00 56.76 H21B N -23.582 1.00 59.30 H21B c -24.883 1.00 57.84 H21B c -26.102 1.00 57.36 H21B c -24.959 1.00 54.25 H21B c -23.642 1.00 62.11 H21B c -23.925 1.00 60.98 H21B 0 -23.406 1.00 66.23 H21B N -23.271 1.00 72.12 H21B c -22.340 1.00 71.68 H21B c -21.013 1.00 74.65 H21B c -20.085 1.00 76.41 H21B c -19.148 1.00 76.12 H21B 0 -20.342 1.00 83.40 H21B N -24.600 1.00 75.46 H21B c -25.593 1.00 76.72 H21B 0 -24.603 1.00 79.41 H21B N -25.795 1.00 81.97 H21B c -25.468 1.00 81.36 H21B c -24.380 1.00 76.16 H21B 0 -26.365 1.00 85.28 H21B c -25.817 1.00 86.88 H21B 0 -27.472 1.00 88.03 H21B N -28.098 1.00 91.52 H21B c -27.373 1.00 93.23 H21B c -26.338 1.00 91.33 H21B 0 -27.925 1.00 97.66 H21B N -27.350 1.00101.03 H21B c -27.793 1.00105.95 H21B c -27.791 1.00101.99 H21B c -28.930 1.00101.78 H21B 0 -26.874 1.00101.94 H21B N -27.124 1.00102.88 H21B c -26.505 1.00106.55 H2 1B c -27.275 1.00112.96 H21B c -26.439 1.00116.32 H21B c -25.253 1.00119.31 H21B 0 -26.963 1.00119.07 H21B 0 -26.607 1.00100.78 H21B c -25.637 1.00 99.72 H21B 0 -27.274 1.00 97.98 H21B N -26.964 1.00 94.70 H21B c 421 WO 2009/026558 PCT/US2008/074097 ATOM 7675 CB VAL 11 60.409 36 ATOM 7 67 6 CGI VAL 11 61.190 38 ATOM 7677 CG2 VAL 11 61.355 35 ATOM 7678 C VAL 11 58.456 37 ATOM 7679 O VAL 11 57.662 38 ATOM 7680 N LYS 12 58.596 38 ATOM 7681 CA LYS 12 57.657 39 ATOM 7682 CB LYS 12 56.660 38 ATOM 7683 CG LYS 12 55.735 37 ATOM 7684 CD LYS 12 54.466 38 ATOM 7685 CE LYS 12 53.732 37 ATOM 7686 NZ LYS 12 52.793 38 ATOM 7687 C LYS 12 58.358 40 ATOM 7688 0 LYS 12 59.426 40 ATOM 7689 N LYS 13 57.744 41 ATOM 7690 CA LYS 13 58.303 43 ATOM 7691 CB LYS 13 57.899 44 ATOM 7692 CG LYS 13 58.547 44 ATOM 7693 CD LYS 13 58.100 45 ATOM 7694 CE LYS 13 58.853 45 ATOM 7695 NZ LYS 13 58.325 46 ATOM 7696 C LYS 13 57.778 43 ATOM 7697 0 LYS 13 56.745 42 ATOM 7698 N PRO 14 58.480 44 ATOM 7699 CD PRO 14 59.782 44 ATOM 7700 CA PRO 14 57.962 44 ATOM 7701 CB PRO 14 58.893 45 ATOM 7702 CG PRO 14 60.177 45 ATOM 7703 C PRO 14 56.506 45 ATOM 7704 O PRO 14 56.044 45 ATOM 7705 N GLY 15 55.781 44 ATOM 7706 CA GLY 15 54.388 45 ATOM 7707 C GLY 15 53.404 44 ATOM 7708 0 GLY 15 52.208 44 ATOM 7709 N ALA 16 53.892 43 ATOM 7710 CA ALA 16 53.016 42 ATOM 7711 CB ALA 16 53.634 42 ATOM 7712 C ALA 16 52.686 41 ATOM 7713 0 ALA 16 52.973 41 ATOM 7714 N SER 17 52.079 40 ATOM 7715 CA SER 17 51.619 38 ATOM 7716 CB SER 17 50.116 39 ATOM 7717 OG SER 17 49.819 40 ATOM 7718 C SER 17 51.942 37 ATOM 7719 O SER 17 51.745 37 ATOM 7720 N VAL 18 52.440 36 ATOM 7721 CA VAL 18 52.538 35 ATOM 7722 CB VAL 18 53.959 34 ATOM 7723 CGI VAL 18 54.718 35 ATOM 7724 CG2 VAL 18 54.693 35 ATOM 7725 C VAL 18 51.615 34 ATOM 7726 O VAL 18 51.310 34 ATOM 7727 N LYS 19 51.190 33 ATOM 7728 CA LYS 19 50.429 32 ATOM 7729 CB LYS 19 48.989 32 ATOM 7730 CG LYS 19 48.025 31 ATOM 7731 CD LYS 19 46.632 31 ATOM 7732 CE LYS 19 45.643 30 ATOM 7733 NZ LYS 19 44.243 30 ATOM 7734 C LYS 19 51.130 31 ATOM 7735 0 LYS 19 51.354 30 ATOM 7736 N VAL 20 51.471 30 ATOM 7737 CA VAL 20 52.219 28 ATOM 7738 CB VAL 20 53.465 28 ATOM 7739 CGI VAL 20 54.133 27 ATOM 7740 CG2 VAL 20 54.454 29 ATOM 7741 C VAL 20 51.361 27 ATOM 7742 O VAL 20 50.687 27 ATOM 7743 N SER 21 51.405 26 ATOM 7744 CA SER 21 50.636 25 ATOM 7745 CB SER 21 50.209 25 ATOM 7746 OG SER 21 49.534 26 ATOM 7747 C SER 21 51.426 24 ATOM 7748 O SER 21 52.644 24 ATOM 7749 N CYS 22 50.714 23 ATOM 7750 CA CYS 22 51.288 22 -28. ,061 1. , 00 94 , .26 H21B c -27 , .722 1. , 00 94 , .82 H21B c -2 8 . , 192 1. . 00 93, .77 H21B c -26, .799 1. , 00 90. ,98 H21B c -27 , . 678 1. , 00 90. ,99 H21B 0 -25 , .669 1. , 00 86, .92 H21B N -25 , .256 1. , 00 82 , .85 H21B c -24 , .225 1. , 00 83 , .38 H21B c -24 .752 1. , 00 83 , .33 H21B c -25 , .388 1. , 00 84 , .59 H21B c -26, .250 1. , 00 85 , .71 H21B c -27 , .2 02 1. , 00 88 , .33 H21B N -24 .668 1, . 00 79, .74 H21B c -24 , . 070 1. , 00 79, .34 H21B 0 -24 .850 1. , 00 76, . 15 H21B N -24 .367 1. , 00 73. . 12 H21B c -25 .282 1, . 00 72 .80 H21B c -26, . 64 4 1, . 00 72 , .33 H21B c -27 , .465 0 , . 50 75, . 00 H21B c -28 , .778 1, . 00 76, .22 H21B c -29, . 614 1, . 00 79, . 14 H21B N -22 , . 975 1, . 00 69, . 85 H21B c -22 , .589 1, . 00 70 , . 18 H21B 0 -22 , .201 1. . 00 66, .74 H21B N -22 .443 1, . 00 64. .63 H21B c -20 , . 867 1, . 00 65, .80 H21B c -2 0 , .372 1, . 00 63, .65 H21B c -21, . 067 1, . 00 63, .20 H21B c -20 , .935 1, . 00 64 .83 H21B c -21, . 975 1, . 00 65, . 82 H21B 0 -19, .836 1, . 00 63, .25 H21B N -19, .789 1, . 00 60, .95 H21B c -2 0 , .443 1, . 00 60, . 18 H21B c -20 , . 176 1, . 00 60, . 15 H21B 0 -21. ,293 1, . 00 58 , .86 H21B N -22 . 013 1, . 00 57 , . 51 H21B c -2 3, .352 1, . 00 56, . 81 H21B c -21, .234 1, . 00 56 . 45 H21B c -20, . 034 1, . 00 54 , .45 H21B 0 -21. , 944 1, . 00 55 , .06 H21B N -21. , 355 1, . 00 54 , . 13 H21B c -21, .119 1, . 00 52 .63 H21B c -20 , . 184 1, . 00 52 .89 H21B 0 -22 . 186 1, . 00 54 , . 17 H21B c -23, .401 1, . 00 54 .06 H21B 0 -21. , 522 1, . 00 54 , .75 H21B N -22 , . 122 1, . 00 55 .21 H21B c -22 , . 042 1, . 00 54 .56 H21B c -23 .313 1, . 00 55 .71 H21B c -20 , . 836 1, . 00 53 . 13 H21B c -21, . 477 1, . 00 54 .61 H21B c -20 , .288 1, . 00 52 .93 H21B 0 -22 .2 92 1, . 00 55 .58 H21B N -21. , 834 1, . 00 56 .30 H21B c -22 .368 1, . 00 57 .21 H21B c -21, .704 1, . 00 59 .70 H21B c -22 .314 1, . 00 64 . 05 H21B c -21, . 438 1, . 00 67 .96 H21B c -21, . 843 1, . 00 77 .89 H21B N -22 .354 1, . 00 55 . 43 H21B c -23, . 555 1, .00 56 .86 H21B 0 -21, .439 1, . 00 53 . 48 H21B N -21, .745 1, . 00 51, .91 H21B c -20 .822 1, . 00 52 .28 H21B c -20 .967 1, . 00 51, . 32 H21B c -21, .164 1, . 00 49 . 80 H21B c -21 .571 1, . 00 51, .11 H21B c -2 0 .554 1, . 00 50 .92 H21B 0 -22 .557 1, . 00 49 . 84 H21B N -22 .538 1, . 00 49 . 48 H21B c -23 . 954 1, . 00 47 . 62 H21B c -24 .630 1, . 00 45 .69 H21B 0 -21, .961 1, . 00 51, . 01 . H21B c -22 . 061 1, . 00 53 . 07 H21B 0 -21, . 388 1, . 00 52 .61 ' H21B N -20 . 914 1, . 00 53 . 01 H21B c 422 WO 2009/026558 PCT/US2008/074097 ATOM 7751 c CYS 22 50.295 20 ATOM 7752 0 CYS 22 49.179 20 ATOM 7753 CB CYS 22 51.486 22 ATOM 7754 SG CYS 22 52.311 20 ATOM 7755 N LYS 23 50.689 20 ATOM 7756 CA LYS 23 49.755 19 ATOM 7757 CB LYS 23 49.727 18 ATOM 7758 CG LYS 23 48.465 19 ATOM 7759 CD LYS 23 47.553 18 ATOM 7760 CE LYS 23 48.115 17 ATOM 7761 NZ LYS 23 47.296 16 ATOM 7762 C LYS 23 50.155 17 ATOM 7763 0 LYS 23 51.310 17 ATOM 7764 N ALA 24 49.194 16 ATOM 7765 CA ALA 24 49.479 15 ATOM 7766 CB ALA 24 48.990 15 ATOM 7767 C ALA 24 48.871 14 ATOM 7768 0 ALA 24 47.842 14 ATOM 7769 N SER 25 49.523 13 ATOM 7770 CA SER 25 49.035 12 ATOM 7771 CB SER 25 49.605 11 ATOM 7772 OG SER 25 50.986 11 ATOM 7773 C SER 25 49.511 11 ATOM 7774 O SER 25 50.546 11 ATOM 7775 N GLY 26 48.754 9 ATOM 7776 CA GLY 26 49.281 8 ATOM 7777 C GLY 26 49.093 8 ATOM 7778 0 GLY 26 49.749 7 ATOM 7779 N TYR 27 48.203 9 ATOM 7780 CA TYR 27 47.809 9 ATOM 7781 CB TYR 27 48.888 9 ATOM 7782 CG TYR 27 48.984 11 ATOM 7783 CDl TYR 27 49.651 11 ATOM 7784 CEl TYR 27 49.720 13 ATOM 7785 CD2 TYR 27 48.392 11 ATOM 7786 CE2 TYR 27 48.455 13 ATOM 7787 CZ TYR 27 49.118 13 ATOM 7788 OH TYR 27 49.157 15 ATOM 7789 C TYR 27 46.495 9 ATOM 7790 O TYR 27 46.059 10 ATOM 7791 N THR 28 45.865 9 ATOM 7792 CA THR 28 44.567 10 ATOM 7793 CB THR 28 43.865 9 ATOM 7794 OG1 THR 28 43.650 7 ATOM 7795 CG2 THR 28 42.531 9 ATOM 7796 C THR 28 44.731 11 ATOM 7797 O THR 28 45.152 11 ATOM 7798 N LEU 29 44.369 12 ATOM 7799 CA LEU 29 44.654 13 ATOM 7800 CB LEU 29 44.044 14 ATOM 7801 CG LEU 29 44.477 14 ATOM 7802 CDl LEU 29 43.533 15 ATOM 7803 CD2 LEU 29 45.909 14 ATOM 7804 C LEU 29 44.112 14 ATOM 7805 O LEU 29 44.683 15 ATOM 7806 N THR 30 43.004 13 ATOM 7807 CA THR 30 42.347 14 ATOM 7808 CB THR 30 40.859 13 ATOM 7809 OG1 THR 30 40.722 12 ATOM 7810 CG2 THR 30 40.133 14 ATOM 7811 C THR 30 43.046 13 ATOM 7812 O THR 30 42.609 13 ATOM 7813 N SER 31 44.160 12 ATOM 7814 CA SER 31 44.955 12 ATOM 7815 CB SER 31 45.561 10 ATOM 7816 OG SER 31 44.999 9 ATOM 7817 C SER 31 46.063 13 ATOM 7818 O SER 31 46.625 12 ATOM 7819 N TYR 32 46.375 14 ATOM 7820 CA TYR 32 47.539 14 ATOM 7821 CB TYR 32 48.660 14 ATOM 7822 CG TYR 32 49.372 13 ATOM 7823 CDl TYR 32 49.287 12 ATOM 7824 CEl TYR 32 49.872 11 ATOM 7825 CD2 TYR 32 50.075 13 ATOM 7826 CE2 TYR 32 50.664 12 -21.235 1.00 54.06 H21B c -20.726 1.00 53.18 H21B 0 -19.402 1.00 52.59 H21B c -18.625 1.00 50.07 H21B s -22.069 1.00 56.00 H21B N -22.496 1.00 58.44 H21B c. -24.020 1.00 59.90 H21B c -24.661 1.00 63.71 H21B c -25.077 1.00 71.14 H21B c -26.270 1.00 75.82 H21B c -26.613 1.00 81.04 H21B N -21.911 1.00 58.80 H21B c -22.004 1.00 59.77 H21B 0 -21.312 1.00 59.37 H21B N -20.637 1.00 60.19 H21B c -19.204 1.00 61.61 H21B c -21.342 1.00 60.44 H21B c -22.013 1.00 61.03 H21B 0 -21.180 1.00 59.33 H21B N -21.759 1.00 57.93 H21B c -23.154 1.00 56.24 H21B c -23.076 1.00 52.37 H21B 0 -20.879 1.00 59.09 H21B c -20.221 1.00 60.76 H21B 0 -20.862 1.00 57.10 H21B N -20.341 1.00 54.77 H21B c -18.853 1.00 52.65 H21B c -18.240 1.00 51.57 H21B 0 -18.264 1.00 50.72 H21B N -16.883 1.00 4 9.62 H21B c -15.934 1.00 48.68 H21B c -15.900 1.00 48.27 H21B c -16.898 1.00 48.25 H21B c -16.875 1.00 47.93 H21B c -14.878 1.00 4 6.65 H21B c -14.852 1.00 46.51 H21B c -15.850 1.00 46.31 H21B c -15.823 1.00 45.63 H21B 0 -16.661 1.00 49.46 H21B c -17.509 1.00 50.28 H21B 0 -15.523 1.00 49.35 H21B N -15.186 1.00 47.73 H21B c -14.114 1.00 47.99 H21B c -14.603 1.00 45.83 H21B 0 -13.753 1.00 46.00 H21B c -14.647 1.00 47.40 H21B c -13.509 1.00 46.65 H21B 0 -15.470 1.00 48.24 H21B N -15.203 1.00 48.79 H21B c -16.310 1.00 51.03 H21B c -17.750 1.00 51.75 H21B c -18.741 1.00 51.69 H21B c -17.940 1.00 54.49 H21B c -13.856 1.00 47.85 H21B c -13.214 1.00 46.44 H21B 0 -13.435 1.00 48.64 H21B N -12.219 1.00 50.74 H21B c -12.211 1.00 49.03 H21B c -12.389 1.00 50.94 H21B 0 -13.317 1.00 47.98 H21B c -11.027 1.00 50.98 H21B c -9.889 1.00 50.89 H21B 0 -11.305 1.00 53.19 H21B N -10.263 1.00 55.07 H21B c -10.764 1.00 56.35 H21B c -10.045 1.00 56.82 H21B 0 -9.751 1.00 55.17 H21B c -8.692 1.00 53.88 H2li 0 -10.493 1.00 55.54 H21B N -10.144 1.00 55.48 H21B c -11.095 1.00 60.47 H21B c -10.654 1.00 64.82 H21B c -11.386 1.00 67.41 • H21B c -10.943 1.00 69.47 H21B c -9.465 1.00 66.41 ' H21B c -9.020 1.00 68.99 H21B c 423 WO 2009/026558 PCT/US2008/074097 ATOM 7827 cz TYR 32 50.561 11 ATOM 7828 OH TYR 32 51.172 9 ATOM 7829 C TYR 32 47.440 16 ATOM 7830 O TYR 32 47.609 16 ATOM 7831 N GLY 33 47.201 17 ATOM 7832 CA GLY 33 47.374 18 ATOM 7833 C GLY 33 48.767 19 ATOM 7834 0 GLY 33 49.703 18 ATOM 7835 N ILE 34 48.933 20 ATOM 7836 CA ILE 34 50.162 20 ATOM 7837 CB ILE 34 49.857 21 ATOM 7838 CG2 ILE 34 51.147 21 ATOM 7839 CGI ILE 34 49.265 20 ATOM 7840 CD1 ILE 34 50.188 19 ATOM 7841 C ILE 34 50.946 21 ATOM 7842 0 ILE 34 50.397 22 ATOM 7843 N SER 35 52.205 21 ATOM 7844 CA SER 35 53.030 22 ATOM 7845 CB SER 35 54.135 22 ATOM 7846 OG SER 35 53.665 21 ATOM 7847 C SER 35 53.660 23 ATOM 7848 O SER 35 53.982 22 ATOM 7849 N TRP 36 53.810 24 ATOM 7850 CA TRP 36 54.652 25 ATOM 7851 CB TRP 36 53.929 26 ATOM 7852 CG TRP 36 52.810 26 ATOM 7853 CD2 TRP 36 52.851 26 ATOM 7854 CE2 TRP 36 51.585 25 ATOM 7855 CE3 TRP 36 53.836 26 ATOM 7856 CD1 TRP 36 51.565 26 ATOM 7857 NEl TRP 36 50.817 25 ATOM 7858 CZ2 TRP 36 51.277 25 ATOM 7859 CZ3 TRP 36 53.543 26 ATOM 7860 CH2 TRP 36 52.266 25 ATOM 7861 C TRP 36 55.935 25 ATOM 7862 O TRP 36 55.868 26 ATOM 7863 N VAL 37 57.085 25 ATOM 7864 CA VAL 37 58.381 26 ATOM 7865 CB VAL 37 59.361 24 ATOM 7866 CGI VAL 37 60.629 25 ATOM 7867 CG2 VAL 37 58.711 23 ATOM 7868 C VAL 37 58.958 27 ATOM 7869 O VAL 37 58.892 26 ATOM 7870 N ARG 38 59.511 28 ATOM 7871 CA ARG 38 60.403 28 ATOM 7872 CB ARG 38 59.987 30 ATOM 7873 CG ARG 38 59.939 31 ATOM 7874 CD ARG 38 60.930 32 ATOM 7875 NE ARG 38 60.691 33 ATOM 7876 CZ ARG 38 60.035 34 ATOM 7877 NHl ARG 38 59.550 34 ATOM 7878 NH2 ARG 38 59.861 34 ATOM 7879 C ARG 38 61.835 28 ATOM 7880 O ARG 38 62.080 28 ATOM 7881 N GLN 39 62.773 28 ATOM 7882 CA GLN 39 64 .213 29 ATOM 7883 CB GLN 39 64.818 27 ATOM 7884 CG GLN 39 66.312 27 ATOM 7885 CD GLN 39 66.784 26 ATOM 7886 OE1 GLN 39 66.623 25 ATOM 7887 NE2 GLN 39 67.349 25 ATOM 7888 C GLN 39 64.898 30 ATOM 7889 0 GLN 39 65.002 29 ATOM 7890 N ALA 40 65.354 31 ATOM 7891 CA ALA 40 66.033 32 ATOM 7892 CB ALA 40 66.068 33 ATOM 7893 C ALA 40 67.449 31 ATOM 7894 0 ALA 40 68.057 31 ATOM 7895 N PRO 41 68.008 32 ATOM 7896 CD PRO 41 67.494 33 ATOM 7897 CA PRO 41 69.325 31 ATOM 7898 CB PRO 41 69.695 32 ATOM 7899 CG PRO 41 68.385 33 ATOM 7900 C PRO 41 70.356 31 ATOM 7901 O PRO 41 70.466 32 ATOM 7902 N GLY 42 71.092 30
-9.761 1.00 70.12 H21B c -9.328 1.00 72.42 H21B 0 -10. Oil 1.00 53.36 H21B c -8.907 1.00 53.86 H21B 0 -11.123 1.00 50.34 H21B N -11.157 1.00 46.78 H21B c -11.621 1.00 44.17 H21B c -11.676 1.00 45.33 H21B 0 -11.936 1.00 38.23 H21B N -12.580 1.00 34.77 H21B c -13.943 1.00 32.05 H21B c -14.562 1.00 33.10 H21B c -14.838 1.00 32.22 H21B c -15.056 1.00 32.13 H21B c -11.623 1.00 32.84 H21B c -11.165 1.00 32.86 H21B 0 -11.280 1.00 30.04 H21B N -10.782 1.00 28.79 H21B c -9.875 1.00 30.88 H21B c -8.608 1.00 33.45 H21B 0 -11.940 1.00 29.43 H21B c -12.991 1.00 27.88 H21B 0 -11.739 1.00 32.51 H21B N -12.620 1.00 33.33 H21B c -13.099 1.00 30.43 H21B c -13.964 1.00 27.81 H21B c -15.378 1.00 25.61 H21B c -15.765 1.00 25.73 H21B c -16.346 1.00 24.81 H21B c -13.563 1.00 25.80 H21B c -14.636 1.00 25.45 H21B N -17.077 1.00 26.10 H21B c -17.636 1.00 28.16 H21B c -18.002 1.00 31.41 H21B c -11.890 1.00 34.86 H21B c -10.769 1.00 34.06 H21B 0 -12.510 1.00 35.54 H21B N -12.061 1.00 39.02 H21B c -11.867 1.00 39.94 H21B c -11.198 1.00 40.01 H21B c -11.077 1.00 41.21 H21B c -13. 111 1.00 40.36 H21B c -14.306 1.00 38.98 H21B 0 -12.674 1.00 42.91 H21B N -13.548 1.00 43.59 H21B c -13.614 1.00 43.48 H21B c -12.277 1.00 47.20 H21B c -12.199 1.00 51.45 H21B c -11.037 1.00 57.33 H21B N -11.083 1.00 60.44 H21B c -12.236 1.00 61.49 H21B N -9.974 1.00 62.75 H21B N -13.061 1.00 43.70 H21B C -11.868 1.00 42.17 H21B 0 -14.001 1.00 44.87 H21B N -13.709 1.00 45.12 H21B C -13.955 1.00 41.61 H21B c -13.851 1.00 38.69 H21B c -14.143 1.00 38.75 H21B c -15.267 1.00 38.09 H21B 0 -13.131 1.00 34.80 H21B N -14.607 1.00 46.70 H21B c -15.813 1.00 48.11 H21B 0 -14.032 1.00 48.34 H21B N -14.821 1.00 50.36 H21B c -14.048 1.00 48.17 H21B c -15.175 1.00 51.42 H21B c -14.469 1.00 51.99 H21B 0 -16.260 1.00 53.51 H21B N -17.055 1.00 53.56 H21B c -16.732 1.00 54.44 H21B c -17.811 1.00 53.16 H21B c -18.267 1.00 54.68 . H21B c -15.607 1.00 54.76 H21B c -14.833 1.00 54.35 H21B 0 -15.517 1.00 54.62 H21B N 424 WO 2009/026558 PCT/US2008/074097 ATOM 7903 CA GLY 42 72.067 30.602 -14.458 1.00 55.36 H21B c ATOM 7904 C GLY 42 71.510 30.605 -13.039 1.00 57.03 H21B c ATOM 7905 0 GLY 42 72.285 30.695 -12.087 1.00 57.54 H21B 0 ATOM 7906 N GLN 43 70.190 30.499 -12.882 1.00 57.38 H21B N ATOM 7907 CA GLN 43 69.556 30.603 -11.564 1.00 57.89 H21B c ATOM 7908 CB GLN 43 68.480 31.688 -11.585 1.00 62.24 H21B c ATOM 7909 CG GLN 43 69.024 33.096 -11.723 1.00 70.32 H21B c ATOM 7910 CD GLN 43 69.786 33.529 -10.490 1.00 74.85 H21B c ATOM 7911 OE1 GLN 43 71.014 33.621 -10.506 1.00 78.51 H21B 0 ATOM 7912 NE2 GLN 43 69.059 33.790 -9.404 1.00 79.48 H21B N ATOM 7913 C GLN 43 68.935 29.301 -11.058 1.00 55.77 H21B c ATOM 7914 0 GLN 43 68.991 28.269 -11.725 1.00 54.47 H21B 0 ATOM 7915 N GLY 44 68.333 29.358 -9.873 1.00 53.17 H21B N ATOM 7916 CA GLY 44 67.761 28.153 -9.291 1.00 51.51 H21B c ATOM 7917 C GLY 44 66.307 27.935 -9.655 1.00 49.20 H21B c ATOM 7918 0 GLY 44 65.633 28.875 -10.067 1.00 50.15 H21B 0 ATOM 7919 N LEU 45 65.812 26.709 -9.512 1.00 46.56 H21B N ATOM 7920 CA LEU 45 64.408 26.437 -9.803 1.00 45.04 H21B c ATOM 7921 CB LEU 45 64. 111 24.944 -9.692 1.00 41.43 H21B c ATOM 7922 CG LEU 45 64.932 23.987 -10.558 1.00 40.15 H21B c ATOM 7923 CDl LEU 45 64.566 22.569 -10.200 1.00 37.42 H21B c ATOM 7924 CD2 LEU 45 64.680 24.240 -12.030 1.00 39.47 H21B c ATOM 7925 C LEU 45 63.515 27.195 -8.819 1.00 45.66 H21B c ATOM 7 92 6 O LEU 45 63.787 27.230 -7.621 1.00 44.89 H21B 0 ATOM 7927 N GLU 46 62.4 52 27.808 -9.332 1.00 45.83 H21B N ATOM 7928 CA GLU 46 61.463 28.445 -8.482 1.00 45.79 H21B c ATOM 7929 CB GLU 46 61.532 29.950 -8.679 1.00 47.33 H21B c ATOM 7930 CG GLU 46 61.516 30.727 -7.380 1.00 52.65 H21B c ATOM 7931 CD GLU 46 62.013 32.152 -7.546 1.00 56.81 H21B c ATOM 7932 OE1 GLU 46 61.922 32.92 9 -6.566 1.00 59.52 H21B 0 ATOM 7933 OE2 GLU 46 62.496 32.492 -8.654 1.00 58.17 H21B 0 ATOM 7934 C GLU 46 60.043 27.937 -8.760 1.00 45.68 H21B c ATOM 7935 0 GLU 46 59.580 27.906 -9.909 1.00 44.98 H21B 0 ATOM 7936 N TRP 47 59.344 27.539 -7.705 1.00 44.68 H21B N ATOM 7937 CA TRP 47 57.964 27.103 -7.860 1.00 43.70 H21B c ATOM 7938 CB TRP 47 57.612 26.090 -6.780 1.00 46.89 H21B c ATOM 7939 CG TRP 47 56.206 25.542 -6.845 1.00 50.28 H21B c ATOM 7940 CD2 TRP 47 55.053 26.055 -6.164 1.00 51.83 H21B c ATOM 7941 CE2 TRP 47 53.994 25.161 -6.407 1.00 51.66 H21B c ATOM 7942 CE3 TRP 47 54.818 27.181 -5.367 1.00 53.50 H21B c ATOM 7943 CDl TRP 47 55.800 24.395 -7.470 1.00 47.94 H21B c ATOM 7944 NEl TRP 47 54.475 24.159 -7.207 1.00 50.10 H21B N ATOM 7945 CZ2 TRP 47 52.721 25.358 -5.882 1.00 53.80 H21B c ATOM 7946 CZ3 TRP 47 53.556 27.375 -4.849 1.00 54.46 H21B c ATOM 7947 CH2 TRP 47 52.524 26.469 -5.105 1.00 54.87 H21B c ATOM 7948 C TRP 47 57.025 28.294 -7.776 1.00 41.76 H21B c ATOM 7949 O TRP 47 57.174 29.156 -6.914 1.00 40.43 H21B 0 ATOM 7950 N MET 48 56.054 28.319 -8.683 1.00 40.99 H21B N ATOM 7951 CA MET 48 55.148 29.449 -8.853 1.00 39.09 H21B c ATOM 7952 CB MET 48 55.137 29.903 -10.300 1.00 39.03 H21B c ATOM 7953 CG MET 48 56.506 30.115 -10.893 1.00 43.44 H21B c ATOM 7954 SD MET 48 56.347 30.353 -12.653 1.00 43.36 H21B s ATOM 7955 CE MET 48 56.015 32.072 -12.708 1.00 46.47 H21B c ATOM 7956 C MET 48 53.735 29.074 -8.480 1.00 38.15 H21B c ATOM 7957 0 MET 48 52.944 29.929 -8.102 1.00 38.64 H21B 0 ATOM 7958 N GLY 49 53.401 27.799 -8.620 1.00 37.00 H21B N ATOM 7959 CA GLY 49 52.054 27.391 -8.300 1.00 35.84 H21B c ATOM 7960 C GLY 49 51.577 26.060 -8.833 1.00 35.29 H21B c ATOM 7961 0 GLY 49 52.330 25.301 -9.442 1.00 33.34 H21B 0 ATOM 7962 N TRP 50 50.300 25.788 -8.584 1.00 35.95 H21B N ATOM 7963 CA TRP 50 49.687 24.522 -8.948 1.00 38.80 H21B c ATOM 7964 CB TRP 50 49.799 23.571 -7.736 1.00 40.20 H21B c ATOM 7965 CG TRP 50 49.008 22.290 -7.818 1.00 27.92 H21B c ATOM 7966 CD2 TRP 50 47.607 22.144 -7.581 1.00 30.40 H21B c ATOM 7967 CE2 TRP 50 47.296 20.770 -7.682 1.00 33.19 H21B c ATOM 7968 CE3 TRP 50 46.572 23.046 -7.278 1.00 30.96 H21B c ATOM 7969 CDl TRP 50 49.491 21.028 -8.057 1.00 29.31 H21B c ATOM 7970 NEl TRP 50 48.471 20.108 -7.977 1.00 32.07 H2 IB N ATOM 7971 CZ2 TRP 50 46.003 20.271 -7.493 1.00 31.29 H21B c ATOM 7972 CZ3 TRP 50 45.290 22.553 -7.086 1.00 33.31 H21B c ATOM 7973 CH2 TRP 50 45.015 21.178 -7.192 1.00 32.81 H21B c ATOM 7974 C TRP 50 48.221 24.759 -9.387 1.00 41.34 H21B c ATOM 7975 O TRP 50 47.544 25.645 -8.864 1.00 40.95 . H21B 0 ATOM 7976 N VAL 51 47.766 23.996 -10.382 1.00 43.51 H21B N ATOM 7977 CA VAL 51 46.375 24.028 -10.841 1.00 44.71 H21B c ATOM 7978 CB VAL 51 46.245 24.400 -12.333 1.00 44.92 H21B c 425 WO 2009/026558 PCT/US2008/074097 ATOM 7979 CGI VAL 51 45.148 25 ATOM 7980 CG2 VAL 51 47.561 24 ATOM 7981 C VAL 51 45.813 22 ATOM 7982 O VAL 51 46.561 21 ATOM 7983 N SER 52 44.491 22 ATOM 7984 CA SER 52 43.800 21 ATOM 7985 CB SER 52 42.812 21 ATOM 7986 OG SER 52 42.020 20 ATOM 7987 C SER 52 43.046 20 ATOM 7988 O SER 52 42.243 21 ATOM 7989 N PHE 53 43.297 19 ATOM 7990 CA PHE 53 42.536 19 ATOM 7991 CB PHE 53 43.238 18 ATOM 7992 CG PHE 53 43.992 18 ATOM 7993 CDl PHE 53 45.359 18 ATOM 7994 CD2 PHE 53 43.330 18 ATOM 7995 CEl PHE 53 46.046 18 ATOM 7996 CE2 PHE 53 44.015 19 ATOM 7997 CZ PHE 53 45.372 19 ATOM 7998 C PHE 53 41.158 18 ATOM 7999 O PHE 53 40.161 19 ATOM 8000 N TYR 54 41.119 18 ATOM 8001 CA TYR 54 39.872 17 ATOM 8002 CB TYR 54 40.162 17 ATOM 8003 CG TYR 54 38.949 16 ATOM 8004 CDl TYR 54 38.655 17 ATOM 8005 CEl TYR 54 37.555 17 ATOM 8006 CD2 TYR 54 38.096 15 ATOM 8007 CE2 TYR 54 36.990 15 ATOM 8008 CZ TYR 54 36.720 16 ATOM 8009 OH TYR 54 35.618 15 ATOM 8010 C TYR 54 38.835 18 ATOM 8011 O TYR 54 37.946 18 ATOM 8012 N ASN 55 38.923 19 ATOM 8013 CA ASN 55 38.057 20 ATOM 8014 CB ASN 55 37.730 21 ATOM 8015 CG ASN 55 38.841 21 ATOM 8016 OD1 ASN 55 38.616 20 ATOM 8017 ND2 ASN 55 40.054 21 ATOM 8018 C ASN 55 38.717 22 ATOM 8019 0 ASN 55 38.675 22 ATOM 8020 N GLY 56 39.336 23 ATOM 8021 CA GLY 56 40.142 23 ATOM 8022 C GLY 56 40.842 24 ATOM 8023 0 GLY 56 41.260 25 ATOM 8024 N ASN 57 40.959 24 ATOM 8025 CA ASN 57 41.543 25 ATOM 8026 CB ASN 57 41.483 24 ATOM 8027 CG ASN 57 40.069 23 ATOM 8028 OD1 ASN 57 39.142 24 ATOM 8029 ND2 ASN 57 39.892 22 ATOM 8030 C ASN 57 42.978 25 ATOM 8031 0 ASN 57 43.665 24 ATOM 8032 N THR 58 43.422 26 ATOM 8033 CA THR 58 44.770 27 ATOM 8034 CB THR 58 44.751 28 ATOM 8035 OG1 THR 58 43.878 29 ATOM 8036 CG2 THR 58 44.265 28 ATOM 8037 C THR 58 45.492 27 ATOM 8038 O THR 58 44.864 27 ATOM 8039 N ASN 59 46.817 27 ATOM 8040 CA ASN 59 47.611 27 ATOM 8041 CB ASN 59 48.109 26 ATOM 8042 CG ASN 59 48.845 26 ATOM 8043 OD1 ASN 59 48.733 27 ATOM 8044 ND2 ASN 59 49.609 25 ATOM 8045 C ASN 59 48.780 28 ATOM 8046 0 ASN 59 49.547 27 ATOM 8047 N TYR 60 48.899 29 ATOM 8048 CA TYR 60 49.915 30 ATOM 8049 CB TYR 60 49.286 31 ATOM 8050 CG TYR 60 48.377 31 ATOM 8051 CDl TYR 60 48.894 31 ATOM 8052 CEl TYR 60 48.061 31 ATOM 8053 CD2 TYR 60 47.005 31 ATOM 8054 CE2 TYR 60 46.176 31 -12.516 1.00 41.58 H21B c -12.877 1.00 42.14 H21B c -10.730 1.00 46.39 H21B c -10.773 1.00 47.07 H21B 0 -10.621 1.00 46.89 H21B N -10.530 1.00 47.12 H21B c -9.373 1.00 46.23 H21B c -9.375 1.00 43.24 H21B 0 -11.802 1.00 48.99 H21B c -12.297 1.00 47.79 H21B 0 -12.329 1.00 51.06 H21B N -13.468 1.00 51.62 H21B c -14.110 1.00 49.15 H21B c -15.352 1.00 47.00 H21B c -15.433 1.00 45.85 H21B c -16.444 1.00 45.21 H21B c -16.582 1.00 44 . 88 H21B c -17.599 1.00 44 . 11 H21B c -17.668 1.00 43.18 H21B c -12.986 1.00 52.99 H21B c -13.620 1.00 51.55 H21B 0 -11.848 1.00 55.64 H21B N -11.202 1.00 58.44 H21B c -9.777 1.00 54.87 H21B c -9.001 1.00 51.36 H21B c -7.774 1.00 48.87 H21B c -7.058 1.00 49.07 H21B c -9.494 1.00 47.97 H21B c -8.786 1.00 47.93 H21B c -7.563 1.00 49.35 H21B c -6.836 1.00 48.60 H21B 0 -11.192 1.00 62.29 H21B c -12.039 1.00 63.00 H21B 0 -10.236 1.00 67.02 H21B N -10.293 1.00 71.09 H21B c -8.894 1.00 68.84 H21B c -7.921 1.00 67.93 H21B c -6.797 1.00 67.67 H21B 0 -8.338 1.00 69.63 H21B N -11.118 1.00 74.37 H21B c -12.347 1.00 75.61 H21B 0 -10.449 1.00 76.48 H21B N -11.163 1.00 78.11 H21B c -10.142 1.00 80.92 H21B c -10.426 1.00 81.59 H21B 0 -8.935 1.00 83.69 H21B N -7.846 1.00 84.39 H21B c -6.559 1.00 88.07 H21B c -6.121 1.00 90.83 H21B c -6.501 1.00 92.97 H21B 0 -5.319 1.00 92.57 H21B N -8.172 1.00 81.95 H21B c -8.883 1.00 82.38 H21B 0 -7.663 1.00 77.98 H21B N -7.924 1.00 74.72 H21B c -8.715 1.00 76.41 H21B c -8.070 1.00 77.32 H21B 0 -10.131 1.00 77.44 H21B c -6.609 1.00 71.58 H21B c -5.569 1.00 70.30 H21B 0 -6.649 1.00 69.82 H21B N -5.500 1.00 68.25 H21B c -4.740 1.00 65.64 H21B c -3.473 1.00 64.96 H21B c -2.966 1.00 65.43 H21B 0 .-2.953 1.00 65.84 H21B N -6.034 1.00 68.81 H21B c -6.851 1.00 68.36 H21B 0 -5.588 1.00 70.01 H21B N -6.115 1.00 70.19 H21B c -6.547 1.00 64.48 H21B c -7.747 1.00 56.84 H21B c -9.029 1.00 54.39 . H21B c -10.120 1.00 49.77 H21B c -7.594 1.00 52.06 H21B c -8.672 1.00 47.45 H21B c 426 WO 2009/026558 PCT/US2008/074097 ATOM 8055 cz TYR 60 46.706 31 ATOM 8056 OH TYR 60 45.873 31 ATOM 8057 c TYR 60 51.011 30 ATOM 8058 0 TYR 60 50.773 30 ATOM 8059 N ALA 61 52.216 31 ATOM 8060 CA ALA 61 53.339 31 ATOM 8061 CB ALA 61 54.629 31 ATOM 8062 C ALA 61 53.236 33 ATOM 8063 0 ALA 61 52.501 33 ATOM 8064 N GLN 62 53.972 33 ATOM 8065 CA GLN 62 53.978 34 ATOM 8066 CB GLN 62 55.022 35 ATOM 8067 CG GLN 62 54.598 36 ATOM 8068 CD GLN 62 53.632 35 ATOM 8069 OE1 GLN 62 53.671 36 ATOM 8070 NE2 GLN 62 52.756 34 ATOM 8071 C GLN 62 54.282 35 ATOM 8072 0 GLN 62 53.402 36 ATOM 8073 N LYS 63 55.532 35 ATOM 8074 CA LYS 63 55.975 36 ATOM 8075 CB LYS 63 57.238 36 ATOM 8076 CG LYS 63 58.518 36 ATOM 8077 CD LYS 63 59.760 36 ATOM 8078 CE LYS 63 61.026 36 ATOM 8079 NZ LYS 63 62.235 36 ATOM 8080 C LYS 63 54.892 36 ATOM 8081 0 LYS 63 54.362 37 ATOM 8082 N LEU 64 54.558 35 ATOM 8083 CA LEU 64 53.576 35 ATOM 8084 CB LEU 64 53.597 34 ATOM 8085 CG LEU 64 54.806 34 ATOM 8086 CDl LEU 64 54.818 35 ATOM 8087 CD2 LEU 64 56.100 34 ATOM 8088 C LEU 64 52.187 35 ATOM 8089 O LEU 64 51.278 35 ATOM 8090 N GLN 65 52.027 37 ATOM 8091 CA GLN 65 50.749 37 ATOM 8092 CB GLN 65 50.948 37 ATOM 8093 CG GLN 65 49.744 37 ATOM 8094 CD GLN 65 49.179 36 ATOM 8095 OE1 GLN 65 47.964 36 ATOM 8096 NE2 GLN 65 50.064 35 ATOM 8097 C GLN 65 49.958 38 ATOM 8098 0 GLN 65 50.422 39 ATOM 8099 N GLY 66 48.750 38 ATOM 8100 CA GLY 66 47.966 38 ATOM 8101 C GLY 66 48.484 38 ATOM 8102 0 GLY 66 47.711 38 ATOM 8103 N ARG 67 49.806 38 ATOM 8104 CA ARG 67 50.467 38 ATOM 8105 CB ARG 67 51.980 38 ATOM 8106 CG ARG 67 52.424 40 ATOM 8107 CD ARG 67 53.594 40 ATOM 8108 NE ARG 67 54.808 39 ATOM 8109 CZ ARG 67 55.549 39 ATOM 8110 NHl ARG 67 55.197 39 ATOM 8111 NH2 ARG 67 56.643 38 ATOM 8112 C ARG 67 50.183 37 ATOM 8113 O ARG 67 50.251 37 ATOM 8114 N GLY 68 49.879 36 ATOM 8115 CA GLY 68 49.791 35 ATOM 8116 C GLY 68 48.384 34 ATOM 8117 0 GLY 68 47.615 34 ATOM 8118 N THR 69 48.058 33 ATOM 8119 CA THR 69 4 6.8 02 33 ATOM 8120 CB THR 69 45.755 33 ATOM 8121 OG1 THR 69 45.372 35 ATOM 8122 CG2 THR 69 44.536 32 ATOM 8123 C THR 69 47.002 31 ATOM 8124 O THR 69 47.148 31 ATOM 8125 N MET 70 46.997 30 ATOM 8126 CA MET 70 46.975 29 ATOM 8127 CB MET 70 47.990 28 ATOM 8128 CG MET 70 48.171 28 ATOM 8129 SD MET 70 49.850 28 ATOM 8130 CE MET 70 49.867 28 -9.930 1.00 47.20 H21B c -10.999 1.00 45.04 H21B 0 -5.101 1.00 73.82 H21B c -3.899 1.00 74.53 H21B 0 -5.608 1.00 79.37 H21B N -4.791 1.00 86.15 H21B _c. -5.508 1.00 79.56 H21B c -4.518 1.00 93.30 H21B c -5.194 1.00 94.02 H21B 0 -3.523 1.00102.91 H21B N -3.199 1.00111.50 H21B c -2.123 1.00113.10 H21B c -1.105 1.00114.99 H21B c -0.080 1.00115.65 H21B c 1.096 1.00115.70 H21B 0 -0.521 1.00116.17 H21B N -4.426 1.00115.83 H21B c -4.953 1.00118.69 H21B 0 -4.877 1.00120.29 H21B N -5.965 1.00123.83 H21B c -6.623 1.00126.62 H21B c -5.828 1.00129.64 H21B c -6.696 1.00132.38 H21B c -5.951 1.00134.60 H21B c -6.816 1.00135.68 H21B N -7.018 1.00125.33 H21B c -7.210 1.00125.28 H21B 0 -7.695 1.00127.68 H21B N -8.764 1.00130.37 H21B c -9.568 1.00132.98 H21B c -10.494 1.00136.29 H21B c -11.518 1.00138.41 H21B c -9.685 1.00138.56 H21B c -8.198 1.00130.44 H21B c -8.400 1.00130.29 H21B 0 -7.489 1.00129.19 H21B N -6.870 1.00127.17 H21B c -5.451 1.00131.48 H21B c -4.556 1.00137.16 H21B c -4.742 1.00140.29 H21B c -4.713 1.00142.41 H21B 0 -4.936 1.00142.71 H21B N -7.676 1.00121.86 H21B c -7.930 1.00123.39 H21B 0 -8.059 1.00114.88 H21B N -8.993 1.00104.98 H21B c -10.400 1.00 96.86 H21B c -11.334 1.00 97.14 H21B 0 -10.538 1.00 88.00 H21B N -11.838 1.00 78.28 H21B c -11.662 1.00 79.16 H21B c -11.021 1.00 78.42 H21B c -11.775 1.00 76.25 H21B c -11.670 1.00 70.42 H21B N -12.711 1.00 67.25 H21B c -13.941 1.00 63.82 H21B N -12.522 1.00 62.44 H21B N -12.587 1.00 72.34 H21B C -13.818 1.00 67.98 H21B 0 -11.831 1.00 67.36 H21B N -12.411 1.00 61.33 H21B C -12.429 1.00 57.15 H21B c -11.487 1.00 54.96 H21B 0 -13.519 1.00 52.86 H21B N -13.640 1.00 49.43 H21B c -:14.466 1.00 47.25 H21B c -13.771 1.00 46.17 H21B 0 -14.699 1.00 43.40 H21fi c -14.325 1.00 46.56 H21B c -15.539 1.00 46.53 H21B 0 -13.558 1.00 44.10 H21B N -14.185 1.00 42.39 H21B c -13.551 1.00 41.28 • H21B c -12.084 1.00 40.21 H21B c -11.687 1.00 39.87 ' H21B s -10.019 1.00 44.15 H21B c 427 WO 2009/026558 PCT/US2008/074097 ATOM 8131 c MET 70 45.613 28 ATOM 8132 0 MET 70 44.851 28 ATOM 8133 N THR 71 45.329 27 ATOM 8134 CA THR 71 44.026 27 ATOM 8135 CB THR 71 43.219 28 ATOM 8136 OG1 THR 71 43.930 28 ATOM 8137 CG2 THR 71 42.978 29 ATOM 8138 C THR 71 44.154 26 ATOM 8139 O THR 71 45.248 25 ATOM 8140 N THR 72 43.015 25 ATOM 8141 CA THR 72 42.960 24 ATOM 8142 CB THR 72 42.802 23 ATOM 8143 OG1 THR 72 44.095 22 ATOM 8144 CG2 THR 72 41.942 21 ATOM 8145 C THR 72 41.803 23 ATOM 8146 O THR 72 40.699 24 ATOM 8147 N ASP 73 42.083 23 ATOM 8148 CA ASP 73 41.046 22 ATOM 8149 CB ASP 73 41.142 23 ATOM 8150 CG ASP 73 40.250 22 ATOM 8151 OD1 ASP 73 40.367 22 ATOM 8152 OD2 ASP 73 39.429 21 ATOM 8153 C ASP 73 41.216 21 ATOM 8154 0 ASP 73 42.090 20 ATOM 8155 N PRO 74 40.375 20 ATOM 8156 CD PRO 74 39.411 20 ATOM 8157 CA PRO 74 40.518 18 ATOM 8158 CB PRO 74 39.543 18 ATOM 8159 CG PRO 74 39.364 19 ATOM 8160 C PRO 74 40.207 18 ATOM 8161 O PRO 74 40.761 17 ATOM 8162 N SER 75 39.320 18 ATOM 8163 CA SER 75 38.854 18 ATOM 8164 CB SER 75 37.682 18 ATOM 8165 OG SER 75 38.122 20 ATOM 8166 C SER 75 39.989 18 ATOM 8167 O SER 75 40.015 17 ATOM 8168 N THR 76 40.934 19 ATOM 8169 CA THR 76 42.126 19 ATOM 8170 CB THR 76 42.418 20 ATOM 8171 OG1 THR 76 42.689 21 ATOM 8172 CG2 THR 76 41.239 20 ATOM 8173 C THR 76 43.378 18 ATOM 8174 O THR 76 44.479 18 ATOM 8175 N SER 77 43.205 18 ATOM 8176 CA SER 77 44.314 17 ATOM 8177 CB SER 77 44.801 16 ATOM 8178 OG SER 77 44.105 15 ATOM 8179 C SER 77 45.451 18 ATOM 8180 O SER 77 46.607 18 ATOM 8181 N THR 78 45.100 19 ATOM 8182 CA THR 78 46.027 21 ATOM 8183 CB THR 78 45.777 21 ATOM 8184 OG1 THR 78 46.092 20 ATOM 8185 CG2 THR 78 46.641 23 ATOM 8186 C THR 78 45.909 22 ATOM 8187 O THR 78 44.816 22 ATOM 8188 N ALA 79 47.046 22 ATOM 8189 CA ALA 79 47.082 23 ATOM 8190 CB ALA 79 47.823 22 ATOM 8191 C ALA 79 47.791 24 ATOM 8192 0 ALA 79 48.574 24 ATOM 8193 N TYR 80 47.521 25 ATOM 8194 CA TYR 80 48.086 26 ATOM 8195 CB TYR 80 47.013 27 ATOM 8196 CG TYR 80 46.386 27 ATOM 8197 CDl TYR 80 45.311 26 ATOM 8198 CEl TYR 80 44.719 25 ATOM 8199 CD2 TYR 80 46.856 27 ATOM 8200 CE2 TYR 80 46.268 26 ATOM 8201 CZ TYR 80 45.200 25 ATOM 8202 OH TYR 80 44.619 25 ATOM 8203 C TYR 80 48.731 27 ATOM 8204 O TYR 80 48.313 27 ATOM 8205 N MET 81 49.755 28 ATOM 8206 CA MET 81 50.388 29 -14.181 1.00 40.27 H21B c -13.230 1.00 40 .48 H21B 0 -15.273 1.00 4 0.53 H21B N -15.512 1.00 41.99 H21B c -16.470 1.00 41.68 H21B c -17.710 1.00 40.43 H21B .0. -15.841 1.00 39.62 H21B c -16.112 1.00 43.75 H21B c -16.296 1.00 41.50 H21B 0 -16.422 1.00 48.73 H21B N -16.873 1.00 53.25 H21B c -15.652 1.00 52.17 H21B c -15.216 1.00 53.13 H21B 0 -15.981 1.00 53.23 H21B c -17.865 1.00 55.94 H21B c -17.663 1.00 56.70 H21B 0 -18.954 1.00 57.69 H21B N -19.811 1.00 58.33 H21B c -21.238 1.00 61.28 H21B c -22.218 1.00 63.71 H21B c -23.442 1.00 64.93 H21B 0 -21.768 1.00 64.36 H21B 0 -19.849 1.00 57.27 H21B c -20.529 1.00 58.48 H21B 0 -19.110 1.00 56.40 H21B N -18.097 1.00 55.90 H21B c -19.105 1.00 56.74 H21B c -18.015 1.00 55.19 H21B c -17.157 1.00 53.64 H21B c -20.460 1.00 56.88 H21B c -20.816 1.00 57.34 H21B 0 -21.221 1.00 57.92 H21B N -22.428 1.00 58.36 H21B c -23.039 1.00 57.07 H21B c -23.637 1.00 57.34 H21B 0 -23.426 1.00 58.17 H21B c -24.251 1.00 60.52 H21B 0 -23.342 1.00 56.65 H21B N -24.184 1.00 54.54 H21B c -24.850 1.00 55.46 H21B c -23.846 1.00 57.17 H21B 0 -25.679 1.00 55.89 H21B c -23.419 1.00 52.21 H21B c -23.955 1.00 51.31 H21B 0 -22.175 1.00 50.10 H21B N -21.369 1.00 48.00 H21B c -21.905 1.00 48.42 H21B c -23.088 1.00 50.53 H21B 0 -21.383 1.00 46.50 H21B c -21.612 1.00 45.85 H21B 0 -21.128 1.00 44.26 H21B N -21.253 1.00 42.27 H21B c -22.577 1.00 43.01 H21B c -23.666 1.00 42.58 H21B 0 -22.676 1.00 41.56 H21B c -20.084 1.00 41.93 H21B c -19.739 1.00 41.80 H21B 0 -19.477 1.00 41.30 H21B N -18.415 1.00 43.41 H21B c -17.197 1.00 39.93 H21B c -18.944 1.00 46.13 H21B c -19.899 1.00 4 6.64 H21B 0 -18.337 1.00 47.82 H21B N -18.843 1.00 50.58 H21B c -19.561 1.00 51.23 H21B c -20.743 1.00 51.15 H21B c -20.572 1.00 51.00 H21B c -21.650 1.00 52.73 H21B c -22.034 1.00 51.74 H21B c -23.126 1.00 53.17 H21B c -22.928 1.00 55.28 H21B c -24.006 1.00 58.32 H21B 0 -17.772 1.00 51.42 . 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ffi ffi ffi EC EC ffi EC EC ffi ffi ffi EC EC ffi EC ffi ffi EC EC ffi EC EC ffi EC ffi ffi ffi ffi EC EC ffi ffi ffi ffi ffi ffi EC EC ffi EC ffi ffi EC EC ffi EC EC ffi EC ffi ffi ffi ffi EC EC ffi ffi ffi ffi ffi ffi EC EC ffi EC EC ffi ffi ffi ffi EC z ffi ffi EC ffi K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) K) μ-ΐ 1—1 1—1 1—1 μ-ΐ 1—1 1—1 1—1 1—1 1—1 1—1 |—1 |—1 1—1 |—1 1—1 1—1 1—1 |—1 1—1 1—1 1—1 1—1 1—1 1—1 1—1 1—1 1—1 μ-ι μ-ι μ-ι μ-ι μ-ι H* μ-ι μ-ι μ-ι H* μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-ι μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-ι μ-* μ-* μ-ι μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* μ-* Cd Cd Cd Cd Cd Cd Cd Cd Cd· Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd Cd (D (D z o (D o o (D (D (D Z O (D O (D (D Z O (D Z Z (D Z (D (D (D (D Z O (D (D (D (D (D (D Z o (D O (D (D Z o (D Z Z (D Z (D (D (D (D Z o (D (D (D (D (D (D Z o (D o o (D (D (D (D Z o (D (D CO (D (D WO 2009/026558 PCT/US2008/074097 WO 2009/026558 PCT/US2008/074097 ATOM 8283 CG ASP 90 58.318 38.488 -15.329 1.00 61.61 H21B c ATOM 8284 OD1 ASP 90 58.704 38.408 -14.145 1.00 62.01 H21B 0 ATOM 8285 OD2 ASP 90 57.385 39.235 -15.696 1.00 62.33 H21B 0 ATOM 8286 C ASP 90 61.026 36.382 -17.033 1.00 57.28 H21B c ATOM 8287 O ASP 90 60.504 35.356 -17.451 1.00 57.29 H21B 0 ATOM 8288 N THR 91 62.145 36.873 -17.533 1.00 53.21 H21B _N ATOM 8289 CA THR 91 62.907 36.114 -18.499 1.00 50.91 H21B C ATOM 8290 CB THR 91 64.019 36.957 -19.130 1.00 51.25 H21B C ATOM 8291 OG1 THR 91 63.440 37.861 -20.079 1.00 52.40 H21B O ATOM 8292 CG2 THR 91 65.025 36.065 -19.834 1.00 49.86 H21B C ATOM 8293 C THR 91 63.526 34.900 -17.832 1.00 47.55 H21B c ATOM 8294 O THR 91 64.316 35.024 -16.892 1.00 46.34 H21B 0 ATOM 8295 N ALA 92 63.156 33.726 -18.334 1.00 43.20 H21B N ATOM 8296 CA ALA 92 63.539 32.482 -17.700 1.00 40.41 H21B c ATOM 8297 CB ALA 92 63.041 32.459 -16.267 1.00 40.90 H21B c ATOM 8298 C ALA 92 62.990 31.292 -18.456 1.00 37.21 H21B c ATOM 8299 0 ALA 92 62.242 31.430 -19.415 1.00 38.12 H21B 0 ATOM 8300 N VAL 93 63.380 30.109 -18.027 1.00 34.64 H21B N ATOM 8301 CA VAL 93 62.733 28.919 -18.513 1.00 32.99 H21B c ATOM 8302 CB VAL 93 63.750 27.793 -18.666 1.00 30.83 H21B c ATOM 8303 CGI VAL 93 63.044 26.455 -18.927 1.00 26.30 H21B c ATOM 8304 CG2 VAL 93 64.672 28.142 -19.822 1.00 25.24 H21B c ATOM 8305 C VAL 93 61.595 28.521 -17.574 1.00 31.86 H21B c ATOM 8306 O VAL 93 61.729 28.533 -16.348 1.00 29.01 H21B 0 ATOM 8307 N TYR 94 60.458 28.214 -18.180 1.00 32.50 H21B N ATOM 8308 CA TYR 94 59.251 27.901 -17.441 1.00 34.02 H21B c ATOM 8309 CB TYR 94 58. 111 28.813 -17.900 1.00 31.77 H21B c ATOM 8310 CG TYR 94 58.243 30.236 -17.393 1.00 30.96 H21B c ATOM 8311 CDl TYR 94 57.570 30.650 -16.240 1.00 29.84 H21B c ATOM 8312 CEl TYR 94 57.696 31.944 -15.754 1.00 27.78 H21B c ATOM 8313 CD2 TYR 94 59.047 31.164 -18.049 1.00 28.53 H21B c ATOM 8314 CE2 TYR 94 59.179 32.472 -17.564 1.00 28.29 H21B c ATOM 8315 CZ TYR 94 58.503 32.852 -16.412 1.00 28.76 H21B c ATOM 8316 OH TYR 94 58.659 34.126 -15.884 1.00 29.65 H21B 0 ATOM 8317 C TYR 94 58.907 26.443 -17.681 1.00 33.72 H21B c ATOM 8318 O TYR 94 58.750 26.005 -18.821 1.00 34.33 H21B 0 ATOM 8319 N TYR 95 58.824 25.694 -16.591 1.00 35.12 H21B N ATOM 8320 CA TYR 95 58.441 24.289 -16.634 1.00 35.54 H21B c ATOM 8321 CB TYR 95 59.442 23.437 -15.862 1.00 37.61 H21B c ATOM 8322 CG TYR 95 60.852 23.484 -16.396 1.00 39.36 H21B c ATOM 8323 CDl TYR 95 61.187 22.835 -17.578 1.00 40.65 H21B c ATOM 8324 CEl TYR 95 62.476 22.841 -18.055 1.00 40.50 H21B c ATOM 8325 CD2 TYR 95 61.856 24.146 -15.703 1.00 39.61 H21B c ATOM 8326 CE2 TYR 95 63.155 24.155 -16.173 1.00 40.63 H21B c ATOM 8327 CZ TYR 95 63.460 23.502 -17.351 1.00 40.83 H21B c ATOM 8328 OH TYR 95 64.750 23.515 -17.834 1.00 41.60 H21B 0 ATOM 8329 C TYR 95 57.066 24.073 -16.024 1.00 34.62 H21B c ATOM 8330 O TYR 95 56.654 24.772 -15.087 1.00 29.49 H21B 0 ATOM 8331 N CYS 96 56.358 23.095 -16.570 1.00 36.69 H21B N ATOM 8332 CA CYS 96 55.310 22.427 -15.825 1.00 39.27 H21B c ATOM 8333 C CYS 96 55.813 21.042 -15.431 1.00 40.20 H21B c ATOM 8334 0 CYS 96 56.535 20.390 -16.182 1.00 38.24 H21B 0 ATOM 8335 CB CYS 96 54.026 22.325 -16.657 1.00 38.82 H21B c ATOM 8336 SG CYS 96 54.180 21.44Ό -18.241 1.00 47.25 H21B s ATOM 8337 N ALA 97 55.453 20.620 -14.229 1.00 42.79 H21B N ATOM 8338 CA ALA 97 55.651 19.248 -13.802 1.00 45.99 H21B c ATOM 8339 CB ALA 97 56.701 19.189 -12.703 1.00 47.19 H21B c ATOM 8340 C ALA 97 54.320 18.724 -13.281 1.00 48.49 H21B c ATOM 8341 0 ALA 97 53.412 19.504 -12.983 1.00 46.95 H21B 0 ATOM 8342 N ARG 98 54.207 17.401 -13.187 1.00 51.41 H21B N ATOM 8343 CA ARG 98 53.047 16.760 -12.588 1.00 53.37 H21B c ATOM 8344 CB ARG 98 53.046 15.269 -12.932 1.00 51.25 H21B c ATOM 8345 CG ARG 98 51.663 14.667 -13.187 1.00 49.60 H21B c ATOM 8346 CD ARG 98 51.753 13.294 -13.836 1.00 45.00 H21B c ATOM 8347 NE ARG 98 52.484 12.364 -12.984 1.00 44.76 H21B N ATOM 8348 CZ ARG 98 52.421 11.041 -13.085 1.00 43.23 H21B c ATOM 8349 NHl ARG 98 51.657 10.481 -14.007 1.00 44.12 H21B N ATOM 8350 NH2 ARG 98 53.126 10.279 -12.262 1.00 42.06 H21B' N ATOM 8351 C ARG 98 53.123 16.958 -11.075 1.00 56.47 H21B C ATOM 8352 O ARG 98 53.021 16.006 -10.315 1.00 57.42 H21B 0 ATOM 8353 N GLY 99 53.323 18.208 -10.653 1.00 59.29 H21B N ATOM 8354 CA GLY 99 53.343 18.538 -9.238 1.00 59.64 H21B C ATOM 8355 C GLY 99 52.179 17.874 -8.542 1.00 60.62 . H21B c ATOM 8356 0 GLY 99 51.325 17.298 -9.215 1.00 60.20 H21B 0 ATOM 8357 N TYR 100 52.130 17.940 -7.213 1.00 62.03 H21B N ATOM 8358 CA TYR 100 53.124 18.643 -6.419 1.00 62.23 H21B c 430 WO 2009/026558 PCT/US2008/074097 ATOM 8359 CB TYR 100 52.62 6 18 ATOM 8360 CG TYR 100 51.617 19 ATOM 8361 CDl TYR 100 50.253 19 ATOM 8362 CEl TYR 100 49.326 20 ATOM 8363 CD2 TYR 100 52.026 21 ATOM 8364 CE2 TYR 100 51.105 22 ATOM 8365 CZ TYR 100 49.757 21 ATOM 8366 OH TYR 100 48.846 22 ATOM 8367 C TYR 100 54.467 17 ATOM 8368 O TYR 100 55.521 18 ATOM 8369 N GLY 101 54.432 16 ATOM 8370 CA GLY 101 55.663 15 ATOM 8371 C GLY 101 56.609 16 ATOM 8372 0 GLY 101 57.785 15 ATOM 8373 N MET 102 56.099 16 ATOM 8374 CA MET 102 56.917 16 ATOM 8375 CB MET 102 57.841 18 ATOM 8376 CG MET 102 57.128 19 ATOM 8377 SD MET 102 57.934 20 ATOM 8378 CE MET 102 57.347 22 ATOM 8379 C MET 102 57.756 15 ATOM 8380 0 MET 102 58.982 15 ATOM 8381 N ASP 103 57.084 14 ATOM 8382 CA ASP 103 57.756 13 ATOM 8383 CB ASP 103 56.997 12 ATOM 8384 CG ASP 103 55.590 12 ATOM 8385 OD1 ASP 103 55.088 12 ATOM 8386 OD2 ASP 103 54.986 10 ATOM 8387 C ASP 103 57.890 13 ATOM 8388 O ASP 103 58.508 12 ATOM 8389 N VAL 104 57.314 14 ATOM 8390 CA VAL 104 57.535 14 ATOM 8391 CB VAL 104 56.421 13 ATOM 8392 CGI VAL 104 56.696 13 ATOM 8393 CG2 VAL 104 56.334 12 ATOM 8394 C VAL 104 57.539 15 ATOM 8395 O VAL 104 56.611 16 ATOM 8396 N TRP 105 58.562 16 ATOM 8397 CA TRP 105 58.631 17 ATOM 8398 CB TRP 105 59.989 18 ATOM 8399 CG TRP 105 60.236 18 ATOM 8400 CD2 TRP 105 60.423 19 ATOM 8401 CE2 TRP 105 60.619 18 ATOM 8402 CE3 TRP 105 60.449 20 ATOM 8403 CDl TRP 105 60.327 17 ATOM 8404 NEl TRP 105 60.557 17 ATOM 8405 CZ2 TRP 105 60.831 19 ATOM 8406 CZ3 TRP 105 60.663 21 ATOM 8407 CH2 TRP 105 60.849 21 ATOM 8408 C TRP 105 58.393 17 ATOM 8409 O TRP 105 58.790 16 ATOM 8410 N GLY 106 57.749 18 ATOM 8411 CA GLY 106 57.772 18 ATOM 8412 C GLY 106 59.143 19 ATOM 8413 0 GLY 106 60.004 19 ATOM 8414 N GLN 107 59.353 1? ATOM 8415 CA GLN 107 60.664 20 ATOM 8416 CB GLN 107 60.642 20 ATOM 8417 CG GLN 107 59.401 19 ATOM 8418 CD GLN 107 58.376 20 ATOM 8419 OE1 GLN 107 58.653 21 ATOM 8420 NE2 GLN 107 57.180 20 ATOM 8421 C GLN 107 61.091 21 ATOM 8422 0 GLN 107 62.263 21 ATOM 8423 N GLY 108 60.117 22 ATOM 8424 CA GLY 108 60.402 23 ATOM 8425 C GLY 108 59.968 24 ATOM 8426 0 GLY 108 59.909 24 ATOM 8427 N THR 109 59.638 25 ATOM 8428 CA THR 109 59.567 26 ATOM 8429 CB THR 109 58.099 27 ATOM 8430 OG1 THR 109 57.978 28 ATOM 8431 CG2 THR 109 57.140 26 ATOM 8432 C THR 109 60.267 28 ATOM 8433 O THR 109 60.179 28 ATOM 8434 N THR 110 61.002 28
-4.981 1.00 63.21 H21B c -4.795 1.00 66.99 H21B c -4.865 1.00 69.20 H21B c -4.719 1.00 69.60 H21B c -4.570 1.00 67.54 H21B c -4.423 1.00 70.27 H21B c -4.499 1.00 69.88 H21B c -4.357 1.00 68.94 H21B 0 -6.412 1.00 61.98 H21B c -6.522 1.00 63.49 H21B 0 -6.292 1.00 59.53 H21B N -6.187 1.00 55.46 H21B c -7.351 1.00 52.91 H21B c -7.281 1.00 52.82 H21B 0 -8.427 1.00 50.64 H21B N -9.603 1.00 49.55 H21B c -9.334 1.00 45.02 H21B c -9.291 1.00 40.44 H21B c -8.250 1.00 32.66 H21B s -8.992 1.00 41.41 H21B c -9.985 1.00 50.20 H21B c -9.873 1.00 50.67 H21B 0 -10.433 1.00 4 9.62 H21B N -10.757 1.00 47.87 H21B c -10.138 1.00 49.38 H21B c -10.729 1.00 50.48 H21B c -11.449 1.00 49.77 H21B 0 -10.469 1.00 49.50 H21B 0 -12.272 1.00 45.83 H21B c -12.745 1.00 44.29 H21B 0 -13.029 1.00 42.93 H21B N -14.471 1.00 42.13 H21B c -15.264 1.00 42.15 H21B c -16.763 1.00 38.31 H21B c -14.846 1.00 39.07 H21B c -14.941 1.00 41.93 H21B c -14.645 1.00 43.60 H21B 0 -15.692 1.00 41.64 H21B N -16.202 1.00 41.31 H21B c -15.860 1.00 37.08 H21B c -14.398 1.00 32.86 H21B c -13.638 1.00 30.58 H21B c -12.293 1.00 31.25 H21B c -13.960 1.00 2 9.62 H21B c -13.508 1.00 32.58 H21B c -12.242 1.00 30.54 H21B N -11.268 1.00 28.75 H21B c -12.934 1.00 28.89 H21B c -11.610 1.00 29.51 H21B c -17.706 1.00 43.85 H21B c -18.462 1.00 43.17 H21B 0 -18.134 1.00 48.37 H21B N -19.539 1.00 54.07 H21B c -19.961 1.00 58.35 H21B c -19.114 1.00 58.59 H21B 0 -21.266 1.00 62.46 H21B N -21.785 1.00 66.67 H21B c -23.311 1.00 71.29 H21B c -23.927 1.00 81.85 H21B c -24.264 1.00 87.17 H21B c -24.192 1.00 91.77 H21B 0 -24.639 1.00 91.59 H21B N -21.256 1.00 66.02 H21B c -20.971 1.00 65.68 H21B 0 -21.121 1.00 65.26 H21B N -20.760 1.00 61.19 H21B c -21.879 1.00 58.99 H21B c -23.038 1.00 55.89 H21B 0 -21.534 1.00 59.00 H21B N -22.540 1.00 59.69 H21B c -22.949 1.00 59.41 H21B c -23.313 1.00 59.56 H21B 0 -21.832 1.00 58.39 . H21B c -22.067 1.00 57.64 H21B c -20.903 1.00 57.85 H21B 0 -22.977 1.00 56.06 H21B N 431 WO 2009/026558 PCT/US2008/074097 ATOM 8435 CA THR 110 61.757 29 ATOM 8436 CB THR 110 63.106 29 ATOM 8437 OG1 THR 110 62.861 30 ATOM 8438 CG2 THR 110 63.896 28 ATOM 8439 C THR 110 60.929 31 ATOM 8440 O THR 110 60.340 31 ATOM 8441 N VAL 111 60.883 32 ATOM 8442 CA VAL 111 60.165 33 ATOM 8443 CB VAL 111 59.024 33 ATOM 8444 CGI VAL 111 58.293 34 ATOM 8445 CG2 VAL 111 58.086 32 ATOM 8446 C VAL 111 61.127 34 ATOM 8447 O VAL 111 61.634 34 ATOM 8448 N THR 112 61.372 35 ATOM 8449 CA THR 112 62.345 36 ATOM 8450 CB THR 112 63.131 36 ATOM 8451 OG1 THR 112 63.445 35 ATOM 8 4 52 CG2 THR 112 64.422 37 ATOM 8453 C THR 112 61.640 37 ATOM 8454 O THR 112 60.806 37 ATOM 8455 N VAL 113 61.979 38 ATOM 8456 CA VAL 113 61.405 39 ATOM 8457 CB VAL 113 60.719 39 ATOM 8458 CGI VAL 113 60.127 41 ATOM 8459 CG2 VAL 113 59.654 38 ATOM 8460 C VAL 113 62.457 40 ATOM 8461 O VAL 113 63.230 41 ATOM 8462 N SER 114 62.4 68 41 ATOM 8463 CA SER 114 63.407 42 ATOM 8464 CB SER 114 64.642 42 ATOM 8465 OG SER 114 65.609 43 ATOM 8466 C SER 114 62.795 43 ATOM 8467 O SER 114 61.954 43 ATOM 8468 N SER 115 63.229 44 ATOM 8469 CA SER 115 63.224 45 ATOM 8470 CB SER 115 63.221 47 ATOM 8471 OG SER 115 62.095 47 ATOM 8472 C SER 115 64.512 45 ATOM 8473 O SER 115 64.797 44 ATOM 8474 N ALA 116 65.296 46 ATOM 8475 CA ALA 116 66.653 46 ATOM 8476 CB ALA 116 67.319 45 ATOM 8477 C ALA 116 66.718 46 ATOM 8478 0 ALA 116 66.907 45 ATOM 8479 N SER 117 66.569 47 ATOM 8480 CA SER 117 66.897 47 ATOM 8481 CB SER 117 66.318 48 ATOM 8482 OG SER 117 66.935 48 ATOM 8483 C SER 117 68.403 47 ATOM 8484 O SER 117 69.087 48 ATOM 8485 N THR 118 68.910 46 ATOM 8486 CA THR 118 70.340 46 ATOM 8487 CB THR 118 70.612 46 ATOM 8488 OG1 THR 118 71.785 47 ATOM 8489 CG2 THR 118 69.411 46 ATOM 8490 C THR 118 71.048 48 ATOM 8491 O THR 118 70.704 49 ATOM 8492 N LYS 119 72.034 48 ATOM 8493 CA LYS 119 72.906 49 ATOM 8494 CB LYS 119 72.642 49 ATOM 8495 CG LYS 119 73.647 50 ATOM 8496 CD LYS 119 73.521 51 ATOM 8497 CE LYS 119 74.717 52 ATOM 8498 NZ LYS 119 75.119 52 ATOM 8499 C LYS 119 74.375 48 ATOM 8500 0 LYS 119 74.735 47 ATOM 8501 N GLY 120 75.220 49 ATOM 8502 CA GLY 120 76.646 49 ATOM 8503 C GLY 120 77.327 49 ATOM 8504 0 GLY 120 76.802 50 ATOM 8505 N PRO 121 78.506 49 ATOM 8506 CD PRO 121 79.208 48 ATOM 8507 CA PRO 121 79.171 49 ATOM 8508 CB PRO 121 80.132 48 ATOM 8509 CG PRO 121 80.452 48 ATOM 8510 C PRO 121 79.893 50 -22.648 1.00 53.48 H21B c -23.417 1.00 52.52 H21B c -24.814 1.00 51.93 H21B 0 -23.226 1.00 51.81 H21B c -23.025 1.00 51.15 H21B c -24.098 1.00 49.63 H21B 0 -22.130 1.00 50.86 H21B N -22.382 1.00 53.09 H21B c -21.381 1.00 53.31 H21B c -21.651 1.00 52.94 H21B c -21.466 1.00 51.89 H21B c -22.230 1.00 54.49 H21B c -21.139 1.00 54.27 H21B 0 -23.320 1.00 56.71 H21B N -23.315 1.00 59.52 H21B c -24.627 1.00 60.00 H21B c -25.044 1.00 60.97 H21B 0 -24.437 1.00 59.68 H21B c -23.164 1.00 61.20 H21B c -23.981 1.00 62.07 H21B 0 -22.123 1.00 63.91 H21B N -21.939 1.00 65.56 H21B c -20.578 1.00 65.05 H21B c -20.438 1.00 63.91 H21B c -20.434 1.00 64.43 H21B c -22.039 1.00 67.13 H21B c -21.106 1.00 68.10 H21B 0 -23.172 1.00 68.21 H21B N -23.403 1.00 68.04 H21B c -24.137 1.00 67.93 H21B c -24.290 1.00 68.98 H21B 0 -24.219 1.00 68.45 H21B c -25.090 1.00 67.57 H21B 0 -23.938 1.00 69.36 H21B N -24.961 1.00 69.76 H21B c -24.320 1.00 70.24 H21B c -23.474 1.00 72.93 H21B 0 -25.731 1.00 69.56 H21B c -26.131 1.00 71.87 H21B 0 -25.933 1.00 67.88 H21B N -26.425 1.00 66.75 H21B c -25.711 1.00 67.94 H21B c -27.925 1.00 66.13 H21B c -28.387 1.00 65.19 H21B 0 -28.679 1.00 65.90 H21B N -30.100 1.00 64.00 H21B c -30.787 1.00 64.23 H21B c -32.050 1.00 63.88 H21B 0 -30.222 1.00 62.28 H21B c -29.347 1.00 62.29 H21B 0 -31.316 1.00 60.02 H21B N -31.579 1.00 58.31 H21B c -33.050 1.00 58.63 H21B c -33.508 1.00 59.03 H21B 0 -33.926 1.00 55.99 H21B c -31.262 1.00 56.38 H21B c -31.794 1.00 57.50 H21B 0 -30.376 1.00 53.48 H21B N -30.091 1.00 49.19 H21B c -28.693 1.00 47.24 H21B c -28.288 1.00 48.71 H21B c -26.829 1.00 47.72 H21B c -26.443 1.00 4 7.92 H21B c -25.016 1.00 50.67 H21B N -30.200 1.00 47.21 H21B c -29.963 1.00 45.25 H21B 0 -30.570 1.00 44.35 H21B N -30.652 1.00 40.92 H21B c -29.326 1.00 38.58 H21B c -28.474 1.00 36.46 H21B 0 -29.114 1.00 36.94 H21B N -30.042 1.00 35.27 H21B c -27.813 1.00 36.50 . H21B c -27.839 1.00 34.63 H21B c -29.285 1.00 36.69 H21B c -27.558 1.00 37.73 H21B c 432 WO 2009/026558 PCT/US2008/074097 ATOM 8511 0 PRO 121 80.301 51 ATOM 8512 N SER 122 80.049 51 ATOM 8513 CA SER 122 81.072 51 ATOM 8514 CB SER 122 80.612 52 ATOM 8515 OG SER 122 79.510 53 ATOM 8516 C SER 122 82.326 51 ATOM 8517 O SER 122 82.277 50 ATOM 8518 N VAL 123 83.451 51 ATOM 8519 CA VAL 123 84.702 50 ATOM 8520 CB VAL 123 85.525 50 ATOM 8521 CGI VAL 123 86.827 49 ATOM 8522 CG2 VAL 123 84.713 49 ATOM 8523 C VAL 123 85.529 51 ATOM 8524 O VAL 123 85.920 52 ATOM 8525 N PHE 124 85.776 51 ATOM 8526 CA PHE 124 86.671 52 ATOM 8527 CB PHE 124 86.008 52 ATOM 8528 CG PHE 124 84.785 53 ATOM 8529 CD1 PHE 124 84.885 54 ATOM 8530 CD2 PHE 124 83.534 52 ATOM 8531 CEl PHE 124 83.757 55 ATOM 8532 CE2 PHE 124 82.411 53 ATOM 8533 CZ PHE 124 82.526 54 ATOM 8534 C PHE 124 87.966 51 ATOM 8535 O PHE 124 87.992 50 ATOM 8536 N PRO 125 89.069 51 ATOM 8537 CD PRO 125 89.202 53 ATOM 8538 CA PRO 125 90.351 51 ATOM 8539 CB PRO 125 91.357 52 ATOM 8540 CG PRO 125 90.632 53 ATOM 8541 C PRO 125 90.474 50 ATOM 8542 O PRO 125 90.186 51 ATOM 8543 N LEU 126 90.911 49 ATOM 8544 CA LEU 126 91.369 49 ATOM 8545 CB LEU 126 90.912 47 ATOM 8546 CG LEU 126 89.403 47 ATOM 8547 CD1 LEU 126 89.058 46 ATOM 8548 CD2 LEU 126 88.714 48 ATOM 8549 C LEU 126 92.897 49 ATOM 8550 O LEU 126 93.620 48 ATOM 8551 N ALA 127 93.367 50 ATOM 8552 CA ALA 127 94.789 50 ATOM 8553 CB ALA 127 94.968 52 ATOM 8554 C ALA 127 95.527 49 ATOM 8555 0 ALA 127 94.996 49 ATOM 8556 N PRO 128 96.778 49 ATOM 8557 CD PRO 128 97.532 49 ATOM 8558 CA PRO 128 97.578 48 ATOM 8559 CB PRO 128 98.792 48 ATOM 8560 CG PRO 128 98.925 49 ATOM 8561 C PRO 128 97.966 48 ATOM 8562 O PRO 128 98.194 49 ATOM 8563 N SER 129 98.041 47 ATOM 8564 CA SER 129 98.268 47 ATOM 8565 CB SER 129 98.539 46 ATOM 8566 OG SER 129 97.610 45 ATOM 8567 C SER 129 99.444 48 ATOM 8568 O SER 129 100.343 48 ATOM 8569 N GLY 135 104.091 39 ATOM 8570 CA GLY 135 105.514 39 ATOM 8571 C GLY 135 106.108 40 ATOM 8572 0 GLY 135 106.017 41 ATOM 8573 N GLY 136 106.728 39 ATOM 8574 CA GLY 136 107.222 40 ATOM 8575 C GLY 136 106.106 40 ATOM 8576 0 GLY 136 106.272 41 ATOM 8577 N THR 137 104.957 40 ATOM 8578 CA THR 137 103.792 40 ATOM 8579 CB THR 137 103.096 39 ATOM 8580 OG1 THR 137 102.819 38 ATOM 8581 CG2 THR 137 103.979 38 ATOM 8582 C THR 137 102.783 41 ATOM 8583 O THR 137 102.556 41 ATOM 8584 N ALA 138 102.188 42 ATOM 8585 CA ALA 138 101.075 43 ATOM 8586 CB ALA 138 101.440 44 -28.487 1.00 35.85 H21B 0 -26.284 1.00 37.92 H21B N -25.896 1.00 38.88 H21B C -24.689 1.00 39.55 H21B c -25.028 1.00 41.26 H21B 0 -25.552 1.00 38.81 H21B _c -24.805 1.00 39.06 H21B 0 -26.114 1.00 37.51 H21B N -25.770 1.00 36.15 H21B c -27.024 1.00 34.75 H21B c -26.615 1.00 32.49 H21B c -27.955 1.00 31.95 H21B c -24.851 1.00 35.96 H21B c -25.230 1.00 37.71 H21B 0 -23.639 1.00 34.63 H21B N -22.688 1.00 33.18 H21B c -21.319 1.00 29.98 H21B c -21.322 1.00 30.01 H21B c -21.582 1.00 30.04 H21B c -21.043 1.00 28.86 H21B c -21.560 1.00 28.02 H21B c -21.022 1.00 27.96 H21B c -21.279 1.00 28.14 H21B c -22.531 1.00 33.73 H21B c -22.596 1.00 34.72 H21B 0 -22.314 1.00 35.69 H21B N -22.358 1.00 34.56 H21B c -22.040 1.00 36.09 H21B c -22.339 1.00 34.77 H21B c -21.941 1.00 34.99 H21B c -20.598 1.00 36.79 H21B c -19.645 1.00 36.75 H21B 0 -20.449 1.00 35.96 H21B N -19.155 1.00 38.37 H21B c -18.959 1.00 3 6.93 H21B c -19.047 1.00 32.95 H21B c -18.690 1.00 30.64 H21B c -18.114 1.00 33.63 H21B c -18.994 1.00 41.03 H21B c -19.232 1.00 40.02 H21B 0 -18.568 1.00 44.45 H21B N -18.423 1.00 48.51 H21B c -17.860 1.00 46.45 H21B c -17.546 1.00 51.79 H21B c -16.552 1.00 50.48 H21B 0 -17.902 1.00 55.84 H21B N -18.971 1.00 58.16 H21B c -17.232 1.00 61.96 H21B c -18.141 1.00 61.86 H21B c -18.799 1.00 59.88 H21B c -15.818 1.00 66.51 H21B c -15.551 1.00 67.81 H21B 0 -14.926 1.00 71.65 H21B N -13.496 1.00 76.44 H21B c -12.778 1.00 76.87 H21B c -13.171 1.00 74.76 H21B 0 -13.269 1.00 80.19 H21B c -14.109 1.00 81.78 H21B 0 -12.189 1.00119.83 H21B N -12.396 1.00119.78 H21B c -13.424 1.00119.10 H21B c -13.283 1.00120.34 H21B 0 -14.458 1.00116.59 H21B N -15.557 1.00111.70 H21B c -16.526 1.00107.95 H21B c -17.444 1.00108.38 H21B 0 -16.313 1.00103.31 H21B N -17.166 1.00 97.68 H21B c -17.453 1.00 98.99 H21B c -16.215 1.00100.61 H21B 0 -18.314 1.00 99.84 H21B c -16.512 1.00 92.44 H21B c -15.303 1.00 91.69 . H21B 0 -17.316 1.00 86.07 H21B N -16.861 1.00 79.49 H21B c -16.949 1.00 79.63 H21B c 433 WO 2009/026558 PCT/US2008/074097 ATOM 8587 c ALA 138 99.834 42 ATOM 8588 0 ALA 138 99.937 42 ATOM 8589 N ALA 139 98.663 43 ATOM 8590 CA ALA 139 97.404 42 ATOM 8591 CB ALA 139 96.487 41 ATOM 8592 C ALA 139 96.716 44 ATOM 8593 0 ALA 139 96.707 45 ATOM 8594 N LEU 140 96.154 44 ATOM 8595 CA LEU 140 95.516 45 ATOM 8596 CB LEU 140 96.535 46 ATOM 8597 CG LEU 140 97.142 45 ATOM 8598 CDl LEU 140 96.234 46 ATOM 8599 CD2 LEU 140 98.506 46 ATOM 8600 C LEU 140 94.501 44 ATOM 8601 O LEU 140 94.544 43 ATOM 8602 N GLY 141 93.600 45 ATOM 8603 CA GLY 141 92.610 45 ATOM 8604 C GLY 141 91.581 46 ATOM 8605 0 GLY 141 91.850 47 ATOM 8606 N CYS 142 90.406 46 ATOM 8607 CA CYS 142 89.360 47 ATOM 8608 C CYS 142 87.936 46 ATOM 8609 0 CYS 142 87.595 45 ATOM 8610 CB CYS 142 89.459 47 ATOM 8611 SG CYS 142 88.981 46 ATOM 8612 N LEU 143 87.119 47 ATOM 8613 CA LEU 143 85.750 47 ATOM 8614 CB LEU 143 85.345 47 ATOM 8615 CG LEU 143 83.870 47 ATOM 8616 CDl LEU 143 83.550 46 ATOM 8617 CD2 LEU 143 83.602 48 ATOM 8618 C LEU 143 84.787 47 ATOM 8619 O LEU 143 84.717 48 ATOM 8 62 0 N VAL 144 84.047 46 ATOM 8 621 CA VAL 144 83.069 46 ATOM 8622 CB VAL 144 83.162 45 ATOM 8623 CGI VAL 144 82.203 46 ATOM 8624 CG2 VAL 144 84.594 45 ATOM 8 62 5 C VAL 144 81.683 46 ATOM 8 62 6 O VAL 144 81.134 45 ATOM 8627 N LYS 145 81.120 47 ATOM 8628 CA LYS 145 79.997 48 ATOM 8 62 9 CB LYS 145 80.342 49 ATOM 8630 CG LYS 145 79.385 49 ATOM 8631 CD LYS 145 80.143 49 ATOM 8632 CE LYS 145 79.965 51 ATOM 8633 NZ LYS 145 78.551 51 ATOM 8634 C LYS 145 78.725 48 ATOM 8635 0 LYS 145 78.764 49 ATOM 8636 N ASP 146 77.620 47 ATOM 8637 CA ASP 146 76.255 48 ATOM 8638 CB ASP 146 75.997 49 ATOM 8639 CG ASP 146 75.619 49 ATOM 8640 OD1 ASP 146 75.227 48 ATOM 8641 OD2 ASP 146 75.708 50 ATOM 8642 C ASP 146 75.812 4 8 ATOM 8643 O ASP 146 75.271 49 ATOM 8644 N TYR 147 76.012 46 ATOM 8645 CA TYR 147 75.641 46 ATOM 8646 CB TYR 147 76.847 46 ATOM 8647 CG TYR 147 77.413 44 ATOM 8648 CDl TYR 147 77.005 43 ATOM 8649 CEl TYR 147 77.585 42 ATOM 8650 CD2 TYR 147 78.408 44 ATOM 8651 CE2 TYR 147 78.989 43 ATOM 8652 CZ TYR 147 78.583 42 ATOM 8653 OH TYR 147 79.240 41 ATOM 8654 C TYR 147 74.501 45 ATOM 8655 O TYR 147 74.063 45 ATOM 8656 N PHE 148 74.038 45 ATOM 8657 CA PHE 148 72.928 44 ATOM 8658 CB PHE 148 71.654 45 ATOM 8659 CG PHE 148 70.495 44 ATOM 8660 CDl PHE 148 69.885 43 ATOM 8661 CD2 PHE 148 70.046 43 ATOM 8662 CEl PHE 148 68.861 43 -17.704 1.00 74.95 H21B c -18.884 1.00 73.87 H21B 0 -17.087 1.00 68.95 H21B N -17.784 1.00 63.72 H21B c -16.944 1.00 63.98 H21B c -18.104 1.00 60.62 H21B c -17.289 1.00 59.40 H21B 0 -19.306 1.00 55.59 H21B N -19.795 1.00 51.29 H21B c -20.494 1.00 50.60 H21B c -21.799 1.00 50.41 H21B c -22.988 1.00 49.55 H21B c -22.014 1.00 49.82 H21B c -20.803 1.00 49.58 H21B c -21.210 1.00 48.85 H21B 0 -21.219 1.00 47.47 H21B N -22.201 1.00 47.38 H21B c -22.427 1.00 47.35 H21B c -22.143 1.00 47.11 H21B 0 -22.931 1.00 47.21 H21B N -23.024 1.00 47.00 H21B c -22.781 1.00 43.01 H21B c -23.137 1.00 42.06 H21B 0 -24.371 1.00 50.45 H21B c -25.834 1.00 59.47 H21B s -22.161 1.00 38.35 H21B N -21.766 1.00 34.87 H21B c -20.513 1.00 35.86 H21B c -20.078 1.00 33.46 H21B c -19.524 1.00 32.08 H21B c -19.035 1.00 31.98 H21B c -22.886 1.00 34.34 H21B c -23.302 1.00 31.63 H21B 0 -23.372 1.00 34.47 H21B N -24.419 1.00 35.66 H21B c -25.533 1.00 34.46 H21B c -26.664 1.00 35.75 H21B c -26.042 1.00 33.25 H21B c -23.783 1.00 38.56 H21B c -23.460 1.00 38.50 H21B 0 -23.620 1.00 38.89 H21B N -22.734 1.00 39.76 H21B c -21.801 1.00 41.45 H21B c -20.642 1.00 41.62 H21B c -19.415 1.00 44.51 H21B c -19.152 1.00 47.71 H21B c -18.786 1.00 52.84 H21B N -23.548 1.00 40.29 H21B c -24.546 1.00 37.61 H21B 0 -23.124 1.00 41.41 H21B N -23.480 1.00 42.07 H21B c -23.000 1.00 44.43 H21B c -21.539 1.00 4 9.82 H21B c -21.020 1.00 49.91 H21B 0 -20.915 1.00 52.78 H21B 0 -24.933 1.00 40.90 H21B c -25.475 1.00 40.19 H21B 0 -25.545 1.00 39.23 H21B N -26.939 1.00 40.02 H21B c -27.733 1.00 38.54 H21B c -27.241 1.00 38.05 H21B c -27.799 1.00 36.64 H21B c -27.406 1.00 35.87 H21B c -26.261 1.00 37.18 H21B c -25.863 1.00 36.14 H21B c -26.445 1.00 35.73 H21B c -26.130 1.00 33.54 H21B 0 -27.090 1.00 41.03 H21B c -26.121 1.00 39.81 H21B 0 -28.321 1.00 42.76 H21B N -28.589 1.00 44.38 H21B c -27.916 1.00 47.16 H21B c -28.013 1.00 51.60 . H21B c -29.231 1.00 52.66 H21B c -26.893 1.00 53.38 H21B c -29.336 1.00 53.99 H21B c 434 WO 2009/026558 PCT/US2008/074097 ATOM 8663 CE2 PHE 148 69.021 42 ATOM 8664 cz PHE 148 68.426 42 ATOM 8 665 c PHE 148 72.690 44 ATOM 8666 0 PHE 148 72.795 45 ATOM 8667 N PRO 149 72.363 43 ATOM 8668 CD PRO 149 71.924 43 ATOM 8669 CA PRO 149 72.424 42 ATOM 8670 CB PRO 149 71.744 41 ATOM 8671 CG PRO 149 72.009 41 ATOM 8672 C PRO 149 73.874 41 ATOM 8673 O PRO 149 74.748 42 ATOM 8674 N GLU 150 74.116 40 ATOM 8675 CA GLU 150 75.421 39 ATOM 8 67 6 CB GLU 150 75.544 38 ATOM 8677 CG GLU 150 75.465 38 ATOM 8678 CD GLU 150 76.823 38 ATOM 8679 OE1 GLU 150 77.643 39 ATOM 8680 OE2 GLU 150 77.073 37 ATOM 8681 C GLU 150 75.507 39 ATOM 8682 0 GLU 150 74.527 39 ATOM 8683 N PRO 151 76.680 39 ATOM 8684 CD PRO 151 76.847 38 ATOM 8685 CA PRO 151 77.943 39 ATOM 8686 CB PRO 151 78.688 38 ATOM 8687 CG PRO 151 78.279 38 ATOM 8688 C PRO 151 78.701 40 ATOM 8689 O PRO 151 78.303 41 ATOM 8690 N VAL 152 79.796 40 ATOM 8691 CA VAL 152 80.856 41 ATOM 8692 CB VAL 152 81.098 42 ATOM 8693 CGI VAL 152 79.869 43 ATOM 8694 CG2 VAL 152 81.432 41 ATOM 8695 C VAL 152 82.112 40 ATOM 8696 O VAL 152 82.258 39 ATOM 8697 N THR 153 83.018 41 ATOM 8698 CA THR 153 84.279 40 ATOM 8699 CB THR 153 84.458 39 ATOM 8700 OG1 THR 153 84.342 41 ATOM 8701 CG2 THR 153 83.372 38 ATOM 8702 C THR 153 85.399 41 ATOM 8703 O THR 153 85.273 42 ATOM 8704 N VAL 154 86.485 40 ATOM 8705 CA VAL 154 87.588 41 ATOM 8706 CB VAL 154 87.654 41 ATOM 8707 CGI VAL 154 88.723 42 ATOM 8708 CG2 VAL 154 86.336 42 ATOM 8709 C VAL 154 88.944 41 ATOM 8710 O VAL 154 89.225 40 ATOM 8711 N SER 155 89.779 42 ATOM 8712 CA SER 155 91.058 41 ATOM 8713 CB SER 155 90.953 42 ATOM 8714 OG SER 155 92.205 42 ATOM 8715 C SER 155 92.100 42 ATOM 8716 O SER 155 91.742 43 ATOM 8717 N TRP 156 93.377 42 ATOM 8718 CA TRP 156 94.425 4 3 ATOM 8719 CB TRP 156 94.963 42 ATOM 8720 CG TRP 156 94.025 42 ATOM 8721 CD2 TRP 156 93.881 43 ATOM 8722 CE2 TRP 156 92.913 43 ATOM 8723 CE3 TRP 156 94.477 44 ATOM 8724 CDl TRP 156 93.157 41 ATOM 8725 NEl TRP 156 92.486 42 ATOM 8726 CZ2 TRP 156 92.529 44 ATOM 8727 CZ3 TRP 156 94.097 45 ATOM 8728 CH2 TRP 156 93.129 45 ATOM 8729 C TRP 156 95.583 43 ATOM 8730 O TRP 156 96.211 42 ATOM 8731 N ASN 157 95.878 44 ATOM 8732 CA ASN 157 96.870 45 ATOM 8733 CB ASN 157 98.284 44 ATOM 8734 CG ASN 157 98.725 45 ATOM 8735 OD1 ASN 157 98.165 46 ATOM 8736 ND2 ASN 157 99.731 45 ATOM 8737 C ASN 157 96.515 44 ATOM 8738 0 ASN 157 97.389 44 -26.992 1.00 54.37 H21B c -28.218 1.00 55.54 H21B c -30.087 1.00 43.47 H21B c -30.809 1.00 43.90 H21B 0 -30.577 1.00 43.17 H21B N -31.969 1.00 43.32 H21B _c -29.863 1.00 44.42 H21B c -30.818 1.00 42.48 H21B c -32.152 1.00 41.77 H21B c -29.635 1.00 44.50 H21B c -29.653 1.00 46.03 H21B 0 -29.413 1.00 44.54 H21B N -29.666 1.00 45.89 H21B c -28.977 1.00 46.98 H21B c -27.465 1.00 48.70 H21B c -26.821 1.00 49.44 H21B c -26.905 1.00 48.89 H21B 0 -26.241 1.00 48.71 H21B 0 -31.172 1.00 44.93 H21B c -31.886 1.00 4 5.62 H21B 0 -31.676 1.00 42.42 H21B N -33.034 1.00 40.81 H21B c -30.940 1.00 42.36 H21B c -31.588 1.00 4 0.92 H21B c -33.025 1.00 39.66 H21B c -31.104 1.00 42.20 H21B c -31.874 1.00 43.34 H21B 0 -30.374 1.00 40.37 H21B N -30.763 1.00 39.57 H21B C -29.689 1.00 39.88 H21B C -29.558 1.00 40.66 H21B C -28.355 1.00 38.69 H21B C -30.924 1.00 40.03 H21B c -30.288 1.00 38.78 H21B 0 -31.780 1.00 40.25 H21B N -31.900 1.00 42.37 H21B c -33.336 1.00 44 .70 H21B c -34.231 1.00 49.27 H21B 0 -33.683 1.00 46.36 H21B c -31.504 1.00 4 3.32 H21B c -31.688 1.00 44.64 H21B 0 -30.941 1.00 43.33 H21B N -30.518 1.00 42.48 H21B c -28.985 1.00 40.02 H21B c -28.587 1.00 39.30 H21B c -28.452 1.00 39.07 H21B c -31.038 1.00 44.23 H21B c -31.084 1.00 45.14 H21B 0 -31.436 1.00 46.16 H21B N -32.053 1.00 49.14 H21B c -33.568 1.00 50.30 H21B c -34.151 1.00 52.89 H21B 0 -31.429 1.00 51.51 H21B c -30.870 1.00 52.21 H21B 0 -31.508 1.00 51.65 H21B N -30.892 1.00 53.25 H21B c -29.636 1.00 51.30 H21B c -28.473 1.00 48.72 H21B c -27.533 1.00 46.26 H21B c -26.592 1.00 45.15 H21B c -27.396 1.00 43.80 H21B c -28.077 1.00 47.86 H21B c -26.945 1.00 45.30 H21B N -25.526 1.00 44.56 H21B c -26.340 1.00 43.81 H21B c -25.416 1.00 42.87 H21B c -31.828 1.00 56.08 H21B c -32.388 1.00 55.96 H2 IB 0 -31.977 1.00 60.61 H21B N -32.952 1.00 64.41 H21B c -32.479 1.00 65.66 H21B c -31.206 1.00 66.78 H21B c -30.860 1.00 66.57 . H21B 0 -30.515 1.00 63.54 H21B N -34 .287 1.00 66.14 ' H21B c -35.031 1.00 66.39 H21B 0 435 WO 2009/026558 PCT/US2008/074097 ATOM 8739 N SER 158 95.211 44 ATOM 8740 CA SER 158 94.688 44 ATOM 8741 CB SER 158 95.198 44 ATOM 8742 OG SER 158 94.876 46 ATOM 8743 C SER 158 95.052 42 ATOM 8744 O SER 158 94.963 42 ATOM 8745 N GLY 159 95.4 64 41 ATOM 8746 CA GLY 159 95.792 40 ATOM 8747 C GLY 159 97.208 40 ATOM 8748 0 GLY 159 97.498 39 ATOM 8749 N ALA 160 98.093 41 ATOM 8750 CA ALA 160 99.512 41 ATOM 8751 CB ALA 160 100.271 42 ATOM 8752 C ALA 160 99.731 40 ATOM 8753 0 ALA 160 100.796 39 ATOM 8754 N LEU 161 98.716 40 ATOM 8755 CA LEU 161 98.813 40 ATOM 8756 CB LEU 161 98.713 41 ATOM 8757 CG LEU 161 99.008 41 ATOM 8758 CDl LEU 161 100.385 40 ATOM 8759 CD2 LEU 161 98.927 42 ATOM 8760 C LEU 161 97.703 39 ATOM 8761 O LEU 161 96.541 39 ATOM 8762 N THR 162 98.063 37 ATOM 8763 CA THR 162 97.090 36 ATOM 8764 CB THR 162 97.079 35 ATOM 8765 OG1 THR 162 98.431 35 ATOM 8766 CG2 THR 162 96.367 36 ATOM 8767 C THR 162 97.417 36 ATOM 8768 O THR 162 96.528 35 ATOM 8769 N SER 163 98.703 35 ATOM 8770 CA SER 163 99.130 35 ATOM 8771 CB SER 163 100.646 35 ATOM 8772 OG SER 163 101.019 33 ATOM 8773 C SER 163 98.720 36 ATOM 8774 O SER 163 98.861 37 ATOM 8775 N GLY 164 98.203 35 ATOM 8776 CA GLY 164 97.882 36 ATOM 8777 C GLY 164 96.541 36 ATOM 8778 0 GLY 164 96.106 37 ATOM 8779 N VAL 165 95.891 36 ATOM 8780 CA VAL 165 94.596 37 ATOM 8781 CB VAL 165 94.320 37 ATOM 8782 CGI VAL 165 92.857 38 ATOM 8783 CG2 VAL 165 95.225 38 ATOM 8784 C VAL 165 93.490 36 ATOM 8785 O VAL 165 93.344 35 ATOM 8786 N HIS 166 92.716 37 ATOM 8787 CA HIS 166 91.531 36 ATOM 8788 CB HIS 166 91.764 35 ATOM 8789 CG HIS 166 91.226 34 ATOM 8790 CD2 HIS 166 91.738 33 ATOM 8791 NDl HIS 166 90.012 34 ATOM 8792 CEl HIS 166 89.800 32 ATOM 8793 NE2 HIS 166 90.832 32 ATOM 8794 C HIS 166 90.306 37 ATOM 8795 0 HIS 166 90.182 38 ATOM 8796 N THR 167 89.406 36 ATOM 8797 CA THR 167 88.176 37 ATOM 8798 CB THR 167 87.855 37 ATOM 8799 OG1 THR 167 89.000 38 ATOM 8800 CG2 THR 167 86.705 38 ATOM 8801 C THR 167 86.994 36 ATOM 8802 O THR 167 86.444 36 ATOM 8803 N PHE 168 86.605 37 ATOM 8804 CA PHE 168 85.631 36 ATOM 8805 CB PHE 168 85.690 37 ATOM 8806 CG PHE 168 86.901 37 ATOM 8807 CDl PHE 168 88.035 37 ATOM 8808 CD2 PHE 168 86.896 35 ATOM 8809 CEl PHE 168 89.141 37 ATOM 8810 CE2 PHE 168 88.003 35 ATOM 8811 CZ PHE 168 89.122 36 ATOM 8812 C PHE 168 84.199 36 ATOM 8813 O PHE 168 83.829 37 ATOM 8814 N PRO 169 83.367 35
-34.558 1.00 67.60 H21B N -35.843 1.00 68.35 H21B C -36.968 1.00 68.48 H21B C -36.726 1.00 69.06 H21B 0 -36.141 1.00 69.01 H21B c -37.282 1.00 69.30 H21B 0 -35.103 1.00 69.36 H21B N -35.255 1.00 69.78 H21B c -34.819 1.00 70.12 H21B c -34.331 1.00 69.25 H21B 0 -34.985 1.00 71.83 H21B N -34.717 1.00 73.36 H21B c -34.871 1.00 73.77 H21B c -33.320 1.00 74.01 H21B c -33.022 1.00 75.23 H21B 0 -32.469 1.00 73.29 H21B N -31.093 1.00 71.19 H21B c -30.135 1.00 71.12 H21B c -28.659 1.00 7 0.62 H21B c -28.515 1.00 72.48 H21B c -27.897 1.00 69.65 H21B c -30.793 1.00 70.20 H21B c -30.655 1.00 69.33 H21B 0 -30.699 1.00 69.03 H21B N -30.376 1.00 69.44 H21B c -31.444 1.00 70.49 H21B c -31.752 1.00 72.93 H21B 0 -32.697 1.00 69.81 H21B c -29.024 1.00 69.37 H21B c -28.220 1.00 68.44 H21B 0 -28.773 1.00 68.77 H21B N -27.550 1.00 68.52 H21B c -27.577 1.00 68.30 H21B c -26.874 1.00 69.26 H21B 0 -26.319 1.00 68.15 H21B c -26.300 1.00 69.61 H21B 0 -25.300 1.00 66.79 H21B N -24.033 1.00 63.70 H21B c -24.043 1.00 61.53 H21B c -23.038 1.00 59.15 H21B 0 -25.200 1.00 60.65 H21B N -25.381 1.00 61.21 H21B c -26.867 1.00 60.77 H21B c -27.064 1.00 61.36 H21B c -27.365 1.00 61.58 H21B c -24.842 1.00 61.45 H21B c -25.271 1.00 62.50 H21B 0 -23.903 1.00 61.14 H21B N -23.404 1.00 61.29 H21B c -21.964 1.00 65.46 H21B c -21.675 1.00 72.03 H21B c -21.92 3 1.00 74.47 H21B c -21.051 1.00 74.85 H21B N -20.926 1.00 7 6.37 H21B c -21.447 1.00 76.73 H21B N -23.481 1.00 58.26 H21B C -22.728 1.00 57.57 H21B 0 -24.404 1.00 54.96 H21B N -24.574 1.00 52.16 H21B C -26.068 1.00 52.06 H21B c -26.743 1.00 52.50 H21B 0 -26.241 1.00 50.49 H21B c -23.883 1.00 49.74 H21B c -24.396 1.00 49.74 H21B 0 -22.722 1.00 46.79 H21B N -21.854 1.00 44.69 H21B c -20.469 1.00 42.76 H21B c -19.682 1.00 41.19 H21B c -19.707 1.00 40.51 H21B c -18.896 1.00 42.33 H21B c -18.962 1.00 40.25 H21B c -18.148 1.00 41.44 H21B c -18.180 1.00 40.34 . H21B c -22.373 1.00 43.71 H21B c -23.077 1.00 45.06 ' H21B 0 -22.014 1.00 42.61 H21B N 436 WO 2009/026558 PCT/US2008/074097 ATOM 8815 CD PRO 169 83.682 34 ATOM 8816 CA PRO 169 81.976 35 ATOM 8817 CB PRO 169 81.472 34 ATOM 8818 CG PRO 169 82.714 33 ATOM 8819 C PRO 169 81.201 37 ATOM 8820 O PRO 169 81.511 37 ATOM 8821 N ALA 170 80.201 37 ATOM 8822 CA ALA 170 79.512 38 ATOM 8823 CB ALA 170 78.573 39 ATOM 8824 C ALA 170 78.735 38 ATOM 8825 0 ALA 170 78.762 37 ATOM 8826 N VAL 171 78.049 39 ATOM 8827 CA VAL 171 77.162 39 ATOM 8828 CB VAL 171 77.784 40 ATOM 8829 CGI VAL 171 77.820 41 ATOM 8830 CG2 VAL 171 77.008 39 ATOM 8831 C VAL 171 75.921 40 ATOM 8832 O VAL 171 76.035 41 ATOM 8833 N LEU 172 74.742 39 ATOM 8834 CA LEU 172 73.507 40 ATOM 8835 CB LEU 172 72.403 39 ATOM 8836 CG LEU 172 72.171 39 ATOM 8837 CDl LEU 172 71.366 38 ATOM 8838 CD2 LEU 172 71.459 40 ATOM 8839 C LEU 172 73.088 41 ATOM 8840 O LEU 172 73.104 40 ATOM 8841 N GLN 173 72.719 42 ATOM 8842 CA GLN 173 72.562 43 ATOM 8843 CB GLN 173 72.867 45 ATOM 8844 CG GLN 173 74.312 45 ATOM 8845 CD GLN 173 75.172 45 ATOM 8846 OE1 GLN 173 74.729 45 ATOM 8847 NE2 GLN 173 76.410 46 ATOM 8848 C GLN 173 71.166 43 ATOM 8849 0 GLN 173 70.259 42 ATOM 8850 N SER 174 71.007 44 ATOM 8851 CA SER 174 69.697 44 ATOM 8852 CB SER 174 69.846 45 ATOM 8853 OG SER 174 70.638 46 ATOM 8854 C SER 174 68.839 45 ATOM 8855 O SER 174 67.741 45 ATOM 8856 N SER 175 69.352 45 ATOM 8857 CA SER 175 68.678 46 ATOM 8858 CB SER 175 69.153 47 ATOM 8859 OG SER 175 70.555 47 ATOM 8860 C SER 175 68.868 45 ATOM 8861 O SER 175 69.097 46 ATOM 8862 N GLY 176 68.769 44 ATOM 8863 CA GLY 176 68.736 43 ATOM 8864 C GLY 176 70.029 43 ATOM 8865 0 GLY 176 70.210 43 ATOM 8866 N LEU 177 70.931 44 ATOM 8867 CA LEU 177 72.141 45 ATOM 8868 CB LEU 177 72.484 46 ATOM 8869 CG LEU 177 71.501 47 ATOM 8870 CDl LEU 177 71.938 4 8 ATOM 8871 CD2 LEU 177 71.436 4 6 ATOM 8872 C LEU 177 73.357 44 ATOM 8873 O LEU 177 73.426 43 ATOM 8874 N TYR 178 74.312 44 ATOM 8875 CA TYR 178 75.484 43 ATOM 8876 CB TYR 178 75.706 42 ATOM 8877 CG TYR 178 74.710 41 ATOM 8878 CDl TYR 178 75.084 39 ATOM 8879 CEl TYR 178 74.190 38 ATOM 8880 CD2 TYR 178 73.400 41 ATOM 8881 CE2 TYR 178 72.499 40 ATOM 8882 CZ TYR 178 72.904 39 ATOM 8883 OH TYR 178 72.014 38 ATOM 8884 C TYR 178 76.790 43 ATOM 8885 O TYR 178 76.992 45 ATOM 8886 N SER 179 77.678 43 ATOM 8887 CA SER 179 79.030 43 ATOM 8888 CB SER 179 79.101 44 ATOM 8889 OG SER 179 78.480 45 ATOM 8890 C SER 179 80.025 42 -21.144 1.00 41.27 H21B c -22.477 1.00 42.04 H21B c -21.975 1.00 40 .17 H21B c -21.619 1.00 39.86 H21B c -21.867 1.00 41.81 H21B c -20.757 1.00 40.70 H21B 0 -22.587 1.00 41.85 H21B N -22.184 1.00 43.47 H21B c -23.285 1.00 42.59 H21B c -20.879 1.00 45.43 H21B c -20.255 1.00 46.51 H21B 0 -20.465 1.00 47.55 H21B N -19.323 1.00 50.15 H21B c -18.077 1.00 49.03 H21B c -18.287 1.00 46.37 H21B c -16.817 1.00 47.04 H21B c -19.788 1.00 54.76 H21B c -20.502 1.00 54.18 H21B 0 -19.423 1.00 60.45 H21B N -19.741 1.00 66.51 H21B c -20.094 1.00 69.05 H21B c -21.602 1.00 71.42 H21B c -21.963 1.00 70.43 H21B c -22.037 1.00 71.49 H21B c -18.564 1.00 69.67 H21B c -17.423 1.00 70.14 H21B 0 -18.851 1.00 73.42 H21B N -17.823 1.00 77.15 H21B c -18.404 1.00 79.75 H21B c -18.827 1.00 83.55 H21B c -17.698 1.00 85.89 H21B c -16.548 1.00 86.83 H21B 0 -18.020 1.00 87.03 H21B N -17.216 1.00 78.60 H21B c -17.669 1.00 79.70 H21B 0 -16.181 1.00 79.33 H21B N -15.607 1.00 79.53 H21B c -14.344 1.00 81.67 H21B c -14.601 1.00 84.74 H21B 0 -16.629 1.00 78.22 H21B c -16.306 1.00 77.64 H21B 0 -17.855 1.00 76.80 H21B N -18.916 1.00 74.39 H21B c -18.914 1.00 74.01 H21B c -19.114 1.00 75.07 H21B 0 -20.311 1.00 72.21 H21B c -21.280 1.00 71.78 H21B 0 -20.415 1.00 70.15 H21B N -21.728 1.00 66.86 H21B c -22.527 1.00 65.20 H21B c -23.485 1.00 64.83 H21B 0 -22.137 1.00 62.07 H21B N -22.913 1.00 57.24 H21B c -22.838 1.00 57.31 H21B c -23.584 1.00 57.05 H21B c -23.476 1.00 57 .20 H21B c -25.032 1.00 57.12 H21B c -22.511 1.00 54.53 H21B c -21.405 1.00 54.83 H21B 0 -23.428 1.00 51.17 H21B N -23.240 1.00 48.45 H21B c -24.488 1.00 50.40 H21B c -24.665 1.00 54.91 H21B c -24.470 1.00 56.36 H21B c -24.662 1.00 55.89 H21B c -25.057 1.00 56.50 H21B c -25.251 1.00 57.35 H21B c -25.052 1.00 56.84 H2 1B c -25.249 1.00 58.94 H21B 0 -22.922 1.00 45.48 H21B c -23.331 1.00 42.53 H21B 0 -22.203 1.00 42.07 H21B N -21.992 1.00 41.79 . H21B c -20.721 1.00 40.35 H21B c -20.886 1.00 39.39 H21B 0 -21.868 1.00 40.86 H21B c 437 WO 2009/026558 PCT/US2008/074097 ATOM 8891 0 SER 179 79.888 41 ATOM 8892 N LEU 180 81.025 42 ATOM 8893 CA LEU 180 82.168 41 ATOM 8894 CB LEU 180 82.356 40 ATOM 8895 CG LEU 180 82.521 41 ATOM 8896 CD1 LEU 180 83.775 42 ATOM 8897 CD2 LEU 180 82.624 40 ATOM 8898 C LEU 180 83.403 42 ATOM 8899 O LEU 180 83.321 43 ATOM 8900 N SER 181 84.540 42 ATOM 8901 CA SER 181 85.803 42 ATOM 8902 CB SER 181 86.069 43 ATOM 8903 OG SER 181 85.701 42 ATOM 8904 C SER 181 86.931 41 ATOM 8905 O SER 181 86.928 40 ATOM 8906 N SER 182 87.881 42 ATOM 8907 CA SER 182 88.983 41 ATOM 8908 CB SER 182 89.139 41 ATOM 8909 OG SER 182 90.164 40 ATOM 8910 C SER 182 90.262 41 ATOM 8911 O SER 182 90.544 43 ATOM 8912 N VAL 183 91.022 40 ATOM 8913 CA VAL 183 92.246 41 ATOM 8914 CB VAL 183 92.213 40 ATOM 8915 CGI VAL 183 93.340 39 ATOM 8916 CG2 VAL 183 92.335 41 ATOM 8917 C VAL 183 93.384 40 ATOM 8918 O VAL 183 93.262 39 ATOM 8919 N VAL 184 94.486 41 ATOM 8920 CA VAL 184 95.714 40 ATOM 8921 CB VAL 184 96.204 41 ATOM 8922 CGI VAL 184 96.653 42 ATOM 8923 CG2 VAL 184 97.322 40 ATOM 8924 C VAL 184 96.786 40 ATOM 8925 O VAL 184 96.842 41 ATOM 8926 N THR 185 97.604 39 ATOM 8927 CA THR 185 98.753 39 ATOM 8928 CB THR 185 98.912 38 ATOM 8929 OG1 THR 185 99.015 37 ATOM 8930 CG2 THR 185 97.728 38 ATOM 8931 C THR 185 100.028 40 ATOM 8932 O THR 185 100.246 39 ATOM 8933 N VAL 186 100.863 40 ATOM 8934 CA VAL 186 102.081 41 ATOM 8935 CB VAL 186 101.834 42 ATOM 8936 CGI VAL 186 100.857 42 ATOM 8937 CG2 VAL 186 101.306 43 ATOM 8938 C VAL 186 103.187 41 ATOM 8939 O VAL 186 102.917 42 ATOM 8940 N PRO 187 104.453 41 ATOM 8941 CD PRO 187 104.854 41 ATOM 8942 CA PRO 187 105.618 42 ATOM 8943 CB PRO 187 106.789 41 ATOM 8944 CG PRO 187 106.303 40 ATOM 8945 C PRO 187 105.524 43 ATOM 8946 O PRO 187 105.373 44 ATOM 8947 N SER 188 105.619 43 ATOM 8948 CA SER 188 105.532 45 ATOM 8949 CB SER 188 105.372 45 ATOM 8950 OG SER 188 106.304 44 ATOM 8951 C SER 188 106.756 45 ATOM 8952 O SER 188 106.805 47 ATOM 8953 N SER 189 107.746 45 ATOM 8954 CA SER 189 108.873 46 ATOM 8955 CB SER 189 109.991 45 ATOM 8956 OG SER 189 109.521 43 ATOM 8957 C SER 189 108.413 46 ATOM 8958 O SER 189 108.841 47 ATOM 8959 N SER 190 107.530 45 ATOM 8960 CA SER 190 107.110 46 ATOM 8961 CB SER 190 106.444 45 ATOM 8962 OG SER 190 106.386 45 ATOM 8963 C SER 190 106.156 47 ATOM 8964 O SER 190 105.962 48 ATOM 8965 N LEU 191 105.562 47 ATOM 8966 CA LEU 191 104.711 48 -20.998 1.00 41.44 H21B 0 -22.740 1.00 39.48 H21B N -22.495 1.00 38.55 H21B C -23.644 1.00 38.54 H21B c -25.080 1.00 39.73 H21B c -25.212 1.00 40.85 H21B c. -26.010 1.00 39.95 H21B c -22.334 1.00 38.44 H21B c -22.463 1.00 38.53 H21B 0 -22.033 1.00 37.53 H21B N -22.001 1.00 37.68 H21B c -20.607 1.00 37.05 H21B c -19.566 1.00 37.89 H21B 0 -22.408 1.00 38.52 H21B c -22.067 1.00 38.90 H21B 0 -23.174 1.00 39.83 H21B N -23.659 1.00 39.81 H21B c -25.166 1.00 39.45 H21B c -25.641 1.00 41.46 H21B 0 -22.964 1.00 40.20 H21B c -22.828 1.00 38.40 H21B 0 -22.507 1.00 40.90 H21B N -21.767 1.00 42.48 H21B c -20.356 1.00 41.50 H21B c -20.229 1.00 41.59 H21B c -19.273 1.00 40.00 H21B c -22.544 1.00 43.84 H21B c -23.007 1.00 43.94 H21B 0 -22.694 1.00 44.89 H21B N -23.142 1.00 47.11 H21B c -24.477 1.00 45.90 H21B c -24 .269 1.00 45.60 H21B c -25.050 1.00 46.59 H21B c -22.053 1.00 49.55 H21B c -21.353 1.00 48.61 H21B 0 -21.887 1.00 51.80 H21B N -20.986 1.00 54 .28 H21B c -20.125 1.00 55 .24 H21B c -20.977 1.00 57.32 H21B 0 -19.188 1.00 56.03 H21B c -21.791 1.00 57.09 H21B c -22.793 1.00 56.47 H21B 0 -21.340 1.00 60.48 H21B N -22.045 1.00 63.14 H21B c -22.931 1.00 63.28 H21B c -24.023 1.00 63.21 H21B c -22.082 1.00 63.11 H21B c -21.059 1.00 67.74 H21B c -19.909 1.00 67.37 H21B 0 -21.505 1.00 72.12 H21B N -22.788 1.00 71.71 H21B c -20.718 1.00 73.03 H21B c -21.659 1.00 72.51 H21B c -22.576 1.00 71.49 H21B c -20.312 1.00 76.95 H21B c -21.165 1.00 78.69 H21B 0 -19.009 1.00 80.50 H21B N -18.464 1.00 82.60 H21B c -16.946 1.00 82.32 H21B c -16.387 1.00 81.51 H21B 0 -18.819 1.00 83.71 H21B c -18.543 1.00 84 .16 H21B 0 -19.420 1.00 84.52 H21B N -20.027 1.00 85.15 H21B c -20.320 1.00 84.73 H21B c -21.154 1.00 84 . 01 H21B 0 -21.328 1.00 86.33 H21B c -21.675 1.00 85.19 H 2 1B 0 -22.042 1.00 87.47 H21B N -23.361 1.00 88.98 H21B c -24.102 1.00 89.63 H21B c -25.496 1.00 90.22 H21B 0 -23.282 1.00 88.95 • H21B c -24.264 1.00 89.75 H21B 0 -22.113 1.00 88.06 H21B N -21.912 1.00 87.45 H21B c 438 WO 2009/026558 PCT/US2008/074097 ATOM 8967 CB LEU 191 104.184 49 ATOM 8968 CG LEU 191 103.411 47 ATOM 8969 CDl LEU 191 103.043 47 ATOM 8970 CD2 LEU 191 102.159 47 ATOM 8971 C LEU 191 105.534 50 ATOM 8972 O LEU 191 106.747 50 ATOM 8973 N GLY 192 104.882 51 ATOM 8974 CA GLY 192 105.593 52 ATOM 8975 C GLY 192 106.283 52 ATOM 8976 O GLY 192 106.279 53 ATOM 8977 N THR 193 106.877 51 ATOM 8978 CA THR 193 107.531 51 ATOM 8979 CB THR 193 108.976 50 ATOM 8980 OG1 THR 193 108.990 49 ATOM 8981 CG2 THR 193 109.791 51 ATOM 8982 C THR 193 106.795 50 ATOM 8983 O THR 193 107.223 50 ATOM 8984 N GLN 194 105.695 49 ATOM 8985 CA GLN 194 104.795 49 ATOM 8986 CB GLN 194 104.771 47 ATOM 8987 CG GLN 194 103.816 46 ATOM 8988 CD GLN 194 104.129 46 ATOM 8989 OE1 GLN 194 104.621 47 ATOM 8990 NE2 GLN 194 103.844 45 ATOM 8991 C GLN 194 103.381 49 ATOM 8992 0 GLN 194 102.820 49 ATOM 8993 N THR 195 102.813 49 ATOM 8994 CA THR 195 101.447 50 ATOM 8995 CB THR 195 101.205 51 ATOM 8996 OG1 THR 195 101.519 50 ATOM 8997 CG2 THR 195 102.077 52 ATOM 8998 C THR 195 100.521 49 ATOM 8999 O THR 195 100.749 48 ATOM 9000 N TYR 196 99.487 49 ATOM 9001 CA TYR 196 98.466 48 ATOM 9002 CB TYR 196 98.425 47 ATOM 9003 CG TYR 196 99.661 46 ATOM 9004 CDl TYR 196 100.738 47 ATOM 9005 CEl TYR 196 101.898 46 ATOM 9006 CD2 TYR 196 99.773 45 ATOM 9007 CE2 TYR 196 100.927 44 ATOM 9008 CZ TYR 196 101.987 45 ATOM 9009 OH TYR 196 103.143 44 ATOM 9010 C TYR 196 97.109 48 ATOM 9011 O TYR 196 96.591 49 ATOM 9012 N ILE 197 96.553 48 ATOM 9013 CA ILE 197 95.256 48 ATOM 9014 CB ILE 197 95.323 49 ATOM 9015 CG2 ILE 197 93.937 49 ATOM 9016 CGI ILE 197 96.218 50 ATOM 9017 CDl ILE 197 96.068 51 ATOM 9018 C ILE 197 94.266 47 ATOM 9019 0 ILE 197 94.502 46 ATOM 9020 N CYS 198 93.148 47 ATOM 9021 CA CYS 198 92.029 46 ATOM 9022 C CYS 198 91.039 47 ATOM 9023 O CYS 198 90.588 4 8 ATOM 9024 CB CYS 198 91.394 46 ATOM 9025 SG CYS 198 89.863 47 ATOM 9026 N ASN 199 90.735 46 ATOM 9027 CA ASN 199 89.775 47 ATOM 9028 CB ASN 199 90.440 47 ATOM 9029 CG ASN 199 91.497 46 ATOM 9030 OD1 ASN 199 91.202 44 ATOM 9031 ND2 ASN 199 92.743 46 ATOM 9032 C ASN 199 88.541 46 ATOM 9033 0 ASN 199 88.638 45 ATOM 9034 N VAL 200 87.384 46 ATOM 9035 CA VAL 200 86.151 46 ATOM 9036 CB VAL 200 85.492 46 ATOM 9037 CGI VAL 200 84.361 45 ATOM 9038 CG2 VAL 200 86.530 47 ATOM 9039 C VAL 200 85.173 46 ATOM 9040 O VAL 200 85.173 47 ATOM 9041 N ASN 201 84.338 45 ATOM 9042 CA ASN 201 83.464 45 -20.474 1.00 86.50 H21B c -19.980 1.00 84.98 H21B c -18.519 1.00 83.28 H21B c -20.819 1.00 84.31 H21B c -22.192 1.00 88.10 H21B c -21.974 1.00 88.98 H21B 0 -22.686 1.00 88.53 H21B N -22.956 1.00 89.47 H21B c -24.314 1.00 90.10 H21B c -24.971 1.00 90.36 H21B 0 -24.739 1.00 89.29 H21B N -26.043 1.00 88.82 H21B c -25.928 1.00 88.80 H21B c -25.336 1.00 89.49 H21B 0 -25.080 1.00 88.67 H21B c -26.992 1.00 88.83 H21B c -28.129 1.00 88.87 H21B 0 -26.515 1.00 88.58 H21B N -27.387 1.00 87.54 H21B c -27.010 1.00 87.84 H21B c -27.853 1.00 87.81 H21B c -29.333 1.00 87.69 H21B c -29.844 1.00 88.63 H21B 0 -30.033 1.00 88.04 H21B N -27.337 1.00 86.21 H21B c -26.264 1.00 85.43 H21B 0 -28.514 1.00 84.94 H21B N -28.602 1.00 8 3.65 H21B c -29.918 1.00 84.72 H21B c -31.043 1.00 84.98 H21B 0 -29.959 1.00 85.59 H21B c -28.547 1.00 80.85 H21B c -29.227 1.00 79.88 H21B 0 -27.719 1.00 78.25 H21B N -27.700 1.00 76.01 H21B c -26.326 1.00 77.54 H21B c -26.046 1.00 79.65 H21B c -25.342 1.00 81.11 H21B c -25.132 1.00 81.59 H21B c -26.528 1.00 80.81 H21B c -26.323 1.00 81.26 H21B c -25.628 1.00 81.91 H21B c -25.455 1.00 81.33 H21B 0 -28.059 1.00 73.03 H21B c -27.362 1.00 72.39 H21B 0 -29.170 1.00 68.83 H21B N -29.634 1.00 64.42 H21B c -31.055 1.00 63.76 H21B c -31.516 1.00 59.55 H21B c -31.064 1.00 63.89 H21B c -32.321 1.00 66.94 H21B c -29.670 1.00 61.31 H21B c -30.296 1.00 61.15 H21B 0 -28.990 1.00 57.57 H21B N -29.052 1.00 52.01 H21B c -30.085 1.00 47.01 H21B c -30.004 1.00 44 . 41 H21B 0 -27.665 1.00 52.51 H21B c -27.408 1.00 57.12 H21B s -31.088 1.00 44.35 H21B N -32.096 1.00 42.24 H21B c -33.472 1.00 41.57 H21B c -33.630 1.00 39.25 H21B c -33.614 1.00 37.00 H21B 0 -33.779 1.00 37.76 H21B N -32.110 1.00 40.58 H21B c -32.287 1.00 39.56 H21B 0 -31.919 1.00 39.66 H21B N -31.582 1.00 40.25 H21B c -30.333 1.00 38.62 H21B c -29.842 1.00 37.80 H21B c -29.237 1.00 35.75 H21B c -32.748 1.00 41.51 . H21B c -33.515 1.00 41.66 H21B 0 -32.887 1.00 43.17 ' H21B N -34.034 1.00 4 6.02 H21B c 439 WO 2009/026558 PCT/US2008/074097 ATOM 9043 CB ASN 201 84.057 44 ATOM 9044 CG ASN 201 84.087 44 ATOM 9045 OD1 ASN 201 83.056 45 ATOM 9046 ND2 ASN 201 85.273 45 ATOM 9047 C ASN 201 82.092 44 ATOM 9048 0 ASN 201 81.946 43 ATOM 9049 N HIS 202 81.082 45 ATOM 9050 CA HIS 202 79.718 45 ATOM 9051 CB HIS 202 79.070 45 ATOM 9052 CG HIS 202 77.789 45 ATOM 9053 CD2 HIS 202 77.351 44 ATOM 9054 NDl HIS 202 7 6.7 62 46 ATOM 9055 CEl HIS 202 75.743 45 ATOM 9056 NE2 HIS 202 76.076 44 ATOM 9057 C HIS 202 78.942 45 ATOM 9058 0 HIS 202 78.308 46 ATOM 9059 N LYS 203 78.987 43 ATOM 9060 CA LYS 203 78.283 43 ATOM 9061 CB LYS 203 78.396 42 ATOM 9062 CG LYS 203 79.807 42 ATOM 9063 CD LYS 203 80.169 40 ATOM 9064 CE LYS 203 79.219 39 ATOM 9065 NZ LYS 203 79.247 38 ATOM 9066 C LYS 203 76.815 44 ATOM 9067 0 LYS 203 76.298 45 ATOM 9068 N PRO 204 76.129 43 ATOM 9069 CD PRO 204 76.587 42 ATOM 9070 CA PRO 204 74.703 44 ATOM 9071 CB PRO 204 74.311 43 ATOM 9072 CG PRO 204 75.294 42 ATOM 9073 C PRO 204 74.460 45 ATOM 9074 O PRO 204 73.498 46 ATOM 9075 N SER 205 75.354 46 ATOM 9076 CA SER 205 75.254 47 ATOM 9077 CB SER 205 75.774 48 ATOM 9078 OG SER 205 75.929 49 ATOM 9079 C SER 205 76.016 48 ATOM 9080 O SER 205 75.883 49 ATOM 9081 N ASN 206 76.810 47 ATOM 9082 CA ASN 206 77.655 48 ATOM 9083 CB ASN 206 76.796 48 ATOM 9084 CG ASN 206 76.283 47 ATOM 9085 OD1 ASN 206 75.156 48 ATOM 9086 ND2 ASN 206 77.112 46 ATOM 9087 C ASN 206 78.556 49 ATOM 9088 0 ASN 206 78.725 50 ATOM 9089 N THR 207 79.129 49 ATOM 9090 CA THR 207 79.997 49 ATOM 9091 CB THR 207 79.431 50 ATOM 9092 OG1 THR 207 78.105 50 ATOM 9093 CG2 THR 207 80.305 51 ATOM 9094 C THR 207 81.368 49 ATOM 9095 O THR 207 81.475 48 ATOM 9096 N LYS 208 82.414 49 ATOM 9097 CA LYS 208 83.765 49 ATOM 9098 CB LYS 208 84.490 49 ATOM 9099 CG LYS 208 85.846 4 8 ATOM 9100 CD LYS 208 86.654 48 ATOM 9101 CE LYS 208 86.050 47 ATOM 9102 NZ LYS 208 84.704 48 ATOM 9103 C LYS 208 84.519 50 ATOM 9104 0 LYS 208 84.623 51 ATOM 9105 N VAL 209 85.029 50 ATOM 9106 CA VAL 209 85.791 51 ATOM 9107 CB VAL 209 85.220 51 ATOM 9108 CGI VAL 209 86.086 51 ATOM 9109 CG2 VAL 209 83.807 51 ATOM 9110 C VAL 209 87.236 50 ATOM 9111 O VAL 209 87.520 49 ATOM 9112 N ASP 210 88.156 51 ATOM 9113 CA ASP 210 89.555 51 ATOM 9114 CB ASP 210 90.434 51 ATOM 9115 CG ASP 210 90.104 50 ATOM 9116 OD1 ASP 210 89.597 49 ATOM 9117 OD2 ASP 210 90.351 51 ATOM 9118 C ASP 210 89.999 52 -35.117 1.00 50.18 H21B c -36.485 1.00 53.80 H21B c -36.991 1.00 55.38 H21B 0 -37.089 1.00 55.20 H21B N -33.657 1.00 46.12 H21B c -33.017 1.00 45.78 H21B 0 -34.065 1.00 46.00 H21B N -33.829 1.00 46.36 H21B c -32.815 1.00 44 .13 H21B c -32.269 1.00 42.81 H21B c -32.119 1.00 40.00 H21B c -31.849 1.00 43.89 H21B N -31.468 1.00 42.77 H21B c -31.623 1.00 40.89 H21B N -35.135 1.00 48.29 H21B C -35.461 1.00 48.19 H21B 0 -35.880 1.00 50.80 H21B N -37.151 1.00 53.50 H21B C -37.777 1.00 54.50 H21B c -38.238 1.00 59.30 H21B c -37.915 1.00 63.35 H21B c -38.598 1.00 66.63 H21B c -38.006 1.00 69.31 H21B N -36.977 1.00 52.84 H21B c -37.715 1.00 53.76 H21B 0 -35.979 1.00 51.43 H21B N -34.926 1.00 50.05 H21B c -35.850 1.00 51.46 H21B c -34.523 1.00 48.83 H21B c -34.338 1.00 48.98 H21B c -35.845 1.00 51.76 H21B c -36.431 1.00 52.73 H21B 0 -35.187 1.00 52.99 H21B N -35.096 1.00 53.35 H21B c -33.744 1.00 53.63 H21B c -33.733 1.00 54.28 H21B 0 -36.203 1.00 53.57 H21B c -36.354 1.00 53.69 H21B 0 -36.975 1.00 54.02 H21B N -37.986 1.00 54.69 H21B c -39.077 1.00 52.53 H21B c -40.060 1.00 52.56 H21B c -40.540 1.00 51.22 H21B 0 -40.373 1.00 51.22 H21B N -37.350 1.00 55.72 H21B c -37.867 1.00 56.49 H21B 0 -36.211 1.00 5 6.16 H21B N -35.464 1.00 55.85 H21B c -34.056 1.00 55.15 H21B c -34.155 1.00 52.50 H21B 0 -33.282 1.00 53.38 H21B c -35.354 1.00 57.06 H21B c -35.000 1.00 56.67 H21B 0 -35.675 1.00 58.26 H21B N -35.437 1.00 59.43 H21B c -36.756 1.00 62.37 H21B c -36.585 1.00 68.71 H21B c -37.877 1.00 76.76 H21B c -38.944 1.00 85.44 H21B c -39.439 1.00 94.28 H21B N -34.629 1.00 57.52 H21B c -35.036 1.00 58.10 H21B 0 -33.476 1.00 54.42 H21B N -32.604 1.00 50.92 H21B c -31.177 1.00 48.81 H21B c -30.313 1.00 48.17 H21B c -31.188 1.00 46.41 H21B c -32.491 1.00 4 9.62 H21B c -32.274 1.00 48.07 H21B 0 -32.626 1.00 50.05 H21B N -32.331 1.00 51.15 H21B c -33.551 1.00 53.47 H21B c -34.753 1.00 57.01 . H21B c -34.558 1.00 57.51 H21B 0 -35.903 1.00 60.50 ' H21B 0 -31.128 1.00 49.56 H21B c 440 WO 2009/026558 PCT/US2008/074097
ATOM 9119 0 ASP 210 89.709 53 ATOM 9120 N LYS 211 90.688 51 ATOM 9121 CA LYS 211 91.069 52 ATOM 9122 CB LYS 211 90.181 51 ATOM 9123 CG LYS 211 90.526 52 ATOM 9124 CD LYS 211 90.131 53 ATOM 9125 CE LYS 211 88.626 53 ATOM 9126 NZ LYS 211 88.191 55 ATOM 9127 C LYS 211 92.518 51 ATOM 9128 0 LYS 211 92.950 50 ATOM 9129 N LYS 212 93.276 52 ATOM 9130 CA LYS 212 94.631 52 ATOM 9131 CB LYS 212 95.538 53 ATOM 9132 CG LYS 212 96.779 53 ATOM 9133 CD LYS 212 97.512 55 ATOM 9134 CE LYS 212 98.557 55 ATOM 9135 NZ LYS 212 99.718 54 ATOM 9136 C LYS 212 94.581 52 ATOM 9137 0 LYS 212 94.098 53 ATOM 9138 N VAL 213 95.070 51 ATOM 9139 CA VAL 213 95.155 51 ATOM 9140 CB VAL 213 94.782 49 ATOM 9141 CGI VAL 213 94.776 49 ATOM 9142 CG2 VAL 213 93.427 49 ATOM 9143 C VAL 213 96.564 51 ATOM 9144 O VAL 213 97.507 50 ATOM 9145 N GLU 214 96.688 52 ATOM 9146 CA GLU 214 97.975 53 ATOM 9147 CB GLU 214 98.196 54 ATOM 9148 CG GLU 214 98.423 54 ATOM 9149 CD GLU 214 98.686 56 ATOM 9150 OE1 GLU 214 99.337 56 ATOM 9151 OE2 GLU 214 98.239 57 ATOM 9152 C GLU 214 98.009 53 ATOM 9153 0 GLU 214 96.981 52 ATOM 9154 N PRO 215 99.199 53 ATOM 9155 CD PRO 215 100.495 52 ATOM 9156 CA PRO 215 99.349 53 ATOM 9157 CB PRO 215 100.858 53 ATOM 9158 CG PRO 215 101.419 52 ATOM 9159 C PRO 215 98.620 54 ATOM 9160 O PRO 215 98.343 55 ATOM 9161 N LYS 216 98.315 54 ATOM 9162 CA LYS 216 97.499 55 ATOM 9163 CB LYS 216 97.121 54 ATOM 9164 CG LYS 216 96.487 53 ATOM 9165 CD LYS 216 96.274 53 ATOM 9166 CE LYS 216 95.639 51 ATOM 9167 NZ LYS 216 95.637 51 ATOM 9168 C LYS 216 98.209 56 ATOM 9169 0 LYS 216 98.520 57 ATOM 9170 OXT LYS 216 98.451 57 TER 9171 LYS 216 END -31.033 1.00 47.85 H21B 0 -30.197 1.00 48.61 H21B N -28.969 1.00 50.47 H21B C -27.828 1.00 48.97 H21B c -26.501 1.00 48.07 H21B c -26.478 1.00 51.05 H21B _c -26.489 1.00 53.67 H21B c -26.529 1.00 57.46 H21B N -28.647 1.00 52.98 H21B c -28.718 1.00 52.69 H21B 0 -28.304 1.00 56.95 H21B N -27.835 1.00 59.46 H21B c -28 .284 1.00 61.77 H21B c -27.410 1.00 65.33 H21B c -27.743 1.00 70.28 H21B c -28.832 1.00 74.23 H21B c -28.339 1.00 79.11 H21B N -26.326 1.00 60.12 H21B c -25.670 1.00 59.63 H21B 0 -25.774 1.00 62.31 H21B N -24.329 1.00 65.85 H21B c -23.860 1.00 64.74 H21B c -22.337 1.00 62.94 H21B c -24.422 1.00 63.10 H21B c -23.875 1.00 68.37 H21B c -24.208 1.00 66.85 H21B 0 -23.120 1.00 73.64 H21B N -22.615 1.00 79.85 H21B c -22.980 1.00 80.72 H21B c -24.465 1.00 83.09 H21B c -24.731 1.00 84.01 H21B c -25.748 1.00 84.45 H21B 0 -23.916 1.00 84.49 H21B 0 -21.100 1.00 83.59 H21B c -20.463 1.00 83.78 H21B 0 -20.505 1.00 86.98 H21B N -21.181 1.00 87.43 H21B c -19.049 1.00 91.94 H21B c -18.852 1.00 90.16 H21B c -20.051 1.00 88.99 H21B c -18.466 1.00 96.26 H21B c -19.167 1.00 96.59 H21B 0 -17.177 1.00102.66 H21B N -16.521 1.00109.92 H21B c -15.109 1.00114.68 H21B c -15.053 1.00120.32 H21B c -13.613 1.00126.26 H21B c -13.570 1.00131.57 H21B c -12.205 1.00135.66 H21B N -16.448 1.00111.87 H21B c -15.326 1.00113.12 H21B 0 -17.519 1.00114.65 H21B H21B 0 441 WO 2009/026558 PCT/US2008/074097
TABLE 35.4 ATOM 1 CB TRP 453 -29.096 34.072 11.297 1.00 62.90 A C ATOM 2 CG TRP 453 -28.288 34.936 10.370 1.00 64.93 A C ATOM 3 CD2 TRP 453 -27.397 34.492 9.339 1.00 66.49 A C ATOM 4 CE2 TRP 453 -26.843 35.642 8.742 1.00 67.05 A c ATOM 5 CE3 TRP 453 -27.013 33.233 8.865 1.00 67.25 A c ATOM 6 CDl TRP 453 -28.241 36.301 10.353 1.00 65.59 A c ATOM 7 NEl TRP 453 -27.375 36.733 9.378 1.00 65.65 A N ATOM 8 CZ2 TRP 453 -25.924 35.571 7.694 1.00 67.23 A c ATOM 9 CZ3 TRP 453 -26.100 33.165 7.824 1.00 67.18 A c ATOM 10 CH2 TRP 453 -25.566 34.327 7.252 1.00 67.55 A c ATOM 11 C TRP 453 -27.142 33.092 12.528 1.00 59.11 A c ATOM 12 O TRP 453 -26.061 33.624 12.777 1.00 59.88 A 0 ATOM 13 N TRP 453 -28.207 35.189 13.329 1.00 61.20 A N ATOM 14 CA TRP 453 -28.450 33.869 12.675 1.00 60.89 A c ATOM 15 N GLN 454 -27.248 31.827 12.137 1.00 55.81 A N ATOM 16 CA GLN 454 -26.072 30.981 11.962 1.00 52.32 A C ATOM 17 CB GLN 454 -26.117 29.821 12.962 1.00 54.31 A c ATOM 18 CG GLN 454 -25.914 28.448 12.353 1.00 57.49 A c ATOM 19 CD GLN 454 -24.637 27.773 12.827 1.00 59.72 A c ATOM 20 OE1 GLN 454 -23.617 28.430 13.055 1.00 60.00 A 0 ATOM 21 NE2 GLN 454 -24.688 26.450 12.973 1.00 59.65 A N ATOM 22 C GLN 454 -2 6.011 30.456 10.530 1.00 47.73 A c ATOM 23 0 GLN 454 -27.041 30.329 9.867 1.00 46.06 A 0 ATOM 24 N LEU 455 -24.808 30.158 10.049 1.00 43.78 A N ATOM 25 CA LEU 455 -24.651 29.736 8.658 1.00 41.00 A c ATOM 26 CB LEU 455 -23.386 30.356 8.063 1.00 41.51 A c ATOM 27 CG LEU 455 -23.082 30.107 6.583 1.00 41.00 A c ATOM 28 CDl LEU 455 -24.272 30.468 5.716 1.00 39.45 A c ATOM 29 CD2 LEU 455 -21.874 30.934 6.191 1.00 42.57 A c ATOM 30 C LEU 455 -24.602 28.217 8.531 1.00 38.55 A c ATOM 31 O LEU 455 -23.744 27.562 9.122 1.00 38.78 A 0 ATOM 32 N PHE 456 -25.540 27.665 7.766 1.00 34.53 A N ATOM 33 CA PHE 456 -25.605 26.226 7.524 1.00 32.19 A c ATOM 34 CB PHE 456 -27.039 25.715 7.711 1.00 30.96 A c ATOM 35 CG PHE 456 -27.517 25.742 9.135 1.00 30.83 A c ATOM 36 CDl PHE 456 -27.303 24.657 9.973 1.00 29.93 A c ATOM 37 CD2 PHE 456 -28.186 26.850 9.636 1.00 30.09 A c ATOM 38 CEl PHE 456 -27.749 24.675 11.291 1.00 30.85 A c ATOM 39 CE2 PHE 456 -28.635 26.877 10.952 1.00 31.15 A c ATOM 40 CZ PHE 456 -28.417 25.789 11.781 1.00 29.38 A c ATOM 41 C PHE 456 -25.154 25.915 6.100 1.00 30.99 A c ATOM 42 O PHE 456 -25.649 26.508 5.148 1.00 30.86 A 0 ATOM 43 N CYS 457 -24.222 24.981 5.957 1.00 30.33 A N ATOM 44 CA CYS 457 -23.812 24.518 4.636 1.00 29.83 A c ATOM 45 C CYS 457 -23.729 23.002 4.598 1.00 29.43 A c ATOM 46 0 CYS 457 -23.477 22.357 5.617 1.00 30.24 A 0 ATOM 47 CB CYS 457 -22.442 25.067 4.260 1.00 30.42 A c ATOM 48 SG CYS 457 -22.270 26.868 4.126 1.00 33.48 A s ATOM 49 N ARG 458 -23.932 22.440 3.412 1.00 28.73 A N ATOM 50 CA ARG 458 -23.732 21.013 3.192 1.00 27.98 A c ATOM 51 CB ARG 458 -25.082 20.295 3.128 1.00 27.46 A c ATOM 52 CG ARG 458 -25.982 20.816 2.021 1.00 27.71 A c ATOM 53 CD ARG 458 -27.371 20.197 2.092 1.00 28.19 A c ATOM 54 NE ARG 458 -28.104 20.474 0.864 1.00 28.26 A N ATOM 55 CZ ARG 458 -28.211 19.619 -0.150 1.00 28.99 A c ATOM 56 NHl ARG 458 -28.891 19.965 -1.235 1.00 28.33 A N ATOM 57 NH2 ARG 458 -27.651 18.416 -0.073 1.00 26.24 A N ATOM 58 C ARG 458 -22.969 20.809 1.889 1.00 26.26 A C ATOM 59 O ARG 458 -22.870 21.721 1.074 1.00 25.98 A 0 ATOM 60 N THR 459 -22.425 19.612 1.705 1.00 24.49 A N ATOM 61 CA THR 459 -21.655 19.296 0.520 1.00 24.90 A C ATOM 62 CB THR 459 -20.334 18.588 0.898 1.00 25.10 A c ATOM 63 OG1 THR 459 -19.493 19.502 1.608 1.00 25.42 A 0 ATOM 64 CG2 THR 459 -19.609 18.094 -0.344 1.00 22.93 A c ATOM 65 C THR 459 -22.476 18.383 -0.379 1.00 26.20 A . c ATOM 66 O THR 459 -23.093 17.428 0.093 1.00 24.85 A 0 ATOM 67 N VAL 460 -22.493 18.690 -1.672 1.00 26.69 A N ATOM 68 CA VAL 460 -23.209 17.869 -2.637 1.00 27.29 A c ATOM 69 CB VAL 460 -24.313 18.676 -3.343 1.00 29.26 A c ATOM 70 CGI VAL 460 -24.981 17.823 -4.419 1.00 26.28 A c ATOM 71 CG2 VAL 460 -25.339 19.146 -2.317 1.00 30.35 * A c ATOM 72 C VAL 460 -22.264 17.321 -3.693 1.00 27.26 . A c ATOM 73 O VAL 460 -21.661 18.078 -4.451 1.00 29.73 A 0 ATOM 74 N TRP 461 -22.140 16.001 -3.740 1.00 26.25 A N 442 WO 2009/026558 PCT/US2008/074097 ATOM 75 CA TRP 461 -21.368 15 ATOM 76 CB TRP 461 -20.764 14 ATOM 77 CG TRP 461 -19.606 14 ATOM 78 CD2 TRP 461 -18.218 13 ATOM 79 CE2 TRP 461 -17.494 14 ATOM 80 CE3 TRP 461 -17.520 13 ATOM 81 CDl TRP 461 -19.660 14 ATOM 82 NEl TRP 461 -18.397 14 ATOM 83 CZ2 TRP 461 -16.103 14 ATOM 84 CZ3 TRP 461 -16.135 13 ATOM 85 CH2 TRP 461 -15.444 13 ATOM 86 C TRP 461 -22.264 15 ATOM 87 O TRP 461 -23.406 14 ATOM 88 N SER 4 62 -21.745 15 ATOM 89 CA SER 4 62 -22.428 15 ATOM 90 CB SER 4 62 -21.732 15 ATOM 91 OG SER 4 62 -20.463 15 ATOM 92 C SER 4 62 -22.384 13 ATOM 93 O SER 462 -21.641 12 ATOM 94 N ALA 463 -23.176 13 ATOM 95 CA ALA 463 -22.921 11 ATOM 96 CB ALA 463 -24.042 11 ATOM 97 C ALA 463 -21.578 11 ATOM 98 O ALA 463 -21.131 12 ATOM 99 N HIS 464 -20.939 10 ATOM 100 CA HIS 464 -19.723 10 ATOM 101 CB HIS 464 -19.297 9 ATOM 102 CG HIS 464 -17.948 8 ATOM 103 CD2 HIS 464 -16.713 8 ATOM 104 NDl HIS 464 -17.772 8 ATOM 105 CEl HIS 464 -16.488 8 ATOM 106 NE2 HIS 464 -15.824 8 ATOM 107 C HIS 464 -19.977 11 ATOM 108 0 HIS 464 -21.080 11 ATOM 109 N SER 465 -18.959 11 ATOM 110 CA SER 465 -19.143 12 ATOM 111 CB SER 465 -17.936 13 ATOM 112 OG SER 465 -16.774 12 ATOM 113 C SER 465 -19.348 11 ATOM 114 O SER 465 -19.898 12 ATOM 115 N GLY 466 -18.890 10 ATOM 116 CA GLY 466 -18.715 9 ATOM 117 C GLY 466 -17.259 9 ATOM 118 0 GLY 466 -16.583 10 ATOM 119 N PRO 467 -16.741 8 ATOM 120 CD PRO 4 67 -17.448 7 ATOM 121 CA PRO 467 -15.304 8 ATOM 122 CB PRO 4 67 -15.085 7 ATOM 123 CG PRO 467 -16.374 6 ATOM 124 C PRO 4 67 -14.787 9 ATOM 125 O PRO 467 -13.596 9 ATOM 126 N THR 468 -15.660 9 ATOM 127 CA THR 468 -15.174 10 ATOM 128 CB THR 468 -16.305 10 ATOM 129 OG1 THR 468 -17.407 11 ATOM 130 CG2 THR 468 -16.766 8 ATOM 131 C THR 468 -14.503 11 ATOM 132 O THR 468 -14.594 12 ATOM 133 N ARG 469 -13.832 12 ATOM 134 CA ARG 469 -12.874 13 ATOM 135 CB ARG 469 -12.178 13 ATOM 136 CG ARG 469 -11.111 14 ATOM 137 CD ARG 469 -10.439 14 ATOM 138 NE ARG 469 -9.440 15 ATOM 139 CZ ARG 469 -8.581 15 ATOM 140 NHl ARG 469 -7.711 16 ATOM 141 NH2 ARG 469 -8.591 14 ATOM 142 C ARG 469 -13.495 14 ATOM 143 O ARG 469 -12.891 15 ATOM 144 N MET 470 -14.698 14 ATOM 145 CA MET 470 -15.328 16 ATOM 146 CB MET 470 -15.904 16 ATOM 147 CG MET 470 -15.563 18 ATOM 148 SD MET 470 -13.788 18 ATOM 149 CE MET 470 -13.271 17 ATOM 150 C MET 470 -16.425 15 -4.788 1.00 26.76 A C -4 .268 1.00 24.57 A C -3.334 1.00 24.74 A C -3.613 1.00 24.43 A c -2.447 1.00 25.75 A c -4.736 1.00 26.44 A c -2.046 1.00 23.71 A c -1.507 1.00 25.76 A N -2.368 1.00 28.09 A c -4.657 1.00 27.37 A c -3.480 1.00 26.66 A c -5.998 1.00 27.35 A c -5.850 1.00 26.99 A 0 -7.189 1.00 25.48 A N -8.432 1.00 25.19 A c -9.626 1.00 24.60 A c -9.866 1.00 24.13 A 0 -8.627 1.00 24.96 A c -7.947 1.00 26.57 A 0 -9.566 1.00 26.08 A N -10.139 1.00 27.25 A c -11.106 1.00 24.94 A c -10.883 1.00 26.16 A c -11.278 1.00 25.40 A 0 -11.066 1.00 26.74 A N -11.873 1.00 29.13 A c -11.991 1.00 30.10 A c -12.610 1.00 31.56 A c -12.055 1.00 30.82 A c -13.959 1.00 32.23 A N -14.208 1.00 31.96 A c -13.068 1.00 31.64 A N -13.272 1.00 29.91 A C -13.804 1.00 32.59 A 0 -13.870 1.00 28.42 A N -15.126 1.00 27.55 A C -15.405 1.00 26.69 A c -15.663 1.00 26.28 A 0 -16.337 1.00 27.89 A c -17.351 1.00 30.42 A 0 -16.247 1.00 24.79 A N -17.457 1.00 22 .23 A c -17.871 1.00 25.15 A c -17.547 1.00 22.33 A 0 -18.574 1.00 25.86 A N -18.894 1.00 26.23 A c -18.831 1.00 24.52 A c -18.999 1.00 25.31 A c -19.524 1.00 24.11 A c -20.029 1.00 24.85 A c -20.152 1.00 25.40 A 0 -20.923 1.00 24.02 A N -22.201 1.00 23.19 A c -23.242 1.00 23.48 A c -22.706 1.00 23.61 A 0 -23.608 1.00 22.59 A c -22.087 1.00 24.90 A c -21.060 1.00 23.76 A 0 -23.159 1.00 23.46 A N -23.115 1.00 24.59 A c -24.476 1.00 25.09 A c -24.558 1.00 26.25 A c -25.935 1.00 27.32 A c -26.040 1.00 27.17 A N -27.046 1.00 25.09 A c -27.044 1.00 24.35 A N -28.047 1.00 23.06 A N -22.736 1.00 25.75 A C -22.009 1.00 23.47 A 0 -23.230 1.00 24.77 A N -22.965 1.00 24.49 A C -24.262 1.00 24.57 A c -24.508 1.00 30.96 . A c -24.583 1.00 31.07 A s -25.959 1.00 31.18 A c -21.908 1.00 24.68 A c 443 WO 2009/026558 PCT/US2008/074097 ATOM 151 0 MET 470 -17.226 16 ATOM 152 N ALA 471 -16.459 14 ATOM 153 CA ALA 471 -17.508 14 ATOM 154 CB ALA 471 -17.371 13 ATOM 155 C ALA 471 -17.452 15 ATOM 156 0 ALA 471 -16.372 15 ATOM 157 N THR 472 -18.617 15 ATOM 158 CA THR 472 -18.675 16 ATOM 159 CB THR 472 -19.181 18 ATOM 160 OG1 THR 472 -20.548 18 ATOM 161 CG2 THR 472 -18.344 18 ATOM 162 C THR 472 -19.620 16 ATOM 163 O THR 4 72 -20.508 15 ATOM 164 N ALA 473 -19.415 16 ATOM 165 CA ALA 473 -20.319 16 ATOM 166 CB ALA 473 -19.560 15 ATOM 167 C ALA 473 -20.900 17 ATOM 168 0 ALA 473 -20.241 18 ATOM 169 N ILE 474 -22.131 17 ATOM 170 CA ILE 474 -22.819 18 ATOM 171 CB ILE 474 -24.026 19 ATOM 172 CG2 ILE 474 -24.883 20 ATOM 173 CGI ILE 474 -23.558 19 ATOM 174 CD1 ILE 474 -22.979 21 ATOM 175 C ILE 474 -23.336 18 ATOM 176 0 ILE 474 -24.055 17 ATOM 177 N ALA 475 -22.974 19 ATOM 178 CA ALA 475 -23.580 19 ATOM 179 CB ALA 475 -22.496 19 ATOM 180 C ALA 475 -24.459 20 ATOM 181 0 ALA 475 -24.063 21 ATOM 182 N ARG 476 -25.655 20 ATOM 183 CA ARG 476 -26.642 21 ATOM 184 CB ARG 476 -27.883 21 ATOM 185 CG ARG 476 -27.672 21 ATOM 186 CD ARG 476 -29.005 21 ATOM 187 NE ARG 476 -28.838 21 ATOM 188 CZ ARG 476 -28.492 20 ATOM 189 NHl ARG 476 -28.277 19 ATOM 190 NH2 ARG 476 -28.356 20 ATOM 191 C ARG 476 -27.093 21 ATOM 192 O ARG 476 -27.077 20 ATOM 193 N CYS 477 -27.519 22 ATOM 194 CA CYS 477 -28.103 22 ATOM 195 C CYS 477 -29.620 22 ATOM 196 0 CYS 477 -30.173 23 ATOM 197 CB CYS 477 -27.664 24 ATOM 198 SG CYS 477 -25.866 24 ATOM 199 N ALA 478 -30.283 22 ATOM 200 CA ALA 478 -31.742 22 ATOM 201 CB ALA 478 -32.228 22 ATOM 202 C ALA 478 -32.240 24 ATOM 203 0 ALA 478 -31.494 25 ATOM 204 N PRO 479 -33.521 24 ATOM 205 CD PRO 479 -34.502 23 ATOM 206 CA PRO 479 -34.054 25 ATOM 207 CB PRO 479 -35.515 25 ATOM 208 CG PRO 479 -35.513 24 ATOM 209 C PRO 479 -33.933 26 ATOM 210 O PRO 479 -33.819 28 ATOM 211 N ASP 480 -33.954 26 ATOM 212 CA ASP 480 -33.879 27 ATOM 213 CB ASP 480 -34.749 26 ATOM 214 CG ASP 480 -34.300 25 ATOM 215 OD1 ASP 480 -34.828 25 ATOM 216 OD2 ASP 480 -33.419 24 ATOM 217 C ASP 480 -32.449 27 ATOM 218 O ASP 480 -32.222 28 ATOM 219 N GLU 481 -31.482 27 ATOM 220 CA GLU 481 -30.087 27 ATOM 221 CB GLU 481 -29.439 25 ATOM 222 CG GLU 481 -30.038 24 ATOM 223 CD GLU 481 -29.692 23 ATOM 224 OE1 GLU 481 -29.930 22 ATOM 225 OE2 GLU 481 -29.186 23 ATOM 226 C GLU 481 -29.292 28 -21.717 1.00 2 3.62 A O -21.220 1.00 24.16 A N -20.238 1.00 24.20 A C -19.687 1.00 20.75 A C -19.096 1.00 25.48 A c -18.693 1.00 27.11 A _0 -18.578 1.00 24.57 A N -17.437 1.00 24.16 A c -17.836 1.00 24.01 A c -18.257 1.00 21.91 A 0 -18.970 1.00 18.59 A c -16.386 1.00 2 5.66 A c -16.690 1.00 24.53 A 0 -15.147 1.00 25.24 A N -14.048 1.00 24.92 A c -12.946 1.00 24.30 A c -13.513 1.00 25.27 A c -13.556 1.00 24.13 A 0 -13.012 1.00 24.89 A N -12.489 1.00 25.52 A c -13.365 1.00 29.25 A c -12.662 1.00 32.52 A c -14.721 1.00 33.35 A c -14.661 1.00 33.21 A c -11.069 1.00 26.48 A c -10.823 1.00 26.94 A 0 -10.140 1.00 25.26 A N -8.811 1.00 2 5.92 A c -7.732 1.00 23.88 A c -8.635 1.00 26.91 A c -8.998 1.00 25.49 A 0 -8.091 1.00 28.07 A N -7.932 1.00 28.54 A c -8.792 1.00 30.18 A c -10.272 1.00 35.86 A c -11.004 1.00 38.60 A c -12.452 1.00 41.19 A N -13.231 1.00 4 3.32 A c -12.698 1.00 43.42 A N -14.538 1.00 44.05 A N -6.488 1.00 28.17 A C -5.783 1.00 27.75 A 0 -6.064 1.00 29.00 A N -4.745 1.00 29.17 A C -4.848 1.00 30.65 A c -5.947 1.00 31.16 A 0 -4.165 1.00 27.94 A c -3.959 1.00 30.04 A s -3.699 1.00 30.57 A N -3.643 1.00 31.86 A c -2.260 1.00 29.25 A c -3.949 1.00 32.09 A c -3.847 1.00 31.96 A 0 -4.322 1.00 32.78 A N -4.550 1.00 31.44 A c -4.691 1.00 32.40 A c -5.061 1.00 32.72 A c -5.458 1.00 31.86 A c -3.592 1.00 32.60 A c -3.884 1.00 32.64 A 0 -2.331 1.00 31.47 A N -1.241 1.00 33.46 A c -0.057 1.00 35.16 A c 0.537 1.00 36.44 A c 1.598 1.00 40.34 A 0 .-0.053 1.00 38.40 A 0 -0.765 1.00 33.71 A c 0.246 1.00 35.25 A 0 -1.492 1.00 32.10 A N -1.086 1.00 30.90 A c -1.016 1.00 30.17 A c 0.041 1.00 30.22 A c -0.191 1.00 31.87 . A c 0.717 1.00 30.65 A 0 -1.285 1.00 33.77 ' A 0 -2.031 1.00 29.33 A c 444 WO 2009/026558 PCT/US2008/074097 uuuozuuouozuuuuzuzz
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Ά Ά ο cj cj cj CJ CJ CJ CJ CJ CJ ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 ,-1 t-l t-l t-l t-l t-l C/J C/J C/J C/J C/J C/J CJ CJ CJ CJ CJ CJ C/J C/J C/J C/J C/J C/J C/J C/J C/J C/J C/J C/J U4 U4 U4 U4 U4 U4 U4 U4 U4 U4 U4 C/J C/J C/J C/J C/J C/J < < < < < < < < < t-H CN t-H CN t-H CN t-H CN t-H CN t-H CN < CQ CO Q ill M c CQ CO u U < CQ CO u U < CQ CO < CQ CJ < CQ CO < CQ CO c CQ CO u u ω UJ ESJ C CQ CO < CQ CO Q ω ESJ X X o 2 CJ CJ CJ CJ o o CJ o 2 CJ CJ CJ CJ CJ CJ o 2 CJ CJ CJ CJ CJ CJ o 2 CJ CJ o CJ o 2 CJ CJ o CJ C/J 2 CJ CJ o CJ o 2 CJ CJ o CJ o 2 CJ CJ CJ CJ CJ CJ CJ CJ CJ o 2 CJ CJ o CJ o 2 CJ CJ CJ CJ 2 CJ 2 2 r> CO <J\ O t-H CN no lO r~ CO <J\ o t-H CN no if) Γ" CO O t-H CN no if) UO r~ CO o t-H CN no if) Γ" CO <T> o t-H CN no if) UO r~ CO <T> o t-H CN no If) r~ CO <T> o t-H CN no lO r~ CO o t-H CN (N (N (N no no no no no no no no no no if) lO if) If) if) if) lO If) If) if) UO Ci> UO UO UO r~ r~ Γ" r~ r~ Γ" r~ r~ Γ" r~ CO CO CO CO CO CO CO CO CO CO <T> <Ts <T> <T> <T> <T> <T> <T> <T> <T> o O O (N (N (N (N CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN no no no r. r. r. r. r. r. r. r. FI ?: FI f: r. r. r. r. r. r. r. T, r. r. r. r. r. r. r. r. r. T, r. r. r. T, r. r. ?: ?: r. T, ?: T, T, T, T, T, T, T, r. T, r. r. r. r. T. r. r. r. ?: r. r. r. r. ?: T, T, T, r. ?: ?: r. ?: ?: r. r. r. o O O O O O O O o o o o o O O O O o O O O O O O O O O O O O o O O O O O O o O o o o o o o o o o O o O O O O O O O O o O O O O o o o o O o o O o o O O O H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < WO 2009/026558 PCT/US2008/074097 ATOM 303 c ARG 491 -7.677 9 ATOM 304 0 ARG 491 -6.731 9 ATOM 305 N SER 4 92 -7.533 9 ATOM 306 CA SER 4 92 -6.246 9 ATOM 307 CB SER 4 92 -6.459 9 ATOM 308 OG SER 4 92 -7.242 9 ATOM 309 C SER 4 92 -5.512 10 ATOM 310 O SER 492 -4.295 10 ATOM 311 N GLY 493 -6.254 11 ATOM 312 CA GLY 493 -5.654 13 ATOM 313 C GLY 493 -5.739 13 ATOM 314 0 GLY 493 -5.287 14 ATOM 315 N LYS 494 -6.316 13 ATOM 316 CA LYS 494 -6.506 13 ATOM 317 CB LYS 494 -6.442 12 ATOM 318 CG LYS 494 -5.080 11 ATOM 319 CD LYS 494 -5.032 10 ATOM 320 CE LYS 494 -3.648 10 ATOM 321 NZ LYS 494 -3.585 9 ATOM 322 C LYS 494 -7.844 14 ATOM 323 0 LYS 494 -8.870 13 ATOM 324 N ARG 495 -7.815 15 ATOM 325 CA ARG 495 -9.025 16 ATOM 326 CB ARG 495 -9.558 16 ATOM 327 CG ARG 495 -8.560 17 ATOM 328 CD ARG 495 -9.082 17 ATOM 329 NE ARG 495 -8.125 18 ATOM 330 CZ ARG 495 -8.424 19 ATOM 331 NH1 ARG 495 -7.472 19 ATOM 332 NH2 ARG 495 -9.672 19 ATOM 333 C ARG 495 -8.661 17 ATOM 334 O ARG 495 -7.486 18 ATOM 335 N ARG 496 -9.660 18 ATOM 336 CA ARG 496 -9.376 19 ATOM 337 CB ARG 496 -9.765 20 ATOM 338 CG ARG 496 -8.775 19 ATOM 339 CD ARG 496 -9.064 19 ATOM 340 NE ARG 496 -10.117 18 ATOM 341 CZ ARG 496 -10.601 19 ATOM 342 NH1 ARG 496 -10.130 20 ATOM 343 NH2 ARG 496 -11.555 18 ATOM 344 C ARG 496 -10.052 20 ATOM 345 O ARG 496 -10.266 22 ATOM 346 N GLY 497 -10.375 20 ATOM 347 CA GLY 497 -10.908 21 ATOM 348 C GLY 497 -12.406 21 ATOM 349 0 GLY 497 -13.126 20 ATOM 350 N GLU 498 -12.880 22 ATOM 351 CA GLU 498 -14.313 23 ATOM 352 CB GLU 498 -14.840 22 ATOM 353 CG GLU 498 -14.497 23 ATOM 354 CD GLU 498 -13.039 23 ATOM 355 OE1 GLU 498 -12.453 22 ATOM 356 OE2 GLU 498 -12.477 24 ATOM 357 C GLU 498 -14.669 24 ATOM 358 0 GLU 498 -13.817 25 ATOM 359 N ARG 499 -15.943 2 4 ATOM 360 CA ARG 499 -16.427 26 ATOM 361 CB ARG 499 -16.477 26 ATOM 362 CG ARG 499 -16.999 27 ATOM 363 CD ARG 499 -17.028 28 ATOM 364 NE ARG 499 -17.154 29 ATOM 365 CZ ARG 499 -16.543 30 ATOM 366 NH1 ARG 499 -16.710 31 ATOM 367 NH2 ARG 499 -15.767 29 ATOM 368 C ARG 499 -17.818 26 ATOM 369 O ARG 499 -18.652 25 ATOM 370 N MET 500 -18.062 27 ATOM 371 CA MET 500 -19.405 27 ATOM 372 CB MET 500 -19.339 28 ATOM 373 CG MET 500 -18.800 28 ATOM 374 SD MET 500 -18.596 29 ATOM 375 CE MET 500 -17.061 29 ATOM 376 C MET 500 -20.118 28 ATOM 377 0 MET 500 -19.589 29 ATOM 378 N GLU 501 -21.314 28
-9.050 1.00 35.22 A C -8.305 1.00 35.69 A O -10.347 1.00 35.60 A N -11.024 1.00 34.80 A C -12.452 1.00 36.97 A C -13.179 1.00 38.02 A 0 -11.068 1.00 35.54 A c -11.258 1.00 3 6.68 A 0 -10.909 1.00 34.28 A N -11.037 1.00 32.69 A c -12.456 1.00 31.91 A c -12.739 1.00 32.88 A 0 -13.357 1.00 31.63 A N -14.728 1.00 32.29 A c -15.693 1.00 34.42 A c -15.758 1.00 38.00 A c -16.909 1.00 39.72 A c -17.078 1.00 42.01 A c -18.279 1.00 43.69 A N -14.870 1.00 29.91 A c -15.169 1.00 28.53 A 0 -14.659 1.00 29.57 A N -14.669 1.00 28.53 A c -13.243 1.00 29.81 A c -12.306 1.00 31.40 A c -10.881 1.00 32.62 A c -10.096 1.00 34.88 A N -9.400 1.00 34.47 A c -8.733 1.00 35.19 A N -9.355 1.00 34.89 A N -15.225 1.00 27.43 A C -15.349 1.00 27.93 A 0 -15.564 1.00 26.03 A N -15.972 1.00 24.54 A C -17.436 1.00 24.73 A c -18.396 1.00 26.29 A c -19.843 1.00 25.61 A c -20.405 1.00 24.57 A N -21.632 1.00 23.57 A c -22.429 1.00 20.57 A N -22.060 1.00 23.67 A N -15.084 1.00 25.65 A C -15.502 1.00 23.54 A 0 -13.853 1.00 25.25 A N -12.900 1.00 25.50 A C -13.026 1.00 25.22 A c -13.524 1.00 24.92 A 0 -12.574 1.00 25.28 A N -12.473 1.00 25.14 A c -11.122 1.00 25.47 A c -9.924 1.00 24.08 A c -9.504 1.00 27.78 A c -9.526 1.00 27.03 A 0 -9.139 1.00 30.19 A 0 -12.640 1.00 26.49 A c -12.521 1.00 26.93 A 0 -12.911 1.00 27.54 A N -13.122 1.00 27.29 A c -14.615 1.00 27.26 A c -14.936 1.00 31.36 A c -16.438 1.00 29.97 A c -16.717 1.00 33.21 A N -17.721 1.00 31.95 A c -17.898 1.00 33.98 A N -18.549 1.00 30.18 A N -12.526 1.00 28.46 A C -12.608 1.00 27.86 A 0 -11.921 1.00 28.00 A ' N -11.492 1.00 28.68 A C -10.259 1.00 29.36 A c -9.033 1.00 31.43 A c -7.594 1.00 35.65 A s -8.031 1.00 30.13 . A c -12.633 1.00 28.47 A c -13.213 1.00 27.47 ' A 0 -12.965 1.00 29.85 A N 446 WO 2009/026558 PCT/US2008/074097 ATOM 379 CA GLU 501 -22.059 28 ATOM 380 CB GLU 501 -22.169 27 ATOM 381 CG GLU 501 -20.816 27 ATOM 382 CD GLU 501 -20.922 26 ATOM 383 OE1 GLU 501 -21.997 25 ATOM 384 OE2 GLU 501 -19.917 25 ATOM 385 C GLU 501 -23.446 29 ATOM 386 0 GLU 501 -24.072 28 ATOM 387 N ALA 502 -23.919 30 ATOM 388 CA ALA 502 -25.231 30 ATOM 389 CB ALA 502 -25.258 32 ATOM 390 C ALA 502 -26.305 30 ATOM 391 O ALA 502 -26.267 30 ATOM 392 N GLN 503 -27.251 29 ATOM 393 CA GLN 503 -28.385 28 ATOM 394 CB GLN 503 -28.315 27 ATOM 395 CG GLN 503 -27.190 26 ATOM 396 CD GLN 503 -27.325 25 ATOM 397 OE1 GLN 503 -28.338 24 ATOM 398 NE2 GLN 503 -26.305 24 ATOM 399 C GLN 503 -29.683 29 ATOM 400 0 GLN 503 -29.988 28 ATOM 401 N GLY 504 -30.449 30 ATOM 402 CA GLY 504 -31.757 30 ATOM 403 C GLY 504 -31.704 31 ATOM 404 0 GLY 504 -32.463 30 ATOM 405 N GLY 505 -30.799 32 ATOM 406 CA GLY 505 -30.714 32 ATOM 407 C GLY 505 -29.851 32 ATOM 408 0 GLY 505 -29.381 32 ATOM 409 N LYS 506 -29.638 30 ATOM 410 CA LYS 506 -28.827 29 ATOM 411 CB LYS 506 -29.567 28 ATOM 412 CG LYS 506 -30.536 28 ATOM 413 CD LYS 506 -31.603 29 ATOM 414 CE LYS 506 -32.608 30 ATOM 415 NZ LYS 506 -33.329 28 ATOM 416 C LYS 506 -27.464 29 ATOM 417 0 LYS 506 -27.327 29 ATOM 418 N LEU 507 -26.459 29 ATOM 419 CA LEU 507 -25.161 28 ATOM 420 CB LEU 507 -24.042 29 ATOM 421 CG LEU 507 -23.892 31 ATOM 422 CDl LEU 507 -22.759 31 ATOM 423 CD2 LEU 507 -23.625 31 ATOM 424 C LEU 507 -25.127 27 ATOM 425 O LEU 507 -25.651 26 ATOM 426 N VAL 508 -24.524 26 ATOM 427 CA VAL 508 -24.238 25 ATOM 428 CB VAL 508 -25.036 24 ATOM 429 CGI VAL 508 -26.513 24 ATOM 430 CG2 VAL 508 -24.469 24 ATOM 431 C VAL 508 -22.761 25 ATOM 432 O VAL 508 -22.026 26 ATOM 433 N CYS 509 -22.344 23 ATOM 434 CA CYS 509 -20.943 23 ATOM 435 C CYS 509 -20.710 22 ATOM 436 0 CYS 509 -21.233 21 ATOM 437 CB CYS 509 -20.572 22 ATOM 438 SG CYS 509 -18.841 22 ATOM 439 N ARG 510 -19.921 22 ATOM 440 CA ARG 510 -19.559 21 ATOM 441 CB ARG 510 -19.838 22 ATOM 442 CG ARG 510 -19.589 21 ATOM 443 CD ARG 510 -19.798 22 ATOM 444 NE ARG 510 -21.158 22 ATOM 445 CZ ARG 510 -22.193 22 ATOM 446 NH1 ARG 510 -23.397 22 ATOM 447 NH2 ARG 510 -22.028 20 ATOM 448 C ARG 510 -18.084 21 ATOM 449 O ARG 510 -17.207 22 ATOM 450 N ALA 511 -17.812 20 ATOM 451 CA ALA 511 -16.436 19 ATOM 452 CB ALA 511 -16.218 18 ATOM 453 C ALA 511 -16.131 19 ATOM 454 O ALA 511 -17.015 18 -14.093 1.00 32.67 A C -15.222 1.00 30.99 A C -15.771 1.00 32.75 A C -16.886 1.00 32.72 A c -17.053 1.00 28.58 A 0 -17.603 1.00 36.53 A _0 -13.633 1.00 35.03 A c -12.823 1.00 33.00 A 0 -14.145 1.00 39.39 A N -13.766 1.00 42.89 A c -13.896 1.00 41.99 A c -14.647 1.00 46.27 A c -15.868 1.00 47.27 A 0 -14.015 1.00 49.35 A N -14.707 1.00 53.23 A c -14.636 1.00 53.57 A c -15.425 1.00 56.31 A c -15.471 1.00 56.99 A c -15.041 1.00 57.97 A 0 -15.991 1.00 56.50 A N -14.048 1.00 55.13 A c -12.927 1.00 56.06 A 0 -14.744 1.00 56.99 A N -14.244 1.00 56.78 A c -12.863 1.00 56.53 A c -11.973 1.00 57.57 A 0 -12.680 1.00 55.20 A N -11.416 1.00 53.52 A c -10.381 1.00 53.23 A c -9.437 1.00 53.62 A 0 -10.548 1.00 50.84 A N -9.604 1.00 49.53 A c -9.183 1.00 51.74 A c -8.019 1.00 54.83 A c -8.324 1.00 59.19 A c -7.177 1.00 59.58 A c -6.895 1.00 58.69 A N -10.190 1.00 46.30 A c -11.397 1.00 46.29 A 0 -9.329 1.00 41.66 A N -9.749 1.00 3 6.60 A c -8.901 1.00 34.82 A c -8.941 1.00 35.36 A c -8.016 1.00 35.13 A c -10.363 1.00 30.11 A c -9.623 1.00 34.72 A c -8.657 1.00 33.92 A 0 -10.607 1.00 31.44 A N -10.492 1.00 29.22 A c -11.505 1.00 31.89 A c -11.437 1.00 30.81 A c -12.895 1.00 29.53 A c -10.724 1.00 28.89 A c -11.192 1.00 26.64 A 0 -10.401 1.00 26.50 A N -10.431 1.00 2 6.63 A c -11.523 1.00 26.83 A c -11.446 1.00 27.38 A 0 -9.076 1.00 27.35 A c -8.815 1.00 29.68 A s -12.530 1.00 26.66 A N -13.600 1.00 25.83 A c -14.973 1.00 24.38 A c -16.148 1.00 26.06 A c -17.504 1.00 24.80 A c -17.661 1.00 25.36 A N -18.049 1.00 28.22 A c -18.166 1.00 2 6.65 A N -18.320 1.00 24.05 A N -13.518 1.00 25.64 A C -13.530 1.00 27.40 A 0 -13.439 1.00 24.50 A N -13.462 1.00 23.75 . A C -12.321 1.00 2 3.65 A c -14.794 1.00 24.97 A c -15.387 1.00 23.22 A 0 447 WO 2009/026558 PCT/US2008/074097 ATOM 455 N HIS 512 -14.872 19 ATOM 456 CA HIS 512 -14.435 18 ATOM 457 CB HIS 512 -13.774 19 ATOM 458 CG HIS 512 -14.711 20 ATOM 459 CD2 HIS 512 -14.982 22 ATOM 4 60 NDl HIS 512 -15.507 20 ATOM 461 CEl HIS 512 -16.229 22 ATOM 4 62 NE2 HIS 512 -15.929 22 ATOM 463 C HIS 512 -13.440 17 ATOM 464 0 HIS 512 -12.452 17 ATOM 4 65 N ASN 513 -13.688 16 ATOM 466 CA ASN 513 -12.757 15 ATOM 467 CB ASN 513 -13.447 14 ATOM 468 CG ASN 513 -12.676 12 ATOM 4 69 OD1 ASN 513 -11.857 12 ATOM 470 ND2 ASN 513 -12.943 11 ATOM 471 C ASN 513 -11.558 15 ATOM 472 O ASN 513 -11.572 16 ATOM 473 N ALA 514 -10.523 15 ATOM 474 CA ALA 514 -9.342 15 ATOM 475 CB ALA 514 -8.116 15 ATOM 476 C ALA 514 -9.066 14 ATOM 477 O ALA 514 -9.501 13 ATOM 478 N PHE 515 -8.340 14 ATOM 479 CA PHE 515 -7.806 13 ATOM 480 CB PHE 515 -6.761 14 ATOM 481 CG PHE 515 -6.124 13 ATOM 482 CDl PHE 515 -6.818 13 ATOM 483 CD2 PHE 515 -4.827 12 ATOM 484 CEl PHE 515 -6.234 12 ATOM 485 CE2 PHE 515 -4.231 12 ATOM 486 CZ PHE 515 -4.936 11 ATOM 487 C PHE 515 -7.170 12 ATOM 488 0 PHE 515 -6.333 12 ATOM 489 N GLY 516 -7.589 11 ATOM 490 CA GLY 516 -6.993 10 ATOM 491 C GLY 516 -7.556 9 ATOM 492 0 GLY 516 -7.309 8 ATOM 493 N GLY 517 -8.310 10 ATOM 494 CA GLY 517 -8.722 10 ATOM 495 C GLY 517 -9.944 9 ATOM 496 0 GLY 517 -10.494 9 ATOM 497 N GLU 518 -10.385 9 ATOM 498 CA GLU 518 -11.479 8 ATOM 499 CB GLU 518 -11.096 7 ATOM 500 CG GLU 518 -10.923 7 ATOM 501 CD GLU 518 -9.561 8 ATOM 502 OE1 GLU 518 -8.719 8 ATOM 503 OE2 GLU 518 -9.332 8 ATOM 504 C GLU 518 -12.779 8 ATOM 505 0 GLU 518 -13.720 8 ATOM 506 N GLY 519 -12.836 10 ATOM 507 CA GLY 519 -14.033 10 ATOM 508 C GLY 519 -13.808 11 ATOM 509 0 GLY 519 -12.808 11 ATOM 510 N VAL 520 -14.738 12 ATOM 511 CA VAL 520 -14.545 13 ATOM 512 CB VAL 520 -14.047 14 ATOM 513 CGI VAL 520 -12.750 14 ATOM 514 CG2 VAL 520 -15.114 15 ATOM 515 C VAL 520 -15.852 13 ATOM 516 0 VAL 520 -16.920 13 ATOM 517 N TYR 521 -15.754 14 ATOM 518 CA TYR 521 -16.922 14 ATOM 519 CB TYR 521 -16.902 13 ATOM 520 CG TYR 521 -16.985 12 ATOM 521 CDl TYR 521 -15.833 11 ATOM 522 CEl TYR 521 -15.901 10 ATOM 523 CD2 TYR 521 -18.216 11 ATOM 524 CE2 TYR 521 -18.296 10 ATOM 525 CZ TYR 521 -17.133 9 ATOM 526 OH TYR 521 -17.196 8 ATOM 527 C TYR 521 -16.945 16 ATOM 528 0 TYR 521 -15.898 16 ATOM 529 N ALA 522 -18.142 16 ATOM 530 CA ALA 522 -18.314 18 -15.233 1.00 24.16 A N -16.559 1.00 24.87 A C -17.323 1.00 25.25 A C -17.660 1.00 25.82 A c -17.021 1.00 26.89 A c -18.785 1.00 27.87 A -N. -18.825 1.00 28.93 A c -17.766 1.00 30.14 A N -16.503 1.00 25.39 A C -15.762 1.00 24.51 A 0 -17.313 1.00 23.79 A N -17.459 1.00 24.72 A C -18.155 1.00 21.47 A c -17.998 1.00 25.11 A c -17.087 1.00 26.09 A 0 -18.887 1.00 20.32 A N -18.285 1.00 23.06 A c -18.843 1.00 23.76 A 0 -18.359 1.00 23.46 A N -19.170 1.00 24.44 A c -18.268 1.00 21.96 A c -20.203 1.00 24.29 A c -20.041 1.00 24.54 A 0 -21.261 1.00 25.86 A N -22 .218 1.00 25.71 A c -23.116 1.00 27.88 A c -24.134 1.00 28.53 A c -25.270 1.00 29.33 A c -23.956 1.00 31.17 A c -26.216 1.00 30.11 A c -24.897 1.00 32.87 A c -26.030 1.00 30.57 A c -21.446 1.00 2 5.67 A c -20.570 1.00 25.88 A 0 -21.745 1.00 25.26 A N -21.095 1.00 25.89 A c -19.725 1.00 28.02 A c -19.228 1.00 29.41 A 0 -19.112 1.00 27.77 A N -17.727 1.00 28.63 A c -17.617 1.00 29.61 A c -18.629 1.00 29.48 A 0 -16.408 1.00 28.88 A N -16.278 1.00 30.08 A c -15.325 1.00 33.06 A c -13.883 1.00 41.55 A c -13.614 1.00 48.72 A c -14.546 1.00 50.19 A 0 -12.467 1.00 53.68 A 0 -15.818 1.00 28.72 A c -15.443 1.00 29.04 A 0 -15.862 1.00 26.44 A N -15.430 1.00 25.94 A c -14.099 1.00 25.37 A c -13.429 1.00 24.07 A 0 -13.715 1.00 24.24 A N -12.557 1.00 24.20 A c -12.988 1.00 25.35 A c -13.781 1.00 23.64 A c -13.824 1.00 21.19 A c -11.800 1.00 24.80 A c -12.302 1.00 25.48 A 0 -10.596 1.00 23.24 A N -9.821 1.00 23.59 A c -8.430 1.00 24.30 A c .-8.457 1.00 26.30 A c -8.533 1.00 25.03 A c -8.597 1.00 29.75 A c -8.440 1.00 23.79 A c -8.505 1.00 28.16 A c -8.587 1.00 30.47 A c -8.694 1.00 35.15 A 0 -9.650 1.00 23.08 - A c -9.504 1.00 22.54 A 0 -9.660 1.00 23.04 A N -9.283 1.00 22.28 A c 448 WO 2009/026558 PCT/US2008/074097 ATOM 531 CB ALA 522 -19.336 18 ATOM 532 C ALA 522 -18.803 18 ATOM 533 O ALA 522 -19.561 17 ATOM 534 N ILE 523 -18.358 19 ATOM 535 CA ILE 52 3 -18.714 19 ATOM 536 CB ILE 52 3 -17.537 18 ATOM 537 CG2 ILE 523 -17.959 18 ATOM 538 CGI ILE 523 -17.083 17 ATOM 539 CDl ILE 523 -15.614 17 ATOM 540 C ILE 523 -19.112 20 ATOM 541 0 ILE 523 -18.282 21 ATOM 542 N ALA 524 -20.393 20 ATOM 543 CA ALA 524 -20.902 22 ATOM 544 CB ALA 524 -22.279 22 ATOM 545 C ALA 524 -20.999 22 ATOM 546 O ALA 524 -21.254 21 ATOM 547 N ARG 525 -20.784 23 ATOM 548 CA ARG 525 -21.076 23 ATOM 549 CB ARG 525 -19.931 24 ATOM 550 CG ARG 525 -19.969 24 ATOM 551 CD ARG 525 -19.724 23 ATOM 552 NE ARG 525 -19.572 23 ATOM 553 CZ ARG 52 5 -19.631 22 ATOM 554 NHl ARG 52 5 -19.480 23 ATOM 555 NH2 ARG 525 -19.838 21 ATOM 556 C ARG 525 -22.374 24 ATOM 557 O ARG 525 -22.457 25 ATOM 558 N CYS 52 6 -23.393 23 ATOM 559 CA CYS 52 6 -24.727 24 ATOM 560 C CYS 526 -25.155 25 ATOM 561 0 CYS 526 -25.183 24 ATOM 562 CB CYS 526 -25.722 23 ATOM 563 SG CYS 526 -25.404 22 ATOM 564 N CYS 527 -25.496 26 ATOM 565 CA CYS 527 -25.764 26 ATOM 566 C CYS 527 -27. 111 27 ATOM 567 0 CYS 527 -27.672 28 ATOM 568 CB CYS 527 -24.653 27 ATOM 569 SG CYS 527 -22.945 27 ATOM 570 N LEU 52 8 -27.626 27 ATOM 571 CA LEU 52 8 -28.801 28 ATOM 572 CB LEU 528 -29.615 28 ATOM 573 CG LEU 52 8 -30.103 26 ATOM 574 CDl LEU 528 -30.984 26 ATOM 575 CD2 LEU 528 -30.858 26 ATOM 576 C LEU 52 8 -28.361 30 ATOM 577 O LEU 52 8 -27.762 30 ATOM 578 N LEU 529 -28.652 30 ATOM 579 CA LEU 52 9 -28.208 32 ATOM 580 CB LEU 529 -26.956 32 ATOM 581 CG LEU 529 -26.141 33 ATOM 582 CDl LEU 529 -25.404 33 ATOM 583 CD2 LEU 529 -25.146 33 ATOM 584 C LEU 529 -29.348 33 ATOM 585 O LEU 529 -29.527 33 ATOM 586 N PRO 530 -30.144 33 ATOM 587 CD PRO 530 -29.972 33 ATOM 588 CA PRO 530 -31.254 34 ATOM 589 CB PRO 530 -31.955 34 ATOM 590 CG PRO 530 -30.872 34 ATOM 591 C PRO 530 -30.773 35 ATOM 592 O PRO 530 -29.729 36 ATOM 593 N GLN 531 -31.544 36 ATOM 594 CA GLN 531 -31.225 37 ATOM 595 CB GLN 531 -31.325 38 ATOM 596 CG GLN 531 -32.722 39 ATOM 597 CD GLN 531 -32.754 40 ATOM 598 OE1 GLN 531 -32.220 41 ATOM 599 NE2 GLN 531 -33.378 40 ATOM 600 C GLN 531 -29.820 37 ATOM 601 0 GLN 531 -29.021 38 ATOM 602 N ALA 532 -29.518 36 ATOM 603 CA ALA 532 -28.234 36 ATOM 604 CB ALA 532 -27.514 35 ATOM 605 C ALA 532 -28.404 36 ATOM 606 O ALA 532 -29.324 36 -10.201 1.00 23.30 A C -7.843 1.00 2 3.52 A C -7.431 1.00 22.23 A O -7.074 1.00 23.74 A N -5.665 1.00 23.56 A C -4.779 1.00 26.23 A c -3.306 1.00 21.95 A c -5.193 1.00 24.93 A c -5.452 1.00 24 .24 A c -5.303 1.00 26.24 A c -5.298 1.00 28.35 A 0 -5.013 1.00 24.72 A N -4.658 1.00 24.50 A c -5.295 1.00 23.50 A c -3.140 1.00 24.77 A c -2.435 1.00 26.27 A 0 -2.646 1.00 26.08 A N -1.259 1.00 25.79 A c -0.678 1.00 26.10 A c 0.825 1.00 27.35 A c 1.575 1.00 26.86 A c 3.001 1.00 26.08 A N 3.963 1.00 28.22 A c 5.225 1.00 24.72 A N 3.671 1.00 28.59 A N -1.259 1.00 26.55 A C -1.877 1.00 27.38 A 0 -0.585 1.00 27.37 A N -0.635 1.00 27.20 A C 0.749 1.00 28.67 A c 1.709 1.00 27.15 A 0 -1.124 1.00 28.62 A c -2.801 1.00 28.40 A s 0.850 1.00 27.75 A N 2.153 1.00 30.68 A c 2.230 1.00 30.03 A c 1.213 1.00 29.33 A 0 2.519 1.00 30.20 A c 2.258 1.00 34.88 A s 3.448 1.00 31.45 A N 3.688 1.00 33.88 A c 4.862 1.00 31.33 A c 4.633 1.00 31.88 A c 5.793 1.00 28.76 A c 3.317 1.00 2 9.32 A c 3.979 1.00 36.14 A c 5.014 1.00 36.49 A 0 3.042 1.00 40.20 A N 3.135 1.00 45.03 A c 2.272 1.00 43.96 A c 2.499 1.00 45.14 A c 3.822 1.00 45.34 A c 1.368 1.00 45.47 A c 2.638 1.00 48.10 A c 1.431 1.00 48.79 A 0 3.570 1.00 48.91 A N 5.021 1.00 48.98 A c 3.259 1.00 50.42 A c 4.603 1.00 49.24 A c 5.604 1.00 50.12 A c 2.687 1.00 49.69 A c 3.080 1.00 48.57 A 0 1.759 1.00 52.50 A N 1 . 182 1.00 54.58 A c 2.247 1.00 57.89 A c , 2.811 1.00 62.33 A c 3.831 1.00 65.19 A c 3.590 1.00 66.51 A 0 4.978 1.00 64.89 A N 0.586 1.00 53.73 A c 0.882 1.00 54.88 A 0 -0.250 1.00 50.22 A N -0.933 1.00 48.20 . A c -0.626 1.00 46.39 A c -2.443 1.00 47.17 ' A c -3.043 1.00 45.39 A 0 449 WO 2009/026558 PCT/US2008/074097 ATOM 607 N ASN 533 -27.520 37 ATOM 608 CA ASN 533 -27.359 37 ATOM 609 CB ASN 533 -27.689 39 ATOM 610 CG ASN 533 -27.745 39 ATOM 611 OD1 ASN 533 -27.459 38 ATOM 612 ND2 ASN 533 -28.117 40 ATOM 613 C ASN 533 -25.910 37 ATOM 614 0 ASN 533 -25.004 38 ATOM 615 N CYS 534 -25.694 36 ATOM 616 CA CYS 534 -24.346 35 ATOM 617 C CYS 534 -24.139 35 ATOM 618 0 CYS 534 -25.031 35 ATOM 619 CB CYS 534 -24.104 34 ATOM 620 SG CYS 534 -24.229 34 ATOM 621 N SER 535 -22.956 36 ATOM 622 CA SER 535 -22.642 36 ATOM 623 CB SER 535 -22.807 37 ATOM 624 OG SER 535 -22.034 38 ATOM 62 5 C SER 535 -21.220 35 ATOM 62 6 O SER 535 -20.364 35 ATOM 627 N VAL 536 -20.975 34 ATOM 62 8 CA VAL 536 -19.659 34 ATOM 62 9 CB VAL 536 -19.752 33 ATOM 630 CGI VAL 536 -18.353 32 ATOM 631 CG2 VAL 536 -20.555 32 ATOM 632 C VAL 536 -18.871 35 ATOM 633 O VAL 536 -19.395 36 ATOM 634 N HIS 537 -17.603 35 ATOM 635 CA HIS 537 -16.743 36 ATOM 636 CB HIS 537 -16.430 37 ATOM 637 CG HIS 537 -17.657 38 ATOM 638 CD2 HIS 537 -18.536 38 ATOM 639 NDl HIS 537 -18.153 39 ATOM 640 CEl HIS 537 -19.285 39 ATOM 641 NE2 HIS 537 -19.540 39 ATOM 642 C HIS 537 -15.482 35 ATOM 643 0 HIS 537 -14.825 35 ATOM 644 N THR 538 -15.160 35 ATOM 645 CA THR 538 -14.130 35 ATOM 646 CB THR 538 -14.745 34 ATOM 647 OG1 THR 538 -15.658 33 ATOM 648 CG2 THR 538 -13.658 33 ATOM 649 C THR 538 -13.027 35 ATOM 650 O THR 538 -13.290 37 ATOM 651 N ALA 539 -11.793 35 ATOM 652 CA ALA 539 -10.713 36 ATOM 653 CB ALA 539 -9.722 36 ATOM 654 C ALA 539 -10.010 34 ATOM 655 O ALA 539 -9.800 33 ATOM 656 N PRO 540 -9.645 35 ATOM 657 CD PRO 540 -9.835 36 ATOM 658 CA PRO 540 -9.058 34 ATOM 659 CB PRO 540 -9.227 34 ATOM 660 CG PRO 540 -9.165 36 ATOM 661 C PRO 540 -7.595 33 ATOM 662 O PRO 540 -6.923 34 ATOM 663 N PRO 541 -7.075 32 ATOM 664 CD PRO 541 -7.795 31 ATOM 665 CA PRO 541 -5.650 32 ATOM 666 CB PRO 541 -5.458 31 ATOM 667 CG PRO 541 -6.794 30 ATOM 668 C PRO 541 -4.788 33 ATOM 669 O PRO 541 -5.053 34 ATOM 670 N ALA 542 -3.759 33 ATOM 671 CA ALA 542 -2.864 35 ATOM 672 CB ALA 542 -3.169 36 ATOM 673 C ALA 542 -1.429 34 ATOM 674 O ALA 542 -1.077 33 ATOM 675 N GLU 543 -0.603 34 ATOM 676 CA GLU 543 0.816 34 ATOM 677 CB GLU 543 1.461 34 ATOM 678 CG GLU 543 2.492 33 ATOM 679 CD GLU 543 1.858 32 ATOM 680 OE1 GLU 543 1.824 31 ATOM 681 OE2 GLU 543 1.396 32 ATOM 682 C GLU 543 1.463 35 -3.052 1.00 46.61 A N -4.500 1.00 45.24 A C -5.130 1.00 48.68 A C -6.657 1.00 52.76 A c -7.259 1.00 55.43 A 0 -7.286 1.00 54.40 A N -4.781 1.00 42.36 A c -4.540 1.00 41.25 A 0 -5.278 1.00 40.03 A N -5.572 1.00 38.85 A c -7.076 1.00 38.60 A c -7.812 1.00 38.28 A 0 -4.980 1.00 38.71 A c -3.170 1.00 39.44 A s -7.525 1.00 35.57 A N -8.943 1.00 35.87 A c -9.523 1.00 34.93 A c -8.795 1.00 37.31 A 0 -9.168 1.00 34.87 A c -8.287 1.00 34.76 A 0 -10.347 1.00 32.81 A N -10.681 1.00 32.05 A c -11.524 1.00 33.02 A c -11.817 1.00 31.62 A c -10.787 1.00 37.22 A c -11.479 1.00 32.35 A c -12.406 1.00 32.68 A 0 -11.129 1.00 32.15 A N -11.854 1.00 32.62 A c -10.974 1.00 32.90 A c -10.534 1.00 38.48 A c -9.534 1.00 39.02 A c -11.211 1.00 39.06 A N -10.650 1.00 40.38 A c -9.630 1.00 41.12 A N -12.268 1.00 31.22 A C -11.446 1.00 32.87 A 0 -13.553 1.00 30.02 A N -14 .162 1.00 28.85 A C -15.259 1.00 30.20 A c -14.652 1.00 2 9.62 A 0 -16.011 1.00 26.80 A c -14.786 1.00 27.41 A c -15.330 1.00 26.94 A 0 -14.704 1.00 2 6.67 A N -15.502 1.00 26.84 A c -14.617 1.00 27.43 A c -16.258 1.00 27.34 A c -15.727 1.00 29.03 A 0 -17.518 1.00 25.34 A N -18.162 1.00 26.40 A c -18.434 1.00 25.56 A c -19.804 1.00 25.71 A c -19.505 1.00 27.40 A c -18.126 1.00 27.52 A c -17.463 1.00 27.04 A 0 -18.636 1.00 27.53 A N -19.435 1.00 28.31 A c -18.522 1.00 29.94 A c -19.510 1.00 26.51 A c -19.562 1.00 28.03 A c -18.875 1.00 32.23 A c -19.848 1.00 30.35 A 0 -18.070 1.00 35.43 A N -18.290 1.00 39.68 A c -.17.298 1.00 41.32 A c -18.125 1.00 41.82 A c -17.108 1.00 43.83 A 0 -19.125 1.00 44.83 A N -19.033 1.00 48.00 A c -20.418 1.00 52.56 A c -20.715 1.00 57.96 A c -21.120 1.00 61.23 . A c -20.277 1.00 62.99 A 0 -22.283 1.00 63.66 A 0 -18.082 1.00 47.94 A c 450 WO 2009/026558 PCT/US2008/074097 ATOM 683 0 GLU 543 2.038 36 ATOM 684 N ALA 544 1.359 35 ATOM 685 CA ALA 544 1.827 36 ATOM 686 CB ALA 544 0.678 37 ATOM 687 C ALA 544 2.418 35 ATOM 688 0 ALA 544 1.998 34 ATOM 689 N SER 545 3.392 36 ATOM 690 CA SER 545 4 . 054 35 ATOM 691 CB SER 545 5.198 36 ATOM 692 OG SER 545 6.381 36 ATOM 693 C SER 545 3.082 35 ATOM 694 O SER 545 3.159 34 ATOM 695 N MET 546 2.171 36 ATOM 696 CA MET 546 1.224 36 ATOM 697 CB MET 546 0.851 37 ATOM 698 CG MET 546 1.973 38 ATOM 699 SD MET 546 1.62 6 40 ATOM 700 CE MET 546 2.137 40 ATOM 701 C MET 546 -0.028 35 ATOM 702 0 MET 546 -1.076 35 ATOM 703 N GLY 547 0.091 34 ATOM 704 CA GLY 547 -0.994 33 ATOM 705 C GLY 547 -2.212 34 ATOM 706 0 GLY 547 -2.119 35 ATOM 707 N THR 548 -3.366 33 ATOM 708 CA THR 548 -4.617 34 ATOM 709 CB THR 548 -5.403 33 ATOM 710 OG1 THR 548 -4.580 32 ATOM 711 CG2 THR 548 -6.664 33 ATOM 712 C THR 548 -5.442 34 ATOM 713 O THR 548 -5.597 34 ATOM 714 N ARG 549 -5.971 36 ATOM 715 CA ARG 549 - 6.562 36 ATOM 716 CB ARG 549 -5.574 37 ATOM 717 CG ARG 549 -4.158 37 ATOM 718 CD ARG 549 -3.155 38 ATOM 719 NE ARG 549 -3.201 38 ATOM 720 CZ ARG 549 -2.454 37 ATOM 721 NHl ARG 549 -2.566 37 ATOM 722 NH2 ARG 549 -1.593 36 ATOM 723 C ARG 549 -7.859 37 ATOM 724 O ARG 549 -7.990 37 ATOM 725 N VAL 550 -8.818 37 ATOM 726 CA VAL 550 -10.054 37 ATOM 727 CB VAL 550 -11.130 37 ATOM 728 CGI VAL 550 -11.547 35 ATOM 729 CG2 VAL 550 -12.329 38 ATOM 730 C VAL 550 -10.530 38 ATOM 731 O VAL 550 -10.261 37 ATOM 732 N HIS 551 -11.222 39 ATOM 733 CA HIS 551 -11.719 39 ATOM 734 CB HIS 551 -10.779 40 ATOM 735 CG HIS 551 -10.856 42 ATOM 736 CD2 HIS 551 -10.404 42 ATOM 737 ND1 HIS 551 -11.460 43 ATOM 738 CEl HIS 551 -11.377 44 ATOM 739 NE2 HIS 551 -10.741 43 ATOM 740 C HIS 551 -13.128 40 ATOM 741 0 HIS 551 -13.585 40 ATOM 742 N CYS 552 -13.815 40 ATOM 743 CA CYS 552 -15.158 40 ATOM 744 C CYS 552 -15.074 42 ATOM 745 0 CYS 552 -14.612 42 ATOM 746 CB CYS 552 -15.875 40 ATOM 747 SG CYS 552 -15.982 38 ATOM 748 N HIS 553 -15.518 42 ATOM 749 CA HIS 553 -15.266 44 ATOM 750 CB HIS 553 -14.882 44 ATOM 751 CG HIS 553 -15.927 44 ATOM 752 CD2 HIS 553 -16.781 45 ATOM 753 ND1 HIS 553 -16.187 43 ATOM 754 CEl HIS 553 -17.155 43 ATOM 755 NE2 HIS 553 -17.533 44 ATOM 756 C HIS 553 -16.442 45 ATOM 757 0 HIS 553 -16.292 46 ATOM 758 N GLN 554 -17.609 44
-18.520 1.00 49.36 A O -16.781 1.00 45.85 A N -15.780 1.00 43.79 A C -15.346 1.00 42.96 A C -14.564 1.00 44.20 A c -14 .210 1.00 42.82 A .0. -13.926 1.00 43.11 A N -12.767 1.00 42.80 A c -12.297 1.00 44.06 A c -13.028 1.00 49.18 A 0 -11.621 1.00 40.42 A c -10.917 1.00 41.59 A 0 -11.435 1.00 37.26 A N -10.337 1.00 37.49 A c -9.869 1.00 36.04 A c -9.119 1.00 37.71 A c -8.851 1.00 38.80 A s -10.406 1.00 47.70 A c -10.718 1.00 37.16 A c -10.083 1.00 37.19 A 0 -11.757 1.00 36.79 A N -12.136 1.00 35.87 A c -12.659 1.00 36.73 A c -13.168 1.00 36.47 A 0 -12.536 1.00 35.43 A N -13.017 1.00 35.74 A c -13.841 1.00 37.13 A c -14.914 1.00 39.98 A 0 -14.416 1.00 38.25 A c -11.808 1.00 34.88 A c -10.866 1.00 36.02 A 0 -11.831 1.00 33.45 A N -10.632 1.00 34.68 A c -9.975 1.00 34.64 A c -9.856 1.00 37.46 A c -9.350 1.00 35.98 A c -7.901 1.00 35.43 A N -7.069 1.00 34.21 A c -5.760 1.00 30.15 A N -7.546 1.00 32.58 A N -10.947 1.00 34.29 A C -11.986 1.00 34.98 A 0 -10.040 1.00 33.25 A N -10.147 1.00 33.71 A C -10.914 1.00 33.51 A c -10.103 1.00 30.56 A c -11.222 1.00 32.51 A c -8.727 1.00 36.76 A c -7.812 1.00 36.18 A 0 -8.530 1.00 38.93 A N -7.200 1.00 43.33 A c -6.506 1.00 4 6.64 A c -7.050 1.00 52.46 A c -8.212 1.00 54.58 A c -6.365 1.00 54.96 A N -7.082 1.00 56.62 A c -8.207 1.00 57.00 A N -7.2 62 1.00 43.49 A C -8.313 1.00 42.88 A 0 -6.128 1.00 44.34 A N -6.045 1.00 47.65 A C -5.943 1.00 51.08 A c -4.937 1.00 50.38 A 0 -4.824 1.00 44.92 A c -4.816 1.00 44.45 A s .-6.990 1.00 55.41 A N -7.120 1.00 60.41 A c -8.565 1.00 63.13 A ' c -9.572 1.00 68.52 A c -10.294 1.00 70.80 A c -9.932 1.00 71.80 A N -10.831 1.00 71.80 A c -11.068 1.00 72.09 A N - 6.685 1.00 60.90 A C -6.524 1.00 62.29 A 0 -6.497 1.00 61.02 A N 451 WO 2009/026558 PCT/US2008/074097 ATOM 759 CA GLN 554 -18.792 45 ATOM 760 CB GLN 554 -20.062 44 ATOM 761 CG GLN 554 -20.209 44 ATOM 7 62 CD GLN 554 -21.646 44 ATOM 763 OE1 GLN 554 -22.313 43 ATOM 764 NE2 GLN 554 -22.133 45 ATOM 765 C GLN 554 -18.831 45 ATOM 766 0 GLN 554 -18.285 45 ATOM 767 N GLN 555 -19.488 46 ATOM 768 CA GLN 555 -19.517 47 ATOM 769 CB GLN 555 -20.092 48 ATOM 770 CG GLN 555 -19.903 49 ATOM 771 CD GLN 555 -18.440 49 ATOM 772 OE1 GLN 555 -17.700 50 ATOM 773 NE2 GLN 555 -18.012 48 ATOM 774 C GLN 555 -20.336 46 ATOM 775 0 GLN 555 -21.532 46 ATOM 776 N GLY 556 -19.683 45 ATOM 777 CA GLY 556 -20.378 45 ATOM 778 C GLY 556 -20.304 43 ATOM 779 0 GLY 556 -20.687 42 ATOM 780 N HIS 557 -19.809 43 ATOM 781 CA HIS 557 -19.772 41 ATOM 782 CB HIS 557 -19.655 41 ATOM 783 CG HIS 557 -20.930 42 ATOM 784 CD2 HIS 557 -21.535 41 ATOM 785 ND1 HIS 557 -21.752 43 ATOM 786 CEl HIS 557 -22.807 43 ATOM 787 NE2 HIS 557 -22.700 42 ATOM 788 C HIS 557 -18.633 41 ATOM 789 0 HIS 557 -17.560 41 ATOM 790 N VAL 558 -18.892 39 ATOM 791 CA VAL 558 -17.934 38 ATOM 792 CB VAL 558 -18.500 38 ATOM 793 CGI VAL 558 -17.454 37 ATOM 794 CG2 VAL 558 -18.964 39 ATOM 795 C VAL 558 -17.628 37 ATOM 796 O VAL 558 -18.538 37 ATOM 797 N LEU 559 -16.351 37 ATOM 798 CA LEU 559 -15.934 36 ATOM 799 CB LEU 559 -14.440 36 ATOM 800 CG LEU 559 -13.822 34 ATOM 801 CD1 LEU 559 -14.328 34 ATOM 802 CD2 LEU 559 -12.300 35 ATOM 803 C LEU 559 -16.220 34 ATOM 804 O LEU 559 -15.760 34 ATOM 805 N THR 560 -16.976 33 ATOM 806 CA THR 560 -17.335 32 ATOM 807 CB THR 560 -18.862 32 ATOM 808 OG1 THR 560 -19.302 32 ATOM 809 CG2 THR 560 -19.602 33 ATOM 810 C THR 560 -16.649 31 ATOM 811 O THR 560 -16.592 30 ATOM 812 N GLY 561 -16.149 31 ATOM 813 CA GLY 561 -15.529 30 ATOM 814 C GLY 561 -14.728 30 ATOM 815 0 GLY 561 -15.044 31 ATOM 816 N CYS 562 -13.684 29 ATOM 817 CA CYS 562 -12.860 30 ATOM 818 C CYS 562 -12.868 28 ATOM 819 0 CYS 562 -12.698 27 ATOM 820 CB CYS 562 -11.414 30 ATOM 821 SG CYS 562 -11.177 32 ATOM 822 N SER 563 -13.060 28 ATOM 823 CA SER 563 -12.994 27 ATOM 824 CB SER 563 -14.372 27 ATOM 825 OG SER 563 -15.267 26 ATOM 826 C SER 563 -11.991 27 ATOM 827 O SER 563 -11.673 29 ATOM 828 N SER 564 -11.506 26 ATOM 829 CA SER 564 -10.543 27 ATOM 830 CB SER 564 -9.121 27 ATOM 831 OG SER 564 -8.171 27 ATOM 832 C SER 564 -10.697 25 ATOM 833 O SER 564 -10.767 24 ATOM 834 N HIS 565 -10.744 26
-6.120 1.00 61.69 A C -6.527 1.00 62.40 A C -8.030 1.00 64.68 A C -8.452 1.00 66.14 A c -7.952 1.00 66.12 A 0 -9.379 1.00 66.69 A N -4.628 1.00 61.75 A C -3.813 1.00 61.46 A O -4.281 1.00 61.73 A N -2.907 1.00 61.26 A C -2.869 1.00 64.04 A C -1.534 1.00 67.91 A C -1.132 1.00 71.48 A C -1.586 1.00 73.49 A O -0.279 1.00 71.05 A N -1.984 1.00 59.47 A C -2.199 1.00 58.75 A O -0.953 1.00 57.33 A N 0.019 1.00 55.06 A C -0.268 1.00 53.72 A C 0.566 1.00 53.32 A O -1.446 1.00 51.42 A N -1.841 1.00 49.50 A C -3.367 1.00 51.95 A C -4.092 1.00 56.53 A C -5.141 1.00 56.76 A C -3.733 1.00 57.67 A N -4.528 1.00 55.39 A C -5.391 1.00 58.10 A N -1.151 1.00 45.78 A C -0.920 1.00 45.56 A O -0.812 1.00 41.36 A N -0.108 1.00 37.02 A C 1.244 1.00 37.11 A C 1.998 1.00 37.46 A C 2.050 1.00 39.30 A C -0.930 1.00 35.05 A C -1.475 1.00 34.44 A O -1.009 1.00 33.22 A N -1.732 1.00 31.06 A C -2.039 1.00 29.73 A C -2.596 1.00 29.66 A C -4.025 1.00 27.03 A C -2.575 1.00 28.88 A C -0.892 1.00 31.01 A C 0.245 1.00 31.89 A O -1.447 1.00 28.29 A N -0.707 1.00 27.77 A C -0.728 1.00 27.86 A C -2.080 1.00 29.50 A O -0.117 1.00 24.95 A C -1.234 1.00 27.81 A C -0.544 1.00 27.32 A O -2.465 1.00 28.51 A N -3.067 1.00 2 6.65 A C -4.312 1.00 28.04 A C -5.035 1.00 29.85 A O -4.555 1.00 26.78 A N -5.745 1.00 28.08 A C -6.535 1.00 28.91 A C -5.965 1.00 29.35 A O -5.358 1.00 29.31 A C -4.523 1.00 30.67 A S -7.845 1.00 27.63 A N -8.721 1.00 27.76 A C -9.321 1.00 25.87 A C -8.341 1.00 29.15 A O -9.839 1.00 27.56 A ' C -10.157 1.00 28.34 A O -10.440 1.00 26.93 A N -11.531 1.00 28.10 A C -10.960 1.00 28.82 A C -11.957 1.00 33.70 . A O -12.502 1.00 26.61 A C -12.083 1.00 27.41 A O -13.797 1.00 26.38 A N 452 WO 2009/026558 PCT/US2008/074097 ATOM 835 CA HIS 565 -10.647 25 ATOM 836 CB HIS 565 -11.995 24 ATOM 837 CG HIS 565 -12.271 25 ATOM 838 CD2 HIS 565 -12.022 25 ATOM 839 NDl HIS 565 -12.881 27 ATOM 840 CEl HIS 565 -12.994 27 ATOM 841 NE2 HIS 565 -12.480 27 ATOM 842 C HIS 565 -9.589 25 ATOM 843 0 HIS 565 -9.282 26 ATOM 844 N TRP 566 -9.029 24 ATOM 845 CA TRP 566 -8.034 24 ATOM 846 CB TRP 566 -6.618 24 ATOM 847 CG TRP 566 -6.428 23 ATOM 848 CD2 TRP 566 -6.786 22 ATOM 849 CE2 TRP 566 -6.434 21 ATOM 850 CE3 TRP 566 -7.369 23 ATOM 851 CDl TRP 566 -5.886 22 ATOM 852 NEl TRP 566 -5.887 21 ATOM 853 CZ2 TRP 566 -6.648 20 ATOM 854 CZ3 TRP 566 -7.578 22 ATOM 855 CH2 TRP 566 -7.220 21 ATOM 856 C TRP 566 -8.267 23 ATOM 857 O TRP 566 -8.687 22 ATOM 858 N GLU 567 -7.990 24 ATOM 859 CA GLU 567 -8.361 23 ATOM 860 CB GLU 567 -8.547 24 ATOM 861 CG GLU 567 -8.779 24 ATOM 8 62 CD GLU 567 -9.514 25 ATOM 863 OE1 GLU 567 -10.669 25 ATOM 864 OE2 GLU 567 -8.939 25 ATOM 865 C GLU 567 -7.333 22 ATOM 866 0 GLU 567 -7.683 21 ATOM 867 N VAL 568 -6.063 22 ATOM 868 CA VAL 568 -4.991 22 ATOM 869 CB VAL 568 -3.874 22 ATOM 870 CGI VAL 568 -2.660 22 ATOM 871 CG2 VAL 568 -4.402 23 ATOM 872 C VAL 568 -4.428 21 ATOM 873 0 VAL 568 -3.985 21 ATOM 874 N GLU 569 -4.465 19 ATOM 875 CA GLU 569 -4.108 18 ATOM 876 CB GLU 569 -4.360 17 ATOM 877 CG GLU 569 -5.837 17 ATOM 878 CD GLU 569 -6.534 17 ATOM 879 OE1 GLU 569 -7.728 17 ATOM 880 OE2 GLU 569 -5.893 18 ATOM 881 C GLU 569 -2.653 19 ATOM 882 0 GLU 569 -1.767 19 ATOM 883 N ASP 570 -2.439 18 ATOM 884 CA ASP 570 -1.185 19 ATOM 885 CB ASP 570 0.027 18 ATOM 886 CG ASP 570 0.493 17 ATOM 887 OD1 ASP 570 0.436 17 ATOM 888 OD2 ASP 570 0.915 16 ATOM 889 C ASP 570 -1.107 20 ATOM 890 0 ASP 570 -0.426 21 ATOM 891 N LEU 571 -1.802 21 ATOM 892 CA LEU 571 -1.922 22 ATOM 893 CB LEU 571 -2.990 22 ATOM 894 CG LEU 571 -2.707 22 ATOM 895 CDl LEU 571 -3.756 22 ATOM 896 CD2 LEU 571 -2.709 20 ATOM 897 C LEU 571 -0.591 23 ATOM 898 0 LEU 571 -0.554 24 ATOM 899 N PRO 577 4.838 27 ATOM 900 CD PRO 577 6.223 27 ATOM 901 CA PRO 577 4.535 28 ATOM 902 CB PRO 577 5.864 28 ATOM 903 CG PRO 577 6.621 27 ATOM 904 C PRO 577 4.057 29 ATOM 905 0 PRO 577 4.654 30 ATOM 906 N VAL 578 2.983 29 ATOM 907 CA VAL 578 2.397 31 ATOM 908 CB VAL 578 0.859 31 ATOM 909 CGI VAL 578 0.260 32 ATOM 910 CG2 VAL 578 0.308 30 -14.814 1.00 24.40 A C -15.510 1.00 23.27 A C -16.603 1.00 24.99 A C -17.934 1.00 25.30 A c -16.375 1.00 25.00 A N -17.517 1.00 26.14 A c -18.479 1.00 24.33 A N -15.850 1.00 24.48 A C -16.046 1.00 25.19 A 0 -16.511 1.00 24.82 A N -17.547 1.00 25.49 A C -16.989 1.00 23.96 A c -16.298 1.00 24.74 A c -14.944 1.00 24.42 A c -14.729 1.00 23.95 A c -13.896 1.00 25.18 A c -16.828 1.00 23.05 A c -15.894 1.00 23.71 A N -13.508 1.00 25.70 A c -12.688 1.00 24.87 A c -12.503 1.00 25.51 A c -18.746 1.00 25.03 A c -18.595 1.00 24.33 A 0 -19.934 1.00 24.46 A N -21.170 1.00 25.18 A c -22.274 1.00 24.46 A c -23.646 1.00 24.68 A c -24.557 1.00 25.49 A c -24.233 1.00 26.55 A 0 -25.596 1.00 28.35 A 0 -21.604 1.00 26.33 A c -22.072 1.00 2 5.57 A 0 -21.453 1.00 26.79 A N -21.955 1.00 2 9.50 A c -22.571 1.00 28.46 A c -22.901 1.00 28.66 A c -23.842 1.00 24.39 A c -20.853 1.00 32.48 A c -19.818 1.00 31.74 A 0 -21.080 1.00 36.29 A N -20.047 1.00 41.85 A c -20.538 1.00 36.99 A c -20.604 1.00 31.58 A c -21.868 1.00 30.99 A c -22.050 1.00 31.44 A 0 -22.687 1.00 28.21 A 0 -19.603 1.00 48.32 A c -20.424 1.00 47.22 A 0 -18.295 1.00 55.96 A N -17.608 1.00 63.65 A c -18.464 1.00 66.25 A c -18.207 1.00 69.76 A c -17.035 1.00 72.02 A 0 -19.172 1.00 69.99 A 0 -17.236 1.00 67.13 A c -17.903 1.00 68.92 A 0 -16.161 1.00 69.67 A N -15.760 1.00 72.16 A c -14.664 1.00 71.90 A c -13.265 1.00 71.59 A c -12.289 1.00 70.61 A c -13.304 1.00 72.02 A c -15.259 1.00 73.82 A c -14.566 1.00 7 5.52 A 0 -10.922 1.00 57.36 A N -11.012 1.00 59.08 A c -9.587 1.00 56.03 A c -8.836 1.00 56.74 A c -9.563 1.00 58.87 A c -9.671 1.00 53.74 A c -10.365 1.00 55.21 A 0 -8.956 1.00 49.44 A N -9.002 1.00 46.13 . A c -8.897 1.00 45.53 A c -8.892 1.00 45.46 ' A c -10.057 1.00 47.41 A c 453 WO 2009/026558 PCT/US2008/074097 u o z u u u u <<<<<<< uuozuuuuzuzzuozuuuuuozuuuuzuzzuozuuozuuuu ozuozuuuuuozuccccccccccccc uuozuozuuu <<<<<<<<<< u o z < < < CJ O < <
(Nhinco^o(Ti(NCorooco'TCor'(NM^HH^OLnroH^<TrO'TLnaun'jLnLn^LnLnLnMh>TCOHOLn'Th'T'THW^Hhcoa)y3hf'iHOLn^co^h^(Nincoa)roM'3,o totr)Li')Li,)00oHLnHO'jf\i^'T'3,^ro(N^oro(or,iminhotrino'TO^'ThLr)Hcoo>Tom(^o(N'TH(N<T'j,^o(D'j,^co'T'3,'j,'TLn(Ni/)hLnoHOO(Nir)'j,o^>T ηηωΦιηιο^(ΝΐθιθιθΦΦωωωωιηιθΦΦ^Φσ^οσ^θΗΗη^ω(Νΐοωσ^σ^^ιο^·τ!^!^!^θ'τοιοοοΦ(^(θ(Τι(ϊ)Γ'(ϊ)σ'ΐηιη(Νθ'θ'Γιΐ(^'3ιΦΓ''τη'Τ'3,Γ'Φ'3,(ΝΗ oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo ^hooncoooLnHco^roin^^MC'iHinHHhcoM'T'TCorocuohcoMCiLncoLncMtNh^^ifiroMin^^cohocMr'rotN'ThH'TiocoLnc'ico^cMr'roHLnci^'Toa' LnoixiLnLOorocor^o^cN^LO^^^r^tHixiOLOtHr^^cocN^roo^LO^^tHror^tHtHtHro^^LntHO^co^^LO^ocNLOocor^^corOtH^r^fNfNfNco^DrooiTi^Do^Dr' cor^t-Ht-Hr^^r^^^t-Ht-H^conoonoa>cNnoLna>nor^LncNCNr^o^conocN^a>^a>nonouo^a>couonoLnnoLncN^oo^or^^^nouo^r^cocoLnot-Hc\jcN(NLnr''Oo<T>cN'42'42 r^^cor^r^cocor^^r^LO^^^Ln^^^^^^^no^^nono^cNi^oot-Hi-Hi-Ht-HocNCNCNCN'^ocNi^cNCNi^Oi-Hi-Hi-HOoOi-Hi-HOt-HOt-Hi-Hooono^nO'T'sr'^O'^O'^OLn'Tno I I I I I ! 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U-. tx* tx* tx* tx* tx* tx* tx* tx* tr. tr. tr. tr. tr. &amp; t-l t-l t-l t-l t-l t-l t-l t-l t-l tr. tr. tr. &amp; tr. &amp; tr. cn cn cn cn cn cn cn cn t-l t-l t-l t-l t-l t-l t-l t-l t-l > > t-l t-l t-l t-l t-l t-l t-l t-l < < < < < < < < < < < U4 uu U4 uu uu uu uu < < < < < < < < < < < O O O O O o o O o u U U U tl< tl< On On tl< On tl< < < < < < < < < U U U U U U U U U t-H (N t-H CN t-H CN t-H CN t-H CN < CQ co u U < CQ co Q ω CN X X Q < CQ U < CQ CO Q ω EN rr; m C C CQ CO Q UJ UJ a < CQ (0 < CQ CO n Q c CQ CO Q M UJ CJ O 2 u U u u U CJ o 2 u u u U 2 CJ 2 2 CJ o 2 CJ CJ CJ CJ CJ O 2 CJ CJ CJ CJ 2 CJ 2 2 CJ o 2 CJ CJ O 2 CJ CJ CJ CJ o 2 CJ O 2 CJ CJ CJ CJ CJ O 2 CJ CJ CJ o 2 CJ o 2 CJ CJ CJ CJ O 2 CJ o t-H (N no ln uo r> CO <T> o t-H CN no lO Γ" CO <T> o t-H CN no if) r> CO O t-H CN no lO r> CO o t-H CN no lO U0 Γ" CO o t-H CN no lO U0 Γ" CO o t-H CN no lO r> CO O t-H no if) UO t-H t-H t-H t-H t-H t-H t-H t-H t-H CN CN CN CN CN CN CN CN CN CN no no no no no no no no no no if) lO if) lO lO if) lO if) lO if) Ci> uo UO Ci> r> r> r> r> r> Γ" r> r> r> CO CO CO CO CO CO CO <T\ <T\ <T> <T> <T> <T> <T> <T\ <T\ <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T\ <T> <T> <T> <T> <T\ <T> <T> <T\ <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> <T> ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: ?: X X X ?: X ?: X X X ?: ?: ?: X ?: ?: X o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O o O o O O O o o o o o o o o o o o O o o o O O H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H Eh Eh Eh Eh Eh Eh Eh < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < < 454 WO 2009/026558 PCT/US2008/074097 ATOM 987 N CYS 588 -9.523 35 ATOM 988 CA CYS 588 -9.140 34 ATOM 989 C CYS 588 -7.901 34 ATOM 990 0 CYS 588 -7.692 35 ATOM 991 CB CYS 588 -10.256 33 ATOM 992 SG CYS 588 -11.771 33 ATOM 993 N VAL 589 -7.106 33 ATOM 994 CA VAL 589 -5.879 33 ATOM 995 CB VAL 589 -4.644 33 ATOM 996 CGI VAL 589 -3.364 33 ATOM 997 CG2 VAL 589 -4.750 34 ATOM 998 C VAL 589 -5.761 31 ATOM 999 O VAL 589 -5.867 30 ATOM 1000 N GLY 590 -5.540 31 ATOM 1001 CA GLY 590 -5.365 30 ATOM 1002 C GLY 590 -4.067 30 ATOM 1003 0 GLY 590 -3.375 31 ATOM 1004 N HIS 591 -3.732 29 ATOM 1005 CA HIS 591 -2.535 28 ATOM 1006 CB HIS 591 -2.343 27 ATOM 1007 CG HIS 591 -2.045 26 ATOM 1008 CD2 HIS 591 -2.848 25 ATOM 1009 NDl HIS 591 -0.788 26 ATOM 1010 CEl HIS 591 -0.830 25 ATOM 1011 NE2 HIS 591 -2.069 25 ATOM 1012 C HIS 591 -2.614 29 ATOM 1013 0 HIS 591 -3.699 30 ATOM 1014 N ARG 592 -1.464 30 ATOM 1015 CA ARG 592 -1.443 31 ATOM 1016 CB ARG 592 -0.004 31 ATOM 1017 CG ARG 592 0.995 30 ATOM 1018 CD ARG 592 2.258 30 ATOM 1019 NE ARG 592 3.009 31 ATOM 1020 CZ ARG 592 3.575 32 ATOM 1021 NHl ARG 592 4.247 33 ATOM 1022 NH2 ARG 592 3.465 32 ATOM 1023 C ARG 592 -2.112 30 ATOM 1024 O ARG 592 -2.566 31 ATOM 1025 N GLU 593 -2.192 29 ATOM 1026 CA GLU 593 -2.877 28 ATOM 1027 CB GLU 593 -2.181 27 ATOM 1028 CG GLU 593 -0.983 27 ATOM 1029 CD GLU 593 0.219 27 ATOM 1030 OE1 GLU 593 0.553 27 ATOM 1031 OE2 GLU 593 0.828 28 ATOM 1032 C GLU 593 -4.350 28 ATOM 1033 0 GLU 593 -5.019 27 ATOM 1034 N ALA 594 -4.855 28 ATOM 1035 CA ALA 594 -6.236 28 ATOM 1036 CB ALA 594 -6.283 27 ATOM 1037 C ALA 594 -7.092 29 ATOM 1038 O ALA 594 -6.584 30 ATOM 1039 N SER 595 -8.396 29 ATOM 1040 CA SER 595 -9.335 30 ATOM 1041 CB SER 595 -10.656 30 ATOM 1042 OG SER 595 -10.490 30 ATOM 1043 C SER 595 -9.580 30’ ATOM 1044 O SER 595 -9.479 29 ATOM 1045 N ILE 596 -9.891 31 ATOM 1046 CA ILE 596 -10.212 31 ATOM 1047 CB ILE 596 -9.165 32 ATOM 1048 CG2 ILE 596 -9.259 33 ATOM 1049 CGI ILE 596 -9.375 32 ATOM 1050 CDl ILE 596 -8.902 31 ATOM 1051 C ILE 596 -11.619 32 ATOM 1052 0 ILE 596 -12.005 33 ATOM 1053 N HIS 597 -12.385 31 ATOM 1054 CA HIS 597 -13.795 31 ATOM 1055 CB HIS 597 -14.689 30 ATOM 1056 CG HIS 597 -14.325 30 ATOM 1057 CD2 HIS 597 -13.774 29 ATOM 1058 NDl HIS 597 -14.579 30 ATOM 1059 CEl HIS 597 -14.206 30 ATOM 1060 NE2 HIS 597 -13.715 29 ATOM 1061 C HIS 597 -14.076 32 ATOM 10 62 0 HIS 597 -13.767 31 -5.847 1.00 29.94 A N -6.138 1.00 2 9.32 A C -7.018 1.00 28.74 A C -7.850 1.00 30.51 A 0 -6.880 1.00 28.96 A c -5.926 1.00 34.01 A s -6.866 1.00 27.74 A N -7.644 1.00 28.03 A c -6.752 1.00 28.90 A c -7.568 1.00 28.12 A c -6.123 1.00 29.60 A c -8.273 1.00 29.72 A c -7.580 1.00 29.20 A 0 -9.585 1.00 29.03 A N -10.255 1.00 29.41 A c -11.037 1.00 30.32 A c -11.179 1.00 31.55 A 0 -11.549 1.00 31.69 A N -12.367 1.00 34.04 A c -12.727 1.00 36.27 A c -11.546 1.00 44.11 A c -10.796 1.00 46.70 A c -10.986 1.00 46.49 A N -9.940 1.00 46.26 A c -9.803 1.00 49.17 A N -13.640 1.00 34.21 A C -14.077 1.00 32.59 A 0 -14.234 1.00 33.67 A N -15.393 1.00 36.88 A C -15.716 1.00 39.26 A c -15.710 1.00 45.79 A c -16.456 1.00 50.53 A c -15.787 1.00 53.30 A N -16.420 1.00 55.13 A c -15.740 1.00 55.24 A N -17.738 1.00 57.78 A N -16.634 1.00 35.10 A C -17.506 1.00 35.39 A 0 -16.709 1.00 34.62 A N -17.823 1.00 33.78 A C -18.189 1.00 36.33 A c -19.098 1.00 4 6.12 A c -18.362 1.00 52.97 A c -17.284 1.00 55.60 A 0 -18.861 1.00 57.96 A 0 -17.558 1.00 32.11 A c -18.388 1.00 29.63 A 0 -16.406 1.00 28.88 A N -16.046 1.00 28.39 A c -14.687 1.00 2 6.56 A c -16.018 1.00 28.13 A c -15.843 1.00 28.06 A 0 -16.197 1.00 25.46 A N -15.844 1.00 25.16 A c -16.588 1.00 24.79 A c -17.976 1.00 27.76 A 0 -14.338 1.00 24.98 A c -13.720 1.00 24.48 A 0 -13.752 1.00 25.25 A N -12.333 1.00 25.69 A c -11.577 1.00 27.15 A c -12.023 1.00 29.13 A c -10.067 1.00 26.07 A c -9.490 1.00 24.57 A c -12.154 1.00 24.88 A c -12.849 1.00 24.39 A 0 -11.235 1.00 23.51 A N -11.062 1.00 22.95 A c -11.522 1.00 23.62 A c -12.863 1.00 22.44 A c -13.213 1.00 25.26 A c -14.042 1.00 23.06 A N -15.063 1.00 23.37 , A c -14.588 1.00 24.84 A N -9.586 1.00 25.18 A C -8.735 1.00 25.64 A 0 455 WO 2009/026558 PCT/US2008/074097 ATOM 1063 N ALA 598 -14.672 33 ATOM 1064 CA ALA 598 -14.969 33 ATOM 1065 CB ALA 598 -14.384 35 ATOM 1066 C ALA 598 -16.472 33 ATOM 1067 O ALA 598 -17.224 34 ATOM 1068 N SER 599 -16.907 33 ATOM 1069 CA SER 599 -18.286 33 ATOM 1070 CB SER 599 -18.775 32 ATOM 1071 OG SER 599 -20.054 32 ATOM 1072 C SER 599 -18.387 34 ATOM 1073 O SER 599 -17.861 34 ATOM 1074 N CYS 600 -19.064 35 ATOM 1075 CA CYS 600 -19.170 36 ATOM 1076 C CYS 600 -20.606 37 ATOM 1077 0 CYS 600 -21.520 37 ATOM 1078 CB CYS 600 -18.744 38 ATOM 1079 SG CYS 600 -17.010 37 ATOM 1080 N CYS 601 -20.816 37 ATOM 1081 CA CYS 601 -22.175 37 ATOM 1082 C CYS 601 -22.415 38 ATOM 1083 0 CYS 601 -21.636 39 ATOM 1084 CB CYS 601 -22.511 36 ATOM 1085 SG CYS 601 -22.373 34 ATOM 1086 N HIS 602 -23.510 39 ATOM 1087 CA HIS 602 -24.081 40 ATOM 1088 CB HIS 602 -24.858 41 ATOM 1089 CG HIS 602 -25.222 42 ATOM 1090 CD2 HIS 602 -24.451 43 ATOM 1091 NDl HIS 602 -26.526 43 ATOM 1092 CEl HIS 602 -26.543 44 ATOM 1093 NE2 HIS 602 -25.297 44 ATOM 1094 C HIS 602 -25.017 39 ATOM 1095 0 HIS 602 -26.025 39 ATOM 1096 N ALA 603 -24.661 39 ATOM 1097 CA ALA 603 -25.450 39 ATOM 1098 CB ALA 603 -25.006 37 ATOM 1099 C ALA 603 -25.287 39 ATOM 1100 O ALA 603 -24.183 39 ATOM 1101 N PRO 604 -26.394 40 ATOM 1102 CD PRO 604 -27.775 40 ATOM 1103 CA PRO 604 -26.349 41 ATOM 1104 CB PRO 604 -27.808 41 ATOM 1105 CG PRO 604 -28.600 40 ATOM 1106 C PRO 604 -25.762 40 ATOM 1107 O PRO 604 -26.291 39 ATOM 1108 N GLY 605 -24.664 41 ATOM 1109 CA GLY 605 -24.084 40 ATOM 1110 C GLY 605 -23.181 39 ATOM 1111 0 GLY 605 -22.695 38 ATOM 1112 N LEU 606 -22.951 38 ATOM 1113 CA LEU 606 -22.048 37 ATOM 1114 CB LEU 606 -22.319 37 ATOM 1115 CG LEU 606 -21.432 36 ATOM 1116 CDl LEU 606 -21.603 35 ATOM 1117 CD2 LEU 606 -21.794 35 ATOM 1118 C LEU 606 -20.599 38 ATOM 1119 O LEU 606 -20.226 39 ATOM 1120 N GLU 607 -19.792 37 ATOM 1121 CA GLU 607 -18.388 37 ATOM 1122 CB GLU 607 -18.194 38 ATOM 1123 CG GLU 607 -16.751 38 ATOM 1124 CD GLU 607 -16.585 38 ATOM 1125 OE1 GLU 607 -17.466 38 ATOM 1126 OE2 GLU 607 -15.564 39 ATOM 1127 C GLU 607 -17.541 36 ATOM 1128 0 GLU 607 -17.845 35 ATOM 1129 N CYS 608 -16.483 36 ATOM 1130 CA CYS 608 -15.634 35 ATOM 1131 C CYS 608 -14.154 35 ATOM 1132 0 CYS 608 -13.724 37 ATOM 1133 CB CYS 608 -15.861 35 ATOM 1134 SG CYS 608 -17.584 34 ATOM 1135 N LYS 609 -13.381 34 ATOM 1136 CA LYS 609 -11.938 34 ATOM 1137 CB LYS 609 -11.566 35 ATOM 1138 CG LYS 609 -11.789 33 -9.289 1.00 25.15 A N -7.909 1.00 26.23 A C -7.606 1.00 23.97 A C -7.680 1.00 27.18 A c -8.508 1.00 27.20 A 0 -6.556 1.00 2 6.97 A N. -6.133 1.00 29.40 A C -5.376 1.00 30.19 A C -4.826 1.00 33.89 A O -5.232 1.00 30.33 A C -4 .120 1.00 31.52 A O -5.728 1.00 32.35 A N -5.036 1.00 35.21 A C -4.591 1.00 36.07 A C -5.413 1.00 35.83 A 0 -5.971 1.00 35.88 A c -6.513 1.00 39.28 A s -3.289 1.00 38.47 A N -2.790 1.00 40.53 A c -2.079 1.00 42.20 A c -1.218 1.00 40.46 A 0 -1.832 1.00 40.11 A c -2.469 1.00 41.58 A s -2.453 1.00 44.38 A N -1.637 1.00 47.94 A c -2.518 1.00 51.93 A c -1.826 1.00 58.56 A c -1.237 1.00 60.81 A c -1.678 1.00 60.77 A N -1.028 1.00 62.59 A c -0.749 1.00 62.85 A N -0.661 1.00 48.23 A C -1.063 1.00 45.88 A 0 0.619 1.00 49.87 A N 1.653 1.00 52.49 A C 1.804 1.00 50.93 A c 2.975 1.00 53.94 A c 3.507 1.00 55.03 A 0 3.530 1.00 55.31 A N 3.105 1.00 56.68 A c 4.721 1.00 55.19 A c 4.931 1.00 56.90 A c 4.278 1.00 57.49 A c 5.951 1.00 53.84 A c 6.429 1.00 53.50 A 0 6.459 1.00 51.66 A N 7.683 1.00 49.75 A c 7.466 1.00 49.32 A c 8.426 1.00 49.78 A 0 6.209 1.00 4 7.32 A N 5.914 1.00 45.14 A c 4.516 1.00 46.10 A c 4.128 1.00 46.60 A c 5.146 1.00 45.47 A c 2.731 1.00 47.85 A c 6.015 1.00 43.35 A c 5.460 1.00 42.73 A 0 6.737 1.00 41.82 A N 6.949 1.00 41.58 A c 8.390 1.00 43.33 A c 8.788 1.00 48.75 A c 10.289 1.00 52.26 A c 11.082 1.00 53.24 A 0 10.675 1.00 52.44 A 0 6.699 1.00 40.02 A c 7.217 1.00 39.94 A 0 5.905 1.00 38.50 A N 5.616 1.00 38.05 A c 5.793 1.00 38.09 A c 5.752 1.00 38.32 A 0 4 . 192 1.00 36.34 A c 3.711 1.00 38.54 A s 5.981 1.00 37.60 . A N 6.132 1.00 37.54 A c 7.611 1.00 36.16 ' A c 8.375 1.00 39.02 A c 456 WO 2009/026558 PCT/US2008/074097 ATOM 1139 CD LYS 609 -11.435 33 ATOM 1140 CE LYS 609 -11.847 32 ATOM 1141 NZ LYS 609 -11.420 32 ATOM 1142 C LYS 609 -11.309 33 ATOM 1143 0 LYS 609 -12.004 32 ATOM 1144 N VAL 610 -9.995 33 ATOM 1145 CA VAL 610 -9.284 32 ATOM 1146 CB VAL 610 -8.484 33 ATOM 1147 CGI VAL 610 -7.745 31 ATOM 1148 CG2 VAL 610 -9.423 33 ATOM 1149 C VAL 610 -8.323 31 ATOM 1150 O VAL 610 -7.599 32 ATOM 1151 N LYS 611 -8.330 30 ATOM 1152 CA LYS 611 -7.388 29 ATOM 1153 CB LYS 611 -8.116 29 ATOM 1154 CG LYS 611 -8.917 30 ATOM 1155 CD LYS 611 -9.432 29 ATOM 1156 CE LYS 611 -8.336 28 ATOM 1157 NZ LYS 611 -8.782 27 ATOM 1158 C LYS 611 -6.718 28 ATOM 1159 0 LYS 611 -7.365 28 ATOM 1160 N GLU 612 -5.429 28 ATOM 1161 CA GLU 612 -4.726 27 ATOM 1162 CB GLU 612 -3.867 28 ATOM 1163 CG GLU 612 -2.809 29 ATOM 1164 CD GLU 612 -2.008 29 ATOM 1165 OE1 GLU 612 -2.592 30 ATOM 1166 OE2 GLU 612 -0.796 29 ATOM 1167 C GLU 612 -3.853 26 ATOM 1168 0 GLU 612 -3.592 27 ATOM 1169 N HIS 613 -3.414 25 ATOM 1170 CA HIS 613 -2.438 24 ATOM 1171 CB HIS 613 -3.140 23 ATOM 1172 CG HIS 613 -2.222 22 ATOM 1173 CD2 HIS 613 -1.137 22 ATOM 1174 NDl HIS 613 -2.381 21 ATOM 1175 CEl HIS 613 -1.435 20 ATOM 1176 NE2 HIS 613 -0.667 21 ATOM 1177 C HIS 613 -1.677 23 ATOM 1178 0 HIS 613 -2.277 23 ATOM 1179 N GLY 614 -0.356 24 ATOM 1180 CA GLY 614 0.460 23 ATOM 1181 C GLY 614 1.295 22 ATOM 1182 0 GLY 614 1.660 22 ATOM 1183 N ILE 615 1.594 21 ATOM 1184 CA ILE 615 2.451 20 ATOM 1185 CB ILE 615 1.643 18 ATOM 1186 CG2 ILE 615 2.575 17 ATOM 1187 CGI ILE 615 0.648 19 ATOM 1188 CDl ILE 615 1.290 19 ATOM 1189 C ILE 615 3.505 19 ATOM 1190 0 ILE 615 3.203 20 ATOM 1191 N PRO 616 4.762 19 ATOM 1192 CD PRO 616 5.226 19 ATOM 1193 CA PRO 616 5.878 19 ATOM 1194 CB PRO 616 7.100 19 ATOM 1195 CG PRO 616 6.684 20 ATOM 1196 C PRO 616 5.717 18 ATOM 1197 O PRO 616 5.755 18 ATOM 1198 N ALA 617 5.539 17 ATOM 1199 CA ALA 617 5.396 15 ATOM 1200 CB ALA 617 6.581 15 ATOM 1201 C ALA 617 4 . 097 15 ATOM 1202 O ALA 617 4.096 14 ATOM 1203 N PRO 618 2.971 15 ATOM 1204 CD PRO 618 2.883 16 ATOM 1205 CA PRO 618 1.660 15 ATOM 1206 CB PRO 618 0.679 15 ATOM 1207 CG PRO 618 1.485 16 ATOM 1208 C PRO 618 1.557 13 ATOM 1209 O PRO 618 1.962 13 ATOM 1210 N GLN 619 1.017 12 ATOM 1211 CA GLN 619 0.972 11 ATOM 1212 CB GLN 619 1.260 10 ATOM 1213 CG GLN 619 2.736 10 ATOM 1214 CD GLN 619 3.405 9 9.849 1.00 42.30 A C 10.614 1.00 42.81 A C 12.039 1.00 44.87 A N 5.538 1.00 37.29 A C 5.264 1.00 37.32 A 0 5.351 1.00 36.83 A . N 4.743 1.00 36.94 A C 3.511 1.00 37.85 A c 2.902 1.00 38.22 A c 2.488 1.00 37.85 A c 5.729 1.00 37.80 A c 6.446 1.00 38.87 A 0 5.761 1.00 37.56 A N 6.568 1.00 38.62 A c 7.684 1.00 38.63 A c 8.625 1.00 42.75 A c 9.793 1.00 42.52 A c 10.342 1.00 44.58 A c 11.559 1.00 48.18 A N 5.664 1.00 39.23 A c 4.791 1.00 39.27 A 0 5.874 1.00 39.16 A N 5.094 1.00 42.41 A c 4.025 1.00 44.71 A c 4.571 1.00 49.08 A c 3.465 1.00 53.20 A c 2.699 1.00 54.07 A 0 3.360 1.00 53.71 A 0 5.970 1.00 42.48 A c 7.127 1.00 43.10 A 0 5.415 1.00 41.33 A N 6.074 1.00 42.62 A c 7.025 1.00 44.30 A c 7.658 1.00 44.52 A c 8.453 1.00 44.27 A c 7.498 1.00 45.05 A N 8.167 1.00 43.50 A c 8.755 1.00 44.92 A N 5.003 1.00 44.32 A C 4 .183 1.00 44.33 A 0 5.000 1.00 45.57 A N 4.010 1.00 4 6.92 A C 4.609 1.00 48.04 A c 5.779 1.00 48.09 A 0 3.801 1.00 50.58 A N 4.214 1.00 53.77 A c 4.407 1.00 55.20 A c 4.701 1.00 54.79 A c 5.551 1.00 55.97 A c 6.820 1.00 58.58 A c 3.143 1.00 55.43 A c 1.950 1.00 55.42 A 0 3.559 1.00 57.06 A N 4.952 1.00 57.57 A c 2.627 1.00 58.08 A c 3.541 1.00 58.83 A c 4.792 1.00 58.90 A c 1.768 1.00 58.68 A c 0.540 1.00 59.30 A 0 2.420 1.00 58.67 A N 1.704 1.00 60.47 A c 2.006 1.00 60.68 A c 2.095 1.00 60.64 A c 2.876 1.00 60.93 A 0 1.541 1.00 60.54 A N 0.417 1.00 60.69 A c 1.929 1.00 60.60 A c 1.079 1.00 60.68 A c -0.093 1.00 61.12 A c 1.673 1.00 60.54 A c 0.621 1.00 60.46 A 0 2.647 1.00 61.08 A N 2.585 1.00 62.08 . A c 3.963 1.00 64.75 A c 4.294 1.00 69.13 A c 3.650 1.00 72.41 A c 457 WO 2009/026558 PCT/US2008/074097 ATOM 1215 OE1 GLN 619 4.597 9 ATOM 1216 NE2 GLN 619 2.636 8 ATOM 1217 C GLN 619 -0.366 10 ATOM 1218 0 GLN 619 -0.690 9 ATOM 1219 N GLY 620 -1.140 11 ATOM 1220 CA GLY 620 -2.412 11 ATOM 1221 C GLY 620 -3.476 12 ATOM 1222 0 GLY 620 -4.332 12 ATOM 1223 N GLN 621 -3.433 13 ATOM 1224 CA GLN 621 -4.334 14 ATOM 1225 CB GLN 621 -5.715 14 ATOM 1226 CG GLN 621 -5.783 13 ATOM 1227 CD GLN 621 -7.187 13 ATOM 1228 OE1 GLN 621 -8.035 12 ATOM 1229 NE2 GLN 621 -7.440 13 ATOM 1230 C GLN 621 -3.793 15 ATOM 1231 0 GLN 621 -2.991 15 ATOM 1232 N VAL 622 -4.230 16 ATOM 1233 CA VAL 622 -3.895 17 ATOM 1234 CB VAL 622 -3.022 18 ATOM 1235 CGI VAL 622 -2.539 20 ATOM 1236 CG2 VAL 622 -1.858 18 ATOM 1237 C VAL 622 -5.216 18 ATOM 1238 O VAL 622 -6.068 18 ATOM 1239 N THR 623 -5.392 18 ATOM 1240 CA THR 623 -6.656 19 ATOM 1241 CB THR 623 -7.387 18 ATOM 1242 OG1 THR 623 -6.629 18 ATOM 1243 CG2 THR 623 -7.559 17 ATOM 1244 C THR 623 -6.457 20 ATOM 1245 O THR 623 -5.388 21 ATOM 1246 N VAL 624 -7.495 21 ATOM 1247 CA VAL 624 -7.583 22 ATOM 1248 CB VAL 624 -6.990 24 ATOM 1249 CGI VAL 624 -7.790 24 ATOM 1250 CG2 VAL 624 -6.973 25 ATOM 1251 C VAL 624 -9.058 22 ATOM 1252 O VAL 62 4 -9.925 22 ATOM 1253 N ALA 625 -9.346 23 ATOM 1254 CA ALA 625 -10.723 23 ATOM 1255 CB ALA 625 -10.971 22 ATOM 1256 C ALA 625 -11.060 24 ATOM 1257 0 ALA 625 -10.185 25 ATOM 1258 N CYS 62 6 -12.335 25 ATOM 1259 CA CYS 62 6 -12.840 26 ATOM 1260 C CYS 62 6 -13.170 26 ATOM 1261 0 CYS 62 6 -13.781 25 ATOM 12 62 CB CYS 626 -14.110 26 ATOM 1263 SG CYS 626 -13.999 27 ATOM 1264 N GLU 627 -12.770 27 ATOM 1265 CA GLU 627 -13.077 26 ATOM 1266 CB GLU 627 -12.212 27 ATOM 1267 CG GLU 627 -12.348 29 ATOM 1268 CD GLU 627 -11.403 29 ATOM 1269 OE1 GLU 627 -10.990 30 ATOM 1270 OE2 GLU 627 -11.071 28 ATOM 1271 C GLU 627 -14.551 27 ATOM 1272 0 GLU 627 -15.252 27 ATOM 1273 N GLU 62 8 -15.022 26 ATOM 1274 CA GLU 62 8 -16.438 26 ATOM 1275 CB GLU 628 -16.740 26 ATOM 1276 CG GLU 628 -16.323 27 ATOM 1277 CD GLU 628 -16.746 26 ATOM 1278 OE1 GLU 628 -16.934 27 ATOM 1279 OE2 GLU 628 -16.889 25 ATOM 1280 C GLU 628 -16.840 28 ATOM 1281 0 GLU 628 -16.043 29 ATOM 1282 N GLY 62 9 -18.077 28 ATOM 1283 CA GLY 629 -18.499 29 ATOM 1284 C GLY 629 -18.411 30 ATOM 1285 0 GLY 629 -19.083 31 ATOM 1286 N TRP 630 -17.582 29 ATOM 1287 CA TRP 630 -17.418 29 ATOM 1288 CB TRP 630 -15.966 30 ATOM 1289 CG TRP 630 -15.498 31 ATOM 1290 CD2 TRP 630 -15.352 32 3.844 1.00 75.41 A O 2.879 1.00 73.28 A N 2.082 1.00 60.67 A C 2.248 1.00 61.39 A O 1.463 1.00 58.38 A N 0.902 1.00 55.08 A C 0.959 1.00 52.97 A C 0.076 1.00 52.81 A 0 1.998 1.00 49.05 A N 2.084 1.00 46.66 A c 2.571 1.00 48.24 A c 4.038 1.00 50.90 A c 4.471 1.00 52.62 A c 3.645 1.00 53.23 A 0 5.774 1.00 53.97 A N 2.998 1.00 44.42 A c 3.894 1.00 43.84 A 0 2.742 1.00 41.31 A N 3.57 6 1.00 38.86 A c 2.814 1.00 37.61 A c 3.759 1.00 39.32 A c 2.162 1.00 38.06 A c 3.935 1.00 38.57 A c 3.068 1.00 38.51 A 0 5.207 1.00 35.77 A N 5.664 1.00 33.79 A c 6.604 1.00 34.25 A c 7.810 1.00 33.79 A 0 5.932 1.00 33.56 A c 6.407 1.00 33.76 A c 6.968 1.00 33.37 A 0 6.401 1.00 32.04 A N 7.310 1.00 31.45 A c 6.674 1.00 32.64 A c 5.446 1.00 31.89 A c 7.699 1.00 31.91 A c 7.630 1.00 33.28 A c 6.789 1.00 32.07 A 0 8.852 1.00 33.71 A N 9.305 1.00 35.41 A c 10.434 1.00 33.24 A c 9.768 1.00 37.55 A c 10.200 1.00 38.33 A 0 9.661 1.00 39.75 A N 10.286 1.00 41.17 A c 11.743 1.00 43.54 A c 12.024 1.00 44.60 A 0 9.575 1.00 39.19 A c 7.765 1.00 41.43 A s 12.669 1.00 45.20 A N 14.085 1.00 47.32 A c 14.966 1.00 47.58 A c 14.660 1.00 49.95 A c 13.566 1.00 52.51 A c 13.592 1.00 55.13 A 0 12.681 1.00 52.16 A 0 14.362 1.00 47.35 A c 13.522 1.00 46.45 A 0 15.538 1.00 47.46 A N 15.857 1.00 48.46 A c 17.243 1.00 53.92 A c 18.415 1.00 59.91 A c 19.765 1.00 63.80 A c 20.719 1.00 63.78 A 0 19.873 1.00 66.46 A 0 15.815 1.00 46.20 A c 16.132 1.00 46.72 A 0 15.410 1.00 42.69 A ' N 15.171 1.00 40.02 A c 13.700 1.00 39.40 A c 13.250 1.00 40.26 A 0 12.947 1.00 37.59 A N 11.515 1.00 35.74 . A c 11.191 1.00 33.84 A c 11.807 1.00 36.54 A c 11.155 1.00 36.10 A c 458 WO 2009/026558 PCT/US2008/074097 ATOM 1291 CE2 TRP 630 -14.864 33 ATOM 1292 CE3 TRP 630 -15.584 33 ATOM 1293 CD1 TRP 630 -15.104 31 ATOM 1294 NEl TRP 630 -14.721 32 ATOM 1295 CZ2 TRP 630 -14.607 34 ATOM 1296 CZ3 TRP 630 -15.328 34 ATOM 1297 CH2 TRP 630 -14.844 35 ATOM 1298 C TRP 630 -17.821 28 ATOM 1299 O TRP 630 -17.703 27 ATOM 1300 N THR 631 -18.285 28 ATOM 1301 CA THR 631 -18.715 27 ATOM 1302 CB THR 631 -20.210 27 ATOM 1303 OG1 THR 631 -20.961 27 ATOM 1304 CG2 THR 631 -20.686 26 ATOM 1305 C THR 631 -17.900 27 ATOM 1306 O THR 631 -17.683 28 ATOM 1307 N LEU 632 -17.443 26 ATOM 1308 CA LEU 632 -16.662 26 ATOM 1309 CB LEU 632 -16.011 24 ATOM 1310 CG LEU 632 -15.186 24 ATOM 1311 CD1 LEU 632 -14.066 25 ATOM 1312 CD2 LEU 632 -14.624 23 ATOM 1313 C LEU 632 -17.550 26 ATOM 1314 O LEU 632 -18.496 25 ATOM 1315 N THR 633 -17.256 27 ATOM 1316 CA THR 633 -18.047 27 ATOM 1317 CB THR 633 -18.520 29 ATOM 1318 OG1 THR 633 -17.382 30 ATOM 1319 CG2 THR 633 -19.320 29 ATOM 1320 C THR 633 -17.271 27 ATOM 1321 O THR 633 -17.864 26 ATOM 1322 N GLY 634 -15.946 27 ATOM 1323 CA GLY 634 -15.131 27 ATOM 1324 C GLY 634 -13.850 26 ATOM 1325 0 GLY 634 -13.244 26 ATOM 1326 N CYS 635 -13.432 25 ATOM 1327 CA CYS 635 -12.296 24 ATOM 1328 C CYS 635 -11.526 24 ATOM 1329 0 CYS 635 -12.107 23 ATOM 1330 CB CYS 635 -12.798 23 ATOM 1331 SG CYS 635 -11.559 21 ATOM 1332 N SER 636 -10.222 24 ATOM 1333 CA SER 636 -9.392 24 ATOM 1334 CB SER 636 -9.557 25 ATOM 1335 OG SER 636 -9.043 26 ATOM 1336 C SER 636 -7.916 24 ATOM 1337 O SER 636 -7.526 24 ATOM 1338 N ALA 637 -7.099 24 ATOM 1339 CA ALA 637 -5.653 23 ATOM 1340 CB ALA 637 -5.063 22 ATOM 1341 C ALA 637 -5.038 25 ATOM 1342 0 ALA 637 -5.468 25 ATOM 1343 N LEU 638 -4.036 25 ATOM 1344 CA LEU 638 -3.236 26 ATOM 1345 CB LEU 638 -2.161 27 ATOM 1346 CG LEU 638 -1.633 28 ATOM 1347 CD1 LEU 638 -2.751 29 ATOM 1348 CD2 LEU 638 -0.505 28 ATOM 1349 C LEU 638 -2.583 26 ATOM 1350 O LEU 638 -2.027 25 ATOM 1351 N PRO 639 -2.654 27 ATOM 1352 CD PRO 639 -3.210 28 ATOM 1353 CA PRO 639 -2.072 27 ATOM 1354 CB PRO 639 -2.528 28 ATOM 1355 CG PRO 639 -2.731 29 ATOM 1356 C PRO 639 -0.551 26 ATOM 1357 O PRO 639 0.128 27 ATOM 1358 N GLY 640 -0.021 25 ATOM 1359 CA GLY 640 1.417 25 ATOM 1360 C GLY 640 1.913 24 ATOM 1361 0 GLY 640 1.201 24 ATOM 1362 N THR 641 3.129 24 ATOM 1363 CA THR 641 3.606 22 ATOM 1364 CB THR 641 5.134 22 ATOM 1365 OG1 THR 641 5.489 22 ATOM 1366 CG2 THR 641 5.888 23 12.118 1.00 38.43 A C 9.853 1.00 36.07 A C 13.105 1.00 37.06 A C 13.297 1.00 3 6.65 A N 11.818 1.00 36.82 A C 9.556 1.00 37.24 A C 10.535 1.00 37.91 A c 10.701 1.00 35.13 A c 11.165 1.00 35.66 A 0 9.481 1.00 32.78 A N 8.626 1.00 31.14 A c 8.289 1.00 31.87 A c 9.508 1.00 28.32 A 0 7.452 1.00 28.98 A c 7.337 1.00 30.23 A c 6.708 1.00 29.72 A 0 6.956 1.00 2 9.92 A N 5.739 1.00 28.80 A c 5.746 1.00 27.20 A c 4.510 1.00 30.81 A c 4.346 1.00 30.24 A c 4.657 1.00 31.20 A c 4 . 498 1.00 28.43 A c 4.309 1.00 28.53 A 0 3.660 1.00 26.00 A N 2.449 1.00 27.86 A c 2.306 1.00 27.33 A c 2.156 1.00 25.74 A 0 3.530 1.00 23.90 A c 1 .188 1.00 2 9.32 A c 0.160 1.00 29.29 A 0 1.267 1.00 29.44 A N 0.096 1.00 29.46 A c 0.437 1.00 29.50 A c 1.485 1.00 30.22 A 0 -0.454 1.00 28.04 A N -0.190 1.00 28.82 A c -1.477 1.00 29.22 A c -2.477 1.00 29.78 A 0 0.372 1.00 27.17 A c 0.583 1.00 31.95 A s -1.449 1.00 29.87 A N -2.635 1.00 31.98 A c -3.567 1.00 30.53 A c -2.957 1.00 32.60 A 0 -2.276 1.00 33.39 A c -1.113 1.00 33.25 A 0 -3.289 1.00 35.31 A N -3.117 1.00 37.57 A c -3.937 1.00 35.81 A c -3.554 1.00 38.81 A c -4.537 1.00 39.80 A 0 -2.811 1.00 40.54 A N -3.216 1.00 41.27 A c -2.163 1.00 41.30 A c -1.974 1.00 43.45 A c -1.502 1.00 43.30 A c -0.952 1.00 44.32 A c -4.536 1.00 43.36 A c -4.665 1.00 43.89 A 0 -5.541 1.00 44.54 A N -5.535 1.00 42.27 A c -6.838 1.00 45.55 A c -7.764 1.00 44 .15 A c -6.849 1.00 44.46 A c -6.745 1.00 48.67 A c -6.530 1.00 49.10 A 0 -6.895 1.00 52.08 A N -6.809 1.00 55.68 A c -7.849 1.00 58.10 A c -8.802 1.00 58.79 A 0 -7.679 1.00 61.04 A N -8.532 1.00 64.61 . A c -8.392 1.00 65.87 A c -7.006 1.00 67.03 ' A 0 -9.048 1.00 66.73 A c 459 WO 2009/026558 PCT/US2008/074097 ATOM 1367 c THR 641 2.883 21.653 -8.152 1.00 66.27 A C ATOM 1368 0 THR 641 3.336 20.548 -8.461 1.00 67.72 A O ATOM 1369 N SER 642 1.740 21.824 -7.492 1.00 67.29 A N ATOM 1370 CA SER 642 0.977 20.732 -6.901 1.00 66.68 A C ATOM 1371 CB SER 642 -0.227 21.301 -6.138 1.00 68.50 A C ATOM 1372 OG SER 642 0.163 22.269 -5.174 1.00 65.92 A 0 ATOM 1373 C SER 642 0.480 19.719 -7.927 1.00 66.01 A c ATOM 1374 O SER 642 0.079 20.081 -9.031 1.00 66.17 A 0 ATOM 1375 N HIS 643 0.507 18.445 -7.548 1.00 65.59 A N ATOM 1376 CA HIS 643 -0.260 17.419 -8.250 1.00 63.85 A c ATOM 1377 CB HIS 643 0.565 16.134 -8.445 1.00 68.67 A c ATOM 1378 CG HIS 643 2.049 16.339 -8.398 1.00 73.45 A c ATOM 1379 CD2 HIS 643 2.830 17.348 -8.853 1.00 75.15 A c ATOM 1380 NDl HIS 643 2.905 15.423 -7.823 1.00 75.08 A N ATOM 1381 CEl HIS 643 4 .148 15.859 -7.925 1.00 7 6.32 A c ATOM 1382 NE2 HIS 643 4 . 130 17.025 -8.546 1.00 76.69 A N ATOM 1383 C HIS 643 -1.461 17.099 -7.368 1.00 59.62 A C ATOM 1384 0 HIS 643 -1.347 16.321 -6.418 1.00 61.00 A 0 ATOM 1385 N VAL 644 -2.606 17.697 -7.672 1.00 53.01 A N ATOM 1386 CA VAL 644 -3.775 17.546 -6.813 1.00 47.88 A C ATOM 1387 CB VAL 644 -4.312 18.931 -6.395 1.00 48.74 A c ATOM 1388 CGI VAL 644 -5.721 18.813 -5.835 1.00 46.18 A c ATOM 1389 CG2 VAL 644 -3.379 19.535 -5.359 1.00 4 6.52 A c ATOM 1390 C VAL 644 -4.894 16.729 -7.456 1.00 44.30 A c ATOM 1391 O VAL 644 -5.270 16.973 -8.605 1.00 41.49 A 0 ATOM 1392 N LEU 645 -5.416 15.756 -6.711 1.00 39.48 A N ATOM 1393 CA LEU 645 -6.514 14.921 -7.198 1.00 35.69 A c ATOM 1394 CB LEU 645 -6.636 13.646 -6.359 1.00 34.50 A c ATOM 1395 CG LEU 645 -5.395 12.749 -6.310 1.00 33.63 A c ATOM 1396 CDl LEU 645 -5.668 11.520 -5.449 1.00 29.01 A c ATOM 1397 CD2 LEU 645 -5.014 12.337 -7.722 1.00 32.25 A c ATOM 1398 C LEU 645 -7.820 15.699 -7.120 1.00 33.69 A c ATOM 1399 O LEU 645 -8.741 15.482 -7.911 1.00 33.63 A 0 ATOM 1400 N GLY 646 -7.889 16.615 -6.164 1.00 30.73 A N ATOM 1401 CA GLY 646 -9.099 17.387 -5.980 1.00 29.59 A c ATOM 1402 C GLY 646 -9.210 17.891 -4.559 1.00 29.58 A c ATOM 1403 0 GLY 646 -8.271 17.766 -3.767 1.00 29.34 A 0 ATOM 1404 N ALA 647 -10.362 18.466 -4.238 1.00 27.24 A N ATOM 1405 CA ALA 647 -10.592 19.040 -2.927 1.00 26.99 A c ATOM 1406 CB ALA 647 -10.043 20.453 -2.878 1.00 23.24 A c ATOM 1407 C ALA 647 -12.091 19.044 -2.660 1.00 27.99 A c ATOM 1408 0 ALA 647 -12.898 19.142 -3.590 1.00 2 6.92 A 0 ATOM 1409 N TYR 648 -12.4 62 18.923 -1.391 1.00 26.93 A N ATOM 1410 CA TYR 648 -13.865 18.949 -1.011 1.00 28.19 A c ATOM 1411 CB TYR 648 -14.535 17.621 -1.373 1.00 27.10 A c ATOM 1412 CG TYR 648 -13.744 16.397 -0.960 1.00 29.81 A c ATOM 1413 CDl TYR 648 -13.822 15.899 0.336 1.00 28.83 A c ATOM 1414 CEl TYR 648 -13.090 14.788 0.725 1.00 30.03 A c ATOM 1415 CD2 TYR 648 -12.912 15.747 -1.862 1.00 29.05 A c ATOM 1416 CE2 TYR 648 -12.179 14.635 -1.486 1.00 32.30 A c ATOM 1417 CZ TYR 648 -12.272 14.160 -0.187 1.00 31.60 A c ATOM 1418 OH TYR 648 -11.544 13.057 0.195 1.00 33.44 A 0 ATOM 1419 C TYR 648 -14.021 19.210 0.477 1.00 30.20 A c ATOM 1420 O TYR 648 -13.126 18.905 1.272 1.00 30.34 A 0 ATOM 1421 N ALA 649 -15.166 19.768 0.851 1.00 28.57 A N ATOM 1422 CA ALA 649 -15.455 20.020 2.251 1.00 29.86 A c ATOM 1423 CB ALA 649 -16.394 21.210 2.380 1.00 28.48 A c ATOM 1424 C ALA 649 -16.083 18.783 2.884 1.00 32.30 A c ATOM 1425 0 ALA 649 -16.920 18.115 2.276 1.00 33.16 A 0 ATOM 1426 N VAL 650 -15.653 18.469 4 .101 1.00 33.30 A N ATOM 1427 CA VAL 650 -16.356 17.509 4.939 1.00 33.70 A c ATOM 1428 CB VAL 650 -15.487 16.269 5.234 1.00 34.68 A c ATOM 1429 CGI VAL 650 -16.177 15.385 6.257 1.00 35.80 A c ATOM 1430 CG2 VAL 650 -15.251 15.487 3.954 1.00 33.77 A c ATOM 1431 C VAL 650 -16.683 18.220 6.242 1.00 33.54 A c ATOM 1432 O VAL 650 -15.784 18.580 7.005 1.00 34.44 A 0 ATOM 1433 N ASP 651 -17.970 18.436 ' 6.484 1.00 32.32 A N ATOM 1434 CA ASP 651 -18.396 19.313 7.560 1.00 33.07 A ' c ATOM 1435 CB ASP 651 -18.048 18.692 8.914 1.00 34.55 A c ATOM 1436 CG ASP 651 -18.678 17.316 9.101 1.00 37.44 A c ATOM 1437 ODl ASP 651 -19.927 17.218 9.110 1.00 36.19 A 0 ATOM 1438 OD2 ASP 651 -17.925 16.328 9.235 1.00 39.42 A 0 ATOM 1439 C ASP 651 -17.696 20.658 7.382 1.00 33.97 . A c ATOM 1440 O ASP 651 -17.885 21.319 6.360 1.00 34.64 A 0 ATOM 1441 N ASN 652 -16.884 21.060 8.357 1.00 32.48 A N ATOM 1442 CA ASN 652 -16.196 22.346 8.273 1.00 32.00 A c 460 WO 2009/026558 PCT/US2008/074097 ATOM 1443 CB ASN 652 -16.502 23 ATOM 1444 CG ASN 652 -17.927 23 ATOM 1445 OD1 ASN 652 -18.527 23 ATOM 1446 ND2 ASN 652 -18.474 24 ATOM 1447 C ASN 652 -14.693 22 ATOM 1448 O ASN 652 -13.908 23 ATOM 1449 N THR 653 -14.309 21 ATOM 1450 CA THR 653 -12.921 20 ATOM 1451 CB THR 653 -12.510 19 ATOM 1452 OG1 THR 653 -12.589 19 ATOM 1453 CG2 THR 653 -11.095 19 ATOM 1454 C THR 653 -12.712 20 ATOM 1455 O THR 653 -13.452 20 ATOM 1456 N CYS 654 -11.705 21 ATOM 1457 CA CYS 654 -11.330 21 ATOM 1458 C CYS 654 -10.320 20 ATOM 1459 0 CYS 654 -9.254 20 ATOM 1460 CB CYS 654 -10.709 22 ATOM 1461 SG CYS 654 -10.081 22 ATOM 1462 N VAL 655 -10.649 19 ATOM 1463 CA VAL 655 -9.761 18 ATOM 1464 CB VAL 655 -10.500 16 ATOM 1465 CGI VAL 655 -9.552 15 ATOM 1466 CG2 VAL 655 -11.058 16 ATOM 1467 C VAL 655 -9.187 18 ATOM 1468 O VAL 655 -9.929 18 ATOM 1469 N VAL 656 -7.864 18 ATOM 1470 CA VAL 656 -7.199 18 ATOM 1471 CB VAL 656 -6.140 19 ATOM 1472 CGI VAL 656 -5.368 19 ATOM 1473 CG2 VAL 656 -6.827 20 ATOM 1474 C VAL 656 -6.526 17 ATOM 1475 O VAL 656 -5.797 16 ATOM 1476 N ARG 657 -6.787 16 ATOM 1477 CA ARG 657 -6.201 15 ATOM 1478 CB ARG 657 -7.260 14 ATOM 1479 CG ARG 657 -8.393 13 ATOM 1480 CD ARG 657 -8.058 12 ATOM 1481 NE ARG 657 -7.781 11 ATOM 1482 CZ ARG 657 -8.701 10 ATOM 1483 NHl ARG 657 -8.358 9 ATOM 1484 NH2 ARG 657 -9.966 10 ATOM 1485 C ARG 657 -5.048 15 ATOM 1486 0 ARG 657 -5.200 15 ATOM 1487 N SER 658 -3.888 14 ATOM 1488 CA SER 658 -2.685 14 ATOM 1489 CB SER 658 -1.502 15 ATOM 1490 OG SER 658 -1.412 14 ATOM 1491 C SER 658 -2.392 13 ATOM 14 92 0 SER 658 -2.864 12 ATOM 1493 N ARG 659 -1.617 13 ATOM 1494 CA ARG 659 -1.109 12 ATOM 1495 CB ARG 659 -0.700 12 ATOM 1496 CG ARG 659 0.009 11 ATOM 1497 CD ARG 659 -0.801 9 ATOM 1498 NE ARG 659 -0.729 9 ATOM 1499 CZ ARG 659 -1.329 8 ATOM 1500 NHl ARG 659 -2.049 7 ATOM 1501 NH2 ARG 659 -1.212 7 ATOM 1502 C ARG 659 0.091 11 ATOM 1503 0 ARG 659 -0.051 10 ATOM 1504 N GLU 670 5.942 19 ATOM 1505 CA GLU 670 6.378 19 ATOM 1506 CB GLU 670 7.326 20 ATOM 1507 CG GLU 670 8.652 20 ATOM 1508 CD GLU 670 8.570 20 ATOM 1509 OE1 GLU 670 7.987 21 ATOM 1510 OE2 GLU 670 9.101 19 ATOM 1511 C GLU 670 5.291 19 ATOM 1512 0 GLU 670 4 . 489 18 ATOM 1513 N ALA 671 5.273 20 ATOM 1514 CA ALA 671 4.300 20 ATOM 1515 CB ALA 671 4.729 22 ATOM 1516 C ALA 671 2.878 21 ATOM 1517 0 ALA 671 2.685 21 ATOM 1518 N VAL 672 1.8 92 20
9.511 1.00 32.46 A C 9.500 1.00 35.25 A C 8.433 1.00 32.30 A 0 10.687 1.00 33.95 A N 8.102 1.00 31.47 A C 8.451 1.00 30.18 A 0 7.544 1.00 29.69 A N 7.225 1.00 28.78 A C 7.809 1.00 27.92 A C 9.237 1.00 29.55 A 0 7.395 1.00 28.75 A C 5.707 1.00 28.67 A C 4.978 1.00 29.58 A 0 5.236 1.00 28.76 A N 3.827 1.00 27.76 A C 3.598 1.00 28.97 A C 4.215 1.00 31.24 A 0 3.399 1.00 28.74 A C 1.685 1.00 32.18 A S 2.700 1.00 28.34 A N 2.378 1.00 28.21 A C 2.459 1.00 28.71 A C 2.103 1.00 28.30 A C 3.851 1.00 29.74 A C 0.971 1.00 29.61 A C -0.011 1.00 2 9.60 A 0 0.877 1.00 29.42 A N -0.411 1.00 29.18 A C -0.579 1.00 29.20 A C -1.887 1.00 23.76 A C -0.575 1.00 25.50 A C -0.522 1.00 30.76 A C 0.376 1.00 29.50 A 0 -1.625 1.00 33.71 A N -1.863 1.00 35.25 A C -2.409 1.00 35.66 A C -1.438 1.00 37.10 A C -0.541 1.00 37.52 A C -1.310 1.00 36.14 A N -1.637 1.00 39.36 A C -2.339 1.00 39.27 A N -1.264 1.00 38.06 A N -2.848 1.00 37.95 A C -3.960 1.00 37.69 A 0 -2.433 1.00 41.37 A N -3.254 1.00 44.93 A C -2.397 1.00 45.44 A C -1.223 1.00 50.04 A 0 -3.858 1.00 46.73 A C -3.357 1.00 45.37 A 0 -4.936 1.00 50.91 A N -5.457 1.00 56.06 A C -6.920 1.00 60.94 A C -7.473 1.00 66.87 A C -7.244 1.00 70.25 A C -5.863 1.00 73.87 A N -5.418 1.00 75.97 A C -6.247 1.00 76.24 A N -4.144 1.00 76.11 A N -4.643 1.00 57.33 A C -3.709 1.00 59.34 A 0 -5.234 1.00 59.80 A N -3.843 1.00 59.19 A C -3.727 1.00 60.88 A C -3.026 1.00 65.12 A C -1.508 1.00 68.07 A C -0.974 1.00 68.75 A 0 -0.839 1.00 70.08 A 0 -2.765 1.00 57.96 A C -2.544 1.00 56.88 A 0 -2.089 1.00 55.53 A N -1.013 1.00 52.14 A C -0.160 1.00 50.35 . A C -1.532 1.00 50.50 A C -2.660 1.00 49.31 A 0 -0.689 1.00 48.22 A N 461 WO 2009/026558 PCT/US2008/074097 ATOM 1519 CA VAL 672 0.485 21 ATOM 1520 CB VAL 672 -0.264 19 ATOM 1521 CGI VAL 672 -1.765 19 ATOM 1522 CG2 VAL 672 0.127 19 ATOM 1523 C VAL 672 -0.164 21 ATOM 1524 O VAL 672 -0.012 21 ATOM 1525 N THR 673 -0.876 22 ATOM 1526 CA THR 673 -1.535 23 ATOM 1527 CB THR 673 -1.014 25 ATOM 1528 OG1 THR 673 0.405 25 ATOM 1529 CG2 THR 673 -1.654 25 ATOM 1530 C THR 673 -3.052 23 ATOM 1531 O THR 673 -3.554 23 ATOM 1532 N ALA 674 -3.775 23 ATOM 1533 CA ALA 674 -5.228 23 ATOM 1534 CB ALA 674 -5.809 22 ATOM 1535 C ALA 674 -5.700 24 ATOM 1536 0 ALA 674 -5.196 25 ATOM 1537 N VAL 675 -6.669 25 ATOM 1538 CA VAL 675 -7.155 26 ATOM 1539 CB VAL 675 -6.893 27 ATOM 1540 CGI VAL 675 -7.362 29 ATOM 1541 CG2 VAL 675 -5.423 27 ATOM 1542 C VAL 675 -8.652 26 ATOM 1543 O VAL 675 -9.436 26 ATOM 1544 N ALA 67 6 -9.046 27 ATOM 1545 CA ALA 67 6 -10.446 27 ATOM 1546 CB ALA 67 6 -10.631 26 ATOM 1547 C ALA 67 6 -10.965 28 ATOM 1548 0 ALA 67 6 -10.342 29 ATOM 1549 N ILE 677 -12.112 28 ATOM 1550 CA ILE 677 -12.853 30 ATOM 1551 CB ILE 677 -13.511 30 ATOM 1552 CG2 ILE 677 -14.405 31 ATOM 1553 CGI ILE 677 -12.424 31 ATOM 1554 CD1 ILE 677 -12.949 31 ATOM 1555 C ILE 677 -13.925 29 ATOM 1556 0 ILE 677 -14.759 28 ATOM 1557 N CYS 678 -13.880 30 ATOM 1558 CA CYS 678 -14.780 30 ATOM 1559 C CYS 678 -15.661 31 ATOM 1560 0 CYS 678 -15.180 32 ATOM 1561 CB CYS 678 -13.966 30 ATOM 1562 SG CYS 678 -12.794 28 ATOM 1563 N CYS 679 -16.949 31 ATOM 1564 CA CYS 679 -17.842 32 ATOM 1565 C CYS 679 -18.750 32 ATOM 1566 0 CYS 679 -18.970 31 ATOM 1567 CB CYS 679 -18.712 32 ATOM 1568 SG CYS 679 -17.854 32 ATOM 1569 N ARG 680 -19.282 33 ATOM 1570 CA ARG 680 -20.257 33 ATOM 1571 CB ARG 680 -19.547 33 ATOM 1572 CG ARG 680 -18.769 34 ATOM 1573 CD ARG 680 -18.249 35 ATOM 1574 NE ARG 680 -17.474 36 ATOM 1575 CZ ARG 680 -16.716 36 ATOM 1576 NH1 ARG 680 -16.043 37 ATOM 1577 NH2 ARG 680 -16.629 35 ATOM 1578 C ARG 680 -21.146 34 ATOM 1579 O ARG 680 -20.924 35 ATOM 1580 N SER 681 -22.152 34 ATOM 1581 CA SER 681 -23.029 36 ATOM 1582 CB SER 681 -24.423 35 ATOM 1583 OG SER 681 -24.392 35 ATOM 1584 C SER 681 -22.486 37 ATOM 1585 O SER 681 -21.714 36 ATOM 1586 N ARG 682 -22.896 38 ATOM 1587 CA ARG 682 -22.616 39 ATOM 1588 CB ARG 682 -21.647 40 ATOM 1589 CG ARG 682 -20.316 39 ATOM 1590 CD ARG 682 -19.510 40 ATOM 1591 NE ARG 682 -20.383 41 ATOM 1592 CZ ARG 682 -19.966 42 ATOM 1593 NH1 ARG 682 -20.839 43 ATOM 1594 NH2 ARG 682 -18.678 42
-0.993 1.00 46.40 A C -1.175 1.00 46.60 A C -1.123 1.00 45.09 A C -2.500 1.00 45.84 A c 0.140 1.00 44.64 A c 1.308 1.00 44.63 A 0 -0.205 1.00 42.97 A N 0.803 1.00 42.42 A c 0.769 1.00 41.83 A c 0.961 1.00 43.57 A 0 1.874 1.00 43.03 A c 0.609 1.00 40.73 A c -0.491 1.00 40.35 A 0 1.684 1.00 37.65 A N 1.651 1.00 36.09 A c 2.589 1.00 32.65 A c 2.054 1.00 35.70 A c 3.014 1.00 35.06 A 0 1.313 1.00 33.36 A N 1.554 1.00 31.12 A c 0.344 1.00 32.06 A c 0.648 1.00 30.35 A c -0.015 1.00 31.11 A c 1.814 1.00 32.06 A c 0.962 1.00 33.53 A 0 2.991 1.00 31.39 A N 3.369 1.00 31.28 A c 4.731 1.00 30.37 A c 3.425 1.00 32.21 A c 4.026 1.00 32.29 A 0 2.799 1.00 30.97 A N 3.046 1.00 31.18 A c 1.755 1.00 30.16 A c 2.071 1.00 28.01 A c 0.749 1.00 29.28 A c -0.653 1.00 31.33 A c 4.094 1.00 32.12 A c 3.925 1.00 29.55 A 0 5.181 1.00 33.00 A N 6.316 1.00 34.13 A c 6.478 1.00 33.65 A c 6.384 1.00 33.63 A 0 7.594 1.00 35.39 A c 7.523 1.00 37.76 A s 6.718 1.00 33.05 A N 6.892 1.00 36.46 A c 8.113 1.00 39.97 A c 8.639 1.00 37.89 A 0 5.658 1.00 36.27 A c 4.054 1.00 36.27 A s 8.547 1.00 43.34 A N 9.630 1.00 48.28 A c 10.983 1.00 47.10 A c 11.195 1.00 50.25 A c 12.610 1.00 50.93 A c 12.786 1.00 53.09 A N 13.846 1.00 53.83 A c 13.919 1.00 54.26 A N 14.829 1.00 53.05 A N 9.479 1.00 49.82 A C 8.600 1.00 49.14 A 0 10.339 1.00 53.31 A N 10.378 1.00 58.05 A C 10.837 1.00 58.41 A c 12.195 1.00 60.93 A 0 11.346 1.00 59.77 A c 12.248 1.00 60.55 A 0 11.154 1.00 62.76 A ' N 12.122 1.00 66.03 A c 11.528 1.00 68.33 A c 11.085 1.00 71.05 A c 10.368 1.00 73.61 A c 9.641 1.00 76.11 . A N 8.723 1.00 76.34 A c 8.117 1.00 74.95 ' A N 8.409 1.00 77.06 A N 462 WO 2009/026558 PCT/US2008/074097 ATOM 1595 c ARG 682 -23.909 40 ATOM 1596 0 ARG 682 -24.947 39 ATOM 1597 OXT ARG 682 -23.867 40 TER 1598 ARG 682 ATOM 3134 CB ALA -2 -22.599 17 ATOM 3135 c ALA -2 -20.735 18 ATOM 3136 0 ALA -2 -19.631 17 ATOM 3137 N ALA -2 -20.438 17 ATOM 3138 CA ALA -2 -21.422 18 ATOM 3139 N LEU -1 -21.382 18 ATOM 3140 CA LEU -1 -20.904 18 ATOM 3141 CB LEU -1 -20.620 19 ATOM 3142 CG LEU -1 -20.062 19 ATOM 3143 CDl LEU -1 -18.735 19 ATOM 3144 CD2 LEU -1 -19.875 21 ATOM 3145 C LEU -1 -21.939 17 ATOM 3146 O LEU -1 -23.076 18 ATOM 3147 N GLN 1 -21.543 16 ATOM 3148 CA GLN 1 -22.440 15 ATOM 3149 CB GLN 1 -22.229 14 ATOM 3150 CG GLN 1 -23.162 13 ATOM 3151 CD GLN 1 -23.290 11 ATOM 3152 OE1 GLN 1 -24.374 11 ATOM 3153 NE2 GLN 1 -22.185 11 ATOM 3154 C GLN 1 -22.148 16 ATOM 3155 0 GLN 1 -21.038 15 ATOM 3156 N SER 2 -23.143 16 ATOM 3157 CA SER 2 -22.984 17 ATOM 3158 CB SER 2 -23.663 18 ATOM 3159 OG SER 2 -22.995 19 ATOM 3160 C SER 2 -23.579 15 ATOM 3161 O SER 2 -24.551 15 ATOM 3162 N VAL 3 -22.990 15 ATOM 3163 CA VAL 3 -23.345 14 ATOM 3164 CB VAL 3 -22.173 14 ATOM 3165 CGI VAL 3 -22.604 13 ATOM 3166 CG2 VAL 3 -20.970 13 ATOM 3167 C VAL 3 -24.573 14 ATOM 3168 O VAL 3 -25.360 14 ATOM 3169 N LEU 4 -24.736 16 ATOM 3170 CA LEU 4 -25.909 16 ATOM 3171 CB LEU 4 -25.540 17 ATOM 3172 CG LEU 4 -24.396 17 ATOM 3173 CDl LEU 4 -24.060 18 ATOM 3174 CD2 LEU 4 -24.793 16 ATOM 3175 C LEU 4 -26.996 17 ATOM 3176 O LEU 4 -26.701 17 ATOM 3177 N THR 5 -28.251 17 ATOM 3178 CA THR 5 -29.365 17 ATOM 3179 CB THR 5 -30.419 16 ATOM 3180 OG1 THR 5 -29.813 15 ATOM 3181 CG2 THR 5 -31.584 16 ATOM 3182 C THR 5 -30.062 18 ATOM 3183 O THR 5 -30.597 18 ATOM 3184 N GLN 6 -30.048 19 ATOM 3185 CA GLN 6 -30.806 20 ATOM 3186 CB GLN 6 -29.889 22 ATOM 3187 CG GLN 6 -28.913 22 ATOM 3188 CD GLN 6 -28.010 23 ATOM 3189 OE1 GLN 6 -26.843 23 ATOM 3190 NE2 GLN 6 -28.548 24 ATOM 3191 C GLN 6 -31.770 21 ATOM 3192 0 GLN 6 -31.475 20 ATOM 3193 N PRO 7 -32.921 21 ATOM 3194 CD PRO 7 -33.416 22 ATOM 3195 CA PRO 7 -33.756 22 ATOM 3196 CB PRO 7 -34.944 22 ATOM 3197 CG PRO 7 -34.421 23 ATOM 3198 C PRO 7 -32.961 23 ATOM 3199 O PRO 7 -32.206 24 ATOM 3200 N PRO 8 -33.113 23 ATOM 3201 CD PRO 8 -33.901 22 ATOM 3202 CA PRO 8 -32.380 23 ATOM 3203 CB PRO 8 -32.755 23 ATOM 3204 CG PRO 8 -33.254 21 ATOM 3205 C PRO 8 -32.747 25 12.514 1.00 66.85 A C 11.873 1.00 67.78 A 0 13.448 1.00 68.38 A 0 A -50.667 1.00 30.97 LI c -49.294 1.00 31.14 LI c -49.156 1.00 30.83 LI 0 -51.719 1.00 31.98 LI N -50.655 1.00 32.78 LI c -48.290 1.00 30.72 LI N -46.923 1.00 31.40 LI C -46.300 1.00 30.42 LI c -44.872 1.00 32.48 LI c -44.874 1.00 32.58 LI c -44.314 1.00 31.47 LI c -46.090 1.00 32.90 LI c -45.930 1.00 31.46 LI 0 -45.565 1.00 32.45 LI N -44.739 1.00 36.30 LI c -45.006 1.00 39.00 LI c -44.229 1.00 46.21 LI c -44.857 1.00 51.70 LI c -44.867 1.00 55.34 LI 0 -45.384 1.00 50.89 LI N -43.282 1.00 36.73 LI c -42.801 1.00 39.33 LI 0 -42.592 1.00 34.09 LI N -41.200 1.00 32.26 LI c -40.951 1.00 33.35 LI c -41.660 1.00 36.24 LI 0 -40.290 1.00 31.17 LI c -40.651 1.00 29.93 LI 0 -39.111 1.00 29.66 LI N -38.242 1.00 27.57 LI c -37.304 1.00 26.77 LI c -36.328 1.00 20.64 LI c -38.135 1.00 24.71 LI c -37.403 1.00 28.78 LI c -37.110 1.00 29.90 LI 0 -37.013 1.00 28.16 LI N -36.239 1.00 28.07 LI c -35.261 1.00 25.10 LI c -34.289 1.00 27.51 LI c -33.483 1.00 27.28 LI c -33.367 1.00 27.59 LI c -37.190 1.00 26.91 LI c -38.282 1.00 25.87 LI 0 -36.777 1.00 27.45 LI N -37.650 1.00 29.69 LI c -37.709 1.00 30.65 LI c -38.227 1.00 32.80 LI 0 -38.615 1.00 30.25 LI c -37.216 1.00 29.39 LI c -36.113 1.00 28.74 LI 0 -38.093 1.00 27.91 LI N -37.885 1.00 28.70 LI c -37.866 1.00 26.66 LI c -36.721 1.00 24.05 LI c -36.872 1.00 25.09 LI c -37.243 1.00 27.47 LI 0 -36.597 1.00 22.42 LI N -39.044 1.00 28.56 LI c -40.170 1.00 27.37 LI 0 -38.789 1.00 30.02 LI N -37.483 1.00 30.00 LI c -39.904 1.00 29.84 LI c -39.215 1.00 30.46 LI c -37.859 1.00 31.08 LI c -40.761 1.00 30.79 LI c -40.242 1.00 30.95 LI 0 -42.087 1.00 29.99 LI N -42.767 1.00 29.60 LI c -43.036 1.00 30.24 . LI c -44.404 1.00 30.10 LI c -44 .113 1.00 31.61 LI c -42.928 1.00 31.73 LI c 463 WO 2009/026558 PCT/US2008/074097 ATOM 3206 0 PRO 8 -31.943 26 ATOM 3207 N SER 9 -33.960 25 ATOM 3208 CA SER 9 -34.446 27 ATOM 3209 CB SER 9 -35.043 27 ATOM 3210 OG SER 9 -36.252 26 ATOM 3211 C SER 9 -35.494 27 ATOM 3212 O SER 9 -36.151 26 ATOM 3213 N ALA 10 -35.637 28 ATOM 3214 CA ALA 10 -36.668 28 ATOM 3215 CB ALA 10 -36.196 28 ATOM 3216 C ALA 10 -36.943 30 ATOM 3217 0 ALA 10 -36.162 31 ATOM 3218 N SER 11 -38.058 30 ATOM 3219 CA SER 11 -38.366 32 ATOM 3220 CB SER 11 -39.055 32 ATOM 3221 OG SER 11 -40.290 31 ATOM 3222 C SER 11 -39.255 32 ATOM 3223 O SER 11 -40.016 32 ATOM 3224 N GLY 12 -39.143 34 ATOM 3225 CA GLY 12 -39.983 34 ATOM 3226 C GLY 12 -40.221 36 ATOM 3227 0 GLY 12 -39.510 36 ATOM 3228 N THR 13 -41.224 36 ATOM 3229 CA THR 13 -41.545 38 ATOM 3230 CB THR 13 -43.057 38 ATOM 3231 OG1 THR 13 -43.732 37 ATOM 3232 CG2 THR 13 -43.389 39 ATOM 3233 C THR 13 -40.834 38 ATOM 3234 O THR 13 -40.768 38 ATOM 3235 N PRO 14 -40.295 40 ATOM 3236 CD PRO 14 -40.243 40 ATOM 3237 CA PRO 14 -39.678 40 ATOM 3238 CB PRO 14 -39.510 42 ATOM 3239 CG PRO 14 -39.338 41 ATOM 3240 C PRO 14 -40.562 40 ATOM 3241 O PRO 14 -41.788 40 ATOM 3242 N GLY 15 -39.933 40 ATOM 3243 CA GLY 15 -40.684 40 ATOM 3244 C GLY 15 -41.091 39 ATOM 3245 0 GLY 15 -41.394 39 ATOM 3246 N GLN 16 -41.101 38 ATOM 3247 CA GLN 16 -41.542 37 ATOM 32 4 8 CB GLN 16 -42.263 36 ATOM 3249 CG GLN 16 -43.514 37 ATOM 3250 CD GLN 16 -44.608 37 ATOM 3251 OE1 GLN 16 -45.367 36 ATOM 3252 NE2 GLN 16 -44.693 38 ATOM 3253 C GLN 16 -40.393 36 ATOM 3254 0 GLN 16 -39.232 36 ATOM 3255 N ARG 17 -40.743 35 ATOM 3256 CA ARG 17 -39.782 34 ATOM 3257 CB ARG 17 -40.225 33 ATOM 3258 CG ARG 17 -39.384 32 ATOM 3259 CD ARG 17 -39.923 31 ATOM 3260 NE ARG 17 -39.086 30 ATOM 3261 CZ ARG 17 -39.155 29 ATOM 3262 NHl ARG 17 -40.019 29 ATOM 32 63 NH2 ARG 17 -38.376 28 ATOM 3264 C ARG 17 -39.697 32 ATOM 3265 O ARG 17 -40.722 32 ATOM 3266 N VAL 18 -38.480 32 ATOM 3267 CA VAL 18 -38.269 31 ATOM 3268 CB VAL 18 -37.688 31 ATOM 3269 CGI VAL 18 -38.642 32 ATOM 3270 CG2 VAL 18 -36.331 32 ATOM 3271 C VAL 18 -37.320 30 ATOM 3272 O VAL 18 -36.493 30 ATOM 3273 N THR 19 -37.447 29 ATOM 3274 CA THR 19 -36.532 28 ATOM 3275 CB THR 19 -37.231 27 ATOM 3276 OG1 THR 19 -38.256 26 ATOM 3277 CG2 THR 19 -37.839 27 ATOM 3278 C THR 19 -35.932 27 ATOM 3279 O THR 19 -36.581 27 ATOM 3280 N ILE 20 -34.680 26 ATOM 32 81 CA ILE 20 -34.013 26 -43.258 1.00 31.46 LI O -42.467 1.00 30.72 LI N -42.450 1.00 32.53 LI C -43.808 1.00 35.18 LI C -44.038 1.00 39.78 LI 0 -41.382 1.00 32.20 LI c -40.933 1.00 32.14 LI 0 -40.982 1.00 32.09 LI N -40.049 1.00 30.01 LI c -38.611 1.00 29.34 LI c -40.294 1.00 31.41 LI c -40.958 1.00 31.03 LI 0 -39.770 1.00 30.95 LI N -39.876 1.00 33.18 LI c -41.205 1.00 31.83 LI c -41.292 1.00 34.06 LI 0 -38.731 1.00 33.60 LI c -38.175 1.00 34.21 LI 0 -38.379 1.00 33.24 LI N -37.344 1.00 34.06 LI c -37.594 1.00 34.78 LI c -38.377 1.00 35.73 LI 0 -36.926 1.00 35.43 LI N -37.055 1.00 35.76 LI c -36.915 1.00 37.03 LI c -37.980 1.00 40.63 LI 0 -36.959 1.00 38.80 LI c -35.949 1.00 34.79 LI c -34.817 1.00 33.06 LI 0 -36.261 1.00 33.81 LI N -37.579 1.00 33.59 LI c -35.213 1.00 35.17 LI c -35.881 1.00 35.17 LI c -37.339 1.00 32.62 LI c -33.970 1.00 37.04 LI c -34.076 1.00 36.13 LI 0 -32.798 1.00 37.53 LI N -31.554 1.00 37.21 LI c -31.044 1.00 37.71 LI c -29.864 1.00 39.10 LI 0 -31.918 1.00 38.28 LI N -31.514 1.00 39.95 LI c -32.673 1.00 42.22 LI c -33.166 1.00 4 9.57 LI c -32.108 1.00 53.19 LI c -31.889 1.00 55.70 LI 0 -31.449 1.00 53.13 LI N -31.017 1.00 39.30 LI c -30.998 1.00 36.61 LI 0 -30.608 1.00 39.04 LI N -30.142 1.00 4 0.32 LI c -28.779 1.00 40.01 LI c -28.239 1.00 43.34 LI c -26.898 1.00 41.71 LI c -26.277 1.00 43.61 LI N -26.565 1.00 4 3.68 LI c -27.471 1.00 44.38 LI N -25.933 1.00 4 3.92 LI N -31.148 1.00 39.25 LI C -31.548 1.00 40.22 LI 0 -31.562 1.00 38.21 LI N -32.410 1.00 36.63 LI C -33.790 1.00 37.42 LI c -34.510 1.00 37.93 LI c -33.624 1.00 37.49 LI c -31.755 1.00 36.06 LI c -30.918 1.00 37.18 LI 0 -32.127 1.00 34.19 LI N -31.635 1.00 33.85 LI c -30.699 1.00 34.73 LI c -31.422 1.00 36.14 LI 0 -29.510 1.00 36.05 LI c -32.788 1.00 33.77 . LI c -33.804 1.00 34.31 LI 0 -32.627 1.00 32.67 LI N -33.619 1.00 30.93 LI c 464 WO 2009/026558 PCT/US2008/074097 ATOM 3282 CB ILE 20 -32.856 26 ATOM 3283 CG2 ILE 20 -32.090 25 ATOM 3284 CGI ILE 20 -33.410 28 ATOM 3285 CD1 ILE 20 -32.348 29 ATOM 3286 C ILE 20 -33.479 24 ATOM 3287 0 ILE 20 -32.825 25 ATOM 3288 N SER 21 -33.772 23 ATOM 3289 CA SER 21 -33.418 22 ATOM 3290 CB SER 21 -34.577 21 ATOM 3291 OG SER 21 -34.646 20 ATOM 3292 C SER 21 -32.183 21 ATOM 3293 O SER 21 -31.850 22 ATOM 3294 N CYS 22 -31.514 21 ATOM 3295 CA CYS 22 -30.300 20 ATOM 3296 C CYS 22 -30.378 18 ATOM 3297 0 CYS 22 -30.482 18 ATOM 3298 CB CYS 22 -29.078 21 ATOM 3299 SG CYS 22 -27.428 20 ATOM 3300 N SER 23 -30.349 17 ATOM 3301 CA SER 23 -30.434 16 ATOM 3302 CB SER 23 -31.691 15 ATOM 3303 OG SER 23 -31.715 15 ATOM 3304 C SER 23 -29.202 15 ATOM 3305 O SER 23 -28.689 15 ATOM 3306 N GLY 24 -28.734 15 ATOM 3307 CA GLY 24 -27.548 14 ATOM 3308 C GLY 24 -27.832 12 ATOM 3309 0 GLY 24 -28.902 12 ATOM 3310 N SER 25 -26.886 12 ATOM 3311 CA SER 25 -27.045 10 ATOM 3312 CB SER 25 -26.747 9 ATOM 3313 OG SER 25 -25.400 10 ATOM 3314 C SER 25 -26.113 10 ATOM 3315 O SER 25 -25.447 11 ATOM 3316 N SER 26 -26.066 9 ATOM 3317 CA SER 26 -25.345 9 ATOM 3318 CB SER 26 -25.588 7 ATOM 3319 OG SER 26 -25.038 6 ATOM 3320 C SER 26 -23.847 9 ATOM 3321 O SER 26 -23.153 9 ATOM 3322 N SER 27 -23.347 9 ATOM 3323 CA SER 27 -21.916 9 ATOM 3324 CB SER 27 -21.495 8 ATOM 3325 OG SER 27 -21.943 9 ATOM 3326 C SER 27 -21.521 11 ATOM 3327 O SER 27 -20.342 11 ATOM 3328 N ASN 28 -22.497 11 ATOM 3329 CA ASN 28 -22.197 13 ATOM 3330 CB ASN 28 -22.302 14 ATOM 3331 CG ASN 28 -23.467 13 ATOM 3332 OD1 ASN 28 -24.629 13 ATOM 3333 ND2 ASN 28 -23.154 13 ATOM 3334 C ASN 28 -23.028 14 ATOM 3335 0 ASN 28 -22.578 14 ATOM 3336 N ILE 29 -24 .230 14 ATOM 3337 CA ILE 29 -24.995 15 ATOM 3338 CB ILE 29 -26.300 15 ATOM 3339 CG2 ILE 29 -27.128 16 ATOM 3340 CGI ILE 29 -25.951 16 ATOM 3341 CD1 ILE 29 -27.146 17 ATOM 3342 C ILE 29 -25.313 14 ATOM 3343 0 ILE 29 -25.448 15 ATOM 3344 N GLY 30 -25.401 13 ATOM 3345 CA GLY 30 -25.640 12 ATOM 3346 C GLY 30 -24.619 12 ATOM 3347 0 GLY 30 -24.952 12 ATOM 3348 N SER 31 -23.376 12 ATOM 3349 CA SER 31 -22.342 13 ATOM 3350 CB SER 31 -21.104 12 ATOM 3351 OG SER 31 -21.357 10 ATOM 3352 C SER 31 -21.905 14 ATOM 3353 O SER 31 -21.490 14 ATOM 3354 N ASN 32 -21.991 15 ATOM 3355 CA ASN 32 -21.240 16 ATOM 3356 CB ASN 32 -20.279 16 ATOM 3357 CG ASN 32 -19.380 15 -34.267 1.00 30.89 LI C -35.202 1.00 32.28 LI c -35.010 1.00 31.02 LI c -35.461 1.00 29.96 LI c -32.912 1.00 29.12 LI c -31.877 1.00 27.11 LI 0 -33.460 1.00 28.13 LI N -32.791 1.00 27.04 LI c -32.857 1.00 28.51 LI c -34.144 1.00 36.31 LI 0 -33.404 1.00 27.38 LI c -34.576 1.00 26.13 LI 0 -32.599 1.00 26.91 LI N -33.012 1.00 28.14 LI c -32.407 1.00 27.39 LI c -31.191 1.00 26.72 LI 0 -32.470 1.00 28.78 LI c -32.716 1.00 33.98 LI s -33.246 1.00 26.59 LI N -32.722 1.00 29.26 LI c -33.244 1.00 30.37 LI c -34.653 1.00 40.04 LI 0 -33.053 1.00 27.58 LI c -34.171 1.00 25.14 LI 0 -32.049 1.00 27.83 LI N -32.195 1.00 28.19 LI c -31.632 1.00 29.00 LI c -31.867 1.00 29.40 LI 0 -30.878 1.00 26.84 LI N -30.372 1.00 27.01 LI c -31.478 1.00 26.36 LI c -31.879 1.00 26.75 LI 0 -29.209 1.00 26.30 LI c -28.746 1.00 27.16 LI 0 -28.742 1.00 25.37 LI N -27.522 1.00 25.52 LI c -27.143 1.00 26.57 LI c -28.119 1.00 32 .72 LI 0 -27.673 1.00 25.31 LI c -26.688 1.00 26.31 LI 0 -28.904 1.00 25.12 LI N -29.129 1.00 23.38 LI c -30.472 1.00 22.37 LI c -31.551 1.00 24.28 LI 0 -29.085 1.00 24.26 LI c -28.959 1.00 23.93 LI 0 -29.195 1.00 23.53 LI N -29.020 1.00 23.52 LI c -30.361 1.00 21.17 LI c -31.228 1.00 23.34 LI c -30.908 1.00 23.92 LI 0 -32.345 1.00 21.27 LI N -27.937 1.00 23.95 LI c -26.799 1.00 25.36 LI 0 -28.267 1.00 24.55 LI N -27.300 1.00 24.06 LI c -27.929 1.00 26.12 LI c -26.883 1.00 21.66 LI c -29.103 1.00 21.86 LI c -29.766 1.00 26.70 LI c -26.040 1.00 25.43 LI c -24.956 1.00 24.34 LI 0 -26.170 1.00 25.71 LI N -25.000 1.00 25.17 LI c -23.875 1.00 28.74 LI c -22.702 1.00 28.98 LI 0 -24 .217 1.00 26.07 LI N -23.207 1.00 2 5.52 LI c -23.511 1.00 25.93 LI c -23.314 1.00 27.84 LI 0 -23.092 1.00 26.39 LI c -22.022 1.00 25.97 LI 0 -24.192 1.00 25.12 . LI N -24.316 1.00 2 5.92 LI c -25.494 1.00 22.78 LI c -25.362 1.00 25.36 LI c 465 WO 2009/026558 PCT/US2008/074097 ATOM 3358 OD1 ASN 32 -18.840 14 ATOM 3359 ND2 ASN 32 -19.220 14 ATOM 3360 C ASN 32 -22.087 17 ATOM 3361 0 ASN 32 -23.258 17 ATOM 3362 N THR 33 -21.477 18 ATOM 3363 CA THR 33 -22.153 20 ATOM 3364 CB THR 33 -21.272 21 ATOM 3365 OG1 THR 33 -20.054 21 ATOM 3366 CG2 THR 33 -20.937 20 ATOM 3367 C THR 33 -22.478 20 ATOM 3368 O THR 33 -21.778 20 ATOM 3369 N VAL 34 -23.542 21 ATOM 3370 CA VAL 34 -23.901 21 ATOM 3371 CB VAL 34 -25.422 21 ATOM 3372 CGI VAL 34 -25.765 22 ATOM 3373 CG2 VAL 34 -25.849 20 ATOM 3374 C VAL 34 -23.497 23 ATOM 3375 O VAL 34 -23.588 24 ATOM 3376 N ASN 35 -23.062 23 ATOM 3377 CA ASN 35 -22.553 25 ATOM 3378 CB ASN 35 -21.028 25 ATOM 3379 CG ASN 35 -20.345 24 ATOM 3380 OD1 ASN 35 -20.061 24 ATOM 3381 ND2 ASN 35 -20.092 23 ATOM 3382 C ASN 35 -23.190 25 ATOM 3383 0 ASN 35 -23.363 24 ATOM 3384 N TRP 36 -23.535 26 ATOM 3385 CA TRP 36 -24.249 27 ATOM 3386 CB TRP 36 -25.637 28 ATOM 3387 CG TRP 36 -26.565 26 ATOM 3388 CD2 TRP 36 -27.466 26 ATOM 3389 CE2 TRP 36 -28.163 25 ATOM 3390 CE3 TRP 36 -27.754 26 ATOM 3391 CDl TRP 36 -26.744 26 ATOM 3392 NEl TRP 36 -27.706 25 ATOM 3393 CZ2 TRP 36 -29.131 24 ATOM 3394 CZ3 TRP 36 -28.718 25 ATOM 3395 CH2 TRP 36 -29.393 24 ATOM 3396 C TRP 36 -23.492 28 ATOM 3397 O TRP 36 -22.862 29 ATOM 3398 N TYR 37 -23.580 28 ATOM 3399 CA TYR 37 -22.890 30 ATOM 3400 CB TYR 37 -21.710 29 ATOM 3401 CG TYR 37 -20.751 28 ATOM 3402 CDl TYR 37 -21.020 27 ATOM 3403 CEl TYR 37 -20.220 26 ATOM 3404 CD2 TYR 37 -19.639 29 ATOM 3405 CE2 TYR 37 -18.826 28 ATOM 3406 CZ TYR 37 -19.127 27 ATOM 3407 OH TYR 37 -18.359 26 ATOM 3408 C TYR 37 -23.845 30 ATOM 3409 O TYR 37 -24.741 30 ATOM 3410 N GLN 38 -23.640 32 ATOM 3411 CA GLN 38 -24.395 32 ATOM 3412 CB GLN 38 -24.986 34 ATOM 3413 CG GLN 38 -25.560 35 ATOM 3414 CD GLN 38 -25.992 36 ATOM 3415 OE1 GLN 38 -25.167 37 ATOM 3416 NE2 GLN 38 -27.292 36 ATOM 3417 C GLN 38 -23.428 33 ATOM 3418 0 GLN 38 -22.313 33 ATOM 3419 N GLN 39 -23.839 33 ATOM 3420 CA GLN 39 -22.977 33 ATOM 3421 CB GLN 39 -22.396 32 ATOM 3422 CG GLN 39 -21.371 33 ATOM 3423 CD GLN 39 -20.727 31 ATOM 3424 OE1 GLN 39 -21.345 30 ATOM 3425 NE2 GLN 39 -19.476 32 ATOM 3426 C GLN 39 -23.697 34 ATOM 3427 0 GLN 39 -24.718 34 ATOM 3428 N LEU 40 -23.143 35 ATOM 3429 CA LEU 40 -23.601 36 ATOM 3430 CB LEU 40 -23.473 38 ATOM 3431 CG LEU 40 -24.221 38 ATOM 3432 CDl LEU 40 -23.977 40 ATOM 3433 CD2 LEU 40 -25.711 38 -24.284 1.00 24.71 LI O -26.451 1.00 23.92 LI N -24.445 1.00 26.14 LI C -24.833 1.00 26.61 LI O -24.106 1.00 25.64 LI N -24.125 1.00 25.44 LI C -23.484 1.00 26.18 LI C -24.231 1.00 27.99 LI 0 -22.040 1.00 25.80 LI c -25.553 1.00 24.65 LI c -26.492 1.00 23.55 LI 0 -25.713 1.00 22.97 LI N -27.024 1.00 20.22 LI c -27.273 1.00 20.79 LI c -28.640 1.00 17.13 LI c -27.162 1.00 18.86 LI c -27.126 1.00 20.72 LI c -26.153 1.00 20.35 LI 0 -28.311 1.00 21.11 LI N -28.515 1.00 20.37 LI c -28.673 1.00 20.30 LI c -27.513 1.00 20.02 LI c -26.477 1.00 20.69 LI 0 -27.675 1.00 18.74 LI N -29.765 1.00 23.63 LI c -30.750 1.00 25.23 LI 0 -29.728 1.00 24.33 LI N -30.828 1.00 23.53 LI c -30.361 1.00 24.65 LI c -30.058 1.00 23.30 LI c -30.973 1.00 21.45 LI c -30.257 1.00 22.89 LI c -32.330 1.00 24.38 LI c -28.853 1.00 22.85 LI c -28.965 1.00 22.07 LI N -30.853 1.00 23.37 LI c -32.920 1.00 24.94 LI c -32.181 1.00 23.94 LI c -31.393 1.00 24.76 LI c -30.651 1.00 24.29 LI 0 -32.710 1.00 23.23 LI N -33.419 1.00 25.41 LI c -34.223 1.00 23.97 LI c -33.348 1.00 24.70 LI c -32.993 1.00 23.14 LI c -32.095 1.00 24.44 LI c -32.789 1.00 21.55 LI c -31.887 1.00 23.33 LI c -31.541 1.00 23.69 LI c -30.618 1.00 20.32 LI 0 -34.360 1.00 26.66 LI c -34.946 1.00 27.88 LI 0 -34.492 1.00 26.80 LI N -35.423 1.00 28.14 LI c -34.674 1.00 29.55 LI c -35.559 1.00 29.51 LI c -34.764 1.00 32.32 LI c -34.364 1.00 32.45 LI 0 -34.526 1.00 31.43 LI N -36.497 1.00 27.48 LI c -36.181 1.00 27.04 LI 0 -37.760 1.00 27.49 LI N -38.838 1.00 28.01 LI c -39.630 1.00 28.56 LI c -40.684 1.00 25.91 LI c -41.412 1.00 26.00 LI c -41.602 1.00 25.62 LI 0 -41.832 1.00 22.22 LI ' N -39.800 1.00 29.88 LI c -40.387 1.00 28.22 LI 0 -39.957 1.00 32.04 LI N -40.957 1.00 34.34 LI c -40.418 1.00 33.92 . LI c -39.117 1.00 37.04 LI c -38.729 1.00 38.63 LI c -39.297 1.00 37.35 LI c 466 WO 2009/026558 PCT/US2008/074097 ATOM 3434 c LEU 40 -22.765 36 ATOM 3435 0 LEU 40 -21.658 36 ATOM 3436 N PRO 41 -23.285 37 ATOM 3437 CD PRO 41 -24.597 37 ATOM 3438 CA PRO 41 -22.597 36 ATOM 3439 CB PRO 41 -23.531 37 ATOM 3440 CG PRO 41 -24.884 37 ATOM 3441 C PRO 41 -21.197 37 ATOM 3442 O PRO 41 -20.978 38 ATOM 3443 N GLY 42 -20.248 36 ATOM 3444 CA GLY 42 -18.901 37 ATOM 3445 C GLY 42 -18.135 37 ATOM 3446 0 GLY 42 -17.077 38 ATOM 3447 N THR 43 -18.655 36 ATOM 3448 CA THR 43 -17.972 37 ATOM 3449 CB THR 43 -18.660 38 ATOM 3450 OG1 THR 43 -17.927 38 ATOM 3451 CG2 THR 43 -20.073 37 ATOM 3452 C THR 43 -17.898 35 ATOM 3453 O THR 43 -18.693 34 ATOM 3454 N ALA 44 -16.924 35 ATOM 3455 CA ALA 44 -16.748 34 ATOM 3456 CB ALA 44 -15.469 34 ATOM 3457 C ALA 44 -17.944 34 ATOM 3458 O ALA 44 -18.588 35 ATOM 3459 N PRO 45 -18.249 32 ATOM 3460 CD PRO 45 -17.620 31 ATOM 3461 CA PRO 45 -19.282 32 ATOM 3462 CB PRO 45 -19.254 31 ATOM 3463 CG PRO 45 -18.623 30 ATOM 3464 C PRO 45 -18.922 33 ATOM 3465 O PRO 45 -17.745 33 ATOM 3466 N LYS 46 -19.934 33 ATOM 3467 CA LYS 46 -19.718 34 ATOM 3468 CB LYS 46 -20.324 35 ATOM 3469 CG LYS 46 -20.595 36 ATOM 3470 CD LYS 46 -21.447 37 ATOM 3471 CE LYS 46 -21.611 38 ATOM 3472 NZ LYS 46 -22.445 39 ATOM 3473 C LYS 46 -20.366 33 ATOM 3474 0 LYS 46 -21.527 32 ATOM 3475 N LEU 47 -19.611 32 ATOM 3476 CA LEU 47 -20.108 32 ATOM 3477 CB LEU 47 -18.971 31 ATOM 3478 CG LEU 47 -19.368 30 ATOM 3479 CDl LEU 47 -19.762 29 ATOM 3480 CD2 LEU 47 -18.207 30 ATOM 3481 C LEU 47 -21.233 32 ATOM 3482 O LEU 47 -21.056 33 ATOM 3483 N LEU 48 -22.376 32 ATOM 3484 CA LEU 48 -23.540 32 ATOM 3485 CB LEU 48 -24.814 32 ATOM 3486 CG LEU 48 -25.021 33 ATOM 3487 CDl LEU 48 -26.383 32 ATOM 3488 CD2 LEU 48 -24.938 34 ATOM 3489 C LEU 48 -23.757 31 ATOM 3490 O LEU 48 -24.070 32 ATOM 3491 N ILE 49 -23.608 30 ATOM 3492 CA ILE 49 -23.903 29 ATOM 3493 CB ILE 49 -25.270 29 ATOM 3494 CG2 ILE 49 -25.514 28 ATOM 3495 CGI ILE 49 -26.387 30 ATOM 3496 CDl ILE 49 -26.846 30 ATOM 3497 C ILE 49 -22.830 28 ATOM 3498 0 ILE 49 -22.472 28 ATOM 3499 N TYR 50 -22.314 28 ATOM 3500 CA TYR 50 -21.466 27 ATOM 3501 CB TYR 50 -20.003 27 ATOM 3502 CG TYR 50 -19.748 28 ATOM 3503 CDl TYR 50 -19.874 30 ATOM 3504 CEl TYR 50 -19.645 30 ATOM 3505 CD2 TYR 50 -19.383 28 ATOM 3506 CE2 TYR 50 -19.153 28 ATOM 3507 CZ TYR 50 -19.288 30 ATOM 3508 OH TYR 50 -19.085 31 ATOM 3509 C TYR 50 -21.976 26 -42.226 1.00 36.40 LI C -42.194 1.00 35.68 LI 0 -43.366 1.00 38.85 LI N -43.534 1.00 38.64 LI C -44.651 1.00 38.77 LI c -45.659 1.00 40.02 LI c -45.000 1.00 38.99 LI c -44.668 1.00 38.74 LI c -44.162 1.00 38.74 LI 0 -45.236 1.00 38.68 LI N -45.382 1.00 40.14 LI c -44.080 1.00 40.18 LI c -44.042 1.00 41.17 LI 0 -43.007 1.00 37.47 LI N -41.732 1.00 36.70 LI c -40.841 1.00 38.93 LI c -39.619 1.00 44.97 LI 0 -40.529 1.00 40.28 LI c -41.007 1.00 33.58 LI c -41.268 1.00 32.26 LI 0 -40.114 1.00 29.37 LI N -39.368 1.00 29.17 LI c -38.542 1.00 24.98 LI c -38.453 1.00 28.88 LI c -38.022 1.00 28.39 LI 0 -38.139 1.00 28.41 LI N -38.670 1.00 2 6.65 LI c -37.143 1.00 27.06 LI c -37.036 1.00 25.83 LI c -38.310 1.00 27.18 LI c -35.818 1.00 28.11 LI c -35.520 1.00 29.04 LI 0 -35.029 1.00 27.77 LI N -33.720 1.00 29.30 LI c -33.693 1.00 30.36 LI c -32.309 1.00 35.69 LI c -32.398 1.00 38.46 LI c -31.040 1.00 41.17 LI c -31.131 1.00 43.66 LI N -32.654 1.00 27.70 LI c -32.784 1.00 28.72 LI 0 -31.609 1.00 25.77 LI N -30.530 1.00 26.00 LI c -29.556 1.00 22.43 LI c -28.294 1.00 24.81 LI c -28.680 1.00 20.56 LI c -27.298 1.00 22.63 LI c -29.772 1.00 26.08 LI c -29.312 1.00 25.15 LI 0 -29.642 1.00 26.83 LI N -28.934 1.00 28.45 LI c -29.763 1.00 30.33 LI c -31.042 1.00 35.48 LI c -31.613 1.00 35.81 LI c -30.756 1.00 34.18 LI c -27.589 1.00 27.72 LI c -26.588 1.00 27.24 LI 0 -27.590 1.00 27.22 LI N -26.428 1.00 23.99 LI c -26.590 1.00 23.11 LI c -25.427 1.00 23.24 LI c -26.717 1.00 25.09 LI c -25.395 1.00 26.07 LI c -26.293 1.00 24.62 LI c -27.272 1.00 25.83 LI 0 -25.085 1.00 25.53 LI N -24.811 1.00 2 6.67 LI c -24.628 1.00 25.70 LI c -23.408 1.00 2 6.62 LI c -23.466 1.00 26.79 LI c -22.343 1.00 28.90 LI c -22.196 1.00 26.72 LI c -21.071 1.00 28.12 . LI c -21.148 1.00 30.76 LI c -20.026 1.00 29.96 LI 0 -23.563 1.00 25.84 LI c 467 WO 2009/026558 PCT/US2008/074097 ATOM 3510 0 TYR 50 -22.784 27 ATOM 3511 N SER 51 -21.518 25 ATOM 3512 CA SER 51 -21.971 24 ATOM 3513 CB SER 51 -21.436 25 ATOM 3514 OG SER 51 -20.133 24 ATOM 3515 C SER 51 -23.494 24 ATOM 3516 O SER 51 -24.080 24 ATOM 3517 N ASN 52 -24.122 24 ATOM 3518 CA ASN 52 -25.571 24 ATOM 3519 CB ASN 52 -26.051 23 ATOM 3520 CG ASN 52 -25.501 21 ATOM 3521 OD1 ASN 52 -25.299 21 ATOM 3522 ND2 ASN 52 -25.251 21 ATOM 3523 C ASN 52 -26.350 25 ATOM 3524 0 ASN 52 -27.273 25 ATOM 3525 N ASN 53 -25.982 26 ATOM 3526 CA ASN 53 -26.821 27 ATOM 3527 CB ASN 53 -27.830 27 ATOM 3528 CG ASN 53 -27.154 26 ATOM 3529 OD1 ASN 53 -26.023 26 ATOM 3530 ND2 ASN 53 -27.846 25 ATOM 3531 C ASN 53 -26.064 28 ATOM 3532 0 ASN 53 -26.664 29 ATOM 3533 N GLN 54 -24.758 28 ATOM 3534 CA GLN 54 -23.949 29 ATOM 3535 CB GLN 54 -22.620 29 ATOM 3536 CG GLN 54 -22.772 28 ATOM 3537 CD GLN 54 -23.496 29 ATOM 3538 OE1 GLN 54 -22.973 30 ATOM 3539 NE2 GLN 54 -24.708 28 ATOM 3540 C GLN 54 -23.670 30 ATOM 3541 0 GLN 54 -23.343 30 ATOM 3542 N ARG 55 -23.797 32 ATOM 3543 CA ARG 55 -23.526 33 ATOM 3544 CB ARG 55 -24.612 34 ATOM 3545 CG ARG 55 -25.921 33 ATOM 3546 CD ARG 55 -27.002 34 ATOM 3547 NE ARG 55 -27.466 34 ATOM 3548 CZ ARG 55 -27.186 35 ATOM 3549 NH1 ARG 55 -26.442 37 ATOM 3550 NH2 ARG 55 -27.642 35 ATOM 3551 C ARG 55 -22.160 33 ATOM 3552 O ARG 55 -21.785 34 ATOM 3553 N PRO 56 -21.396 34 ATOM 3554 CD PRO 56 -21.569 33 ATOM 3555 CA PRO 56 -20.205 34 ATOM 3556 CB PRO 56 -19.605 34 ATOM 3557 CG PRO 56 -20.196 33 ATOM 3558 C PRO 56 -20.632 36 ATOM 3559 O PRO 56 -21.763 36 ATOM 3560 N SER 57 -19.731 37 ATOM 3561 CA SER 57 -19.946 38 ATOM 3562 CB SER 57 -18.687 39 ATOM 3563 OG SER 57 -18.841 40 ATOM 3564 C SER 57 -20.259 39 ATOM 3565 O SER 57 -19.583 38 ATOM 3566 N GLY 58 -21.290 39 ATOM 3567 CA GLY 58 -21.639 40 ATOM 3568 C GLY 58 -22.635 39 ATOM 3569 0 GLY 58 -22.762 40 ATOM 3570 N VAL 59 -23.329 38 ATOM 3571 CA VAL 59 -24.456 38 ATOM 3572 CB VAL 59 -24.213 36 ATOM 3573 CGI VAL 59 -25.456 36 ATOM 3574 CG2 VAL 59 -23.019 36 ATOM 3575 C VAL 59 -25.710 38 ATOM 3576 O VAL 59 -25.750 38 ATOM 3577 N PRO 60 -26.753 39 ATOM 3578 CD PRO 60 -26.783 39 ATOM 3579 CA PRO 60 -28.000 39 ATOM 3580 CB PRO 60 -28.852 40 ATOM 3581 CG PRO 60 -27.881 40 ATOM 3582 C PRO 60 -28.694 38 ATOM 3583 O PRO 60 -28.709 37 ATOM 3584 N ASP 61 -29.281 38 ATOM 3585 CA ASP 61 -29.944 37 -22.821 1.00 24.72 LI O -23.343 1.00 26.19 LI N -22.198 1.00 26.90 LI C -20.896 1.00 27.94 LI C -20.626 1.00 31.95 LI 0 -22.129 1.00 24.91 LI c -21.060 1.00 22.95 LI 0 -23.275 1.00 24.45 LI N -23.351 1.00 25.66 LI c -22.270 1.00 24.57 LI c -22.463 1.00 25.41 LI c -23.589 1.00 26.77 LI 0 -21.361 1.00 25.99 LI N -23.224 1.00 24.22 LI c -23.999 1.00 24.09 LI 0 -22.251 1.00 25.54 LI N -21.875 1.00 27.46 LI c -20.811 1.00 27.71 LI c -19.570 1.00 33.27 LI c -19.226 1.00 32.11 LI 0 -18.894 1.00 32.47 LI N -21.374 1.00 28.20 LI c -20.766 1.00 26.89 LI 0 -21.625 1.00 27.94 LI N -21.182 1.00 2 6.56 LI c -20.599 1.00 27.00 LI c -19.362 1.00 26.24 LI c -18.222 1.00 29.64 LI c -17.630 1.00 28.40 LI 0 -17.914 1.00 26.55 LI N -22 .294 1.00 28.39 LI c -23.424 1.00 27.97 LI 0 -21.971 1.00 27.97 LI N -22.952 1.00 31.26 LI c -22.897 1.00 31.77 LI c -23.551 1.00 35.02 LI c -23.340 1.00 37.92 LI c -21.956 1.00 40.09 LI N -21.093 1.00 42.88 LI c -21.471 1.00 42.75 LI N -19.845 1.00 42.31 LI N -22.755 1.00 31.34 LI C -21.647 1.00 30.63 LI 0 -23.842 1.00 32.93 LI N -25.162 1.00 30.73 LI C -23.787 1.00 33.81 LI c -25.188 1.00 33.09 LI c -25.754 1.00 33.61 LI c -23.485 1.00 36.31 LI c -23.787 1.00 36.25 LI 0 -22.881 1.00 37.50 LI N -22.683 1.00 41.08 LI c -22.080 1.00 42.30 LI c -21.919 1.00 48.81 LI 0 -24.033 1.00 42.62 LI c -25.028 1.00 41.85 LI 0 -24.068 1.00 43.59 LI N -25.308 1.00 44.33 LI c -26.160 1.00 44.22 LI c -27.362 1.00 46.95 LI 0 -25.545 1.00 41.84 LI N -26.187 1.00 38.40 LI c -26.312 1.00 37.83 LI c -26.854 1.00 35.01 LI c -27.223 1.00 34.54 LI c -25.353 1.00 37.89 LI c -24.172 1.00 36.97 LI 0 -25.967 1.00 38.59 LI " N -27.387 1.00 38.95 LI c -25.281 1.00 39.12 LI c -26.384 1.00 38.57 LI c -27.428 1.00 40.32 LI c -24.657 1.00 39.92 . LI c -25.238 1.00 40.29 LI 0 -23.482 1.00 38.79 LI N -22.780 1.00 39.81 LI c 468 WO 2009/026558 PCT/US2008/074097 ATOM 3586 CB ASP 61 -30.266 37 ATOM 3587 CG ASP 61 -31.094 39 ATOM 3588 OD1 ASP 61 -31.389 39 ATOM 3589 OD2 ASP 61 -31.446 39 ATOM 3590 C ASP 61 -31.213 36 ATOM 3591 O ASP 61 -31.837 35 ATOM 3592 N ARG 62 -31.601 37 ATOM 3593 CA ARG 62 -32.735 36 ATOM 3594 CB ARG 62 -33.302 38 ATOM 3595 CG ARG 62 -32.312 38 ATOM 3596 CD ARG 62 -32.835 39 ATOM 3597 NE ARG 62 -31.860 40 ATOM 3598 CZ ARG 62 -31.799 40 ATOM 3599 NHl ARG 62 -32.664 39 ATOM 3600 NH2 ARG 62 -30.870 40 ATOM 3601 C ARG 62 -32.342 35 ATOM 3602 O ARG 62 -33.199 35 ATOM 3603 N PHE 63 -31.041 35 ATOM 3604 CA PHE 63 -30.561 34 ATOM 3605 CB PHE 63 -29.210 34 ATOM 3606 CG PHE 63 -29.272 35 ATOM 3607 CDl PHE 63 -29.616 34 ATOM 3608 CD2 PHE 63 -28.977 36 ATOM 3609 CEl PHE 63 -29.664 35 ATOM 3610 CE2 PHE 63 -29.023 37 ATOM 3611 CZ PHE 63 -29.367 36 ATOM 3612 C PHE 63 -30.404 33 ATOM 3613 0 PHE 63 -29.770 33 ATOM 3614 N SER 64 -30.982 32 ATOM 3615 CA SER 64 -30.829 31 ATOM 3616 CB SER 64 -31.984 31 ATOM 3617 OG SER 64 -33.196 30 ATOM 3618 C SER 64 -30.777 29 ATOM 3619 0 SER 64 -31.400 29 ATOM 3620 N GLY 65 -30.029 28 ATOM 3621 CA GLY 65 -29.917 27 ATOM 3622 C GLY 65 -30.418 26 ATOM 3623 0 GLY 65 -30.419 26 ATOM 3624 N SER 66 -30.854 25 ATOM 3625 CA SER 66 -31.205 24 ATOM 3626 CB SER 66 -32.708 24 ATOM 3627 OG SER 66 -33.461 23 ATOM 3628 C SER 66 -30.792 22 ATOM 3629 0 SER 66 -30.605 22 ATOM 3630 N LYS 67 -30.636 21 ATOM 3631 CA LYS 67 -30.268 20 ATOM 3632 CB LYS 67 -28.789 20 ATOM 3633 CG LYS 67 -28.422 18 ATOM 3634 CD LYS 67 -26.945 18 ATOM 3635 CE LYS 67 -26.665 17 ATOM 3636 NZ LYS 67 -25.207 16 ATOM 3637 C LYS 67 -31.123 19 ATOM 3638 0 LYS 67 -31.355 19 ATOM 3639 N SER 68 -31.591 18 ATOM 3640 CA SER 68 -32.289 17 ATOM 3641 CB SER 68 -33.788 17 ATOM 3642 OG SER 68 -34.481 16 ATOM 3643 C SER 68 -32.038 16 ATOM 3644 0 SER 68 -32.356 15 ATOM 3645 N GLY 69 -31.470 15 ATOM 3646 CA GLY 69 -31.165 13 ATOM 3647 C GLY 69 -30.148 13 ATOM 3648 0 GLY 69 -2 9.02 6 14 ATOM 3649 N THR 70 -30.531 13 ATOM 3650 CA THR 70 -29.627 13 ATOM 3651 CB THR 70 -29.517 12 ATOM 3652 OG1 THR 70 -30.813 11 ATOM 3653 CG2 THR 70 -28.934 11 ATOM 3654 C THR 70 -30.040 14 ATOM 3655 0 THR 70 -29.630 14 ATOM 3656 N SER 71 -30.841 15 ATOM 3657 CA SER 71 -31.244 16 ATOM 3658 CB SER 71 -32.719 16 ATOM 3659 OG SER 71 -32.874 15 ATOM 3660 C SER 71 -31.003 18 ATOM 3661 0 SER 71 -30.824 18 -21.339 1.00 4 6.00 LI C -21.258 1.00 50.76 LI c -20.123 1.00 53.85 LI 0 -22.317 1.00 52.25 LI 0 -23.467 1.00 37.81 LI c -23.004 1.00 39.35 LI 0 -24.571 1.00 36.57 LI N -25.332 1.00 35.73 LI c -26.248 1.00 36.98 LI c -27.243 1.00 40.00 LI c -27.898 1.00 40.98 LI c -28.836 1.00 38.44 LI N -30.111 1.00 36.96 LI c -30.580 1.00 37.84 LI N -30.905 1.00 36.03 LI N -26.153 1.00 34.56 LI C -26.687 1.00 32.53 LI 0 -26.248 1.00 34.16 LI N -26.738 1.00 33.82 LI C -27.436 1.00 31.07 LI c -28.706 1.00 31.60 LI c -29.903 1.00 30.71 LI c -28.703 1.00 31.31 LI c -31.074 1.00 32.32 LI c -29.875 1.00 33.14 LI c -31.062 1.00 33.35 LI c -25.564 1.00 33.18 LI c -24.568 1.00 34.53 LI 0 -25.676 1.00 31.90 LI N -24.633 1.00 31.99 LI c -23.627 1.00 33.55 LI c -24.176 1.00 34.69 LI 0 -25.226 1.00 30.65 LI c -26.247 1.00 32.44 LI 0 -24.581 1.00 30.08 LI N -25.086 1.00 28.03 LI c -24.097 1.00 28.41 LI c -22.893 1.00 28.15 LI 0 -24.603 1.00 29.78 LI N -23.730 1.00 29.50 LI c -23.439 1.00 30.04 LI c -24.632 1.00 33.58 LI 0 -24.337 1.00 29.31 LI c -25.551 1.00 28.96 LI 0 -23.472 1.00 29.49 LI N -23.886 1.00 31.34 LI c -23.587 1.00 29.79 LI c -23.598 1.00 30.92 LI c -23.271 1.00 31.59 LI c -22.974 1.00 31.18 LI c -22.808 1.00 32.99 LI N -23.119 1.00 32.11 LI c -21.921 1.00 33.29 LI 0 -23.808 1.00 32.41 LI N -23.137 1.00 33.97 LI c -23.098 1.00 35.12 LI c -22.492 1.00 39.24 LI 0 -23.851 1.00 32.19 LI c -25.027 1.00 31.42 LI 0 -23.134 1.00 31.82 LI N -23.750 1.00 30.65 LI c -24.865 1.00 31.46 Ll c -24.623 1.00 31.98 LI 0 -26.087 1.00 30.21 Ll N -27.221 1.00 29.74 Ll c -28.011 1.00 31.03 Ll c -28.472 1.00 32.35 Ll 0 -27.126 1.00 26.28 Ll c -28.179 1.00 29.23 Ll c -29.336 1.00 28.90 Ll 0 -27.687 1.00 28.99 Ll N -28.486 1.00 27.69 Ll c -28.860 1.00 29.27 . Ll c -29.886 1.00 38.45 Ll 0 -27.745 1.00 24.99 Ll c -26.535 1.00 2 5.72 Ll 0 469 WO 2009/026558 PCT/US2008/074097 ATOM 3662 N ALA 72 -30.995 19 ATOM 3663 CA ALA 72 -30.769 20 ATOM 3664 CB ALA 72 -29.272 20 ATOM 3665 C ALA 72 -31.555 21 ATOM 3666 O ALA 72 -32.062 21 ATOM 3667 N SER 73 -31.645 22 ATOM 3668 CA SER 73 -32.438 23 ATOM 3669 CB SER 73 -33.900 23 ATOM 3670 OG SER 73 -34.699 24 ATOM 3671 C SER 73 -31.926 25 ATOM 3672 O SER 73 -31.501 25 ATOM 3673 N LEU 74 -31.955 26 ATOM 3674 CA LEU 74 -31.628 27 ATOM 3675 CB LEU 74 -30.694 28 ATOM 3676 CG LEU 74 -30.226 29 ATOM 3677 CD1 LEU 74 -29.347 29 ATOM 3678 CD2 LEU 74 -29.464 29 ATOM 3679 C LEU 74 -32.931 28 ATOM 3680 O LEU 74 -33.707 28 ATOM 3681 N ALA 75 -33.176 29 ATOM 3682 CA ALA 75 -34.368 30 ATOM 3683 CB ALA 75 -35.148 29 ATOM 3684 C ALA 75 -33.952 31 ATOM 3685 O ALA 75 -33.072 31 ATOM 3686 N ILE 76 -34.575 32 ATOM 3687 CA ILE 76 -34.331 33 ATOM 3688 CB ILE 76 -33.824 33 ATOM 3689 CG2 ILE 76 -33.403 35 ATOM 3690 CGI ILE 76 -32.626 33 ATOM 3691 CD1 ILE 76 -32.170 33 ATOM 3692 C ILE 76 -35.648 34 ATOM 3693 0 ILE 76 -36.586 34 ATOM 3694 N SER 77 -35.722 35 ATOM 3695 CA SER 77 -36.907 35 ATOM 3696 CB SER 77 -37.273 35 ATOM 3697 OG SER 77 -36.215 36 ATOM 3698 C SER 77 -36.655 37 ATOM 3699 O SER 77 -35.503 37 ATOM 3700 N GLY 78 -37.733 38 ATOM 3701 CA GLY 78 -37.585 39 ATOM 3702 C GLY 78 -36.839 39 ATOM 3703 0 GLY 78 -35.946 40 ATOM 3704 N LEU 79 -37.212 38 ATOM 3705 CA LEU 79 -36.506 38 ATOM 3706 CB LEU 79 -37.290 37 ATOM 3707 CG LEU 79 -36.602 37 ATOM 3708 CD1 LEU 79 -35.333 36 ATOM 3709 CD2 LEU 79 -37.583 36 ATOM 3710 C LEU 79 -36.301 40 ATOM 3711 O LEU 79 -37.241 40 ATOM 3712 N GLN 80 -35.064 40 ATOM 3713 CA GLN 80 -34.739 41 ATOM 3714 CB GLN 80 -33.738 42 ATOM 3715 CG GLN 80 -34.200 42 ATOM 3716 CD GLN 80 -33.230 43 ATOM 3717 OE1 GLN 80 -32.224 43 ATOM 3718 NE2 GLN 80 -33.520 4 3 ATOM 3719 C GLN 80 -34.154 41 ATOM 3720 0 GLN 80 -33.627 40 ATOM 3721 N SER 81 -34.243 42 ATOM 3722 CA SER 81 -33.800 41 ATOM 3723 CB SER 81 -34.135 43 ATOM 3724 OG SER 81 -33.438 44 ATOM 3725 C SER 81 -32.298 41 ATOM 3726 O SER 81 -31.857 40 ATOM 3727 N GLU 82 -31.518 42 ATOM 3728 CA GLU 82 -30.085 41 ATOM 3729 CB GLU 82 -29.382 42 ATOM 3730 CG GLU 82 -29.697 44 ATOM 3731 CD GLU 82 -31.072 44 ATOM 3732 OE1 GLU 82 -31.236 44 ATOM 3733 OE2 GLU 82 -31.986 44 ATOM 3734 C GLU 82 -29.860 40 ATOM 3735 O GLU 82 -28.765 39 ATOM 3736 N ASP 83 -30.898 39 ATOM 3737 CA ASP 83 -30.779 38 -28.480 1.00 23.94 LI N -27.884 1.00 26.16 LI C -27.903 1.00 22.79 LI c -28.654 1.00 26.58 LI c -29.742 1.00 26.75 LI 0 -28.102 1.00 28.14 LI N -28.745 1.00 29.91 LI c -28.305 1.00 30.18 LI c -29.010 1.00 37.35 LI 0 -28.453 1.00 28.74 LI c -27.337 1.00 30.53 LI 0 -29.472 1.00 29.11 LI N -29.321 1.00 31.29 LI c -30.449 1.00 28.58 LI c -30.412 1.00 29.48 LI c -29.201 1.00 29.08 LI c -31.694 1.00 28.84 LI c -29.384 1.00 32.05 LI c -30.327 1.00 31.82 LI 0 -28.376 1.00 31.88 LI N -28.374 1.00 32.47 LI c -27.077 1.00 32.36 LI c -28.520 1.00 32.90 LI c -27.803 1.00 33.92 LI 0 -2 9.4 62 1.00 33.40 LI N -29.635 1.00 34.46 LI c -31.058 1.00 34.25 LI c -31.155 1.00 32.73 LI c -31.393 1.00 35.86 LI c -32.847 1.00 35.68 LI c -29.410 1.00 36.20 LI c -30.204 1.00 35.91 LI 0 -28.319 1.00 36.94 LI N -28.038 1.00 38.93 LI c -26.555 1.00 39.60 LI c -25.739 1.00 42.81 LI 0 -28.424 1.00 39.07 LI c -28.574 1.00 37.94 LI 0 -28.600 1.00 37.57 LI N -28.966 1.00 35.79 LI c -30.276 1.00 35.60 LI c -30.423 1.00 33.98 LI 0 -31.236 1.00 35.78 LI N -32.506 1.00 35.73 LI c -33.468 1.00 36.94 LI c -34.738 1.00 37.13 LI c -34.392 1.00 34.89 LI c -35.490 1.00 37.56 LI c -33.124 1.00 36.83 LI c -33.244 1.00 36.62 LI 0 -33.519 1.00 37.09 LI N -34.221 1.00 38.15 LI c -33.403 1.00 42.19 LI c -31.979 1.00 49.70 LI c -31.213 1.00 56.13 LI c -31.764 1.00 58.59 LI 0 -29.932 1.00 58.28 LI N -35.592 1.00 38.49 LI c -35.811 1.00 36.48 LI 0 -36.516 1.00 36.90 LI N -37.881 1.00 38.24 LI c -38.771 1.00 37.34 LI c -38.346 1.00 41.79 LI 0 -37.959 1.00 38.41 LI c -38.876 1.00 39.41 LI 0 -37.001 1.00 37.61 LI N -36.964 1.00 37.59 LI c -35.855 1.00 41.17 LI c -35.838 1.00 50.54 LI c -35.270 1.00 53.17 LI c -34.036 1.00 57.55 LI 0 -36.057 1.00 56.15 LI 0 -36.706 1.00 34.12 . LI c -36.899 1.00 31.06 LI 0 -36.250 1.00 31.15 ' LI N -35.941 1.00 30.79 LI c 470 WO 2009/026558 PCT/US2008/074097 ATOM 3738 CB ASP 83 -31.877 37 ATOM 3739 CG ASP 83 -31.797 38 ATOM 3740 OD1 ASP 83 -30.697 39 ATOM 3741 OD2 ASP 83 -32.834 38 ATOM 3742 C ASP 83 -30.846 37 ATOM 3743 O ASP 83 -30.649 36 ATOM 3744 N GLU 84 -31.121 38 ATOM 3745 CA GLU 84 -31.189 37 ATOM 3746 CB GLU 84 -31.730 38 ATOM 3747 CG GLU 84 -31.723 37 ATOM 3748 CD GLU 84 -32.799 37 ATOM 3749 OE1 GLU 84 -32.515 37 ATOM 3750 OE2 GLU 84 -33.930 38 ATOM 3751 C GLU 84 -29.800 36 ATOM 3752 0 GLU 84 -28.873 37 ATOM 3753 N ALA 85 -29.663 35 ATOM 3754 CA ALA 85 -28.345 34 ATOM 3755 CB ALA 85 -27.499 35 ATOM 3756 C ALA 85 -28.440 33 ATOM 3757 0 ALA 85 -29.522 32 ATOM 3758 N ASP 86 -27.293 32 ATOM 3759 CA ASP 86 -27.171 31 ATOM 3760 CB ASP 86 -26.098 30 ATOM 3761 CG ASP 86 -26.494 30 ATOM 3762 OD1 ASP 86 -27.659 30 ATOM 3763 OD2 ASP 86 -25.639 31 ATOM 3764 C ASP 86 -26.775 30 ATOM 3765 O ASP 86 -25.899 31 ATOM 3766 N TYR 87 -27.419 29 ATOM 3767 CA TYR 87 -27.113 29 ATOM 3768 CB TYR 87 -28.346 29 ATOM 3769 CG TYR 87 -28.702 30 ATOM 3770 CDl TYR 87 -29.451 31 ATOM 3771 CEl TYR 87 -29.708 32 ATOM 3772 CD2 TYR 87 -28.228 31 ATOM 3773 CE2 TYR 87 -28.479 32 ATOM 3774 CZ TYR 87 -29.216 33 ATOM 3775 OH TYR 87 -29.448 34 ATOM 3776 C TYR 87 -26.642 27 ATOM 3777 0 TYR 87 -27.238 27 ATOM 3778 N TYR 88 -25.568 27 ATOM 3779 CA TYR 88 -24.955 26 ATOM 3780 CB TYR 88 -23.557 26 ATOM 3781 CG TYR 88 -23.532 26 ATOM 3782 CDl TYR 88 -23.269 27 ATOM 3783 CEl TYR 88 -23.236 28 ATOM 3784 CD2 TYR 88 -23.763 25 ATOM 3785 CE2 TYR 88 -23.732 25 ATOM 3786 CZ TYR 88 -23.467 27 ATOM 3787 OH TYR 88 -23.430 27 ATOM 3788 C TYR 88 -24.835 25 ATOM 3789 0 TYR 88 -24.509 26 ATOM 3790 N CYS 89 -25.087 24 ATOM 3791 CA CYS 89 -24.701 23 ATOM 3792 C CYS 89 -23.428 22 ATOM 3793 0 CYS 89 -23.127 22 ATOM 3794 CB CYS 89 -25.829 22 ATOM 3795 SG CYS 89 -26.482 21 ATOM 3796 N ALA 90 -22.684 22 ATOM 3797 CA ALA 90 -21.419 22 ATOM 3798 CB ALA 90 -20.279 23 ATOM 3799 C ALA 90 -21.262 21 ATOM 3800 0 ALA 90 -21.575 21 ATOM 3801 N VAL 91 -20.790 20 ATOM 3802 CA VAL 91 -20.699 19 ATOM 3803 CB VAL 91 -21.992 18 ATOM 3804 CGI VAL 91 -21.908 17 ATOM 3805 CG2 VAL 91 -23.211 19 ATOM 3806 C VAL 91 -19.530 18 ATOM 3807 0 VAL 91 -19.298 17 ATOM 3808 N TRP 92 -18.792 17 ATOM 3809 CA TRP 92 -17.749 16 ATOM 3810 CB TRP 92 -16.850 16 ATOM 3811 CG TRP 92 -15.604 16 ATOM 3812 CD2 TRP 92 -14.339 16 ATOM 3813 CE2 TRP 92 -13.453 15 -34.962 1.00 30.65 LI C -33.644 1.00 32.56 LI c -33.289 1.00 34.97 LI 0 -32.961 1.00 31.83 LI 0 -37.194 1.00 2 9.63 LI c -37.113 1.00 28.37 LI 0. -38.348 1.00 2 9.00 LI N -39.588 1.00 30.03 LI c -40.741 1.00 30.22 LI c -42.089 1.00 31.01 LI c -43.050 1.00 35.95 LI c -44.265 1.00 37.52 LI 0 -42.598 1.00 36.88 LI 0 -39.948 1.00 30.69 LI c -40.160 1.00 31.59 LI 0 -40.021 1.00 2 9.97 LI N -40.110 1.00 28.04 LI c -38.915 1.00 28.83 LI c -40.153 1.00 27.69 LI c -39.988 1.00 24.83 LI 0 -40.377 1.00 28.83 LI N -40.263 1.00 27.36 LI c -41.224 1.00 30.73 LI c -42.683 1.00 32.29 LI c -43.017 1.00 36.16 LI 0 -43.497 1.00 33.33 LI 0 -38.835 1.00 26.79 LI c -38.245 1.00 26.47 LI 0 -38.286 1.00 25.78 LI N -36.946 1.00 26.34 LI c -36.043 1.00 26.23 LI c -35.752 1.00 25.63 LI c -36.656 1.00 26.80 LI c -36.434 1.00 27.24 LI c -34.612 1.00 25.13 LI c -34.378 1.00 26.81 LI c -35.292 1.00 27.91 LI c -35.069 1.00 28.02 LI 0 -36.983 1.00 27.87 LI c -37.662 1.00 28.78 LI 0 -36.247 1.00 26.11 LI N -36.230 1.00 23.64 LI c -36.853 1.00 22.55 LI c -38.331 1.00 22.94 LI c -38.768 1.00 23.36 LI c -40.115 1.00 22.59 LI c -39.286 1.00 22.71 LI c -40.645 1.00 22.56 LI c -41.051 1.00 23.14 LI c -42.399 1.00 23.24 LI 0 -34.803 1.00 24.19 LI c -33.887 1.00 23.05 LI 0 -34.613 1.00 23.34 LI N -33.371 1.00 24.76 LI c -33.551 1.00 24 .26 LI c -34.644 1.00 24.97 LI 0 -32.844 1.00 24.95 LI c -33.993 1.00 29.02 LI s -32.467 1.00 22.28 LI N -32.511 1.00 21.93 LI c -32.663 1.00 21.85 LI c -31.229 1.00 22.39 LI c -30.139 1.00 23.97 LI 0 -31.365 1.00 21.91 LI N -30.241 1.00 22.14 LI c -30.112 1.00 22.24 LI c -28.898 1.00 18.74 LI c -30.019 1.00 19.37 LI c -30.487 1.00 23.31 LI c -31.619 1.00 24.62 LI 0 -29.436 1.00 22.18 LI N -29.566 1.00 21.63 LI c -28.331 1.00 20.72 . LI c -28.480 1.00 24.87 LI c -29.011 1.00 23.79 LI c -28.914 1.00 24.92 LI c 471 WO 2009/026558 PCT/US2008/074097 ATOM 3814 CE3 TRP 92 -13.874 17 ATOM 3815 CD1 TRP 92 -15.435 14 ATOM 3816 NEl TRP 92 -14.147 14 ATOM 3817 CZ2 TRP 92 -12.125 15 ATOM 3818 CZ3 TRP 92 -12.551 17 ATOM 3819 CH2 TRP 92 -11.694 16 ATOM 3820 C TRP 92 -18.378 15 ATOM 3821 O TRP 92 -19.333 15 ATOM 3822 N ASP 93 -17.838 14 ATOM 3823 CA ASP 93 -18.303 13 ATOM 3824 CB ASP 93 -18.629 13 ATOM 3825 CG ASP 93 -19.345 11 ATOM 3826 OD1 ASP 93 -20.593 11 ATOM 3827 OD2 ASP 93 -18.662 10 ATOM 3828 C ASP 93 -17.234 12 ATOM 3829 O ASP 93 -16.085 12 ATOM 3830 N ASP 94 -17.622 11 ATOM 3831 CA ASP 94 -16.672 10 ATOM 3832 CB ASP 94 -17.222 10 ATOM 3833 CG ASP 94 -17.423 11 ATOM 3834 OD1 ASP 94 -16.432 11 ATOM 3835 OD2 ASP 94 -18.567 11 ATOM 3836 C ASP 94 -16.291 9 ATOM 3837 O ASP 94 -15.337 8 ATOM 3838 N SER 95 -17.027 9 ATOM 3839 CA SER 95 -16.663 7 ATOM 3840 CB SER 95 -17.913 7 ATOM 3841 OG SER 95 -18.715 6 ATOM 3842 C SER 95 -15.762 8 ATOM 3843 O SER 95 -14.806 7 ATOM 3844 N LEU 96 -16.060 9 ATOM 3845 CA LEU 96 -15.206 10 ATOM 3846 CB LEU 96 -16.022 11 ATOM 3847 CG LEU 96 -17.131 10 ATOM 3848 CD1 LEU 96 -18.143 11 ATOM 3849 CD2 LEU 96 -16.522 10 ATOM 3850 C LEU 96 -14.008 11 ATOM 3851 O LEU 96 -13.029 11 ATOM 3852 N ASN 97 -14.094 11 ATOM 3853 CA ASN 97 -13.032 11 ATOM 3854 CB ASN 97 -11.765 11 ATOM 3855 CG ASN 97 -11.961 9 ATOM 3856 OD1 ASN 97 -12.281 9 ATOM 3857 ND2 ASN 97 -11.794 8 ATOM 3858 C ASN 97 -12.719 13 ATOM 3859 O ASN 97 -11.554 13 ATOM 3860 N GLY 98 -13.764 14 ATOM 3861 CA GLY 98 -13.575 15 ATOM 3862 C GLY 98 -14.900 16 ATOM 3863 0 GLY 98 -15.961 15 ATOM 3864 N TRP 99 -14.835 17 ATOM 3865 CA TRP 99 -16.017 18 ATOM 3866 CB TRP 99 -15.602 19 ATOM 3867 CG TRP 99 -15.097 20 ATOM 3868 CD2 TRP 99 -15.887 20 ATOM 3869 CE2 TRP 99 -14.993 21 ATOM 3870 CE3 TRP 99 -17.264 20 ATOM 3871 CD1 TRP 99 -13.792 20 ATOM 3872 NEl TRP 99 -13.721 21 ATOM 3873 CZ2 TRP 99 -15.429 21 ATOM 3874 CZ3 TRP 99 -17.701 21 ATOM 3875 CH2 TRP 99 -16.782 21 ATOM 3876 C TRP 99 -16.896 17 ATOM 3877 O TRP 99 -16.411 17 ATOM 3878 N VAL 100 -18.196 17 ATOM 3879 CA VAL 100 -19.155 17 ATOM 3880 CB VAL 100 -19.959 16 ATOM 3881 CGI VAL 100 -19.013 15 ATOM 3882 CG2 VAL 100 -20.685 16 ATOM 3883 C VAL 100 -20.094 18 ATOM 3884 O VAL 100 -20.206 19 ATOM 3885 N PHE 101 -20.731 19 ATOM 3886 CA PHE 101 -21.625 20 ATOM 3887 CB PHE 101 -21.052 21 ATOM 3888 CG PHE 101 -19.847 22 ATOM 3889 CD1 PHE 101 -18.558 21 -29.556 1.00 24.00 LI C -28.100 1.00 24.13 LI c -28.356 1.00 26.35 LI N -29.339 1.00 25.22 LI C -29.981 1.00 27.22 LI c -29.868 1.00 26.53 LI c -29.739 1.00 22.42 LI c -29.053 1.00 21.21 LI 0 -30.661 1.00 22.63 LI N -30.847 1.00 22.79 LI c -32.312 1.00 22.67 LI c -32.517 1.00 24.52 LI c -32.528 1.00 24.55 LI 0 -32.662 1.00 24.78 LI 0 -30.393 1.00 23.59 LI c -30.815 1.00 21.15 LI 0 -29.541 1.00 22.22 LI N -28.931 1.00 23.56 LI c -27.579 1.00 22.41 LI c -26.610 1.00 25.03 LI c -26.310 1.00 24.18 LI 0 -26.153 1.00 23.82 LI 0 -29.803 1.00 22.66 LI c -29.498 1.00 23.33 LI 0 -30.885 1.00 23.45 LI N -31.821 1.00 22.75 LI c -32.444 1.00 21.53 LI c -31.450 1.00 19.78 LI 0 -32.918 1.00 24.04 LI c -33.329 1.00 24.34 LI 0 -33.374 1.00 22.90 LI N -34.328 1.00 23.33 LI c -35.076 1.00 25.43 LI c -35.962 1.00 26.90 LI c -36.285 1.00 23.29 LI c -37.226 1.00 27.63 LI c -33.644 1.00 23.40 LI c -34.300 1.00 22.31 LI 0 -32.327 1.00 21.76 LI N -31.564 1.00 2 3.62 LI c -31.594 1.00 23.22 LI c -30.897 1.00 25.94 LI c -29.701 1.00 24.63 LI 0 -31.637 1.00 27.24 LI N -32.054 1.00 24.97 LI c -32.290 1.00 24.92 LI 0 -32.199 1.00 21.90 LI N -32.632 1.00 23.01 LI c -32.796 1.00 22.94 LI c -32.516 1.00 19.38 LI 0 -33.258 1.00 21.48 LI N -33.354 1.00 21.80 LI c -33.485 1.00 20.41 LI c -32.201 1.00 21.29 LI c -31.070 1.00 20.83 LI c -30.052 1.00 21.78 LI c -30.819 1.00 21.01 LI c -31.838 1.00 20.69 LI c -30.548 1.00 18.42 LI N -28.797 1.00 21.72 LI c -29.572 1.00 24.75 LI c -28.575 1.00 23.40 LI c -34.530 1.00 21.60 LI c -35.640 1.00 20.77 LI 0 -34.280 1.00 21.15 LI N -35.366 1.00 20.99 LI c -35.299 1.00 21.63 LI c -35.493 1.00 18.33 LI c -33.965 1.00 20.08 LI c -35.310 1.00 22.73 LI c -34.271 1.00 21.19 LI 0 -36.439 1.00 23.17 LI N -36.556 1.00 24.04 . LI c -37.538 1.00 23.68 LI c -37.015 1.00 25.65 LI c -37.330 1.00 25.40 LI c 472 WO 2009/026558 PCT/US2008/074097 ATOM 3890 CD2 PHE 101 -20.005 23 ATOM 3891 CEl PHE 101 -17.449 22 ATOM 3892 CE2 PHE 101 -18.899 24 ATOM 3893 CZ PHE 101 -17.621 23 ATOM 3894 C PHE 101 -22.995 19 ATOM 3895 O PHE 101 -23.134 18 ATOM 3896 N GLY 102 -24.006 20 ATOM 3897 CA GLY 102 -25.261 20 ATOM 3898 C GLY 102 -25.108 21 ATOM 3899 0 GLY 102 -24.139 21 ATOM 3900 N GLY 103 -26.049 20 ATOM 3901 CA GLY 103 -25.923 21 ATOM 3902 C GLY 103 -26.218 22 ATOM 3903 0 GLY 103 -26.063 23 ATOM 3904 N GLY 104 -26.637 23 ATOM 3905 CA GLY 104 -26.940 25 ATOM 3906 C GLY 104 -28.406 25 ATOM 3907 0 GLY 104 -29.032 24 ATOM 3908 N THR 105 -28.951 26 ATOM 3909 CA THR 105 -30.313 26 ATOM 3910 CB THR 105 -31.161 26 ATOM 3911 OG1 THR 105 -31.235 25 ATOM 3912 CG2 THR 105 -32.574 27 ATOM 3913 C THR 105 -30.275 28 ATOM 3914 O THR 105 -29.776 29 ATOM 3915 N LYS 106 -30.811 28 ATOM 3916 CA LYS 106 -30.958 29 ATOM 3917 CB LYS 106 -31.076 29 ATOM 3918 CG LYS 106 -31.292 31 ATOM 3919 CD LYS 106 -31.505 31 ATOM 3920 CE LYS 106 -32.204 32 ATOM 3921 NZ LYS 106 -31.412 33 ATOM 3922 C LYS 106 -32.204 30 ATOM 3923 0 LYS 106 -33.324 30 ATOM 3924 N LEU 107 -32.002 31 ATOM 3925 CA LEU 107 -33.115 32 ATOM 3926 CB LEU 107 -32.759 32 ATOM 3927 CG LEU 107 -33.833 33 ATOM 3928 CDl LEU 107 -35.095 32 ATOM 3929 CD2 LEU 107 -33.320 33 ATOM 3930 C LEU 107 -33.438 33 ATOM 3931 O LEU 107 -32.583 34 ATOM 3932 N THR 108 -34.668 33 ATOM 3933 CA THR 108 -35.124 34 ATOM 3934 CB THR 108 -35.949 34 ATOM 3935 OG1 THR 108 -35.126 33 ATOM 3936 CG2 THR 108 -36.482 35 ATOM 3937 C THR 108 -35.993 35 ATOM 3938 O THR 108 -36.920 34 ATOM 3939 N VAL 109 -35.685 36 ATOM 3940 CA VAL 109 -36.549 37 ATOM 3941 CB VAL 109 -35.720 38 ATOM 3942 CGI VAL 109 -36.636 39 ATOM 3943 CG2 VAL 109 -34.827 37 ATOM 3944 C VAL 109 -37.469 38 ATOM 3945 O VAL 109 -37.037 39 ATOM 3946 N LEU 110 -38.737 38 ATOM 3947 CA LEU 110 -39.672 38 ATOM 3948 CB LEU 110 -41.047 37 ATOM 3949 CG LEU 110 -41.036 36 ATOM 3950 CDl LEU 110 -42.338 35 ATOM 3951 CD2 LEU 110 -40.828 35 ATOM 3952 C LEU 110 -39.779 39 ATOM 3953 O LEU 110 -40.124 40 ATOM 3954 N GLY 111 -39.468 40 ATOM 3955 CA GLY 111 -39.525 41 ATOM 3956 C GLY 111 -40.510 42 ATOM 3957 0 GLY 111 -40.689 43 ATOM 3958 N GLN 112 -41.150 41 ATOM 3959 CA GLN 112 -42.217 41 ATOM 3960 CB GLN 112 -41.627 41 ATOM 3961 CG GLN 112 -40.857 40 ATOM 3962 CD GLN 112 -40.276 40 ATOM 3963 OE1 GLN 112 -40.967 40 ATOM 3964 NE2 GLN 112 -39.004 41 ATOM 3965 C GLN 112 -43.097 40 -36.253 1.00 25.22 LI C -36.900 1.00 27.16 LI c -35.818 1.00 26.53 LI c -36.144 1.00 25.47 LI c -37.060 1.00 24.46 LI c -37.620 1.00 25.98 LI 0 -36.856 1.00 24.12 LI ν' -37.560 1.00 23.71 LI c -38.930 1.00 24.83 LI c -39.169 1.00 25.59 LI 0 -39.831 1.00 24.86 LI N -41.188 1.00 23.32 LI c -41.301 1.00 23.92 LI c -42.365 1.00 23.16 LI 0 -40.205 1.00 24.09 LI N -40.247 1.00 25.44 LI c -40.535 1.00 26.46 LI c -41.348 1.00 25.23 LI 0 -39.850 1.00 27.15 LI N -40.080 1.00 27.11 LI c -38.801 1.00 26.94 LI c -38.335 1.00 25.27 LI 0 -39.074 1.00 27.18 LI c -40.511 1.00 28.67 LI c -39.770 1.00 28.70 LI 0 -41.693 1.00 27.94 LI N -42.132 1.00 27.78 LI c -43.660 1.00 30.73 LI c -44.224 1.00 34.36 LI c -45.743 1.00 40.73 LI c -46.269 1.00 43.20 LI c -45.992 1.00 43.79 LI N -41.492 1.00 28.25 LI c -41.790 1.00 27.19 LI 0 -40.606 1.00 28.39 LI N -39.965 1.00 29.11 LI c -38.524 1.00 27.84 LI c -37.750 1.00 30.76 LI c -37.646 1.00 28.82 LI c -36.364 1.00 29.24 LI c -40.731 1.00 29.95 LI c -40.881 1.00 30.14 LI 0 -41.222 1.00 29.24 LI N -41.835 1.00 29.21 LI c -43.118 1.00 30.64 LI c -44.107 1.00 30.87 LI 0 -43.686 1.00 30.92 LI c -40.840 1.00 29.75 LI c -40.257 1.00 29.93 LI 0 -40.637 1.00 30.82 LI N -39.837 1.00 31.06 LI c -39.012 1.00 29.89 LI c -38.253 1.00 31.03 LI c -38.043 1.00 30.10 LI c -40.803 1.00 30.26 LI c -41.537 1.00 28.33 LI 0 -40.808 1.00 29.80 LI N -41.844 1.00 30.88 LI c -41.571 1.00 29.96 LI c -41.536 1.00 29.38 LI c -40.950 1.00 28.86 LI c -42.938 1.00 22.82 LI c -41.934 1.00 30.13 LI c -40.962 1.00 30.33 Ll 0 -43.110 1.00 31.70 LI N -43.327 1.00 32.20 Ll c -44.428 1.00 33.43 Ll c -44.768 1.00 35.10 Ll ' 0 -44.990 1.00 33.16 Ll N -45.964 1.00 36.01 Ll c -47.354 1.00 37.16 Ll c -47.931 1.00 37.31 Ll c -49.291 1.00 38.17 . Ll c -50.306 1.00 40.76 Ll 0 -49.320 1.00 35.15 Ll N -45.984 1.00 36.50 Ll c 473 WO 2009/026558 PCT/US2008/074097 ATOM 3966 0 GLN 112 -42.783 39 ATOM 3967 N PRO 113 -44.224 40 ATOM 3968 CD PRO 113 -44.796 41 ATOM 3969 CA PRO 113 -45.108 39 ATOM 3970 CB PRO 113 -46.269 39 ATOM 3971 CG PRO 113 -46.248 41 ATOM 3972 C PRO 113 -44.401 37 ATOM 3973 O PRO 113 -43.603 38 ATOM 3974 N LYS 114 -44.698 36 ATOM 3975 CA LYS 114 -44.209 35 ATOM 3976 CB LYS 114 -44.646 34 ATOM 3977 CG LYS 114 -44.031 34 ATOM 3978 CD LYS 114 -44.233 32 ATOM 3979 CE LYS 114 -43.571 32 ATOM 3980 NZ LYS 114 -43.874 31 ATOM 3981 C LYS 114 -44.754 35 ATOM 3982 0 LYS 114 -45.889 35 ATOM 3983 N ALA 115 -43.936 34 ATOM 3984 CA ALA 115 -44.316 34 ATOM 3985 CB ALA 115 -43.751 36 ATOM 3986 C ALA 115 -43.831 33 ATOM 3987 O ALA 115 -42.635 33 ATOM 3988 N ALA 116 -44.774 32 ATOM 3989 CA ALA 116 -44.469 31 ATOM 3990 CB ALA 116 -45.758 30 ATOM 3991 C ALA 116 -43.724 31 ATOM 3992 O ALA 116 -43.989 32 ATOM 3993 N PRO 117 -42.779 31 ATOM 3994 CD PRO 117 -42.512 29 ATOM 3995 CA PRO 117 -41.904 31 ATOM 3996 CB PRO 117 -40.870 30 ATOM 3997 CG PRO 117 -41.594 29 ATOM 3998 C PRO 117 -42.639 31 ATOM 3999 O PRO 117 -43.584 30 ATOM 4000 N SER 118 -42.193 31 ATOM 4001 CA SER 118 -42.597 31 ATOM 4002 CB SER 118 -42.568 33 ATOM 4003 OG SER 118 -43.416 33 ATOM 4004 C SER 118 -41.621 30 ATOM 4005 O SER 118 -40.406 30 ATOM 4006 N VAL 119 -42.152 29 ATOM 4007 CA VAL 119 -41.313 28 ATOM 4008 CB VAL 119 -41.591 27 ATOM 4009 CGI VAL 119 -40.704 26 ATOM 4010 CG2 VAL 119 -41.344 27 ATOM 4011 C VAL 119 -41.522 28 ATOM 4012 O VAL 119 -42.626 28 ATOM 4013 N THR 120 -40.450 28 ATOM 4014 CA THR 120 -40.470 28 ATOM 4015 CB THR 120 -40.051 30 ATOM 4016 OG1 THR 120 -40.923 31 ATOM 4017 CG2 THR 120 -40.125 30 ATOM 4018 C THR 120 -39.510 27 ATOM 4019 O THR 120 -38.316 27 ATOM 4020 N LEU 121 -40.036 26 ATOM 4021 CA LEU 121 -39.257 25 ATOM 4022 CB LEU 121 -39.920 24 ATOM 4023 CG LEU 121 -39.202 23 ATOM 4024 CDl LEU 121 -37.857 23 ATOM 4025 CD2 LEU 121 -40.061 21 ATOM 4026 C LEU 121 -39.087 25 ATOM 4027 O LEU 121 -40.058 25 ATOM 4028 N PHE 122 -37.846 25 ATOM 4029 CA PHE 122 -37.547 25 ATOM 4030 CB PHE 122 -36.521 26 ATOM 4031 CG PHE 122 -37.013 28 ATOM 4032 CDl PHE 122 -36.678 28 ATOM 4033 CD2 PHE 122 -37.803 28 ATOM 4034 CEl PHE 122 -37.121 30 ATOM 4035 CE2 PHE 122 -38.250 29 ATOM 4036 CZ PHE 122 -37.908 30 ATOM 4037 C PHE 122 -37.009 24 ATOM 4038 O PHE 122 -36.059 23 ATOM 4039 N PRO 123 -37.618 23 ATOM 4040 CD PRO 123 -38.879 23 ATOM 4041 CA PRO 123 -37.079 22 -45.333 1.00 35.56 LI O -46.714 1.00 37.98 LI N -47.415 1.00 38.44 LI C -46.789 1.00 38.56 LI C -47.669 1.00 38.32 LI c -47.550 1.00 38.11 LI c -47.403 1.00 39.28 LI c -48.330 1.00 38.01 LI 0 -46.891 1.00 39.70 LI N -47.515 1.00 43.10 LI c -46.708 1.00 41.99 LI c -45.310 1.00 44 . 06 LI c -44.646 1.00 44.49 LI c -43.276 1.00 4 6.38 LI c -42.529 1.00 47.56 LI N -48.937 1.00 44.55 LI c -49.192 1.00 45.57 LI 0 -49.861 1.00 45.01 LI N -51.267 1.00 45.57 LI c -52.015 1.00 43.32 LI c -51.920 1.00 47.27 LI c -51.918 1.00 47.27 LI 0 -52.478 1.00 47.90 LI N -53.213 1.00 48.80 LI c -53.533 1.00 49.49 LI c -54.500 1.00 49.45 LI c -55.139 1.00 49.52 LI 0 -54.892 1.00 50.68 LI N -54.194 1.00 50.62 LI c -56.055 1.00 52.06 LI c -55.897 1.00 52.12 LI c -55.141 1.00 51.66 LI c -57.385 1.00 53.83 LI c -57.518 1.00 53.40 LI 0 -58.366 1.00 5 6.36 LI N -59.755 1.00 59.62 LI c -60.526 1.00 60.11 LI c -59.935 1.00 62.95 LI 0 -60.406 1.00 60.93 LI c -60.272 1.00 61.04 LI 0 -61.110 1.00 62.70 LI N -61.779 1.00 64.16 LI c -61.236 1.00 63.53 LI c -61.945 1.00 63.21 LI c -59.737 1.00 64.05 LI c -63.293 1.00 65.49 LI c -63.779 1.00 65.80 LI 0 -64.032 1.00 67.43 LI N -65.490 1.00 68.73 LI c -66.117 1.00 68.82 LI c -65.648 1.00 68.76 LI 0 -67.636 1.00 68.58 LI c -65.971 1.00 69.56 LI c -65.669 1.00 69.35 LI 0 -66.720 1.00 70.38 LI N -67.122 1.00 70.76 LI c -66.594 1.00 70.00 LI c -66.926 1.00 69.81 Ll c -66.219 1.00 69.72 LI c -66.496 1.00 70.35 Ll c -68.637 1.00 71.13 Ll c -69.368 1.00 70.75 Ll 0 -69.101 1.00 71.79 Ll N -70.523 1.00 73.09 Ll c -70.944 1.00 72.54 Ll c -70.821 1.00 72.59 Ll c -69.722 1.00 72.06 Ll c -71.813 1.00 72.99 Ll ' c -69.613 1.00 73.02 Ll c -71.711 1.00 72.95 Ll c -70.610 1.00 72.77 Ll c -70.864 1.00 74.17 Ll c -70.243 1.00 74.07 . Ll 0 -71.861 1.00 74.99 Ll N -72.509 1.00 75.22 Ll c -72.430 1.00 74.86 Ll c 474 WO 2009/026558 PCT/US2008/074097 ATOM 4042 CB PRO 123 -38.219 21 ATOM 4043 CG PRO 123 -38.970 22 ATOM 4044 C PRO 123 -35.808 22 ATOM 4045 O PRO 123 -35.491 23 ATOM 4046 N PRO 124 -35.061 21 ATOM 4047 CD PRO 124 -35.268 20 ATOM 4048 CA PRO 124 -33.841 21 ATOM 4049 CB PRO 124 -33.309 20 ATOM 4050 CG PRO 124 -33.908 19 ATOM 4051 C PRO 124 -34.141 22 ATOM 4052 O PRO 124 -35.135 21 ATOM 4053 N SER 125 -33.284 23 ATOM 4054 CA SER 125 -33.440 23 ATOM 4055 CB SER 125 -32.533 25 ATOM 4056 OG SER 125 -31.171 24 ATOM 4057 C SER 125 -33.095 22 ATOM 4058 O SER 125 -32.531 21 ATOM 4059 N SER 126 -33.446 23 ATOM 4060 CA SER 126 -33.135 22 ATOM 4061 CB SER 126 -33.941 22 ATOM 4062 OG SER 126 -35.334 22 ATOM 4063 C SER 126 -31.641 22 ATOM 4064 O SER 126 -31.039 21 ATOM 4065 N GLU 127 -31.051 23 ATOM 4066 CA GLU 127 -29.627 23 ATOM 4067 CB GLU 127 -29.247 25 ATOM 4068 CG GLU 127 -29.826 26 ATOM 4069 CD GLU 127 -31.272 26 ATOM 4070 OE1 GLU 127 -31.928 25 ATOM 4071 OE2 GLU 127 -31.754 27 ATOM 4072 C GLU 127 -28.763 22 ATOM 4073 0 GLU 127 -27.606 22 ATOM 4074 N GLU 128 -29.326 22 ATOM 4075 CA GLU 128 -28.570 21 ATOM 4076 CB GLU 128 -28.967 21 ATOM 4077 CG GLU 128 -28.026 21 ATOM 4078 CD GLU 128 -28.481 21 ATOM 4079 OE1 GLU 128 -27.643 21 ATOM 4080 OE2 GLU 128 -29.674 22 ATOM 4081 C GLU 128 -28.794 20 ATOM 4082 0 GLU 128 -27.845 19 ATOM 4083 N LEU 129 -30.047 19 ATOM 4084 CA LEU 129 -30.367 18 ATOM 4085 CB LEU 129 -31.860 18 ATOM 4086 CG LEU 129 -32.808 18 ATOM 4087 CD1 LEU 129 -34.253 18 ATOM 4088 CD2 LEU 129 -32.476 17 ATOM 4089 C LEU 129 -29.544 17 ATOM 4090 0 LEU 129 -29.147 16 ATOM 4091 N GLN 130 -29.286 18 ATOM 4092 CA GLN 130 -28.463 18 ATOM 4093 CB GLN 130 -28.619 19 ATOM 4094 CG GLN 130 -28.015 20 ATOM 4095 CD GLN 130 -28.181 21 ATOM 4096 OE1 GLN 130 -27.319 22 ATOM 4097 NE2 GLN 130 -29.292 21 ATOM 4098 C GLN 130 -26.997 18 ATOM 4099 0 GLN 130 -2 6.2 60 17 ATOM 4100 N ALA 131 -26.581 19 ATOM 4101 CA ALA 131 -25.210 19 ATOM 4102 CB ALA 131 -24.918 20 ATOM 4103 C ALA 131 -24.971 17 ATOM 4104 0 ALA 131 -23.918 17 ATOM 4105 N ASN 132 -25.959 16 ATOM 4106 CA ASN 132 -25.842 15 ATOM 4107 CB ASN 132 -24.526 15 ATOM 4108 CG ASN 132 -24.503 13 ATOM 4109 OD1 ASN 132 -25.549 12 ATOM 4110 ND2 ASN 132 -23.304 13 ATOM 4111 C ASN 132 -25.920 16 ATOM 4112 0 ASN 132 -25.553 15 ATOM 4113 N LYS 133 -26.400 17 ATOM 4114 CA LYS 133 -26.575 17 ATOM 4115 CB LYS 133 -25.705 18 ATOM 4116 CG LYS 133 -24.278 18 ATOM 4117 CD LYS 133 -23.379 18 -73 .305 1 .00 74 .82 LI C -73, .693 1 .00 75 .30 LI c -73 .238 1 .00 74 .68 LI c -73 .542 1 .00 74 .38 LI 0 -73 .591 1 .00 75 .00 LI N -73 . 198 1 .00 74 .86 LI c -74 .390 1 .00 74 .74 LI c -74 .545 1 .00 74 .36 LI c -73 .404 1 .00 74 . 67 LI c -75 .742 1 .00 74 .62 LI c -76 .387 1 .00 74 .35 LI 0 -76 .167 1 .00 74 .96 LI N -77 .475 1 .00 75 . 14 LI c -77 .591 1, .00 73 .75 LI c -77 .395 1 .00 72 . 15 LI 0 -78 , .563 1 .00 76 .50 LI c -78 .282 1 .00 76 .63 LI 0 -79 .804 1 .00 77 .77 LI N -80 .92 4 1 .00 78 .66 LI c -82 , .160 1 .00 79 .08 LI c -81 .917 1 .00 79 .83 LI 0 -81 .235 1 .00 78 .82 LI c -81 .610 1, .00 78 .71 LI 0 -81, .063 1, .00 79 . 12 LI N -81 .312 1 .00 80 .10 LI c -81 .071 1 .00 80 .24 LI c -82 .078 1, .00 81 .24 LI c -81, .787 1, .00 82 . 17 LI c -80 .993 1, .00 82 . 13 LI 0 -82 , .356 1, .00 81 .88 LI 0 -80, .424 1, .00 80. .55 LI c -80, .742 1, .00 80 .88 LI 0 -79, .308 1, .00 81, .34 LI N -78 , .339 1, .00 82 . .00 LI c -76, .911 1, .00 82 .28 LI c -75, .834 1, .00 81. .82 LI c -74 , .430 1, .00 81. .09 LI c -73, .505 1 , .00 79 .98 LI 0 -74 , .251 1 , .00 81, . 48 LI 0 -78 , .539 1 , .00 82 . .27 LI c -78 , . 510 1 , .00 81. .56 LI 0 -78 , .746 1 , .00 82 . .77 LI N -78 , .984 1 , .00 83 , .70 LI c -79, .282 1 , .00 83 , .20 LI c -78 , . 116 1 , .00 83 . .28 LI c -78 , . 557 1 , .00 82 , . 64 LI c -76, .965 1 , .00 83 , .46 LI c -80, . 154 1, .00 84 . .66 LI c -80, . 172 1 , .00 84 . .88 LI 0 -81, .127 1 , .00 85 . .33 LI N -82 . .275 1 , .00 86. . 17 LI c -83 , .390 1 , .00 86, . 49 LI c -83 , .063 1 , .00 86, . 88 LI c -84 , .191 1 , .00 87 . .75 LI c -84 , .409 1 , .00 87 , . 18 LI 0 -84 , .915 1. .00 86. .91 LI N -81, .863 1 , .00 86. .31 LI c -82 , .342 1, .00 87 , . 49 LI 0 -80, .971 1. .00 85 , .27 LI N -80, .478 1 , .00 84 . .10 LI c -79, .770 1 , .00 83 , .24 Ll c -79, .528 1. .00 83 . .51 LI c -78 . .894 1. .00 83 . .48 Ll 0 -79, .433 1. .00 82 . .74 Ll N -78 , .649 1. .00 82 . .64 Ll c -7 8 , .983 1. .00 82 , .71 Ll c -78 , .508 1. .00 82 , .60 Ll c -78 , .367 1. .00 81. .48 Ll 0 -78 , .261 1. .00 81 , .72 Ll N -77 , .146 1. .00 82 , . 67 Ll c -76. .322 1. .00 82 . .72 Ll 0 -76. .801 1. .00 82 . .45 Ll N -75 . .408 1. .00 81 , .60 . Ll c -75 . .100 1. .00 81. .98 Ll c -75. .616 1. .00 82 . .82 Ll c -74 . . 641 1. .00 84 . .05 Ll c 475 WO 2009/026558 PCT/US2008/074097 ATOM 4118 CE LYS 133 -22.792 18 ATOM 4119 NZ LYS 133 -21.971 20 ATOM 4120 C LYS 133 -28.044 17 ATOM 4121 0 LYS 133 -28.780 18 ATOM 4122 N ALA 134 -28.469 17 ATOM 4123 CA ALA 134 -29.825 18 ATOM 4124 CB ALA 134 -30.769 17 ATOM 4125 C ALA 134 -29.882 18 ATOM 4126 O ALA 134 -29.587 18 ATOM 4127 N THR 135 -30.262 20 ATOM 4128 CA THR 135 -30.332 20 ATOM 4129 CB THR 135 -29.333 21 ATOM 4130 OG1 THR 135 -28.001 21 ATOM 4131 CG2 THR 135 -29.414 22 ATOM 4132 C THR 135 -31.724 21 ATOM 4133 O THR 135 -32.213 22 ATOM 4134 N LEU 136 -32.358 20 ATOM 4135 CA LEU 136 -33.573 21 ATOM 4136 CB LEU 136 -34.423 20 ATOM 4137 CG LEU 136 -35.265 19 ATOM 4138 CDl LEU 136 -34.370 18 ATOM 4139 CD2 LEU 136 -36.016 18 ATOM 4140 C LEU 136 -33.208 22 ATOM 4141 O LEU 136 -32.394 22 ATOM 4142 N VAL 137 -33.808 23 ATOM 4143 CA VAL 137 -33.551 24 ATOM 4144 CB VAL 137 -33.154 26 ATOM 4145 CGI VAL 137 -32.927 27 ATOM 4146 CG2 VAL 137 -31.901 25 ATOM 4147 C VAL 137 -34.783 25 ATOM 4148 0 VAL 137 -35.820 25 ATOM 4149 N CYS 138 -34.662 25 ATOM 4150 CA CYS 138 -35.747 25 ATOM 4151 C CYS 138 -35.386 26 ATOM 4152 0 CYS 138 -34.407 26 ATOM 4153 CB CYS 138 -36.011 24 ATOM 4154 SG CYS 138 -37.540 24 ATOM 4155 N LEU 139 -36.182 27 ATOM 4156 CA LEU 139 -35.925 29 ATOM 4157 CB LEU 139 -35.920 30 ATOM 4158 CG LEU 139 -34.894 30 ATOM 4159 CDl LEU 139 -34.880 31 ATOM 4160 CD2 LEU 139 -33.518 29 ATOM 4161 C LEU 139 -36.957 29 ATOM 4162 0 LEU 139 -38.167 29 ATOM 4163 N ILE 140 -36.462 29 ATOM 4164 CA ILE 140 -37.306 30 ATOM 4165 CB ILE 140 -36.927 29 ATOM 4166 CG2 ILE 140 -38.000 29 ATOM 4167 CGI ILE 140 -36.764 27 ATOM 4168 CDl ILE 140 -35.977 26 ATOM 4169 C ILE 140 -37.097 31 ATOM 4170 0 ILE 140 -35.985 31 ATOM 4171 N SER 141 -38.165 32 ATOM 4172 CA SER 141 -38.045 33 ATOM 4173 CB SER 141 -38.136 34 ATOM 4174 OG SER 141 -39.277 34 ATOM 4175 C SER 141 -39.086 34 ATOM 4176 0 SER 141 -40.109 33 ATOM 4177 N ASP 142 -38.802 35 ATOM 4178 CA ASP 142 -39.777 36 ATOM 4179 CB ASP 142 -40.938 36 ATOM 4180 CG ASP 142 -40.522 37 ATOM 4181 OD1 ASP 142 -40.884 37 ATOM 4182 OD2 ASP 142 -39.832 38 ATOM 4183 C ASP 142 -40.339 35 ATOM 4184 0 ASP 142 -41.513 35 ATOM 4185 N PHE 143 -39.521 34 ATOM 4186 CA PHE 143 -39.969 33 ATOM 4187 CB PHE 143 -39.638 32 ATOM 4188 CG PHE 143 -38.186 31 ATOM 4189 CDl PHE 143 -37.335 31 ATOM 4190 CD2 PHE 143 -37.684 31 ATOM 4191 CEl PHE 143 -36.010 31 ATOM 4192 CE2 PHE 143 -36.360 31 ATOM 4193 CZ PHE 143 -35.522 31 -73.604 1.00 85.60 LI C -74.232 1.00 85.73 LI N -75.156 1.00 81.04 LI C -76.087 1.00 81.66 LI 0 -73.900 1.00 79.38 LI N -73.537 1.00 77.97 LI C. -73.687 1.00 77.34 LI C -72.110 1.00 77.09 LI c -71.147 1.00 76.45 LI 0 -71.983 1.00 75.44 LI N -70.682 1.00 73.38 LI c -70.590 1.00 72.52 LI c -70.806 1.00 71.97 LI 0 -69.221 1.00 71.78 LI c -70.404 1.00 72.81 LI c -71.131 1.00 72.54 LI 0 -69.346 1.00 71.97 LI N -68.833 1.00 71.28 LI c -68.076 1.00 70.86 LI c -68.911 1.00 70.08 LI c -69.858 1.00 70.16 LI c -67.992 1.00 69.02 LI c -67.901 1.00 71.09 LI c -66.987 1.00 71.21 LI 0 -68.141 1.00 69.73 LI N -67.321 1.00 67.62 LI c -68.190 1.00 67.33 LI c -67.311 1.00 65.83 LI c -68.989 1.00 67.16 LI c -66.509 1.00 66.67 LI c -67.067 1.00 66.72 LI 0 -65.188 1.00 65.71 LI N -64.290 1.00 63.89 LI c -63.559 1.00 62.65 LI c -62.812 1.00 62.18 LI 0 -63.268 1.00 64.16 LI c -62.308 1.00 64.86 LI s -63.775 1.00 61.05 LI N -63.156 1.00 59.25 LI c -64.223 1.00 59.69 LI c -65.322 1.00 60.35 LI c -66.302 1.00 61.08 LI c -64.700 1.00 60.90 LI c -62.078 1.00 57.87 LI c -62.317 1.00 57.52 LI 0 -60.893 1.00 55.44 LI N -59.723 1.00 52.95 LI c -58.601 1.00 52.69 LI c -57.525 1.00 50.12 LI c -59.185 1.00 51.28 LI c -58.301 1.00 51.25 LI c -59.230 1.00 52.13 LI c -58.874 1.00 51.51 LI 0 -59.214 1.00 52.05 LI N -58.892 1.00 51.89 LI c -60.176 1.00 52.46 LI c -60.934 1.00 55.32 LI 0 -57.889 1.00 50.72 LI c -57.661 1.00 50.55 LI 0 -57.285 1.00 48.87 LI N -56.470 1.00 47.69 LI c -57.342 1.00 48.13 LI c -58.310 1.00 47.87 LI c -59.500 1.00 49.98 LI 0 -57.879 1.00 48.34 LI 0 -55.298 1.00 46.46 LI c -54.958 1.00 47.09 LI 0 -54.678 1.00 45.07 LI N -53.462 1.00 43.57 LI c -53.483 1.00 45.13 LI c -53.738 1.00 46.48 LI c -52.686 1.00 46.51 LI c -55.032 1.00 46.16 LI c -52.919 1.00 45.94 LI c -55.273 1.00 46.80 LI c -54.217 1.00 46.20 LI c 476 WO 2009/026558 PCT/US2008/074097 ATOM 4194 c PHE 143 -39.377 34 ATOM 4195 0 PHE 143 -38.354 35 ATOM 4196 N TYR 144 -40.050 34 ATOM 4197 CA TYR 144 -39.596 34 ATOM 4198 CB TYR 144 -39.838 36 ATOM 4199 CG TYR 144 -39.404 36 ATOM 4200 CD1 TYR 144 -40.278 37 ATOM 4201 CE1 TYR 144 -39.873 37 ATOM 4202 CD2 TYR 144 -38. 111 37 ATOM 4203 CE2 TYR 144 -37.698 37 ATOM 4204 CZ TYR 144 -38.582 38 ATOM 4205 OH TYR 144 -38.180 38 ATOM 4206 C TYR 144 -40.340 34 ATOM 4207 O TYR 144 -41.560 34 ATOM 4208 N PRO 145 -39.615 33 ATOM 4209 CD PRO 145 -40.238 33 ATOM 4210 CA PRO 145 -38.156 33 ATOM 4211 CB PRO 145 -37.875 33 ATOM 4212 CG PRO 145 -39.073 32 ATOM 4213 C PRO 145 -37.354 33 ATOM 4214 O PRO 145 -37.912 32 ATOM 4215 N GLY 146 -36.041 33 ATOM 4216 CA GLY 146 -35.200 32 ATOM 4217 C GLY 146 -34.687 31 ATOM 4218 0 GLY 146 -33.481 31 ATOM 4219 N ALA 147 -35.603 30 ATOM 4220 CA ALA 147 -35.233 28 ATOM 4221 CB ALA 147 -35.225 28 ATOM 4222 C ALA 147 -36.193 28 ATOM 4223 O ALA 147 -37.394 28 ATOM 4224 N VAL 148 -35.658 27 ATOM 4225 CA VAL 148 -36.448 26 ATOM 4226 CB VAL 148 -36.780 26 ATOM 4227 CGI VAL 148 -37.632 28 ATOM 4228 CG2 VAL 148 -35.495 27 ATOM 4229 C VAL 148 -35.704 24 ATOM 4230 O VAL 148 -34.493 24 ATOM 4231 N THR 149 -36.442 23 ATOM 4232 CA THR 149 -35.835 22 ATOM 4233 CB THR 149 -36.112 21 ATOM 4234 OG1 THR 149 -37.519 21 ATOM 4235 CG2 THR 149 -35.364 21 ATOM 4236 C THR 149 -36.392 22 ATOM 4237 O THR 149 -37.597 22 ATOM 4238 N VAL 150 -35.510 21 ATOM 4239 CA VAL 150 -35.909 21 ATOM 4240 CB VAL 150 -35.024 22 ATOM 4241 CGI VAL 150 -35.498 21 ATOM 4242 CG2 VAL 150 -35.063 23 ATOM 4243 C VAL 150 -35.833 20 ATOM 4244 O VAL 150 -34.762 19 ATOM 4245 N ALA 151 -36.978 19 ATOM 4246 CA ALA 151 -37.034 18 ATOM 4247 CB ALA 151 -38.086 17 ATOM 4248 C ALA 151 -37.364 17 ATOM 4249 O ALA 151 -38.276 18 ATOM 4250 N TRP 152 -36.613 17 ATOM 4251 CA TRP 152 -36.882 16 ATOM 4252 CB TRP 152 -35.579 16 ATOM 4253 CG TRP 152 -34.968 18 ATOM 4254 CD2 TRP 152 -35.151 19 ATOM 4255 CE2 TRP 152 -34.345 20 ATOM 4256 CE3 TRP 152 -35.916 19 ATOM 4257 CD1 TRP 152 -34.088 18 ATOM 4258 NE1 TRP 152 -33.707 20 ATOM 4259 CZ2 TRP 152 -34.281 21 ATOM 4260 CZ3 TRP 152 -35.850 20 ATOM 4261 CH2 TRP 152 -35.038 21 ATOM 4262 C TRP 152 -37.579 15 ATOM 4263 O TRP 152 -37.339 14 ATOM 4264 N LYS 153 -38.440 15 ATOM 4265 CA LYS 153 -39.267 14 ATOM 4266 CB LYS 153 -40.708 14 ATOM 4267 CG LYS 153 -41.453 13 ATOM 4268 CD LYS 153 -41.399 13 ATOM 4269 CE LYS 153 -39.981 13 -52.230 1.00 41.63 LI C -52.311 1.00 39.49 LI 0 -51.098 1.00 39.96 LI N -49.827 1.00 40.17 LI C -49.777 1.00 37.41 LI c -48.468 1.00 36.24 LI c -47.386 1.00 33.84 LI c -46.176 1.00 32.19 LI c -48.300 1.00 34.26 LI c -47.095 1.00 32.36 LI c -46.038 1.00 31.01 LI c -44.844 1.00 32.81 LI 0 -48.680 1.00 4 0.52 LI c -48.728 1.00 42.86 LI 0 -47.633 1.00 40.04 LI N -46.436 1.00 39.62 LI c -47.500 1.00 41.17 LI c -46.080 1.00 40.22 LI c -45.692 1.00 39.21 LI c -48.555 1.00 43.02 LI c -49.340 1.00 42.96 LI 0 -48.569 1.00 44.40 LI N -49.618 1.00 46.46 LI c -49.356 1.00 48.24 LI c -49.233 1.00 47.83 LI 0 -49.279 1.00 49.04 LI N -49.084 1.00 50.76 LI c -47.597 1.00 48.27 LI c -49.825 1.00 52.27 LI c -49.544 1.00 54.27 LI 0 -50.773 1.00 52.98 LI N -51.504 1.00 53.70 LI c -52.935 1.00 52.32 LI c -52.872 1.00 51.32 LI c -53.698 1.00 50.98 LI c -51.615 1.00 54.30 LI c -51.415 1.00 53.75 LI 0 -51.928 1.00 55.67 LI N -52.369 1.00 56.75 LI c -51.373 1.00 5 6.63 LI c -51.115 1.00 55.86 LI 0 -50.071 1.00 55.91 LI c -53.734 1.00 58.18 LI c -53.977 1.00 58.23 LI 0 -54.623 1.00 59.58 LI N -55.983 1.00 62.22 LI c -57.015 1.00 62.03 LI c -58.422 1.00 62.67 LI c -56.768 1.00 62.69 Ll c -56.248 1.00 63.79 Ll c -56.166 1.00 64.56 Ll 0 -56.566 1.00 64.58 Ll N -56.964 1.00 65.49 Ll c -56.144 1.00 64.19 Ll c -58.450 1.00 66.84 Ll c -58.939 1.00 67.66 Ll 0 -59.167 1.00 67.84 Ll N -60.579 1.00 69.16 Ll c -61.380 1.00 67.01 Ll c -61.549 1.00 64.07 Ll c -62.658 1.00 62.91 Ll c -62.422 1.00 62.02 Ll c -63.829 1.00 62.20 Ll c -60.707 1.00 62.61 Ll c -61.225 1.00 61.78 Ll N -63.313 1.00 61.34 Ll c -64.714 1.00 61.43 Ll c -64.451 1.00 61.91 Ll c -60.751 1.00 71.64 Ll c -59.985 1.00 71.81 Ll 0 -61.759 1.00 73.83 Ll N -61.939 1.00 76.53 Ll c -61.520 1.00 77.51 . Ll c -60.900 1.00 78.87 Ll c -59.376 1.00 79.45 ' Ll c -58.855 1.00 80.16 Ll c 477 WO 2009/026558 PCT/US2008/074097 ATOM 4270 NZ LYS 153 -39.927 13 ATOM 4271 C LYS 153 -39.243 13 ATOM 4272 O LYS 153 -39.608 14 ATOM 4273 N ALA 154 -38.809 12 ATOM 4274 CA ALA 154 -38.815 11 ATOM 4275 CB ALA 154 -37.575 11 ATOM 4276 C ALA 154 -40.075 11 ATOM 4277 O ALA 154 -40.234 10 ATOM 4278 N ASP 155 -40.962 11 ATOM 4279 CA ASP 155 -42.319 10 ATOM 4280 CB ASP 155 -42.302 9 ATOM 4281 CG ASP 155 -42.034 9 ATOM 4282 OD1 ASP 155 -42.635 9 ATOM 4283 OD2 ASP 155 -41.225 8 ATOM 4284 C ASP 155 -42.981 11 ATOM 4285 O ASP 155 -43.575 12 ATOM 4286 N SER 156 -42.866 10 ATOM 4287 CA SER 156 -43.383 10 ATOM 4288 CB SER 156 -44.545 9 ATOM 4289 OG SER 156 -45.527 9 ATOM 4290 C SER 156 -42.270 9 ATOM 4291 O SER 156 -42.374 10 ATOM 4292 N SER 157 -41.205 9 ATOM 4293 CA SER 157 -40.101 8 ATOM 4294 CB SER 157 -39.301 7 ATOM 4295 OG SER 157 -40.079 6 ATOM 4296 C SER 157 -39.169 9 ATOM 4297 O SER 157 -38.933 10 ATOM 4298 N PRO 158 -38.631 9 ATOM 4299 CD PRO 158 -39.055 8 ATOM 4300 CA PRO 158 -37.633 10 ATOM 4301 CB PRO 158 -37.393 10 ATOM 4302 CG PRO 158 -38.625 9 ATOM 4303 C PRO 158 -36.352 10 ATOM 4304 O PRO 158 -35.918 9 ATOM 4305 N VAL 159 -35.753 11 ATOM 4306 CA VAL 159 -34.479 11 ATOM 4307 CB VAL 159 -34.463 13 ATOM 4308 CGI VAL 159 -33.084 13 ATOM 4309 CG2 VAL 159 -35.516 12 ATOM 4310 C VAL 159 -33.328 12 ATOM 4311 O VAL 159 -33.329 13 ATOM 4312 N LYS 160 -32.345 11 ATOM 4313 CA LYS 160 -31.199 11 ATOM 4314 CB LYS 160 -30.533 9 ATOM 4315 CG LYS 160 -31.408 8 ATOM 4316 CD LYS 160 -31.257 7 ATOM 4317 CE LYS 160 -32.249 6 ATOM 4318 NZ LYS 160 -32.296 5 ATOM 4319 C LYS 160 -30.180 12 ATOM 4320 0 LYS 160 -30.155 13 ATOM 4321 N ALA 161 -29.352 11 ATOM 4322 CA ALA 161 -28.194 12 ATOM 4323 CB ALA 161 -27.015 11 ATOM 4324 C ALA 161 -28.471 13 ATOM 4325 O ALA 161 -29.578 13 ATOM 4326 N GLY 162 -27.450 14 ATOM 4327 CA GLY 162 -27.592 15 ATOM 4328 C GLY 162 -28.113 16 ATOM 4329 0 GLY 162 -28.263 17 ATOM 4330 N VAL 163 -28.383 16 ATOM 4331 CA VAL 163 -29.013 18 ATOM 4332 CB VAL 163 -29.963 17 ATOM 4333 CGI VAL 163 -30.631 18 ATOM 4334 CG2 VAL 163 -31.006 16 ATOM 4335 C VAL 163 -27.986 19 ATOM 4336 O VAL 163 -27.082 18 ATOM 4337 N GLU 164 -28.139 20 ATOM 4338 CA GLU 164 -27.250 21 ATOM 4339 CB GLU 164 -26.269 21 ATOM 4340 CG GLU 164 -24.859 21 ATOM 4341 CD GLU 164 -24.073 20 ATOM 4342 OE1 GLU 164 -23.934 20 ATOM 4343 OE2 GLU 164 -23.597 20 ATOM 4344 C GLU 164 -28.076 22 ATOM 4345 0 GLU 164 -28.643 23 -57.366 1.00 79.77 LI N -63.389 1.00 77.70 LI C -64.304 1.00 77.96 LI 0 -63.590 1.00 79.25 LI N -64.917 1.00 80.39 LI C -65.098 1.00 79.94 LI c -65.085 1.00 81.09 LI c -64.426 1.00 80.56 LI 0 -65.976 1.00 82.58 LI N -66.034 1.00 84 .19 LI c -66.414 1.00 85.20 LI c -67.893 1.00 86.13 LI c -68.723 1.00 85.84 LI 0 -68.225 1.00 86.10 LI 0 -64.673 1.00 84.53 LI c -64.388 1.00 84.90 LI 0 -63.834 1.00 84.79 LI N -62.472 1.00 84.82 LI c -62.310 1.00 85.15 LI c -63.312 1.00 85.88 LI 0 -61.495 1.00 84.72 LI c -60.295 1.00 84 .40 LI 0 -62.023 1.00 84.73 LI N -61.198 1.00 84.69 LI c -61.946 1.00 84.54 LI c -62.163 1.00 84.37 LI 0 -60.796 1.00 84.54 LI c -61.565 1.00 83.92 LI 0 -59.571 1.00 84.51 LI N -58.521 1.00 84.52 LI c -59.079 1.00 84.62 LI c -57.635 1.00 84.58 LI c -57.263 1.00 84.46 LI c -59.909 1.00 84.68 Ll c -60.333 1.00 84.90 LI 0 -60.141 1.00 84.33 Ll N -60.847 1.00 83.83 Ll c -61.860 1.00 84 . 04 Ll c -62.492 1.00 83.62 Ll c -62.931 1.00 83.67 Ll c -59.864 1.00 83.32 Ll c -59.060 1.00 83.25 Ll 0 -59.937 1.00 82.48 Ll N -59.040 1.00 81.67 Ll c -58.947 1.00 81.53 Ll c -58.305 1.00 81.07 Ll c -58.997 1.00 80.52 Ll c -58.440 1.00 80.19 Ll c -59.240 1.00 80.25 Ll N -59.499 1.00 80.59 Ll c -58.990 1.00 80.48 Ll 0 -60.472 1.00 78.88 Ll N -60.839 1.00 76.98 Ll c -61.163 1.00 77.49 Ll c -62.014 1.00 75.33 Ll c -62.554 1.00 74.70 Ll 0 -62.400 1.00 73.68 Ll N -63.490 1.00 71.48 Ll c -63.013 1.00 70.15 Ll c -63.802 1.00 69.01 Ll 0 -61.713 1.00 69.08 Ll N -61.132 1.00 67.56 Ll c -59.978 1.00 67.21 Ll c -59.406 1.00 66.89 Ll c -60.477 1.00 66.02 Ll c -60.601 1.00 66.76 Ll c -59.846 1.00 65.41 Ll 0 -61.000 1.00 66.54 Ll '' N -60.551 1.00 66.37 Ll c -61.667 1.00 67.88 Ll c -61.192 1.00 69.70 Ll c -60.971 1.00 70.76 Ll c -59.801 1.00 71.18 . Ll 0 -61.969 1.00 71.13 Ll 0 -60.174 1.00 64.94 Ll c -61.041 1.00 64.32 Ll 0 478 WO 2009/026558 PCT/US2008/074097 ATOM 4346 N THR 165 -28.140 22 ATOM 4347 CA THR 165 -28.991 23 ATOM 4348 CB THR 165 -30.086 23 ATOM 4349 OG1 THR 165 -30.918 22 ATOM 4350 CG2 THR 165 -30.947 24 ATOM 4351 C THR 165 -28.192 25 ATOM 4352 O THR 165 -27.360 24 ATOM 4353 N THR 166 -28.455 26 ATOM 4354 CA THR 166 -27.779 27 ATOM 4355 CB THR 166 -27.989 28 ATOM 4356 OG1 THR 166 -29.386 29 ATOM 4357 CG2 THR 166 -27.471 28 ATOM 4358 C THR 166 -28.276 27 ATOM 4359 O THR 166 -29.303 27 ATOM 4360 N THR 167 -27.536 28 ATOM 4361 CA THR 167 -28.032 28 ATOM 4 3 62 CB THR 167 -26.877 29 ATOM 4363 OG1 THR 167 -26.172 30 ATOM 4364 CG2 THR 167 -25.909 28 ATOM 4365 C THR 167 -28.949 30 ATOM 4366 O THR 167 -28.730 30 ATOM 4 3 67 N PRO 168 -29.998 30 ATOM 4368 CD PRO 168 -30.507 29 ATOM 4369 CA PRO 168 -30.894 31 ATOM 4370 CB PRO 168 -31.944 31 ATOM 4371 CG PRO 168 -31.945 29 ATOM 4372 C PRO 168 -30.153 32 ATOM 4373 O PRO 168 -29.358 32 ATOM 4374 N SER 169 -30.413 33 ATOM 4375 CA SER 169 -29.782 34 ATOM 4376 CB SER 169 -28.984 35 ATOM 4377 OG SER 169 -29.775 34 ATOM 4378 C SER 169 -30.821 36 ATOM 4379 O SER 169 -31.943 35 ATOM 4380 N LYS 170 -30.440 37 ATOM 4381 CA LYS 170 -31.375 38 ATOM 4382 CB LYS 170 -30.868 39 ATOM 4383 CG LYS 170 -31.817 40 ATOM 4384 CD LYS 170 -31.307 40 ATOM 4385 CE LYS 170 -31.110 39 ATOM 4386 NZ LYS 170 -32.375 39 ATOM 4387 C LYS 170 -31.590 39 ATOM 4388 O LYS 170 -30.646 39 ATOM 4389 N GLN 171 -32.839 39 ATOM 4390 CA GLN 171 -33.200 40 ATOM 4391 CB GLN 171 -34.559 39 ATOM 4392 CG GLN 171 -34.622 38 ATOM 4393 CD GLN 171 -36.046 37 ATOM 4394 OE1 GLN 171 -36.271 36 ATOM 4395 NE2 GLN 171 -37.018 38 ATOM 4396 C GLN 171 -33.263 41 ATOM 4397 0 GLN 171 -32.982 41 ATOM 4398 N SER 172 -33.637 42 ATOM 4399 CA SER 172 -33.736 43 ATOM 4400 CB SER 172 -33.911 44 ATOM 4401 OG SER 172 -34.948 4 4 ATOM 4402 C SER 172 -34.900 44 ATOM 4403 O SER 172 -34.776 45 ATOM 4404 N ASN 173 -36.026 43 ATOM 4405 CA ASN 173 -37.207 43 ATOM 4406 CB ASN 173 -38.442 43 ATOM 4407 CG ASN 173 -38.286 41 ATOM 4408 OD1 ASN 173 -37.432 41 ATOM 4409 ND2 ASN 173 -39.108 41 ATOM 4410 C ASN 173 -37.062 42 ATOM 4411 O ASN 173 -38.020 42 ATOM 4412 N ASN 174 -35.858 42 ATOM 4413 CA ASN 174 -35.560 41 ATOM 4414 CB ASN 174 -35.930 42 ATOM 4415 CG ASN 174 -34.994 43 ATOM 4416 OD1 ASN 174 -33.839 43 ATOM 4417 ND2 ASN 174 -35.483 45 ATOM 4418 C ASN 174 -36.253 40 ATOM 4419 O ASN 174 -36.163 39 ATOM 4420 N LYS 175 -36.944 39 ATOM 4421 CA LYS 175 -37.315 38
-58.881 1.00 62.91 LI N -58.391 1.00 61.09 LI C -57.441 1.00 60.86 LI C -58.144 1.00 60.45 LI O -56.915 1.00 59.22 LI C -57.649 1.00 59.97 LI C -56.795 1.00 60.22 LI O -57.973 1.00 57.86 LI N -57.312 1.00 57.52 LI C -58.071 1.00 57.94 LI C -58.088 1.00 5 6.92 LI O -59.496 1.00 57.35 LI C -55.883 1.00 56.25 LI C -55.475 1.00 55.75 LI O -55.127 1.00 54.65 LI N -53.860 1.00 54 .27 LI C -52.963 1.00 54.52 LI C -53.623 1.00 53.89 LI O -52.680 1.00 54.44 LI C -54.161 1.00 53.66 LI C -55.121 1.00 52.20 LI O -53.351 1.00 54.17 LI N -52.331 1.00 53.81 LI C -53.544 1.00 53.90 LI C -52.450 1.00 53.59 LI C -52.185 1.00 54.66 LI C -53.427 1.00 53.20 LI C -52.511 1.00 54.37 LI O -54.363 1.00 52.86 LI N -54.360 1.00 52.56 LI C -55.647 1.00 51.77 LI C -56.779 1.00 53.89 LI O -54.224 1.00 52.72 LI C -54.716 1.00 51.23 LI O -53.556 1.00 53.95 LI N -53.266 1.00 55.76 LI C -52.086 1.00 57.25 LI C -51.657 1.00 59.84 LI C -50.417 1.00 60.88 LI C -49.254 1.00 63.31 LI C -48.887 1.00 65.05 LI N -54.478 1.00 55.79 LI C -54.992 1.00 56.34 LI O -54.927 1.00 55.98 LI N -56.032 1.00 56.08 LI C -56.610 1.00 54.88 LI C -57.149 1.00 55.49 LI C -57.439 1.00 56.91 LI C -58.053 1.00 56.50 LI O -56.995 1.00 56.59 LI N -55.567 1.00 57.33 LI C -54.407 1.00 58.32 LI O -56.481 1.00 57.40 LI N -56.178 1.00 57.00 LI C -57.473 1.00 57.43 LI C -58.263 1.00 58.48 LI O -55.233 1.00 56.38 LI C -54.322 1.00 57.23 LI O -55.454 1.00 54.81 LI N -54.613 1.00 52.81 LI C -55.356 1.00 53.01 LI C -55.848 1.00 54.06 LI C -55.364 1.00 54.19 LI O -56.816 1.00 54.46 LI N -53.298 1.00 52.76 LI C -52.540 1.00 51.62 LI O -53.042 1.00 52.25 LI N -51.788 1.00 50.29 LI C -50.615 1.00 53.67 LI C -50.488 1.00 55.99 LI C -50.091 1.00 58.37 LI O -50.830 1.00 56.42 LI N -51.654 1.00 48.00 . LI C -50.611 1.00 45.22 LI O -52.709 1.00 46.20 LI N -52.844 1.00 45.58 LI C 479 WO 2009/026558 PCT/US2008/074097 ATOM 4422 CB LYS 175 -38.486 38 ATOM 4423 CG LYS 175 -39.801 39 ATOM 4424 CD LYS 175 -40.991 38 ATOM 4425 CE LYS 175 -42.325 38 ATOM 4426 NZ LYS 175 -42.567 40 ATOM 4427 C LYS 175 -36.095 37 ATOM 4428 O LYS 175 -35.042 38 ATOM 4429 N TYR 176 -36.229 36 ATOM 4430 CA TYR 176 -35.092 35 ATOM 4431 CB TYR 176 -34.766 34 ATOM 4432 CG TYR 176 -34.098 35 ATOM 4433 CDl TYR 176 -32.771 34 ATOM 4434 CEl TYR 176 -32.160 35 ATOM 4435 CD2 TYR 176 -34.799 36 ATOM 4436 CE2 TYR 176 -34.193 36 ATOM 4437 CZ TYR 176 -32.871 36 ATOM 4438 OH TYR 176 -32.247 36 ATOM 4439 C TYR 176 -35.296 34 ATOM 4440 O TYR 176 -36.421 34 ATOM 4441 N ALA 177 -34.186 34 ATOM 4442 CA ALA 177 -34.201 33 ATOM 4443 CB ALA 177 -33.844 34 ATOM 4444 C ALA 177 -33.212 32 ATOM 4445 O ALA 177 -32.246 32 ATOM 4446 N ALA 178 -33.459 31 ATOM 4447 CA ALA 178 -32.601 30 ATOM 4448 CB ALA 178 -33.021 29 ATOM 4449 C ALA 178 -32.690 29 ATOM 4450 O ALA 178 -33.667 29 ATOM 4451 N SER 179 -31.662 29 ATOM 4452 CA SER 179 -31.650 28 ATOM 4453 CB SER 179 -30.569 28 ATOM 4454 OG SER 179 -30.847 30 ATOM 4455 C SER 179 -31.395 26 ATOM 4456 O SER 179 -30.626 26 ATOM 4457 N SER 180 -32.050 25 ATOM 4458 CA SER 180 -31.746 24 ATOM 4459 CB SER 180 -32.836 23 ATOM 4460 OG SER 180 -32.458 22 ATOM 4461 C SER 180 -31.637 23 ATOM 4462 O SER 180 -32.556 24 ATOM 4463 N TYR 181 -30.505 23 ATOM 4464 CA TYR 181 -30.283 22 ATOM 4465 CB TYR 181 -28.971 23 ATOM 4466 CG TYR 181 -28.972 24 ATOM 4467 CDl TYR 181 -28.789 25 ATOM 4468 CEl TYR 181 -28.756 27 ATOM 4469 CD2 TYR 181 -29.127 25 ATOM 4470 CE2 TYR 181 -29.096 26 ATOM 4471 CZ TYR 181 -28.908 27 ATOM 4472 OH TYR 181 -28.850 28 ATOM 4473 C TYR 181 -30.244 21 ATOM 4474 0 TYR 181 -29.520 20 ATOM 4475 N LEU 182 -31.030 20 ATOM 4476 CA LEU 182 -30.982 19 ATOM 4477 CB LEU 182 -32.388 18. ATOM 4478 CG LEU 182 -32.470 17 ATOM 4479 CDl LEU 182 -31.428 16 ATOM 4480 CD2 LEU 182 -33.870 16 ATOM 4481 C LEU 182 -30.351 18 ATOM 4482 O LEU 182 -30.884 19 ATOM 4483 N SER 183 -29.214 18 ATOM 4484 CA SER 183 -28.553 17 ATOM 4485 CB SER 183 -27.033 17 ATOM 4486 OG SER 183 -26.626 19 ATOM 4487 C SER 183 -28.937 16 ATOM 4488 O SER 183 -28.869 15 ATOM 4489 N LEU 184 -29.353 15 ATOM 4490 CA LEU 184 -29.605 14 ATOM 4491 CB LEU 184 -31.074 14 ATOM 4 4 92 CG LEU 184 -32.149 15 ATOM 4493 CDl LEU 184 -32.186 15 ATOM 4494 CD2 LEU 184 -33.496 14 ATOM 4495 C LEU 184 -29.243 14 ATOM 4496 O LEU 184 -29.060 15 ATOM 4497 N THR 185 -29.124 13
-53. .819 1. , 00 44 , .39 LI C -53 , .348 1. .00 44 . .61 LI c -54 . .048 1. , 00 44 . .52 LI c -53. .593 1. .00 44 , . 60 LI c -54 , .117 1. .00 43. .73 LI N -53. .359 1. .00 46, . 51 LI C -53 , . 590 1. .00 46. . 31 LI 0 -53. . 535 1. .00 47 . .57 LI N -53 , . 940 1. , 00 49. .06 LI C -52 . .847 1. .00 47 , .73 LI C -51. .631 1. . 00 48 . .77 LI C -51. .345 1. .00 49, . 57 LI C -50, .210 1. .00 51. . 42 LI C -50. .743 1. .00 48 . . 10 LI C -49. .600 1. .00 48 . .23 LI C -49. .339 1. .00 50. .96 LI C -48 . .202 1. .00 51. . 85 LI 0 -55 . .260 1, . 00 50. .28 LI C -55 , . 648 1. .00 50, .45 LI 0 -55 , . 937 1, . 00 50, . 51 LI N -57 , . 170 1. .00 52 . .09 LI C -58 . .352 1. .00 50, .29 LI C -57 . .074 1. , 00 53. . 43 LI C -56. .307 1, . 00 52 . .69 LI 0 -57, . 861 1. .00 54 . .62 LI N -57 . .875 1, . 00 55 . .83 LI C -56. .773 1. .00 55 . .75 LI C -59, .230 1, . 00 56. . 94 LI C -59. .958 1, . 00 56. .28 LI 0 -59. .563 1. , 00 58 . .47 LI N -60. .800 1, . 00 59, .49 LI C -61. .742 1. .00 58 . .95 LI C -62. . 130 1. .00 60, .29 LI 0 -60, . 520 1. .00 60. .01 LI C -59. . 625 1. .00 60. .02 LI 0 -61. .290 1. .00 60, . 42 LI N -61. .264 1. , 00 61. .35 LI C -60, . 509 1. , 00 60, . 80 LI C -60. .306 1. , 00 59. .95 LI 0 -62 , . 690 1. , 00 62, . 30 LI C -63. .4 93 1, . 00 61. . 67 LI 0 -63. .003 1, . 00 63. .90 LI N -64 , . 332 1. .00 64 . .83 LI C -64 .904 1. .00 63. .82 LI C -65. . 154 1. .00 64 . .75 LI C -64 .112 1. , 00 64 , . 15 LI C -64 , .346 1. .00 65 .10 LI C -66. .439 1. .00 63. .88 LI C -66. . 682 1. .00 63. .92 LI C -65. . 634 1. .00 65. .26 LI C -65, . 881 1. .00 65. .71 Ll 0 -64 .290 1. .00 66. . 15 LI C -63. .486 1. .00 66, . 57 Ll 0 -65. . 152 1. , 00 67 . .55 Ll N -65. .284 1, . 00 69. .82 Ll C -65. . 181 1, . 00 69. .84 Ll C -65, .479 1, . 00 70. .75 Ll C -64 . . 653 1. , 00 70. .11 Ll C -65, . 179 1. .00 70. .49 Ll C -66. .613 1. .00 70. .96 Ll C -67 . . 683 1. , 00 71. . 15 Ll 0 -66. .536 1. .00 71. .50 Ll N -67 . .728 1. .00 71. .86 Ll C -67 , . 584 1. .00 71. .20 Ll C -67 , . 550 1. .00 70. .56 Ll 0 -67 , .964 1, . 00 72 . .44 Ll C -67 . .057 1, . 00 72 , .17 Ll 0 -69, . 188 1, . 00 73. .34 Ll N -69. .591 1, . 00 74 . .57 Ll C -69. .346 1, . 00 74 . .23 Ll C -69. .697 1. .00 73. .95 Ll C -71. . 194 1, . 00 74 . .22 Ll C -69. .211 1. .00 73. .72 . Ll C -71. .060 1. .00 75. .82 Ll C -71. .791 1. . 00 75 .56 Ll 0 -71. .489 1. .00 77 .26 Ll N 480 WO 2009/026558 PCT/US2008/074097 ATOM 4498 CA THR 185 -28.787 12 ATOM 4499 CB THR 185 -28.252 11 ATOM 4500 OG1 THR 185 -29.259 10 ATOM 4501 CG2 THR 185 -27.001 11 ATOM 4502 C THR 185 -30.023 12 ATOM 4503 O THR 185 -31.148 12 ATOM 4504 N PRO 186 -29.828 13 ATOM 4505 CD PRO 186 -28.522 13 ATOM 4506 CA PRO 186 -30.939 13 ATOM 4507 CB PRO 186 -30.240 14 ATOM 4508 CG PRO 186 -28.889 14 ATOM 4509 C PRO 186 -31.843 12 ATOM 4510 O PRO 186 -33.050 12 ATOM 4511 N GLU 187 -31.242 11 ATOM 4512 CA GLU 187 -31.967 10 ATOM 4513 CB GLU 187 -30.988 8 ATOM 4514 CG GLU 187 -29.896 8 ATOM 4515 CD GLU 187 -28.843 9 ATOM 4516 OE1 GLU 187 -28.057 9 ATOM 4517 OE2 GLU 187 -28.800 10 ATOM 4518 C GLU 187 -33.007 9 ATOM 4519 0 GLU 187 -34.201 9 ATOM 4520 N GLN 188 -32.551 9 ATOM 4521 CA GLN 188 -33.449 9 ATOM 4522 CB GLN 188 -32.645 9 ATOM 4523 CG GLN 188 -31.628 10 ATOM 4524 CD GLN 188 -30.730 10 ATOM 4525 OE1 GLN 188 -29.527 10 ATOM 4526 NE2 GLN 188 -31.312 9 ATOM 4527 C GLN 188 -34.415 10 ATOM 4528 0 GLN 188 -35.455 10 ATOM 4529 N TRP 189 -34.072 12 ATOM 4530 CA TRP 189 -34.980 13 ATOM 4531 CB TRP 189 -34.300 14 ATOM 4532 CG TRP 189 -35.253 15 ATOM 4533 CD2 TRP 189 -36.222 16 ATOM 4534 CE2 TRP 189 -36.888 17 ATOM 4535 CE3 TRP 189 -36.590 16 ATOM 4536 CDl TRP 189 -35.371 15 ATOM 4537 NEl TRP 189 -36.351 16 ATOM 4538 CZ2 TRP 189 -37.900 17 ATOM 4539 CZ3 TRP 189 -37.597 17 ATOM 4540 CH2 TRP 189 -38.239 17 ATOM 4541 C TRP 189 -36.256 12 ATOM 4542 O TRP 189 -37.366 13 ATOM 4543 N LYS 190 -36.086 12 ATOM 4544 CA LYS 190 -37.209 11 ATOM 4545 CB LYS 190 -36.711 11 ATOM 4546 CG LYS 190 -35.788 12 ATOM 4547 CD LYS 190 -36.571 13 ATOM 4548 CE LYS 190 -37.307 13 ATOM 4549 NZ LYS 190 -38.075 14 ATOM 4550 C LYS 190 -37.917 10 ATOM 4551 0 LYS 190 -39.079 10 ATOM 4552 N SER 191 -37.212 9 ATOM 4553 CA SER 191 -37.719 8 ATOM 4554 CB SER 191 -36.556 7 ATOM 4555 OG SER 191 -35.907 8 ATOM 4556 C SER 191 -38.728 8 ATOM 4557 O SER 191 -39.285 7 ATOM 4558 N HIS 192 -38.957 9 ATOM 4559 CA HIS 192 -39.911 9 ATOM 4560 CB HIS 192 -39.214 10 ATOM 4561 CG HIS 192 -38.255 9 ATOM 4562 CD2 HIS 192 -36.938 9 ATOM 4563 NDl HIS 192 -38.625 8 ATOM 4564 CEl HIS 192 -37.578 8 ATOM 4565 NE2 HIS 192 -36.541 8 ATOM 4566 C HIS 192 -41.093 10 ATOM 4567 0 HIS 192 -40.961 11 ATOM 4568 N ARG 193 -42.246 10 ATOM 4569 CA ARG 193 -43.456 11 ATOM 4570 CB ARG 193 -44.650 10 ATOM 4571 CG ARG 193 -45.282 9 ATOM 4572 CD ARG 193 -45.834 9 ATOM 4573 NE ARG 193 -46.143 8
-72.878 1.00 78.90 LI C -73.056 1.00 79.12 LI c -72.664 1.00 79.12 LI 0 -72.210 1.00 78.20 LI c -73.748 1.00 79.76 LI c -73.313 1.00 79.50 LI 0 -74.992 1.00 80.66 LI N -75.608 1.00 80.61 LI c -75.908 1.00 81.88 LI c -77.215 1.00 81.41 LI c -76.788 1.00 8 0.92 LI c -76.068 1.00 83.38 LI c -76.280 1.00 83.33 LI 0 -75.955 1.00 84.89 LI N -76.094 1.00 86.26 LI c -76.050 1.00 86.44 LI c -77.117 1.00 87.62 LI c -76.843 1.00 88.12 LI c -75.886 1.00 88.36 LI 0 -77.587 1.00 87.80 LI 0 -74.987 1.00 86.75 LI c -75.260 1.00 87.11 LI 0 -73.738 1.00 86.85 LI N -72.601 1.00 86.86 LI c -71.310 1.00 86.25 LI c -71.052 1.00 86.47 LI c -69.873 1.00 8 6.63 LI c -69.901 1.00 86.47 LI 0 -68.828 1.00 86.42 LI N -72.466 1.00 87.03 LI c -71.817 1.00 86.87 LI 0 -73.085 1.00 86.98 LI N -73.142 1.00 87.11 LI c -73.847 1.00 87.05 LI c -74.337 1.00 87.49 LI c -73.558 1.00 87.50 LI c -74.430 1.00 87.06 LI c -72.208 1.00 87.12 LI c -75.615 1.00 87.14 LI c -75.679 1.00 87.03 LI N -73.998 1.00 87.27 LI c -71.781 1.00 87.07 LI c -72.673 1.00 87.37 LI c -73.886 1.00 87.39 LI c -73.416 1.00 86.90 LI 0 -75.047 1.00 88.13 LI N -75.910 1.00 88.58 LI c -77.343 1.00 88.28 LI c -77.847 1.00 87.78 LI c -78.371 1.00 87.40 LI c -79.657 1.00 86.94 LI c -80.198 1.00 86.22 Ll N -75.423 1.00 88.94 LI c -75.756 1.00 88.78 Ll 0 -74.631 1.00 89.21 Ll N -74.213 1.00 89.73 Ll c -73.801 1.00 90.11 Ll c -72.639 1.00 90.61 Ll 0 -73.068 1.00 89.98 Ll c -72.645 1.00 89.77 Ll 0 -72.561 1.00 90.04 Ll N -71.474 1.00 89.79 Ll c -70.268 1.00 89.58 Ll c -69.569 1.00 89.63 Ll c -69.776 1.00 89.30 Ll c -68.506 1.00 89.88 Ll N -68.089 1.00 89.37 Ll c -68.843 1.00 89.09 Ll N -71.906 1.00 89.78 Ll C -72.785 1.00 89.72 Ll 0 -71.282 1.00 89.66 Ll N -71.583 1.00 89.47 Ll C -70.812 1.00 90.32 . Ll c -71.468 1.00 91.88 Ll c -72.836 1.00 93.71 ' Ll c -73.648 1.00 94.98 Ll N 481 WO 2009/026558 PCT/US2008/074097 ATOM 4574 cz ARG 193 -46.579 8 ATOM 4575 NHl ARG 193 -46.834 7 ATOM 4576 NH2 ARG 193 -46.761 10 ATOM 4577 C ARG 193 -43.300 12 ATOM 4578 0 ARG 193 -43.756 13 ATOM 4579 N SER 194 -42.658 13 ATOM 4580 CA SER 194 -42.402 14 ATOM 4581 CB SER 194 -43.723 15 ATOM 4582 OG SER 194 -44.394 14 ATOM 4583 C SER 194 -41.537 14 ATOM 4584 O SER 194 -41.534 13 ATOM 4585 N TYR 195 -40.803 15 ATOM 4586 CA TYR 195 -40.034 15 ATOM 4587 CB TYR 195 -38.584 16 ATOM 4588 CG TYR 195 -37.729 15 ATOM 4589 CD1 TYR 195 -36.938 14 ATOM 4590 CEl TYR 195 -36.145 13 ATOM 4591 CD2 TYR 195 -37.703 14 ATOM 4592 CE2 TYR 195 -36.911 13 ATOM 4593 CZ TYR 195 -36.134 12 ATOM 4594 OH TYR 195 -35.332 11 ATOM 4595 C TYR 195 -40.646 17 ATOM 4596 O TYR 195 -41.169 18 ATOM 4597 N SER 196 -40.576 17 ATOM 4598 CA SER 196 -41.152 18 ATOM 4599 CB SER 196 -42.303 17 ATOM 4600 OG SER 196 -43.396 17 ATOM 4601 C SER 196 -40.127 18 ATOM 4602 O SER 196 -39.337 17 ATOM 4603 N CYS 197 -40.153 19 ATOM 4604 CA CYS 197 -39.390 20 ATOM 4605 C CYS 197 -40.296 21 ATOM 4606 0 CYS 197 -41.221 21 ATOM 4607 CB CYS 197 -38.786 21 ATOM 4608 SG CYS 197 -37.815 22 ATOM 4609 N GLN 198 -40.027 20 ATOM 4610 CA GLN 198 -40.866 20 ATOM 4611 CB GLN 198 -41.277 19 ATOM 4612 CG GLN 198 -41.917 18 ATOM 4613 CD GLN 198 -42.165 16 ATOM 4614 OE1 GLN 198 -41.697 16 ATOM 4615 NE2 GLN 198 -42.903 16 ATOM 4616 C GLN 198 -40.140 21 ATOM 4617 0 GLN 198 -39.145 21 ATOM 4618 N VAL 199 -40.647 22 ATOM 4619 CA VAL 199 -40.060 23 ATOM 4 62 0 CB VAL 199 -39.894 25 ATOM 4 621 CGI VAL 199 -39.232 25 ATOM 4622 CG2 VAL 199 -39.072 24 ATOM 4623 C VAL 199 -40.942 23 ATOM 4 62 4 O VAL 199 -42.132 23 ATOM 4625 N THR 200 -40.359 23 ATOM 4 62 6 CA THR 200 -41.100 23 ATOM 4627 CB THR 200 -40.974 22 ATOM 4628 OG1 THR 200 -41.466 21 ATOM 4629 CG2 THR 200 -41.785 22 ATOM 4630 C THR 200 -40.611 24 ATOM 4631 O THR 200 -39.409 24 ATOM 4632 N HIS 201 -41.558 25 ATOM 4633 CA HIS 201 -41.251 26 ATOM 4634 CB HIS 201 -41.224 27 ATOM 4635 CG HIS 201 -41 .179 29 ATOM 4636 CD2 HIS 201 -40.135 29 ATOM 4637 ND1 HIS 201 -42.316 29 ATOM 4638 CEl HIS 201 -41.974 30 ATOM 4639 NE2 HIS 201 -40.657 31 ATOM 4640 C HIS 201 -42.299 26 ATOM 4641 0 HIS 201 -43.491 26 ATOM 4642 N GLU 203 -41.849 26 ATOM 4643 CA GLU 203 -42.749 27 ATOM 4644 CB GLU 203 -43.440 28 ATOM 4645 CG GLU 203 -42.490 29 ATOM 4646 CD GLU 203 -41.781 29 ATOM 4647 OE1 GLU 203 -40.533 29 ATOM 4648 OE2 GLU 203 -42.471 29 ATOM 4649 C GLU 203 -43.800 25 -74.904 1.00 95.50 LI C -75.570 1.00 95.39 LI N -75.492 1.00 95.47 LI N -71.251 1.00 88.54 LI C -72.004 1.00 88.43 LI O -70.121 1.00 87.52 LI N -69.707 1.00 85.86 LI C -69.446 1.00 85.32 LI C -68.318 1.00 83.93 LI 0 -68.450 1.00 84.95 LI c -67.643 1.00 84.18 LI 0 -68.298 1.00 83.96 LI N -67.085 1.00 82.58 LI c -67.439 1.00 82.92 LI c -67.748 1.00 83.66 LI c -66.765 1.00 83.87 LI c -67.042 1.00 84.28 LI c -69.023 1.00 83.62 LI c -69.311 1.00 83.74 LI c -68.317 1.00 84.20 LI c -68.600 1.00 84.08 LI 0 -66.300 1.00 81.49 LI c -66.886 1.00 81.16 LI 0 -64.973 1.00 80.07 LI N -64.106 1.00 78.68 LI c -63.284 1.00 79.05 LI c -64.113 1.00 80.30 LI 0 -63.159 1.00 77.25 LI c -62.530 1.00 76.71 LI 0 -63.063 1.00 75.59 LI N -62.046 1.00 73.09 LI c -60.876 1.00 72.59 LI c -61.020 1.00 72.65 LI 0 -62.628 1.00 71.16 LI c -61.416 1.00 69.32 LI s -59.718 1.00 71.96 LI N -58.542 1.00 71.74 LI c -57.952 1.00 73.01 LI c -58.954 1.00 74.84 LI c -58.373 1.00 76.39 LI c -57.277 1.00 75.67 LI 0 -59.107 1.00 77.19 LI N -57.479 1.00 70.00 LI c -56.905 1.00 70.10 LI 0 -57.217 1.00 67.33 LI N -56.210 1.00 64.63 LI c -56.750 1.00 63.62 LI c -55.700 1.00 62.58 LI c -58.029 1.00 62.84 LI c -54.969 1.00 63.15 LI c -55.059 1.00 62.70 LI 0 -53.810 1.00 62.14 LI N -52.558 1.00 62.84 LI c -51.712 1.00 63.21 LI c -52.461 1.00 63.77 LI 0 -50.429 1.00 62.81 LI c -51.732 1.00 62.22 LI c -51.559 1.00 62.43 LI 0 -51.229 1.00 61.86 LI N -50.481 1.00 61.76 LI c -51.428 1.00 61.02 LI c -50.729 1.00 59.75 LI c -50.306 1.00 59.40 LI c -50.415 1.00 59.04 LI N -49.830 1.00 58.23 LI c -49.752 1.00 58.22 LI N -49.398 1.00 62.27 LI C -49.690 1.00 62.33 LI 0 -48.149 1.00 63.08 LI N -47.009 1.00 64.31 LI C -47.050 1.00 64.10 LI c -46.933 1.00 64.37 LI c -45.593 1.00 66.35 . LI c -45.584 1.00 66.23 LI 0 -44.549 1.00 66.40 LI 0 -46.978 1.00 65.33 LI c 482 WO 2009/026558 PCT/US2008/074097 ATOM 4650 0 GLU 203 -44.909 26 ATOM 4651 N GLY 203 -43.448 24 ATOM 4652 CA GLY 203 -44.328 23 ATOM 4653 C GLY 203 -45.215 23 ATOM 4654 0 GLY 203 -45.869 22 ATOM 4655 N SER 204 -45.240 24 ATOM 4656 CA SER 204 -46.079 24 ATOM 4657 CB SER 204 -46.931 25 ATOM 4658 OG SER 204 -47.605 25 ATOM 4659 C SER 204 -45.237 24 ATOM 4660 O SER 204 -44.322 24 ATOM 4661 N THR 205 -45.555 23 ATOM 4662 CA THR 205 -44.801 22 ATOM 4663 CB THR 205 -44.781 21 ATOM 4664 OG1 THR 205 -44.142 20 ATOM 4665 CG2 THR 205 -44.031 21 ATOM 4666 C THR 205 -45.392 23 ATOM 4667 O THR 205 -46.586 23 ATOM 4668 N VAL 206 -44.548 24 ATOM 4669 CA VAL 206 -44.934 24 ATOM 4670 CB VAL 206 -44.562 26 ATOM 4671 CGI VAL 206 -44.947 26 ATOM 4672 CG2 VAL 206 -45.257 27 ATOM 4673 C VAL 206 -44.207 24 ATOM 4674 O VAL 206 -42.994 23 ATOM 4675 N GLU 207 -44.952 23 ATOM 4676 CA GLU 207 -44.438 22 ATOM 4677 CB GLU 207 -45.033 21 ATOM 4678 CG GLU 207 -44.608 20 ATOM 4679 CD GLU 207 -45.153 18 ATOM 4680 OE1 GLU 207 -45.501 18 ATOM 4681 OE2 GLU 207 -45.235 17 ATOM 4682 C GLU 207 -44.744 23 ATOM 4683 0 GLU 207 -45.837 23 ATOM 4684 N LYS 208 -43.765 22 ATOM 4685 CA LYS 208 -43.973 23 ATOM 4686 CB LYS 208 -43.289 24 ATOM 4687 CG LYS 208 -43.911 25 ATOM 4688 CD LYS 208 -45.400 25 ATOM 4689 CE LYS 208 -45.956 27 ATOM 4690 NZ LYS 208 -45.344 28 ATOM 4691 C LYS 208 -43.433 21 ATOM 4692 0 LYS 208 -42.413 21 ATOM 4693 N THR 209 -44 . 125 21 ATOM 4694 CA THR 209 -43.779 20 ATOM 4695 CB THR 209 -44.889 19 ATOM 4696 OG1 THR 209 -45.127 19 ATOM 4697 CG2 THR 209 -44.482 18 ATOM 4698 C THR 209 -43.566 20 ATOM 4699 O THR 209 -44.209 21 ATOM 4700 N VAL 210 -42.652 20 ATOM 4701 CA VAL 210 -42.468 20 ATOM 4702 CB VAL 210 -41.190 20 ATOM 4703 CGI VAL 210 -41.310 22 ATOM 4704 CG2 VAL 210 -39.970 20 ATOM 4705 C VAL 210 -42.372 18 ATOM 4706 O VAL 210 -41.880 17 ATOM 4707 N ALA 211 -42.851 18 ATOM 4708 CA ALA 211 -42.826 17 ATOM 4709 CB ALA 211 -44.206 17 ATOM 4710 C ALA 211 -41.785 17 ATOM 4711 0 ALA 211 -41.449 18 ATOM 4712 N PRO 212 -41.265 16 ATOM 4713 CD PRO 212 -41.685 14 ATOM 4714 CA PRO 212 -40.227 16 ATOM 4715 CB PRO 212 -39.882 14 ATOM 4716 CG PRO 212 -41.095 13 ATOM 4717 C PRO 212 -40.691 16 ATOM 4718 O PRO 212 -39.878 16 ATOM 4719 N THR 213 -42.005 16 ATOM 4720 CA THR 213 -42.600 16 ATOM 4721 CB THR 213 -44.081 16 ATOM 4722 OG1 THR 213 -44.792 17 ATOM 4723 CG2 THR 213 -44.195 15 ATOM 4724 C THR 213 -42.504 18 ATOM 4725 O THR 213 -41.782 19 -46.490 1.00 65.44 LI O -47.507 1.00 66.98 LI N -47.415 1.00 69.40 LI C -48.631 1.00 71.29 LI C -48.761 1.00 71.55 LI 0 -49.523 1.00 72.19 LI N -50.711 1.00 73.00 LI c -50.821 1.00 74.04 LI c -52.068 1.00 75.31 LI 0 -51.974 1.00 73.53 LI c -52.231 1.00 74.09 LI 0 -52.760 1.00 73.50 LI N -53.971 1.00 72.84 LI c -54.243 1.00 73.16 LI c -53.153 1.00 72.97 LI 0 -55.533 1.00 73.27 LI c -55.193 1.00 72.59 LI c -55.465 1.00 72.07 LI 0 -55.923 1.00 72.50 LI N -57.208 1.00 73.02 LI c -57.302 1.00 72.13 LI c -58.666 1.00 70.61 LI c -56.201 1.00 71.61 LI c -58.310 1.00 74.77 LI c -58.240 1.00 74.80 LI 0 -59.326 1.00 76.39 LI N -60.298 1.00 77.74 LI c -60.011 1.00 78.83 LI c -60.973 1.00 81.28 LI c -60.574 1.00 82.80 LI c -59.386 1.00 84.12 LI 0 -61.445 1.00 83.95 LI 0 -61.735 1.00 77.99 LI c -62.040 1.00 77.18 LI 0 -62.615 1.00 78.59 LI N -64.043 1.00 79.79 LI c -64.515 1.00 79.80 LI c -63.961 1.00 80.02 LI c -64.266 1.00 79.10 LI c -63.964 1.00 79.03 LI c -64.835 1.00 77.78 LI N -64.823 1.00 8 0.92 LI c -64.454 1.00 80.76 LI 0 -65.900 1.00 82.27 LI N -66.679 1.00 83.34 LI c -66.582 1.00 83.02 LI c -65.207 1.00 82.81 LI 0 -67.327 1.00 82.62 LI c -68.151 1.00 85.00 LI c -68.687 1.00 85.03 LI 0 -68.793 1.00 86.55 LI N -70.236 1.00 87.92 LI c -70.590 1.00 87.63 LI c -70.085 1.00 87.34 LI c -69.988 1.00 87.16 LI c -70.848 1.00 89.44 LI c -70.212 1.00 89.28 LI 0 -72.081 1.00 91.11 LI N -72.782 1.00 92.64 LI c -73.356 1.00 92.29 LI c -73.897 1.00 93.85 LI c -74.424 1.00 94.16 LI 0 -74.273 1.00 95.11 LI N -73.774 1.00 95.23 LI c -75.306 1.00 95.91 LI c -75.318 1.00 95.62 LI c -74.776 1.00 95.26 LI c -76.672 1.00 96.68 LI ' c -77.520 1.00 96.58 LI 0 -76.872 1.00 97.41 LI N -78.123 1.00 98.13 LI c -78.209 1.00 98.19 LI c -77.068 1.00 97.41 . LI 0 -78.248 1.00 98.19 LI c -78.277 1.00 98.77 LI c -77.474 1.00 99.20 LI 0 483 WO 2009/026558 PCT/US2008/074097 ATOM 4726 OXT THR 213 -43.142 19.057 -79.208 1.00 99.08 LI 0 TER 4727 THR 213 LI ATOM 4728 CB GLN 1 -10.333 41.335 -26.837 1.00 58.55 HI c ATOM 4729 CG GLN 1 -11.368 41.133 -27.931 1.00 61.95 HI c ATOM 4730 CD GLN 1 -12.786 41.172 -27.394 1.00 64.59 HI c ATOM 4731 OE1 GLN 1 -13.725 40.692 -28.034 1.00 66.92 HI .0 ATOM 4732 NE2 GLN 1 -12.949 41.749 -26.209 1.00 65.52 HI N ATOM 4733 C GLN 1 -8.067 40.598 -27.611 1.00 51.02 HI c ATOM 4734 0 GLN 1 -6.978 40.491 -27.047 1.00 50.88 HI 0 ATOM 4735 N GLN 1 -9.151 42.604 -28.597 1.00 56.41 HI N ATOM 4736 CA GLN 1 -8.969 41.799 -27.352 1.00 54.79 HI c ATOM 4737 N VAL 2 -8.528 39.693 -28.465 1.00 46.33 HI N ATOM 4738 CA VAL 2 -7.658 38.679 -29.042 1.00 40.97 HI C ATOM 4739 CB VAL 2 -8.026 37.266 -28.541 1.00 40.66 HI c ATOM 4740 CGI VAL 2 -7.187 36.223 -29.261 1.00 37.87 HI c ATOM 4741 CG2 VAL 2 -7.800 37.175 -27.041 1.00 39.09 HI c ATOM 4742 C VAL 2 -7.831 38.737 -30.551 1.00 40.14 HI c ATOM 4743 O VAL 2 -8.948 38.863 -31.050 1.00 39.38 HI 0 ATOM 4744 N GLN 3 -6.730 38.672 -31.285 1.00 38.15 HI N ATOM 4745 CA GLN 3 -6.836 38.657 -32.733 1.00 37.80 HI c ATOM 4746 CB GLN 3 -6.288 39.951 -33.340 1.00 41.11 HI c ATOM 4747 CG GLN 3 -6.598 40.078 -34.830 1.00 48.63 HI c ATOM 4748 CD GLN 3 -5.966 41.299 -35.480 1.00 54.48 HI c ATOM 4749 OE1 GLN 3 -5.933 41.412 -36.710 1.00 56.23 HI 0 ATOM 4750 NE2 GLN 3 -5.461 42.221 -34.658 1.00 55.22 HI N ATOM 4751 C GLN 3 -6.097 37.475 -33.315 1.00 34.51 HI c ATOM 4752 0 GLN 3 -4.950 37.209 -32.960 1.00 34.76 HI 0 ATOM 4753 N LEU 4 -6.774 36.764 -34.206 1.00 31.16 HI N ATOM 4754 CA LEU 4 -6.152 35.706 -34.983 1.00 30.62 HI c ATOM 4755 CB LEU 4 -7.036 34.455 -34.966 1.00 26.45 HI c ATOM 4756 CG LEU 4 -6.920 33.556 -33.728 1.00 27.80 HI c ATOM 4757 CDl LEU 4 -7.145 34.374 -32.449 1.00 25.47 HI c ATOM 4758 CD2 LEU 4 -7.930 32.423 -33.831 1.00 26.22 HI c ATOM 4759 C LEU 4 -5.943 36.200 -36.419 1.00 32.23 HI c ATOM 4760 O LEU 4 -6.899 36.554 -37.120 1.00 31.55 HI 0 ATOM 4761 N GLN 5 -4.683 36.229 -36.840 1.00 31.02 HI N ATOM 4762 CA GLN 5 -4.307 36.758 -38.144 1.00 31.99 HI c ATOM 4763 CB GLN 5 -3.168 37.772 -37.976 1.00 35.77 HI c ATOM 4764 CG GLN 5 -2.719 38.446 -39.262 1.00 41.14 HI c ATOM 4765 CD GLN 5 -3.830 39.250 -39.904 1.00 45.66 HI c ATOM 4766 OE1 GLN 5 -3.749 39.625 -41.073 1.00 48.29 HI 0 ATOM 4767 NE2 GLN 5 -4.881 39.519 -39.137 1.00 48.64 HI N ATOM 4768 C GLN 5 -3.863 35.614 -39.050 1.00 29.87 HI c ATOM 4769 0 GLN 5 -2.974 34.842 -38.690 1.00 31.50 HI 0 ATOM 4770 N GLN 6 -4.482 35.509 -40.221 1.00 28.29 HI N ATOM 4771 CA GLN 6 -4.243 34.377 -41.117 1.00 30.55 HI c ATOM 4772 CB GLN 6 -5.564 33.740 -41.540 1.00 29.81 HI c ATOM 4773 CG GLN 6 -6.344 33.071 -40.433 1.00 30.43 HI c ATOM 4774 CD GLN 6 -7.562 32.345 -40.972 1.00 28.63 HI c ATOM 4775 OE1 GLN 6 -8.691 32.631 -40.580 1.00 30.41 HI 0 ATOM 4776 NE2 GLN 6 -7.336 31.408 -41.882 1.00 26.47 HI N ATOM 4777 C GLN 6 -3.511 34.800 -42.376 1.00 30.75 HI c ATOM 4778 0 GLN 6 -3.696 35.916 -42.858 1.00 32.04 HI 0 ATOM 4779 N TRP 7 -2.695 33.904 -42.918 1.00 28.95 HI N ATOM 4780 CA TRP 7 -2.211 34.076 -44.278 1.00 28.90 HI c ATOM 4781 CB TRP 7 -0.966 34.976 -44.301 1.00 2 8.68 HI c ATOM 4782 CG TRP 7 0.236 34.402 -43.598 1.00 27.66 HI c ATOM 4783 CD2 TRP 7 0.704 34.740 -42.286 1.00 25.98 HI c ATOM 4784 CE2 TRP 7 1.888 34.010 -42.063 1.00 27.69 HI c ATOM 4785 CE3 TRP 7 0.238 35.594 -41.282 1.00 26.98 HI c ATOM 4786 CDl TRP 7 1.128 33.499 -44.101 1.00 27.44 HI c ATOM 4787 NEl TRP 7 2.126 33.258 -43.185 1.00 28.36 HI N ATOM 4788 CZ2 TRP 7 2.612 34.109 -40.880 1.00 28.83 HI c ATOM 4789 CZ3 TRP 7 0.956 35.692 -40.111 1.00 28.53 HI c ATOM 4790 CH2 TRP 7 2.132 34.955 -39.917 1.00 30.19 HI c ATOM 4791 C TRP 7 -1.899 32.733 -44.923 1.00 28.22 HI c ATOM 4792 O TRP 7 -2.070 31.681 -44.307 1.00 28.99 HI 0 ATOM 4793 N GLY 8 -1.432 32.783 -46.166 1.00 28.35 HI N ATOM 4794 CA GLY 8 -1.234 31.575 -46.945 1.00 26.37 HI c ATOM 4795 C GLY 8 -1.920 31.683 -48.295 1.00 27.33 HI c ATOM 4796 0 GLY 8 -2.925 32.386 -48.444 1.00 27.76 HI 0 ATOM 4797 N ALA 9 -1.377 30.984 -49.282 1.00 27.19 HI N ATOM 4798 CA ALA 9 -1.887 31.057 -50.646 1.00 28.12 . HI c ATOM 4799 CB ALA 9 -0.828 30.527 -51.619 1.00 2 7.62 HI c ATOM 4800 C ALA 9 -3.179 30.253 -50.791 1.00 28.31 HI c ATOM 4801 O ALA 9 -3.233 29.079 -50.431 1.00 28.12 HI 0 484 WO 2009/026558 PCT/US2008/074097 ATOM 4802 N GLY 10 -4.212 30.888 -51.330 1.00 29.12 HI N ATOM 4803 CA GLY 10 -5.493 30.222 -51.479 1.00 30.10 HI C ATOM 4804 C GLY 10 -5.820 29.691 -52.871 1.00 32.33 HI C ATOM 4805 0 GLY 10 -6.659 28.798 -53.005 1.00 32.38 HI 0 ATOM 4806 N LEU 11 -5.177 30.221 -53.909 1.00 31.52 HI N ATOM 4807 CA LEU 11 -5.494 29.799 -55.275 1.00 33.59 HI c ATOM 4808 CB LEU 11 -5.308 30.959 -56.255 1.00 36.39 HI c ATOM 4809 CG LEU 11 -5.584 30.620 -57.725 1.00 40.88 HI c ATOM 4810 CDl LEU 11 -6.969 29.990 -57.844 1.00 43.73 HI c ATOM 4811 CD2 LEU 11 -5.491 31.877 -58.586 1.00 40.70 HI c ATOM 4812 C LEU 11 -4.626 28.629 -55.697 1.00 34.18 HI c ATOM 4813 O LEU 11 -3.429 28.787 -55.936 1.00 35.52 HI 0 ATOM 4814 N LEU 12 -5.232 27.448 -55.785 1.00 34.06 HI N ATOM 4815 CA LEU 12 -4.470 26.219 -55.974 1.00 33.09 HI c ATOM 4816 CB LEU 12 -4.533 25.358 -54.711 1.00 34.00 HI c ATOM 4817 CG LEU 12 -4.079 25.990 -53.395 1.00 35.02 HI c ATOM 4818 CDl LEU 12 -4.057 24.931 -52.297 1.00 33.56 HI c ATOM 4819 CD2 LEU 12 -2.698 26.606 -53.580 1.00 36.04 HI c ATOM 4820 C LEU 12 -4.979 25.401 -57.147 1.00 33.61 HI c ATOM 4821 O LEU 12 -6.129 25.542 -57.566 1.00 34.76 HI 0 ATOM 4822 N LYS 13 -4.115 24.542 -57.671 1.00 33.61 HI N ATOM 4823 CA LYS 13 -4.533 23.537 -58.638 1.00 35.02 HI c ATOM 4824 CB LYS 13 -3.558 23.486 -59.813 1.00 35.86 HI c ATOM 4825 CG LYS 13 -3.544 24.732 -60.671 1.00 39.05 HI c ATOM 4826 CD LYS 13 -2.763 24.491 -61.952 0.50 41.55 HI c ATOM 4827 CE LYS 13 -2.408 25.800 -62.627 1.00 44.69 HI c ATOM 4828 NZ LYS 13 -1.530 26.633 -61.750 1.00 48.57 HI N ATOM 4829 C LYS 13 -4.584 22.171 -57.967 1.00 35.21 HI c ATOM 4830 0 LYS 13 -3.887 21.924 -56.983 1.00 37.52 HI 0 ATOM 4831 N PRO 14 -5.405 21.258 -58.499 1.00 34.61 HI N ATOM 4832 CD PRO 14 -6.318 21.454 -59.638 1.00 34.09 HI c ATOM 4833 CA PRO 14 -5.476 19.894 -57.969 1.00 34.50 HI c ATOM 4834 CB PRO 14 -6.368 19.169 -58.974 1.00 34.26 HI c ATOM 4835 CG PRO 14 -7.214 20.257 -59.557 1.00 33.95 HI c ATOM 4836 C PRO 14 -4.093 19.253 -57.854 1.00 34.86 HI c ATOM 4837 O PRO 14 -3.222 19.493 -58.690 1.00 35.81 HI 0 ATOM 4838 N SER 15 -3.914 18.455 -56.803 1.00 34.00 HI N ATOM 4839 CA SER 15 -2.684 17.718 -56.515 1.00 34.80 HI c ATOM 4840 CB SER 15 -1.999 17.245 -57.805 1.00 35.51 HI c ATOM 4841 OG SER 15 -1.036 18.192 -58 .234 1.00 38.11 HI 0 ATOM 4842 C SER 15 -1.694 18.534 -55.684 1.00 34.51 HI c ATOM 4843 O SER 15 -0.761 17.980 -55.099 1.00 35.24 HI 0 ATOM 4844 N GLU 16 -1.901 19.845 -55.622 1.00 34.15 HI N ATOM 4845 CA GLU 16 -1.018 20.705 -54.845 1.00 34.52 HI c ATOM 4846 CB GLU 16 -1.183 22.164 -55.283 1.00 36.08 HI c ATOM 4847 CG GLU 16 -0.552 22.478 -56.646 1.00 41.58 HI c ATOM 4848 CD GLU 16 -0.918 23.864 -57.160 1.00 44.69 HI c ATOM 4849 OE1 GLU 16 -1.573 24.626 -56.423 1.00 44.93 HI 0 ATOM 4850 OE2 GLU 16 -0.555 24.193 -58.309 1.00 4 9.52 HI 0 ATOM 4851 C GLU 16 -1.256 20.583 -53.338 1.00 34.67 HI c ATOM 4852 O GLU 16 -2.2 52 20.008 -52.898 1.00 32.76 HI 0 ATOM 4853 N THR 17 -0.319 21.120 -52.559 1.00 33.99 HI N ATOM 4854 CA THR 17 -0.421 21.165 -51.104 1.00 32.35 HI c ATOM 4855 CB THR 17 0.928 20.860 -50.447 1.00 31.91 HI c ATOM 4856 OG1 THR 17 1.289 19.505 -50.722 1.00 35.50 HI 0 ATOM 4857 CG2 THR 17 0.853 21.073 -48.940 1.00 31.69 HI c ATOM 4858 C THR 17 -0.867 22.539 -50.627 1.00 31.96 HI c ATOM 4859 O THR 17 -0.296 23.554 -51.024 1.00 31.96 HI 0 ATOM 4860 N LEU 18 -1.889 22.565 -49.774 1.00 2 9.65 HI N ATOM 4861 CA LEU 18 -2.355 23.812 -49.179 1.00 28.49 HI c ATOM 4 8 62 CB LEU 18 -3.841 23.720 -48.831 1.00 27.90 HI c ATOM 4863 CG LEU 18 -4.387 24.865 -47.973 1.00 27.75 HI c ATOM 4864 CDl LEU 18 -4.433 26.133 -48.808 1.00 28.48 HI c ATOM 4865 CD2 LEU 18 -5.784 24.520 -47.467 1.00 27.32 HI c ATOM 4866 C LEU 18 -1.557 24.086 -47.914 1.00 29.31 HI c ATOM 4867 O LEU 18 -1.324 23.183 -47.105 1.00 29.34 HI 0 ATOM 4868 N SER 19 -1.138 25.332 -47.740 1.00 28.71 HI N ATOM 4869 CA SER 19 -0.342 25.693 -46.580 1.00 28.95 HI c ATOM 4870 CB SER 19 1.136 25.745 -46.969 1.00 29.72 HI c ATOM 4871 OG SER 19 1.927 26.134 -45.861 1.00 37.84 HI 0 ATOM 4872 C SER 19 -0.790 27.032 -46.000 1.00 28.99 HI c ATOM 4873 O SER 19 -0.614 28.084 -46.611 1.00 30.84 HI 0 ATOM 4874 N LEU 20 -1.384 26.985 -44.814 1.00 28.20 . HI N ATOM 4875 CA LEU 20 -1.932 28.179 -44.193 1.00 26.04 HI c ATOM 4876 CB LEU 20 -3.447 28.056 -44.050 1.00 25.36 HI c ATOM 4877 CG LEU 20 -4.265 27.889 -45.334 1.00 26.53 HI c 485 WO 2009/026558 PCT/US2008/074097 ATOM 4878 CDl LEU 20 -5.744 27 ATOM 4879 CD2 LEU 20 -3.999 29 ATOM 4880 C LEU 20 -1.308 28 ATOM 4881 O LEU 20 -0.850 27 ATOM 4882 N THR 21 -1.299 29 ATOM 4883 CA THR 21 -0.685 29 ATOM 4884 CB THR 21 0.691 30 ATOM 4885 OG1 THR 21 1.536 29 ATOM 4886 CG2 THR 21 1.348 30 ATOM 4887 C THR 21 -1.599 30 ATOM 4888 O THR 21 -2.294 31 ATOM 4889 N CYS 22 -1.606 30 ATOM 4890 CA CYS 22 -2.393 31 ATOM 4891 C CYS 22 -1.469 32 ATOM 4892 0 CYS 22 -0.752 31 ATOM 4893 CB CYS 22 -3.564 30 ATOM 4894 SG CYS 22 -4.786 31 ATOM 4895 N ALA 23 -1.481 33 ATOM 4896 CA ALA 23 -0.725 34 ATOM 4897 CB ALA 23 0.187 35 ATOM 4898 C ALA 23 -1.684 34 ATOM 4899 O ALA 23 -2.677 35 ATOM 4900 N VAL 24 -1.375 34 ATOM 4901 CA VAL 24 -2.243 34 ATOM 4902 CB VAL 24 -2.415 33 ATOM 4903 CGI VAL 24 -3.211 34 ATOM 4904 CG2 VAL 24 -3.112 32 ATOM 4905 C VAL 24 -1.708 36 ATOM 4906 O VAL 24 -0.566 36 ATOM 4907 N TYR 25 -2.543 37 ATOM 4908 CA TYR 25 -2.175 38 ATOM 4909 CB TYR 25 -2.177 39 ATOM 4910 CG TYR 25 -1.229 39 ATOM 4911 CDl TYR 25 -1.704 39 ATOM 4912 CEl TYR 25 -0.838 38 ATOM 4913 CD2 TYR 25 0 . 144 39 ATOM 4914 CE2 TYR 25 1.020 39 ATOM 4915 CZ TYR 25 0.523 38 ATOM 4916 OH TYR 25 1.389 38 ATOM 4917 C TYR 25 -3.129 38 ATOM 4918 O TYR 25 -4.289 38 ATOM 4919 N GLY 26 -2.637 38 ATOM 4920 CA GLY 26 -3.465 38 ATOM 4921 C GLY 26 -3.828 37 ATOM 4922 0 GLY 26 -3.801 36 ATOM 4923 N GLY 27 -4.167 37 ATOM 4924 CA GLY 27 -4.515 36 ATOM 4 92 5 C GLY 27 -3.347 35 ATOM 4 92 6 0 GLY 27 -2.258 35 ATOM 4927 N SER 28 -3.570 34 ATOM 4 92 8 CA SER 28 -2.546 33 ATOM 4 92 9 CB SER 28 -2.782 32 ATOM 4930 OG SER 28 -2.050 31 ATOM 4931 C SER 28 -2.535 32 ATOM 4932 O SER 28 -3.569 32 ATOM 4933 N PHE 29 -1.365 31 ATOM 4934 CA PHE 29 -1.246 30 ATOM 4935 CB PHE 29 0.048 31 ATOM 4936 CG PHE 29 0.202 30 ATOM 4937 CDl PHE 29 -0.550 30 ATOM 4938 CD2 PHE 29 1.081 29 ATOM 4939 CEl PHE 29 -0.431 29 ATOM 4940 CE2 PHE 29 1.205 28 ATOM 4941 CZ PHE 29 0.452 28 ATOM 4942 C PHE 29 -1.260 29 ATOM 4943 O PHE 29 -1.893 28 ATOM 4944 N SER 30 -0.566 29 ATOM 4945 CA SER 30 -0.390 27 ATOM 4946 CB SER 30 0.850 27 ATOM 4947 OG SER 30 0.687 28 ATOM 4948 C SER 30 -1.612 27 ATOM 4949 O SER 30 -1.699 26 ATOM 4950 N ALA 31 -2.558 28 ATOM 4951 CA ALA 31 -3.706 27 ATOM 4952 CB ALA 31 -4.175 28 ATOM 4953 C ALA 31 -4.888 27 -44.970 1.00 23.87 HI c -46.288 1.00 25.15 HI c -42.825 1.00 25.77 HI c -42.197 1.00 26.14 HI 0 -42.365 1.00 26.29 HI N -41.093 1.00 27.57 HI _c -41.314 1.00 28.87 HI c -42.072 1.00 30.29 HI 0 -39.988 1.00 26.32 HI c -40.332 1.00 27.47 HI c -40.930 1.00 26.74 HI 0 -39.011 1.00 28.77 HI N -38.175 1.00 2 9.72 HI c -37.082 1.00 30.55 HI c -36.456 1.00 30.73 HI 0 -37.565 1.00 30.30 HI c -36.524 1.00 31.82 HI s -36.864 1.00 29.76 HI N -35.771 1.00 31.19 HI c -36.298 1.00 31.06 HI c -34.732 1.00 29.91 HI c -35.075 1.00 29.39 HI 0 -33.462 1.00 29.49 HI N -32.375 1.00 2 9.62 HI c -31.352 1.00 28.75 HI c -30.149 1.00 28.80 HI c -32.015 1.00 26.06 HI c -31.663 1.00 31.01 HI c -31.206 1.00 32.54 HI 0 -31.567 1.00 31.55 HI N -30.848 1.00 32.59 HI c -31.807 1.00 34.98 HI c -32.968 1.00 36.34 HI c -34.236 1.00 37.36 HI c -35.297 1.00 40.15 HI c -32.788 1.00 38.49 HI c -33.843 1.00 40.50 HI c -35.093 1.00 40.26 HI c -36.142 1.00 44.41 HI 0 -29.689 1.00 32.47 HI c -29.896 1.00 32.98 HI 0 -28.468 1.00 31.79 HI N -27.296 1.00 32.41 HI c -26.537 1.00 32.65 HI c -27.093 1.00 31.74 HI 0 -25.259 1.00 32.32 HI N -24.431 1.00 30.56 HI c -24.311 1.00 31.96 HI c -24.791 1.00 33.98 HI 0 -23.677 1.00 31.00 HI N -23.580 1.00 29.78 HI c -22.340 1.00 27.61 HI c -22.424 1.00 29.12 HI 0 -24.815 1.00 29.77 HI c -25.442 1.00 31.74 HI 0 -25.153 1.00 28.60 HI N -26.301 1.00 28.86 HI c -27.077 1.00 28.06 HI c -28.307 1.00 2 6.67 HI c -29.436 1.00 28.66 HI c -28.327 1.00 27.57 HI c -30.559 1.00 29.40 HI c -29.442 1.00 27.25 HI c -30.560 1.00 28.48 HI c -25.851 1.00 28.91 HI c -26.483 1.00 31.89 HI 0 -24.755 1.00 27.90 HI N -24.311 1.00 29.14 HI c -23.418 1.00 31.78 HI c -22.221 1.00 36.30 HI 0 -23.574 1.00 27.44 HI c -23.340 1.00 26.60 HI 0 -23.227 1.00 27.53 . HI N -22.413 1.00 27.10 HI c -21.580 1.00 23.65 HI c -23.211 1.00 27.46 HI c 486 WO 2009/026558 PCT/US2008/074097 ATOM 4954 O ALA 31 -5.917 ATOM 4955 N TYR 32 -4.743 ATOM 4956 CA TYR 32 -5.864 ATOM 4957 CB TYR 32 -6.393 ATOM 4958 CG TYR 32 -6.878 ATOM 4959 CD1 TYR 32 -6.062 ATOM 4960 CE1 TYR 32 -6.510 ATOM 4961 CD2 TYR 32 -8.161 ATOM 4962 CE2 TYR 32 -8.616 ATOM 4963 CZ TYR 32 -7.790 ATOM 4964 OH TYR 32 -8.250 ATOM 4965 C TYR 32 -5.486 ATOM 4966 O TYR 32 -4.327 ATOM 4967 N TYR 33 -6.471 ATOM 4968 CA TYR 33 -6.348 ATOM 4969 CB TYR 33 -7.374 ATOM 4970 CG TYR 33 -7.016 ATOM 4971 CD1 TYR 33 -6.239 ATOM 4972 CE1 TYR 33 -5.886 ATOM 4973 CD2 TYR 33 -7.440 ATOM 4974 CE2 TYR 33 -7.092 ATOM 4975 CZ TYR 33 -6.311 ATOM 4976 OH TYR 33 -5.941 ATOM 4977 C TYR 33 -6.554 ATOM 4978 O TYR 33 -7.292 ATOM 4979 N TRP 34 -5.887 ATOM 4980 CA TRP 34 -6.012 ATOM 4981 CB TRP 34 -4.650 ATOM 4982 CG TRP 34 -4.247 ATOM 4983 CD2 TRP 34 -4.745 ATOM 4984 CE2 TRP 34 -4.165 ATOM 4985 CE3 TRP 34 -5.629 ATOM 4986 CD1 TRP 34 -3.402 ATOM 4987 NE1 TRP 34 -3.347 ATOM 4988 CZ2 TRP 34 -4.442 ATOM 4989 CZ3 TRP 34 -5.900 ATOM 4990 CH2 TRP 34 -5.309 ATOM 4991 C TRP 34 -6.530 ATOM 4992 O TRP 34 -5.988 ATOM 4993 N ASN 35 -7.578 ATOM 4994 CA ASN 35 -8.355 ATOM 4995 CB ASN 35 -9.841 ATOM 4996 CG ASN 35 -10.101 ATOM 4997 OD1 ASN 35 -10.302 ATOM 4998 ND2 ASN 35 -10.099 ATOM 4999 C ASN 35 -8.236 ATOM 5000 O ASN 35 -8.048 ATOM 5001 N TRP 36 -8.377 ATOM 5002 CA TRP 36 -8.702 ATOM 5003 CB TRP 36 -7.658 ATOM 5004 CG TRP 36 -6.318 ATOM 5005 CD2 TRP 36 -5.956 ATOM 5006 CE2 TRP 36 -4.612 ATOM 5007 CE3 TRP 36 -6.639 ATOM 5008 CD1 TRP 36 -5.208 ATOM 5009 NE1 TRP 36 -4.179 ATOM 5010 CZ2 TRP 36 -3.933 ATOM 5011 CZ3 TRP 36 -5.968 ATOM 5012 CH2 TRP 36 -4.627 ATOM 5013 C TRP 36 -10.087 ATOM 5014 O TRP 36 -10.434 ATOM 5015 N ILE 37 -10.871 ATOM 5016 CA ILE 37 -12.244 ATOM 5017 CB ILE 37 -13.232 ATOM 5018 CG2 ILE 37 -14.669 ATOM 5019 CGI ILE 37 -13.024 ATOM 5020 CD1 ILE 37 -13.704 ATOM 5021 C ILE 37 -12.445 ATOM 5022 O ILE 37 -11.964 ATOM 5023 N ARG 38 -13.134 ATOM 5024 CA ARG 38 -13.417 ATOM 5025 CB ARG 38 -12.680 ATOM 5026 CG ARG 38 -13.113 ATOM 5027 CD ARG 38 -12.272 ATOM 5028 NE ARG 38 -12.792 ATOM 5029 CZ ARG 38 -12.283 -22.633 1.00 28.90 HI 0 -24.527 1.00 26.48 HI N -25.396 1.00 25.86 HI C -26.132 1.00 24.51 HI c -25.223 1.00 27.00 HI c -24.912 1.00 27.70 HI c -24.086 1.00 27.16 HI c -24.681 1.00 25.53 HI c -23.857 1.00 25.30 HI c -23.564 1.00 2 6.69 HI c -22.771 1.00 28.27 HI 0 -26.440 1.00 24.12 HI c -26.856 1.00 24.09 HI 0 -26.887 1.00 22.70 HI N -28.173 1.00 22.68 HI c -28.298 1.00 22.31 HI c -27.492 1.00 21.33 HI c -28.042 1.00 20.79 HI c -27.311 1.00 22.09 HI c -26.173 1.00 22.16 HI c -25.429 1.00 23.42 HI c -26.010 1.00 23.95 HI c -25.298 1.00 23.94 HI 0 -29.299 1.00 22.45 HI c -29.155 1.00 22.76 HI 0 -30.417 1.00 22.98 HI N -31.582 1.00 23.60 HI c -31.885 1.00 23.80 HI c -30.790 1.00 23.49 HI c -30.577 1.00 22.41 HI c -29.385 1.00 25.04 HI c -31.280 1.00 23.05 HI c -29.752 1.00 24.44 HI c -28.900 1.00 23.72 HI N -28.879 1.00 21.78 HI c -30.777 1.00 21.48 HI c -29.587 1.00 22.95 HI c -32.766 1.00 21.45 HI c -33.070 1.00 21.93 HI 0 -33.420 1.00 19.88 HI N -34.392 1.00 20.46 HI c -34.021 1.00 20.89 HI c -32.627 1.00 23.23 HI c -32.428 1.00 24.03 HI 0 -31.650 1.00 22.85 HI N -35.810 1.00 20.87 HI c -36.019 1.00 23.07 HI 0 -36.782 1.00 22.36 HI N -38.152 1.00 22.05 HI c -39.121 1.00 22.90 HI c -39.025 1.00 25.04 HI c -39.619 1.00 22.07 HI c -39.284 1.00 24.03 HI c -40.403 1.00 22.32 HI c -38.370 1.00 20.33 HI c -38.521 1.00 23.82 HI N -39.706 1.00 23.84 HI c -40.821 1.00 24.79 HI c -40.471 1.00 24.85 HI c -38.517 1.00 22.80 HI c -38.193 1.00 21.90 HI 0 -39.187 1.00 22.71 HI N -39.554 1.00 21.18 HI c -38.591 1.00 22.23 HI c -39.039 1.00 20.06 HI c -37.171 1.00 21.40 HI c -36.102 1.00 2 0.52 HI c -40.966 1.00 23.40 HI “ c -41.285 1.00 23.50 HI 0 -41.827 1.00 22.17 HI N -43.151 1.00 23.30 HI c -44.237 1.00 22.10 HI c -44.372 1.00 24.22 . HI c -45.418 1.00 23.06 HI c -45.694 1.00 23.01 HI N -46.587 1.00 22.72 HI c 487 WO 2009/026558 PCT/US2008/074097 ATOM 5030 NHl ARG 38 -11.212 ATOM 5031 NH2 ARG 38 -12.875 ATOM 5032 C ARG 38 -14.906 ATOM 5033 O ARG 38 -15.720 ATOM 5034 N GLN 39 -15.256 ATOM 5035 CA GLN 39 -16.638 ATOM 5036 CB GLN 39 -17.224 ATOM 5037 CG GLN 39 -18.684 ATOM 5038 CD GLN 39 -19.318 ATOM 5039 OE1 GLN 39 -18.788 ATOM 5040 NE2 GLN 39 -20.447 ATOM 5041 C GLN 39 -16.690 ATOM 5042 0 GLN 39 -16.266 ATOM 5043 N PRO 40 -17.213 ATOM 5044 CD PRO 40 -17.750 ATOM 5045 CA PRO 40 -17.377 ATOM 5046 CB PRO 40 -17.779 ATOM 5047 CG PRO 40 -18.437 ATOM 5048 C PRO 40 -18.448 ATOM 5049 O PRO 40 -19.359 ATOM 5050 N PRO 41 -18.345 ATOM 5051 CD PRO 41 -17.406 ATOM 5052 CA PRO 41 -19.204 ATOM 5053 CB PRO 41 -18.839 ATOM 5054 CG PRO 41 -17.449 ATOM 5055 C PRO 41 -20.687 ATOM 5056 O PRO 41 -21.165 ATOM 5057 N GLY 42 -21.406 ATOM 5058 CA GLY 42 -22.837 ATOM 5059 C GLY 42 -23.227 ATOM 5060 0 GLY 42 -24.360 ATOM 5061 N LYS 43 -22.297 ATOM 5062 CA LYS 43 -22.551 ATOM 5063 CB LYS 43 -21.778 ATOM 5064 CG LYS 43 -22.140 ATOM 5065 CD LYS 43 -22.254 ATOM 50 66 CE LYS 43 -23.015 ATOM 5067 NZ LYS 43 -22.406 ATOM 5068 C LYS 43 -22.171 ATOM 5069 O LYS 43 -21.889 ATOM 5070 N GLY 44 -22.160 ATOM 5071 CA GLY 44 -21.927 ATOM 5072 C GLY 44 -20.473 ATOM 5073 0 GLY 44 -19.570 ATOM 5074 N LEU 45 -20.251 ATOM 5075 CA LEU 45 -18.938 ATOM 5076 CB LEU 45 -19.024 ATOM 5077 CG LEU 45 -19.498 ATOM 5078 CDl LEU 45 -19.692 ATOM 5079 CD2 LEU 45 -18.471 ATOM 5080 C LEU 45 -18.379 ATOM 5081 O LEU 45 -19.101 ATOM 5082 N GLU 46 -17.081 ATOM 5083 CA GLU 46 -16.397 ATOM 5084 CB GLU 46 -16.060 ATOM 5085 CG GLU 46 -15.392 ATOM 5086 CD GLU 46 -15.117 ATOM 5087 OE1 GLU 46 -15.068 ATOM 5088 OE2 GLU 46 -14.947 ATOM 5089 C GLU 46 -15.112 ATOM 5090 0 GLU 46 -14.246 ATOM 5091 N TRP 47 -14.994 ATOM 5092 CA TRP 47 -13.810 ATOM 5093 CB TRP 47 -14.124 ATOM 5094 CG TRP 47 -12.985 ATOM 5095 CD2 TRP 47 -12.225 ATOM 5096 CE2 TRP 47 -11.346 ATOM 5097 CE3 TRP 47 -12.209 ATOM 5098 CDl TRP 47 -12.536 ATOM 5099 NEl TRP 47 -11.555 ATOM 5100 CZ2 TRP 47 -10.461 ATOM 5101 CZ3 TRP 47 -11.326 ATOM 5102 CH2 TRP 47 -10.467 ATOM 5103 C TRP 47 -12.687 ATOM 5104 O TRP 47 -12.877 ATOM 5105 N ILE 48 -11.519
-47.310 1.00 18.87 HI N -46.782 1.00 20.60 HI N -43.469 1.00 23.88 HI C -42.863 1.00 23.72 HI O -44.411 1.00 24.72 HI N -44.829 1.00 24.67 HI C -44.238 1.00 25.79 HI C -44.635 1.00 27.90 HI C -43.757 1.00 29.29 HI C -43.633 1.00 32.06 HI O -43.141 1.00 28.85 HI N -46.345 1.00 25.97 HI C -46.947 1.00 25.21 HI O -46.981 1.00 26.39 HI N -46.345 1.00 28.52 HI C -48.433 1.00 29.08 HI C -48.731 1.00 27.66 HI C -47.485 1.00 28.54 HI C -48.836 1.00 32.62 HI C -48.061 1.00 32.18 HI O -50.053 1.00 36.33 HI N -51.105 1.00 37.35 HI C -50.494 1.00 37.78 HI C -51.969 1.00 39.57 HI C -52.074 1.00 40.10 HI C -50.307 1.00 38.36 HI C -50.704 1.00 37.50 HI O -49.682 1.00 40.85 HI N -49.499 1.00 43.07 HI C -48.653 1.00 44.02 HI C -48.727 1.00 44.58 HI O -47.842 1.00 42.75 HI N -47.046 1.00 41.76 HI C -47.627 1.00 44.31 HI C -49.074 1.00 48.96 HI C -49.324 1.00 51.38 HI C -50.617 1.00 54.57 HI C -51.784 1.00 54.57 HI N -45.590 1.00 37.71 HI C -45.175 1.00 40.41 HI O -44.823 1.00 32.46 HI N -43.393 1.00 28.89 HI C -42.949 1.00 28.33 HI C -43.654 1.00 28.78 HI O -41.770 1.00 2 6.37 HI N -41.139 1.00 24.45 HI C -39.766 1.00 23.45 HI C -39.752 1.00 24.17 HI C -38.323 1.00 20.49 HI C -40.474 1.00 23.06 HI C -40.965 1.00 22.98 HI C -40.600 1.00 21.96 HI O -41.208 1.00 22.29 HI N -41.044 1.00 22.11 HI C -42.416 1.00 21.07 HI C -42.342 1.00 23.85 HI C -43.711 1.00 26.12 HI C -44.714 1.00 25.34 HI O -43.779 1.00 28.37 HI O -40.245 1.00 22.69 HI C -40.643 1.00 22.85 HI O -39.113 1.00 23.32 HI N -38.271 1.00 24.50 HI C -36.862 1.00 23.99 HI C -35.899 1.00 23.86 HI C -35.357 1.00 23.15 HI C -34.401 1.00 22.05 HI C -35.584 1.00 22.33 HI C -35.276 1.00 23.05 HI C -34.373 1.00 23.21 HI N -33.665 1.00 20.75 HI C -34.852 1.00 20.87 HI C -33.903 1.00 23.70 . HI C -38.872 1.00 24.58 HI C -39.176 1.00 23.77 HI O -39.042 1.00 24.78 HI N 488 WO 2009/026558 PCT/US2008/074097 ATOM 5106 CA ILE 48 -10.389 ATOM 5107 CB ILE 48 -9.526 ATOM 5108 CG2 ILE 48 -8.285 ATOM 5109 CGI ILE 48 -10.383 ATOM 5110 CDl ILE 48 -9.698 ATOM 5111 C ILE 48 -9.530 ATOM 5112 0 ILE 48 -9.181 ATOM 5113 N GLY 49 -9.207 ATOM 5114 CA GLY 49 -8.387 ATOM 5115 C GLY 49 -7.929 ATOM 5116 0 GLY 49 -8.258 ATOM 5117 N GLU 50 -7.166 ATOM 5118 CA GLU 50 -6.673 ATOM 5119 CB GLU 50 -7.577 ATOM 5120 CG GLU 50 -7.510 ATOM 5121 CD GLU 50 -8.512 ATOM 5122 OE1 GLU 50 -9.378 ATOM 5123 OE2 GLU 50 -8.438 ATOM 5124 C GLU 50 -5.257 ATOM 5125 0 GLU 50 -4.799 ATOM 5126 N ILE 51 -4.577 ATOM 5127 CA ILE 51 -3.275 ATOM 5128 CB ILE 51 -2.151 ATOM 5129 CG2 ILE 51 -2.110 ATOM 5130 CGI ILE 51 -0.805 ATOM 5131 CDl ILE 51 0.268 ATOM 5132 C ILE 51 -3.150 ATOM 5133 0 ILE 51 -3.846 ATOM 5134 N ASN 52 -2.294 ATOM 5135 CA ASN 52 -1.924 ATOM 5136 CB ASN 52 -2.366 ATOM 5137 CG ASN 52 -1.642 ATOM 5138 OD1 ASN 52 -0.514 ATOM 5139 ND2 ASN 52 -2.294 ATOM 5140 C ASN 52 -0.423 ATOM 5141 0 ASN 52 0.293 ATOM 5142 N HIS 53 0.047 ATOM 5143 CA HIS 53 1.391 ATOM 5144 CB HIS 53 1.597 ATOM 5145 CG HIS 53 1.574 ATOM 5146 CD2 HIS 53 0.542 ATOM 5147 NDl HIS 53 2.719 ATOM 5148 CEl HIS 53 2.393 ATOM 5149 NE2 HIS 53 1.077 ATOM 5150 C HIS 53 2.473 ATOM 5151 0 HIS 53 3.621 ATOM 5152 N SER 54 2.115 ATOM 5153 CA SER 54 3.103 ATOM 5154 CB SER 54 2.728 ATOM 5155 OG SER 54 1.673 ATOM 5156 C SER 54 3.207 ATOM 5157 O SER 54 4.033 ATOM 5158 N GLY 55 2.360 ATOM 5159 CA GLY 55 2.456 ATOM 5160 C GLY 55 1.537 ATOM 5161 0 GLY 55 1.519 ATOM 5162 N ARG 56 0.770 ATOM 5163 CA ARG 56 -0.181 ATOM 5164 CB ARG 56 -0.674 ATOM 5165 CG ARG 56 -1.671 ATOM 5166 CD ARG 56 -1.844 ATOM 5167 NE ARG 56 -2.188 ATOM 5168 CZ ARG 56 -3.363 ATOM 5169 NHl ARG 56 -4.318 ATOM 5170 NH2 ARG 56 -3.584 ATOM 5171 C ARG 56 -1.376 ATOM 5172 O ARG 56 -1.861 ATOM 5173 N THR 57 -1.844 ATOM 5174 CA THR 57 -2.908 ATOM 5175 CB THR 57 -2.401 ATOM 5176 OG1 THR 57 -1.806 ATOM 5177 CG2 THR 57 -1.384 ATOM 5178 C THR 57 -4.097 ATOM 5179 O THR 57 -3.968 ATOM 5180 N ASP 58 -5.252 ATOM 5181 CA ASP 58 -6.422 -39.647 1.00 24.00 HI c -40.481 1.00 24.53 HI c -41.038 1.00 24.01 HI c -41.611 1.00 23.41 HI c -42.429 1.00 24.34 HI c -38.575 1.00 23.04 HI c -38.689 1.00 21.34 HI 0 -37.528 1.00 22.63 HI N -36.459 1.00 21.49 HI c -35.502 1.00 22.86 HI c -35.679 1.00 22.27 HI 0 -34.490 1.00 22.34 HI N -33.469 1.00 23.19 HI c -32.234 1.00 23.22 HI c -31.530 1.00 20.57 HI c -30.396 1.00 23.89 HI c -30.251 1.00 22.86 HI 0 -29.656 1.00 20.61 HI 0 -33.053 1.00 25.41 HI c -33.349 1.00 26.68 HI 0 -32.340 1.00 25.24 HI N -31.780 1.00 25.42 HI c -32.768 1.00 25.30 HI c -32.919 1.00 20.77 HI c -32.288 1.00 25.23 HI c -33.364 1.00 2 6.63 HI c -30.492 1.00 25.89 HI c -30.318 1.00 25.01 HI 0 -29.575 1.00 27.77 HI N -28.456 1.00 28.51 HI c -27.119 1.00 31.18 HI c -26.785 1.00 33.23 HI c -27.221 1.00 37.24 HI 0 -25.999 1.00 34.97 HI N -28.463 1.00 2 9.67 HI c -29.327 1.00 29.70 HI 0 -27.505 1.00 30.65 HI N -27.565 1.00 34.02 HI c -26.431 1.00 36.59 HI c -25.077 1.00 41.39 HI c -24.268 1.00 42.73 HI c -24.425 1.00 44.09 HI N -23.273 1.00 43.74 HI c -23.154 1.00 44.27 HI N -27.475 1.00 34.37 HI C -27.819 1.00 34.24 HI 0 -26.999 1.00 34.17 HI N -26.852 1.00 34.95 HI C -25.708 1.00 37.13 HI c -26.090 1.00 44.66 HI 0 -28.140 1.00 35.47 HI c -28.255 1.00 37.27 HI 0 -29.110 1.00 33.32 HI N -30.407 1.00 33.10 HI c -30.649 1.00 30.70 HI c -31.744 1.00 31.90 HI 0 -29.647 1.00 31.34 HI N -29.860 1.00 31.52 HI c -28.520 1.00 33.02 HI c -28.675 1.00 39.22 HI c -27.393 1.00 41.40 HI c -26.239 1.00 44.28 HI N -26.069 1.00 45.93 HI c -26.983 1.00 45.10 HI N -24.980 1.00 46.47 HI N -30.702 1.00 29.42 HI C -30.547 1.00 29.24 HI 0 -31.590 1.00 27.46 HI N -32.518 1.00 28.02 HI C -33.974 1.00 26.99 HI c -34.267 1.00 28.13 HI 0 -34.194 1.00 24.99 HI c -32.442 1.00 27.51 . HI c -31.996 1.00 24.38 HI 0 -32.882 1.00 26.49 HI N -33.141 1.00 26.22 HI c 489 WO 2009/026558 PCT/US2008/074097 ATOM 5182 CB ASP 58 -7.491 15 ATOM 5183 CG ASP 58 -6.973 15 ATOM 5184 ODl ASP 58 -6.604 14 ATOM 5185 OD2 ASP 58 -6.941 16 ATOM 5186 C ASP 58 -6.985 16 ATOM 5187 O ASP 58 -7.107 17 ATOM 5188 N TYR 59 -7.326 15 ATOM 5189 CA TYR 59 -7.818 15 ATOM 5190 CB TYR 59 -6.882 14 ATOM 5191 CG TYR 59 -5.476 15 ATOM 5192 CD1 TYR 59 -5.247 16 ATOM 5193 CEl TYR 59 -3.971 17 ATOM 5194 CD2 TYR 59 -4.378 14 ATOM 5195 CE2 TYR 59 -3.091 14 ATOM 5196 CZ TYR 59 -2.895 16 ATOM 5197 OH TYR 59 -1.624 16 ATOM 5198 C TYR 59 -9.217 14 ATOM 5199 O TYR 59 -9.610 13 ATOM 5200 N ASN 60 -9.960 15 ATOM 52 01 CA ASN 60 -11.180 14 ATOM 5202 CB ASN 60 -11.914 15 ATOM 5203 CG ASN 60 -13.295 15 ATOM 5204 ODl ASN 60 -13.552 14 ATOM 5205 ND2 ASN 60 -14.191 16 ATOM 5206 C ASN 60 -10.766 13 ATOM 5207 0 ASN 60 -9.900 13 ATOM 5208 N PRO 61 -11.383 12 ATOM 5209 CD PRO 61 -12.379 12 ATOM 5210 CA PRO 61 -11.103 11 ATOM 5211 CB PRO 61 -12.156 10 ATOM 5212 CG PRO 61 -12.471 10 ATOM 5213 C PRO 61 -11.199 11 ATOM 5214 O PRO 61 -10.505 10 ATOM 5215 N SER 62 -12.064 12 ATOM 5216 CA SER 62 -12.310 12 ATOM 5217 CB SER 62 -13.540 13 ATOM 5218 OG SER 62 -13.283 14 ATOM 5219 C SER 62 -11.117 13 ATOM 5220 O SER 62 -11.054 13 ATOM 5221 N LEU 63 -10.180 13 ATOM 5222 CA LEU 63 -9.039 14 ATOM 5223 CB LEU 63 -9.206 15 ATOM 5224 CG LEU 63 -10.329 16 ATOM 5225 CDl LEU 63 -10.593 18 ATOM 5226 CD2 LEU 63 -9.939 16 ATOM 5227 C LEU 63 -7.703 14 ATOM 5228 O LEU 63 -6.640 14 ATOM 5229 N LYS 64 -7.773 13 ATOM 5230 CA LYS 64 -6.602 12 ATOM 5231 CB LYS 64 -7.007 11 ATOM 5232 CG LYS 64 -5.877 10 ATOM 5233 CD LYS 64 -6.349 9 ATOM 5234 CE LYS 64 -6.817 10 ATOM 5235 NZ LYS 64 -8.133 10 ATOM 5236 C LYS 64 -5.443 12 ATOM 5237 0 LYS 64 -4.282 12 ATOM 5238 N SER 65 -5.753 11 ATOM 5239 CA SER 65 -4.709 10 ATOM 52 4 0 CB SER 65 -5.299 9 ATOM 52 41 OG SER 65 -6.082 10 ATOM 5242 C SER 65 -3.961 12 ATOM 5243 O SER 65 -2.842 11 ATOM 5244 N ARG 66 -4.573 13 ATOM 5245 CA ARG 66 -3.992 14 ATOM 52 4 6 CB ARG 66 -5.018 14 ATOM 5247 CG ARG 66 -5.552 13 ATOM 5248 CD ARG 66 -6.867 13 ATOM 5249 NE ARG 66 -6.689 15 ATOM 5250 CZ ARG 66 -7.614 16 ATOM 5251 NHl ARG 66 -8.833 16 ATOM 5252 NH2 ARG 66 -7.296 17 ATOM 5253 C ARG 66 -3.495 15 ATOM 5254 O ARG 66 -2.810 16 ATOM 5255 N VAL 67 -3.848 15 ATOM 5256 CA VAL 67 -3.663 16 ATOM 5257 CB VAL 67 -4.944 17 -32.064 1.00 26.18 HI c -30.655 1.00 25.96 HI c -30.349 1.00 28.58 HI 0 -29.849 1.00 25.89 HI 0 -34.506 1.00 25.72 HI c -34.795 1.00 24.91 HI 0 -35.339 1.00 25.29 HI N -36.681 1.00 25.55 HI c -37.743 1.00 24.54 HI c -37.709 1.00 27.17 HI c -37.827 1.00 25.11 HI c -37.782 1.00 28.62 HI c -37.550 1.00 28.77 HI c -37.510 1.00 29.01 HI c -37.622 1.00 28.28 HI c -37.546 1.00 29.69 HI 0 -36.912 1.00 26.93 HI c -36.306 1.00 25.54 HI 0 -37.795 1.00 2 5.64 HI N -38.339 1.00 27.20 HI c -39.193 1.00 27.87 HI c -39.636 1.00 2 9.92 HI c -39.734 1.00 27.12 HI 0 -39.906 1.00 27.79 HI N -39.211 1.00 28.06 HI c -40.076 1.00 26.75 HI 0 -38.988 1.00 28.60 HI N -37.929 1.00 28.36 HI c -39.750 1.00 28.67 HI c -39.243 1.00 30.97 HI c -37.878 1.00 31.87 HI c -41.254 1.00 29.49 HI c -42.016 1.00 30.22 HI 0 -41.682 1.00 29.86 HI N -43.105 1.00 30.55 HI c -43.307 1.00 30.58 HI c -42.854 1.00 31.57 HI 0 -43.799 1.00 31.98 HI c -45.026 1.00 32.06 HI 0 -43.010 1.00 30.93 HI N -43.558 1.00 31.13 HI c -43.293 1.00 29.01 HI c -44.092 1.00 31.66 HI c -43.535 1.00 28.33 HI c -45.575 1.00 28.56 HI c -42.988 1.00 30.49 HI c -43.451 1.00 30.14 HI 0 -41.989 1.00 30.11 HI N -41.257 1.00 32.57 HI c -40.337 1.00 36.89 HI c -39.511 1.00 40.28 HI c -38.706 1.00 44.49 HI c -37.290 1.00 48.41 HI c -37.258 1.00 48.82 HI N -42.153 1.00 34.71 HI c -41.851 1.00 34.00 HI 0 -43.254 1.00 35.63 HI N -44.099 1.00 38.29 HI c -45.043 1.00 39.24 HI c -46.065 1.00 44.72 HI 0 -44.916 1.00 39.01 HI c -45.378 1.00 39.10 HI 0 -45.089 1.00 37.26 HI N -45.937 1.00 35.64 HI c -46.983 1.00 34.32 HI c -47.868 1.00 35.93 HI c -48.513 1.00 35.14 HI c -49.224 1.00 34.04 HI N -49.375 1.00 32.60 HI c -48.867 1.00 24.54 HI N -50.040 1.00 30.85 HI N -45.157 1.00 35.29 HI C -45.713 1.00 36.20 . HI 0 -43.878 1.00 33.06 HI N -43.132 1.00 32.98 HI C -42.347 1.00 34 .24 HI c 490 WO 2009/026558 PCT/US2008/074097 ATOM 5258 CGI VAL 67 -4.725 18 ATOM 5259 CG2 VAL 67 -6.107 17 ATOM 5260 C VAL 67 -2.513 16 ATOM 5261 O VAL 67 -2.260 15 ATOM 52 62 N THR 68 -1.824 17 ATOM 5263 CA THR 68 -0.890 18 ATOM 5264 CB THR 68 0.581 17 ATOM 5265 OG1 THR 68 0.773 16 ATOM 52 66 CG2 THR 68 1.521 18 ATOM 5267 C THR 68 -1.067 19 ATOM 5268 O THR 68 -1.042 20 ATOM 5269 N ILE 69 -1.255 19 ATOM 5270 CA ILE 69 -1.280 20 ATOM 5271 CB ILE 69 -2.548 20 ATOM 5272 CG2 ILE 69 -2.490 22 ATOM 5273 CGI ILE 69 -3.786 20 ATOM 5274 CDl ILE 69 -5. 111 20 ATOM 5275 C ILE 69 -0.034 20 ATOM 5276 0 ILE 69 0.344 19 ATOM 5277 N SER 70 0.620 21 ATOM 5278 CA SER 70 1.825 22 ATOM 5279 CB SER 70 3.066 22 ATOM 5280 OG SER 70 2.970 23 ATOM 5281 C SER 70 1.753 23 ATOM 5282 O SER 70 0.891 24 ATOM 5283 N VAL 71 2.647 23 ATOM 5284 CA VAL 71 2.617 24 ATOM 5285 CB VAL 71 1.970 24 ATOM 5286 CGI VAL 71 2.819 23 ATOM 5287 CG2 VAL 71 1.804 25 ATOM 5288 C VAL 71 4.026 25 ATOM 5289 O VAL 71 4.994 24 ATOM 5290 N ASP 72 4 . 134 26 ATOM 5291 CA ASP 72 5.3 92 27 ATOM 52 92 CB ASP 72 5.876 28 ATOM 5293 CG ASP 72 7.211 28 ATOM 5294 OD1 ASP 72 7.609 28 ATOM 5295 OD2 ASP 72 7.865 29 ATOM 5296 C ASP 72 5.139 28 ATOM 5297 O ASP 72 4.727 29 ATOM 5298 N THR 73 5.376 27 ATOM 5299 CA THR 73 5.012 28 ATOM 5300 CB THR 73 5.158 27 ATOM 5301 OG1 THR 73 6.539 27 ATOM 5302 CG2 THR 73 4.360 26 ATOM 5303 C THR 73 5.877 29 ATOM 5304 O THR 73 5.410 30 ATOM 5305 N SER 74 7.133 29 ATOM 5306 CA SER 74 8.024 30 ATOM 5307 CB SER 74 9.418 30 ATOM 5308 OG SER 74 9.455 30 ATOM 5309 C SER 74 7.423 31 ATOM 5310 O SER 74 7.602 32 ATOM 5311 N LYS 75 6.692 31 ATOM 5312 CA LYS 75 6.081 32 ATOM 5313 CB LYS 75 6.283 32, ATOM 5314 CG LYS 75 7.640 32 ATOM 5315 CD LYS 75 7.552 33 ATOM 5316 CE LYS 75 8.933 33 ATOM 5317 NZ LYS 75 9.706 31 ATOM 5318 C LYS 75 4.591 32 ATOM 5319 0 LYS 75 3.958 33 ATOM 5320 N LYS 76 4.031 31 ATOM 5321 CA LYS 76 2.583 31 ATOM 5322 CB LYS 76 2.129 33 ATOM 5323 CG LYS 76 2.773 33 ATOM 5324 CD LYS 76 2.476 34 ATOM 5325 CE LYS 76 3.315 34 ATOM 5326 NZ LYS 76 3.033 33 ATOM 5327 C LYS 76 1.867 31 ATOM 5328 0 LYS 76 1.027 32 ATOM 5329 N GLN 77 2.234 30 ATOM 5330 CA GLN 77 1.610 30 ATOM 5331 CB GLN 77 2.528 31 ATOM 5332 CG GLN 77 2.730 32 ATOM 5333 CD GLN 77 3.757 32 -41.600 1.00 36.90 HI c -43.297 1.00 38.06 HI c -42.137 1.00 30.38 HI c -41.525 1.00 29.73 HI 0 -41.978 1.00 29.72 HI N -40.878 1.00 31.21 HI c -41.333 1.00 32.80 HI c -41.917 1.00 36.87 HI 0 -40.141 1.00 33.68 HI c -40.291 1.00 31.32 HI c -41. Oil 1.00 31.21 HI 0 -38.980 1.00 27.82 HI N -38.274 1.00 26.11 HI c -37.404 1.00 22.50 HI c -36.539 1.00 21.71 HI c -38.309 1.00 22.12 HI c -37.559 1.00 19.06 HI c -37.399 1.00 26.90 HI c -36.763 1.00 26.17 HI 0 -37.386 1.00 26.96 HI N -36.590 1.00 29.41 HI c -37.490 1.00 29.33 HI c -38.508 1.00 34.80 HI 0 -35.829 1.00 29.15 HI c -36.096 1.00 29.52 HI 0 -34.864 1.00 30.15 HI N -34.029 1.00 30.65 HI c -32.653 1.00 30.44 HI c -31.900 1.00 28.16 HI c -31.842 1.00 32.12 HI c -33.813 1.00 31.95 HI c -33.722 1.00 30.74 HI 0 -33.743 1.00 33.49 HI N -33.405 1.00 35.48 HI c -34.582 1.00 38.44 HI c -34.310 1.00 40.69 HI c -33.131 1.00 41.96 HI 0 -35.279 1.00 43.43 HI 0 -32.187 1.00 35.14 HI c -32.316 1.00 33.42 HI 0 -31.002 1.00 36.86 HI N -29.774 1.00 40.27 HI c -28.545 1.00 41.47 HI c -28.356 1.00 44.90 HI 0 -28.740 1.00 38.24 Hi c -29.569 1.00 4 0.62 HI c -29.039 1.00 41.80 HI 0 -29.998 1.00 41.71 HI N -29.833 1.00 42.42 HI c -30.403 1.00 42.23 HI c -31.811 1.00 45.59 HI 0 -30.542 1.00 41.31 HI c -30. 111 1.00 43.56 HI 0 -31.622 1.00 40.07 HI N -32.402 1.00 37.23 HI c -33.894 1.00 40.70 HI c -34.430 1.00 42.41 HI c -35.925 1.00 45.61 HI c -36.550 1.00 48.78 HI c -36.306 1.00 49.50 HI N -32.129 1.00 34.20 HI c -32.673 1.00 31.98 HI 0 -31.298 1.00 31.53 HI N -31.099 1.00 30.16 HI c -30.301 1.00 31.13 HI c -28.914 1.00 32.98 HI c -28.236 1.00 35.35 HI c -26.976 1.00 42.53 HI c -25.934 1.00 45.06 HI N -32.451 1.00 28.30 HI c -32.773 1.00 26.79 HI 0 -33.248 1.00 28.03 HI N -34.544 1.00 30.21 . HI c -35.685 1.00 29.25 HI c -35.778 1.00 32.24 ' HI c -36.834 1.00 31.77 HI c 491 WO 2009/026558 PCT/US2008/074097 ATOM 5334 OE1 GLN 77 4 . 144 34 ATOM 5335 NE2 GLN 77 4 .198 32 ATOM 5336 C GLN 77 1.353 29 ATOM 5337 0 GLN 77 2.085 28 ATOM 5338 N PHE 78 0.313 28 ATOM 5339 CA PHE 78 0.149 27 ATOM 5340 CB PHE 78 -0.842 26 ATOM 5341 CG PHE 78 -2.240 27 ATOM 5342 CDl PHE 78 -3.272 26 ATOM 5343 CD2 PHE 78 -2.531 28 ATOM 5344 CEl PHE 78 -4.568 26 ATOM 5345 CE2 PHE 78 -3.824 28 ATOM 5346 CZ PHE 78 -4.844 28 ATOM 5347 C PHE 78 -0.291 27 ATOM 5348 O PHE 78 -0.746 28 ATOM 5349 N SER 79 -0.121 26 ATOM 5350 CA SER 79 -0.190 26 ATOM 5351 CB SER 79 1.217 25 ATOM 5352 OG SER 79 1.991 27 ATOM 5353 C SER 79 -1.019 24 ATOM 5354 O SER 79 -1.198 23 ATOM 5355 N LEU 80 -1.492 24 ATOM 5356 CA LEU 80 -2.221 23 ATOM 5357 CB LEU 80 -3.657 24 ATOM 5358 CG LEU 80 -4.499 23 ATOM 5359 CDl LEU 80 -4.684 21 ATOM 5360 CD2 LEU 80 -5.843 23 ATOM 5361 C LEU 80 -1.560 23 ATOM 5362 O LEU 80 -1.283 24 ATOM 5363 N LYS 81 -1.315 22 ATOM 5364 CA LYS 81 -0.952 21 ATOM 5365 CB LYS 81 0.433 20 ATOM 5366 CG LYS 81 1.585 21 ATOM 5367 CD LYS 81 2.892 21 ATOM 5368 CE LYS 81 3.901 22 ATOM 5369 NZ LYS 81 3.752 23 ATOM 5370 C LYS 81 -1.976 20 ATOM 5371 0 LYS 81 -2.286 19 ATOM 5372 N LEU 82 -2.493 20 ATOM 5373 CA LEU 82 -3.388 19 ATOM 5374 CB LEU 82 -4.777 20 ATOM 5375 CG LEU 82 -5.901 19 ATOM 5376 CDl LEU 82 -6.172 18 ATOM 5377 CD2 LEU 82 -7.163 20 ATOM 5378 C LEU 82 -2.815 19 ATOM 5379 O LEU 82 -2.719 20 ATOM 5380 N ASN 83 -2.439 17 ATOM 5381 CA ASN 83 -1.862 17 ATOM 5382 CB ASN 83 -1.143 16 ATOM 5383 CG ASN 83 -0.053 16 ATOM 5384 OD1 ASN 83 0.637 17 ATOM 5385 ND2 ASN 83 0.114 15 ATOM 5386 C ASN 83 -2.907 17 ATOM 5387 0 ASN 83 -4.092 16 ATOM 5388 N SER 84 -2.437 17 ATOM 5389 CA SER 84 -3.175 16 ATOM 5390 CB SER 84 -3.226 14 ATOM 5391 OG SER 84 -1.930 14 ATOM 5392 C SER 84 -4.594 17 ATOM 5393 O SER 84 -5.544 16 ATOM 5394 N VAL 85 -4.737 18 ATOM 5395 CA VAL 85 -6.054 18 ATOM 5396 CB VAL 85 -5.955 20 ATOM 5397 CGI VAL 85 -5.392 20 ATOM 5398 CG2 VAL 85 -5.072 21 ATOM 5399 C VAL 85 -6.815 18 ATOM 5400 O VAL 85 -6.214 18 ATOM 5401 N THR 86 -8.142 18 ATOM 5402 CA THR 86 -8.995 18 ATOM 5403 CB THR 86 -9.725 17 ATOM 5404 OG1 THR 86 -10.653 17 ATOM 5405 CG2 THR 86 -8.725 16 ATOM 5406 C THR 86 -10.038 19 ATOM 5407 O THR 86 -10.059 20 ATOM 5408 N ALA 87 -10.904 19 ATOM 5409 CA ALA 87 -11.891 20 -36.922 1.00 35.74 HI 0 -37.634 1.00 28.74 HI N -34.680 1.00 2 9.69 HI C -34.119 1.00 31.84 HI 0 -35.417 1.00 28.53 HI N -35.817 1.00 28.21 HI C -34.888 1.00 28.77 HI c -34.928 1.00 28.71 HI c -35.469 1.00 28.64 HI c -34.412 1.00 28.33 HI c -35.494 1.00 28.19 HI c -34.434 1.00 28.05 HI c -34.978 1.00 27.78 HI c -37.267 1.00 26.74 HI c -37.820 1.00 26.40 HI 0 -37.884 1.00 26.74 HI N -39.332 1.00 28.66 HI c -39.911 1.00 26.94 HI c -39.670 1.00 37.18 HI 0 -39.751 1.00 27.22 HI c -38.982 1.00 28.89 HI 0 -40.988 1.00 28.24 HI N -41.595 1.00 28.21 HI c -41.873 1.00 27.82 HI c -42.689 1.00 29.21 HI c -41.906 1.00 25.31 HI c -43.000 1.00 29.81 HI c -42.910 1.00 29.34 HI c -43.764 1.00 29.99 HI 0 -43.072 1.00 30.34 HI N -44.372 1.00 32.50 HI c -44.315 1.00 36.42 HI c -44.454 1.00 43.74 HI c -44.778 1.00 47.76 HI c -45.405 1.00 48.81 HI c -44.859 1.00 49.14 HI N -44.830 1.00 32.18 HI c -44.102 1.00 32.47 HI 0 -46.041 1.00 31.45 HI N -46.642 1.00 31.74 HI c -46.853 1.00 29.16 HI c -47.374 1.00 29.44 HI c -46.380 1.00 26.17 HI c -47.579 1.00 27.84 HI c -47.980 1.00 31.38 HI c -48.913 1.00 30.59 HI 0 -48.068 1.00 33.35 HI N -49.294 1.00 34.64 HI c -48.999 1.00 37.82 HI c -47.975 1.00 43.06 HI c -47.924 1.00 45.32 HI 0 -47.141 1.00 42.01 HI N -50.368 1.00 34.00 HI c -50.066 1.00 31.80 HI 0 -51.616 1.00 32.98 HI N -52.733 1.00 32.51 HI c -52.596 1.00 33.13 HI c -52.419 1.00 37.34 HI 0 -52.848 1.00 32.10 HI c -52.918 1.00 32.45 HI 0 -52.870 1.00 30.78 HI N -52.891 1.00 31.67 HI c -52.767 1.00 31.43 HI c -51.400 1.00 31.90 HI c -53.869 1.00 31.67 HI c -54.164 1.00 32.60 HI c -55.180 1.00 34.22 HI 0 -54.090 1.00 31.22 HI ' N -55.275 1.00 31.00 HI c -55.400 1.00 31.98 HI c -54 .316 1.00 34 . 46 HI 0 -55.368 1.00 32.26 HI c -55.152 1.00 30.48 . HI c -54.162 1.00 30.01 HI 0 -56.150 1.00 28.60 HI N -56.145 1.00 29.42 HI c 492 WO 2009/026558 PCT/US2008/074097 ATOM 5410 CB ALA 87 -12.797 20 ATOM 5411 C ALA 87 -12.734 20 ATOM 5412 O ALA 87 -13.204 21 ATOM 5413 N ALA 88 -12.915 19 ATOM 5414 CA ALA 88 -13.753 19 ATOM 5415 CB ALA 88 -14.045 18 ATOM 5416 C ALA 88 -13.147 20 ATOM 5417 O ALA 88 -13.818 20 ATOM 5418 N ASP 89 -11.879 20 ATOM 5419 CA ASP 89 -11.249 21 ATOM 5420 CB ASP 89 -9.752 20 ATOM 5421 CG ASP 89 -9.4 62 19 ATOM 5422 OD1 ASP 89 -9.997 18 ATOM 5423 OD2 ASP 89 -8.704 18 ATOM 5424 C ASP 89 -11.461 22 ATOM 5425 O ASP 89 -11.031 23 ATOM 5426 N THR 90 -12.124 23 ATOM 5427 CA THR 90 -12.500 24 ATOM 5428 CB THR 90 -13.279 24 ATOM 5429 OG1 THR 90 -12.440 24 ATOM 5430 CG2 THR 90 -13.720 26 ATOM 5431 C THR 90 -13.363 24 ATOM 5432 O THR 90 -14.360 24 ATOM 5433 N ALA 91 -12.975 26 ATOM 5434 CA ALA 91 -13.673 26 ATOM 5435 CB ALA 91 -13.718 25 ATOM 5436 C ALA 91 -12.982 27 ATOM 5437 O ALA 91 -11.855 28 ATOM 5438 N VAL 92 -13.663 28 ATOM 5439 CA VAL 92 -13.002 29 ATOM 5440 CB VAL 92 -13.983 30 ATOM 5441 CGI VAL 92 -13.263 31 ATOM 5442 CG2 VAL 92 -14.535 31 ATOM 5443 C VAL 92 -12.436 28 ATOM 5444 O VAL 92 -13.160 27 ATOM 5445 N TYR 93 -11.137 28 ATOM 5446 CA TYR 93 -10.479 28 ATOM 5447 CB TYR 93 -9.135 27 ATOM 5448 CG TYR 93 -9.272 26 ATOM 5449 CD1 TYR 93 -8.895 25 ATOM 5450 CEl TYR 93 -9.047 23 ATOM 5451 CD2 TYR 93 -9.804 26 ATOM 5452 CE2 TYR 93 -9.964 25 ATOM 5453 CZ TYR 93 -9.583 24 ATOM 5454 OH TYR 93 -9.757 22 ATOM 5455 C TYR 93 -10.263 29 ATOM 5456 O TYR 93 -9.700 30 ATOM 5457 N TYR 94 -10.719 28 ATOM 5458 CA TYR 94 -10.583 29 ATOM 5459 CB TYR 94 -11.946 29 ATOM 5460 CG TYR 94 -12.952 30 ATOM 5461 CD1 TYR 94 -12.938 31 ATOM 5462 CEl TYR 94 -13.908 32 ATOM 5463 CD2 TYR 94 -13.962 29 ATOM 5464 CE2 TYR 94 -14.935 30 ATOM 5465 CZ TYR 94 -14.906 31 ATOM 5466 OH TYR 94 -15.889 32 ATOM 5467 C TYR 94 -9.691 28 ATOM 5468 O TYR 94 -9.695 27 ATOM 5469 N CYS 95 -8.938 29 ATOM 5470 CA CYS 95 -8.466 29 ATOM 5471 C CYS 95 -9.410 29 ATOM 5472 0 CYS 95 -10.104 30 ATOM 5473 CB CYS 95 -7.034 29 ATOM 5474 SG CYS 95 -6.561 31 ATOM 5475 N ALA 96 -9.439 29 ATOM 5476 CA ALA 96 -10.354 29 ATOM 5477 CB ALA 96 -11.730 28 ATOM 5478 C ALA 96 -9.782 28 ATOM 5479 O ALA 96 -9.166 27 ATOM 5480 N ARG 97 -9.997 29 ATOM 5481 CA ARG 97 -9.439 29 ATOM 5482 CB ARG 97 -9.076 30 ATOM 5483 CG ARG 97 -8.510 30 ATOM 5484 CD ARG 97 -8.172 31 ATOM 5485 NE ARG 97 -9.342 32
-57.386 1.00 25.14 HI c -54.871 1.00 27.88 HI c -54.415 1.00 29.57 HI 0 -54.301 1.00 2 6.65 HI N -53.115 1.00 26.47 HI C -52.907 1.00 22.83 HI C -51.834 1.00 27.55 HI C -50.800 1.00 25.90 HI O -51.896 1.00 26.38 HI N -50.773 1.00 26.18 HI C -50.735 1.00 24.35 HI C -50.473 1.00 25.95 HI C -49.486 1.00 26.03 HI O -51.262 1.00 25.18 HI O -50.844 1.00 25.45 HI C -49.960 1.00 25.56 HI O -51.901 1.00 24.03 HI N -52.021 1.00 22.80 HI C -53.327 1.00 23.31 HI C -54.434 1.00 23.59 HI O -53.458 1.00 22.37 HI C -50.833 1.00 23.24 HI C -50.512 1.00 23.24 HI O -50.178 1.00 22.25 HI N -48.978 1.00 22.73 HI C -47.943 1.00 18.43 HI C -48.378 1.00 24.17 HI C -48.755 1.00 25.58 HI O -47.447 1.00 23.43 HI N -46.575 1.00 23.10 HI C -46.087 1.00 24.14 HI C -45.147 1.00 23.43 HI C -47.281 1.00 23.45 HI C -45.372 1.00 24.98 HI C -44.675 1.00 26.01 HI O -45.143 1.00 23.58 HI N -44.019 1.00 23.55 HI C -44.471 1.00 20.25 HI C -45.342 1.00 20.65 HI C -44.871 1.00 19.71 HI C -45.651 1.00 20.45 HI C -46.620 1.00 21.99 HI C -47.412 1.00 21.69 HI C -46.918 1.00 21.47 HI C -47.687 1.00 24.56 HI O -42.869 1.00 24.76 HI c -43.064 1.00 26.10 HI 0 -41.676 1.00 22.97 HI N -40.489 1.00 23.93 HI C -39.846 1.00 22.58 HI C -40.702 1.00 25.89 HI C -40.801 1.00 25.89 HI C -41.531 1.00 25.38 HI C -41.365 1.00 26.81 HI c -42.095 1.00 25.75 HI c -42.172 1.00 27.48 HI c -42.874 1.00 28.03 HI 0 -39.446 1.00 24.14 HI c -39.310 1.00 22.75 HI 0 -38.705 1.00 24.10 HI N -37.395 1.00 25.55 HI C -36.338 1.00 25.49 HI C -36.560 1.00 24.75 HI 0 -37.107 1.00 27.36 HI c -37.539 1.00 31.48 HI s -35.192 1.00 24.09 HI N -34.117 1.00 22.01 HI C -34.380 1.00 20.76 HI C -32.813 1.00 22.32 HI C -32.775 1.00 22.28 HI O -31.739 1.00 22.97 HI N -30.450 1.00 22.39 HI C -29.668 1.00 22.09 . HI C -28.276 1.00 21.83 HI C -27.581 1.00 23.69 HI C -26.927 1.00 23.06 HI N 493 WO 2009/026558 PCT/US2008/074097 ATOM 5486 cz ARG 97 -9.273 33 ATOM 5487 NHl ARG 97 -8.090 33 ATOM 5488 NH2 ARG 97 -10.379 33 ATOM 5489 C ARG 97 -10.426 28 ATOM 5490 0 ARG 97 -11.632 28 ATOM 5491 N GLY 98 -9.905 27 ATOM 5492 CA GLY 98 -10.606 27 ATOM 5493 C GLY 98 -11.259 25 ATOM 5494 0 GLY 98 -11.391 25 ATOM 5495 N GLN 99 -11.668 25 ATOM 5496 CA GLN 99 -12.293 23 ATOM 5497 CB GLN 99 -11.253 22 ATOM 5498 CG GLN 99 -11.774 21 ATOM 5499 CD GLN 99 -10.690 20 ATOM 5500 OE1 GLN 99 -10.482 19 ATOM 5501 NE2 GLN 99 -9.992 19 ATOM 5502 C GLN 99 -13.436 23 ATOM 5503 0 GLN 99 -14.550 23 ATOM 5504 N LEU 100 -13.161 24 ATOM 5505 CA LEU 100 -14.182 24 ATOM 5506 CB LEU 100 -13.543 24 ATOM 5507 CG LEU 100 -12.653 22 ATOM 5508 CDl LEU 100 -12.218 23 ATOM 5509 CD2 LEU 100 -13.409 21 ATOM 5510 C LEU 100 -15.133 25 ATOM 5511 O LEU 100 -16.334 25 ATOM 5512 N VAL 101 -14.591 26 ATOM 5513 CA VAL 101 -15.413 27 ATOM 5514 CB VAL 101 -15.146 28 ATOM 5515 CGI VAL 101 -16.083 29 ATOM 5516 CG2 VAL 101 -15.361 28 ATOM 5517 C VAL 101 -15.034 27 ATOM 5518 O VAL 101 -14 .149 28 ATOM 5519 N PRO 102 -15.687 26 ATOM 5520 CD PRO 102 -16.834 25 ATOM 5521 CA PRO 102 -15.148 26 ATOM 5522 CB PRO 102 -15.863 25 ATOM 5523 CG PRO 102 -17.147 25 ATOM 5524 C PRO 102 -15.315 27 ATOM 5525 O PRO 102 -16.411 28 ATOM 5526 N PHE 103 -14.206 27 ATOM 5527 CA PHE 103 -14.223 28 ATOM 5528 CB PHE 103 -15.059 28 ATOM 5529 CG PHE 103 -14.912 26 ATOM 5530 CDl PHE 103 -16.005 25 ATOM 5531 CD2 PHE 103 -13.693 26 ATOM 5532 CEl PHE 103 -15.888 24 ATOM 5533 CE2 PHE 103 -13.565 24 ATOM 5534 CZ PHE 103 -14.666 23 ATOM 5535 C PHE 103 -14.781 30 ATOM 5536 O PHE 103 -15.712 30 ATOM 5537 N ASP 104 -14.215 30 ATOM 5538 CA ASP 104 -14.669 32 ATOM 5539 CB ASP 104 -14.406 32 ATOM 5540 CG ASP 104 -12.945 32 ATOM 5541 OD1 ASP 104 -12.122 31 ATOM 5542 OD2 ASP 104 -12.619 32 ATOM 5543 C ASP 104 -14.021 33 ATOM 5544 O ASP 104 -14.586 34 ATOM 5545 N TYR 105 -12.841 32 ATOM 5546 CA TYR 105 -12.227 33 ATOM 5547 CB TYR 105 -10.971 34 ATOM 5548 CG TYR 105 -11.278 35 ATOM 5549 CDl TYR 105 -11.345 35 ATOM 5550 CEl TYR 105 -11.661 36 ATOM 5551 CD2 TYR 105 -11.534 36 ATOM 5552 CE2 TYR 105 -11.855 37 ATOM 5553 CZ TYR 105 -11.918 37 ATOM 5554 OH TYR 105 -12.255 38 ATOM 5555 C TYR 105 -11.869 33 ATOM 5556 O TYR 105 -11.426 31 ATOM 5557 N TRP 106 -12.065 33 ATOM 5558 CA TRP 106 -11.831 33 ATOM 5559 CB TRP 106 -13.145 33 ATOM 5560 CG TRP 106 -14. 111 32 ATOM 5561 CD2 TRP 106 -14.605 30 -25.993 1.00 26.31 HI c -25.613 1.00 26.46 HI N -25.422 1.00 23.30 HI N -29.636 1.00 24.53 HI C -29.658 1.00 22.12 HI 0 -28.921 1.00 22.25 HI N -27.760 1.00 23.81 HI C -27.913 1.00 23.68 HI c -29.023 1.00 23.49 HI 0 -26.780 1.00 22.67 HI N -26.749 1.00 23.45 HI c -26.419 1.00 22.97 HI c -26.560 1.00 20.76 HI c -26.328 1.00 22.06 HI c -25.202 1.00 22.02 HI 0 -27.395 1.00 21.38 HI N -25.725 1.00 24.22 HI c -26.056 1.00 24 .28 HI 0 -24.485 1.00 23.64 HI N -23.448 1.00 24.07 HI c -22.055 1.00 23.74 HI c -21.697 1.00 23.65 HI c -20.250 1.00 21.96 HI c -21.918 1.00 22.57 HI c -23.642 1.00 26.71 HI c -23.386 1.00 27.08 HI 0 -24.104 1.00 26.05 HI N -24.665 1.00 26.77 Hi c -23.957 1.00 25.01 HI c -24.501 1.00 25.38 HI c -22.453 1.00 24.75 HI c -26.141 1.00 26.59 HI c -26.528 1.00 26.80 HI 0 -26.980 1.00 25.65 HI N -26.646 1.00 23.49 HI c -28.315 1.00 23.89 HI c -28.729 1.00 23.18 HI c -27.954 1.00 25.40 HI c -29.339 1.00 24 .72 HI c -29.550 1.00 24.05 HI 0 -29.974 1.00 22.69 HI N -31.080 1.00 22.97 HI c -32.240 1.00 20.62 Hi c -32.412 1.00 21.68 HI c -32.759 1.00 17.84 HI c -32.185 1.00 19.12 HI c -32.868 1.00 19.25 HI c -32.294 1.00 17.07 HI c -32.634 1.00 18.07 HI c -30.619 1.00 23.73 HI c -31.217 1.00 24.85 HI 0 -29.548 1.00 24.65 HI N -29.069 1.00 24.76 HI c -27.563 1.00 25.91 HI c -27.175 1.00 30.36 HI c -28.036 1.00 31.12 HI 0 -25.987 1.00 28.71 HI 0 -29.856 1.00 27.29 HI c -29.971 1.00 27.52 HI 0 -30.411 1.00 26.93 HI N -31.355 1.00 26.35 HI c -30.743 1.00 25.73 Hi c -29.675 1.00 28.28 HI c -28.334 1.00 26.26 HI c -27.359 1.00 27.70 HI c -30.012 1.00 29.38 HI c -29.044 1.00 29.45 HI c -27.722 1.00 29.50 HI c -26.766 1.00 32.67 HI 0 -32.657 1.00 25.43 HI c -32.641 1.00 24.81 HI 0 -33.774 1.00 24.15 HI N -35.106 1.00 25.25 . HI c -35.879 1.00 21.93 HI c -35.362 1.00 22.83 Hi c -36.072 1.00 21.41 HI c 494 WO 2009/026558 PCT/US2008/074097 ATOM 5562 CE2 TRP 106 -15.566 30 ATOM 5563 CE3 TRP 106 -14.328 30 ATOM 5564 CDl TRP 106 -14.767 32 ATOM 5565 NEl TRP 106 -15.646 31 ATOM 5566 CZ2 TRP 106 -16.258 29 ATOM 5567 CZ3 TRP 106 -15.015 29 ATOM 5568 CH2 TRP 106 -15.970 28 ATOM 5569 C TRP 106 -10.902 34 ATOM 5570 O TRP 106 -10.923 35 ATOM 5571 N GLY 107 -10.114 33 ATOM 5572 CA GLY 107 -9.418 34 ATOM 5573 C GLY 107 -10.379 34 ATOM 5574 0 GLY 107 -11.583 34 ATOM 5575 N GLN 108 -9.852 35 ATOM 5576 CA GLN 108 -10.680 36 ATOM 5577 CB GLN 108 -9.980 37 ATOM 5578 CG GLN 108 -8.939 37 ATOM 5579 CD GLN 108 -7.566 37 ATOM 5580 OE1 GLN 108 -7.395 36 ATOM 5581 NE2 GLN 108 -6.577 37 ATOM 5582 C GLN 108 -10.976 35 ATOM 5583 0 GLN 108 -11.868 35 ATOM 5584 N GLY 109 -10.223 34 ATOM 5585 CA GLY 109 -10.492 33 ATOM 5586 C GLY 109 -9.718 33 ATOM 5587 0 GLY 109 -9.425 34 ATOM 5588 N THR 110 -9.386 32 ATOM 5589 CA THR 110 -8.682 32 ATOM 5590 CB THR 110 -7.285 31 ATOM 5591 OG1 THR 110 -6.522 32 ATOM 5592 CG2 THR 110 -6.554 31 ATOM 5593 C THR 110 -9.476 31 ATOM 5594 O THR 110 -9.712 30 ATOM 5595 N LEU 111 -9.890 32 ATOM 5596 CA LEU 111 -10.616 31 ATOM 5597 CB LEU 111 -11.234 32 ATOM 5598 CG LEU 111 -11.853 32 ATOM 5599 CDl LEU 111 -13.054 31 ATOM 5600 CD2 LEU 111 -12.272 33 ATOM 5601 C LEU 111 -9.659 30 ATOM 5602 O LEU 111 -8.661 31 ATOM 5603 N VAL 112 -9.953 29 ATOM 5604 CA VAL 112 -9.134 28 ATOM 5605 CB VAL 112 -8.700 27 ATOM 5606 CGI VAL 112 -7.986 26 ATOM 5607 CG2 VAL 112 -7.788 27 ATOM 5608 C VAL 112 -9.934 28 ATOM 5609 O VAL 112 -11.012 27 ATOM 5610 N THR 113 -9.405 28 ATOM 5611 CA THR 113 -10.076 27 ATOM 5612 CB THR 113 -10.365 29 ATOM 5613 OG1 THR 113 -11.220 29 ATOM 5614 CG2 THR 113 -11.064 28 ATOM 5615 C THR 113 -9.190 26 ATOM 5616 O THR 113 -8.041 27 ATOM 5617 N VAL 114 -9.721 25 ATOM 5618 CA VAL 114 -8.990 24 ATOM 5619 CB VAL 114 -8.865 23 ATOM 5620 CGI VAL 114 -8.002 22 ATOM 5621 CG2 VAL 114 -8.294 23 ATOM 5622 C VAL 114 -9.745 24 ATOM 5623 O VAL 114 -10.881 23 ATOM 5624 N SER 115 -9.119 24 ATOM 5625 CA SER 115 -9.668 24 ATOM 5626 CB SER 115 -10.785 25 ATOM 5627 OG SER 115 -10.365 25 ATOM 5628 C SER 115 -8.586 24 ATOM 5629 O SER 115 -7.543 24 ATOM 5630 N SER 116 -8.841 23 ATOM 5631 CA SER 116 -7.891 22 ATOM 5632 CB SER 116 -7.763 21 ATOM 5633 OG SER 116 -9.040 20 ATOM 5634 C SER 116 -8.348 23 ATOM 5635 O SER 116 -7.679 23 ATOM 5636 N ALA 117 -9.491 24 ATOM 5637 CA ALA 117 -10.149 24
-35.250 1.00 20.48 HI c -37.326 1.00 20.75 HI c -34.170 1.00 19.87 HI c -34.095 1.00 22.85 HI N -35.637 1.00 20.26 HI C -37.711 1.00 20.27 HI C -36.868 1.00 23.31 HI C -35.906 1.00 27.18 HI C -35.741 1.00 26.73 HI O -36.797 1.00 27.12 HI N -37.797 1.00 27.10 HI C -38.822 1.00 28.57 HI C -38.790 1.00 27.48 HI O -39.737 1.00 28.26 HI N -40.743 1.00 30.59 HI C -41.275 1.00 33.27 HI C -42.371 1.00 36.99 HI C -41.831 1.00 42.07 HI C -40.633 1.00 42.16 HI O -42.720 1.00 40.22 HI N -41.895 1.00 30.47 HI C -42.707 1.00 31.09 HI O -41.953 1.00 29.81 HI N -42.923 1.00 29.09 HI C -44.216 1.00 28.69 HI C -44.619 1.00 28.50 HI O -44.866 1.00 28.50 HI N -46.139 1.00 28.41 HI C -46.021 1.00 29.01 HI C -45.034 1.00 32.03 HI O -47.356 1.00 29.38 HI C -47.193 1.00 29.43 HI C -47.053 1.00 27.15 HI O -48.246 1.00 29.78 HI N -49.328 1.00 29.48 HI C -50.258 1.00 31.55 HI C -51.537 1.00 36.06 HI C -51.180 1.00 35.44 HI C -52.470 1.00 33.87 HI C -50.109 1.00 30.13 HI C -50.664 1.00 30.30 HI O -50.129 1.00 28.78 HI N -50.862 1.00 27.19 HI C -49.964 1.00 27.32 HI C -50.793 1.00 26.80 HI C -48.857 1.00 25.55 HI C -52.039 1.00 28.91 HI C -51.867 1.00 26.37 HI O -53.237 1.00 28.59 HI N -54.457 1.00 31.25 HI C -55.379 1.00 30.80 HI C -54.691 1.00 33.89 HI O -56.658 1.00 32.74 HI C -55.183 1.00 31.51 HI C -55.506 1.00 32.27 HI O -55.406 1.00 32.99 HI N -56.122 1.00 34.40 HI C -55.288 1.00 32.69 HI C -56.026 1.00 30.00 HI C -53.916 1.00 32.66 HI C -57.401 1.00 37.41 HI C -57.349 1.00 37.23 HI O -58.544 1.00 39.18 HI N -59.813 1.00 44.39 HI C -60.277 1.00 45.61 HI C -61.347 1.00 45.98 HI O -60.881 1.00 46.47 HI C -60.796 1.00 45.73 HI O -61.880 1.00 49.79 HI N -62.961 1.00 53.39 HI C -63.230 1.00 52.69 HI C -63.434 1.00 54.43 HI O -64.230 1.00 55.63 . HI C -65.261 1.00 57.09 HI O -64.146 1.00 57.80 HI N -65.329 1.00 60.79 HI C 495 WO 2009/026558 PCT/US2008/074097 ATOM 5638 CB ALA 117 -11.572 25 ATOM 5639 C ALA 117 -9.391 26 ATOM 5640 O ALA 117 -8.832 26 ATOM 5641 N SER 118 -9.380 26 ATOM 5642 CA SER 118 -8.766 27 ATOM 5643 CB SER 118 -7.636 26 ATOM 5644 OG SER 118 -6.810 27 ATOM 5645 C SER 118 -9.807 27 ATOM 5646 O SER 118 -10.856 27 ATOM 5647 N THR 119 -9.505 29 ATOM 5648 CA THR 119 -10.462 30 ATOM 5649 CB THR 119 -9.775 31 ATOM 5650 OG1 THR 119 -9.195 32 ATOM 5651 CG2 THR 119 -10.784 32 ATOM 5652 C THR 119 -11.167 29 ATOM 5653 O THR 119 -10.543 28 ATOM 5654 N LYS 120 -12.477 29 ATOM 5655 CA LYS 120 -13.282 28 ATOM 5656 CB LYS 120 -13.685 27 ATOM 5657 CG LYS 120 -14.595 26 ATOM 5658 CD LYS 120 -15.178 25 ATOM 5659 CE LYS 120 -16.168 25 ATOM 5660 NZ LYS 120 -17.270 25 ATOM 5661 C LYS 120 -14.537 29 ATOM 5662 0 LYS 120 -15.329 30 ATOM 5663 N GLY 121 -14.715 30 ATOM 5664 CA GLY 121 -15.886 31 ATOM 5665 C GLY 121 -17.159 30 ATOM 5666 0 GLY 121 -17.129 29 ATOM 5667 N PRO 122 -18.303 30 ATOM 5668 CD PRO 122 -18.403 32 ATOM 5669 CA PRO 122 -19.596 30 ATOM 5670 CB PRO 122 -20.492 31 ATOM 5671 CG PRO 122 -19.885 32 ATOM 5672 C PRO 122 -20.173 29 ATOM 5673 O PRO 122 -19.899 30 ATOM 5674 N SER 123 -20.972 28 ATOM 5675 CA SER 123 -21.822 28 ATOM 5676 CB SER 123 -21.828 26 ATOM 5677 OG SER 123 -22.886 26 ATOM 5678 C SER 123 -23.238 28 ATOM 5679 O SER 123 -23.796 28 ATOM 5680 N VAL 124 -23.814 29 ATOM 5681 CA VAL 124 -25.099 30 ATOM 5682 CB VAL 124 -25.035 31 ATOM 5683 CGI VAL 124 -26.356 32 ATOM 5684 CG2 VAL 124 -23.886 32 ATOM 5685 C VAL 124 -26.244 29 ATOM 5686 O VAL 124 -26.151 28 ATOM 5687 N PHE 125 -27.324 29 ATOM 5688 CA PHE 125 -28.510 28 ATOM 5689 CB PHE 125 -28.723 27 ATOM 5690 CG PHE 125 -27.641 26 ATOM 5691 CDl PHE 125 -27.704 25 ATOM 5692 CD2 PHE 125 -26.560 25 ATOM 5693 CEl PHE 125 -26.712 24, ATOM 5694 CE2 PHE 125 -25.564 25 ATOM 5695 CZ PHE 125 -25.639 24 ATOM 5696 C PHE 125 -29.749 29 ATOM 5697 O PHE 125 -29.803 30 ATOM 5698 N PRO 126 -30.760 29 ATOM 5699 CD PRO 126 -30.705 28 ATOM 5700 CA PRO 126 -32.048 29 ATOM 5701 CB PRO 126 -32.641 29 ATOM 5702 CG PRO 126 -32.099 28 ATOM 5703 C PRO 126 -32.951 29 ATOM 5704 O PRO 126 -33.020 27 ATOM 5705 N LEU 127 -33.643 29 ATOM 5706 CA LEU 127 -34.690 29 ATOM 5707 CB LEU 127 -34.451 29 ATOM 5708 CG LEU 127 -33.138 29 ATOM 5709 CDl LEU 127 -33.050 29 ATOM 5710 CD2 LEU 127 -33.061 27 ATOM 5711 C LEU 127 -36.039 29 ATOM 5712 O LEU 127 -36.562 30 ATOM 5713 N ALA 128 -36.595 29
-64.983 1.00 60.52 HI c -65.946 1.00 62.07 HI c -65.240 1.00 62.18 HI 0 -67.274 1.00 64.43 HI N -67.996 1.00 65.80 HI c -68.890 1.00 66.05 HI c -69.309 1.00 68.87 HI 0 -68.845 1.00 65.94 HI c -69.164 1.00 65.51 HI 0 -69.211 1.00 66.97 HI N -69.893 1.00 67.67 HI c -70.430 1.00 67.99 HI c -69.339 1.00 68.98 HI 0 -71.146 1.00 67.51 HI c -71.054 1.00 67.83 HI c -71.848 1.00 67.72 HI 0 -71.141 1.00 67.80 HI N -72.217 1.00 68.20 HI c -71.889 1.00 67.62 HI c -72.931 1.00 67.51 HI c -72.436 1.00 69.11 HI c -73.437 1.00 69.25 HI c -73.782 1.00 70.85 HI N -72.432 1.00 69.04 HI c -71.508 1.00 69.38 HI 0 -73.659 1.00 69.06 HI N -73.982 1.00 68.10 HI c -73.922 1.00 68.13 HI c -74.089 1.00 67.67 HI 0 -73.678 1.00 67.96 HI N -73.433 1.00 67.50 HI c -73.523 1.00 68.40 HI c -72.925 1.00 68.31 HI c -73.381 1.00 68.44 HI c -74.819 1.00 69.03 HI c -75.906 1.00 69.06 HI 0 -74.688 1.00 69.50 HI N -75.776 1.00 70.46 HI c -75.823 1.00 70.16 HI c -76.631 1.00 70.42 HI 0 -75.532 1.00 71.61 HI c -74.450 1.00 71.85 HI 0 -76.536 1.00 71.93 HI N -76.368 1.00 71.46 HI c -76.898 1.00 70.79 HI c -76.640 1.00 69.89 HI c -76.236 1.00 68.40 HI c -77.073 1.00 72.64 HI c -78.255 1.00 73.01 HI 0 -76.338 1.00 73.89 HI N -76.894 1.00 75.85 HI c -76.247 1.00 76.97 HI c -76.557 1.00 78.42 Hi c -77.702 1.00 78.83 HI c -75.704 1.00 78.71 HI c -77.992 1.00 79.49 HI c -75.987 1.00 79.38 Hi c -77.134 1.00 80.12 HI c -76.671 1.00 77.12 HI c -75.731 1.00 76.96 HI 0 -77.543 1.00 78.18 HI N -78.793 1.00 78.12 Hi c -77.388 1.00 78.24 HI c -78.789 1.00 77.98 HI c -79.358 1.00 77.57 HI c -76.376 1.00 78.94 HI c -76.344 1.00 78.95 HI 0 -75.555 1.00 80.12 HI ' N -74.695 1.00 81.26 HI c -73.239 1.00 80.50 HI c -72.604 1.00 79.91 HI c -71.171 1.00 79.12 HI c -72.647 1.00 79.76 . HI c -75.174 1.00 82.39 HI c -74.639 1.00 82.90 Hi 0 -76.187 1.00 83.36 HI N 496 WO 2009/026558 PCT/US2008/074097
ATOM 5714 CA ALA 128 -37.769 29.753 -76.891 1.00 84.32 HI c ATOM 5715 CB ALA 128 -37.982 28.959 -78.174 1.00 84.16 HI c ATOM 5716 C ALA 128 -39.031 29.711 -76.036 1.00 85.07 HI c ATOM 5717 O ALA 128 -39.252 28.766 -75.275 1.00 85.35 HI 0 ATOM 5718 N PRO 129 -39.884 30.740 -76.164 1.00 85.56 HI N ATOM 5719 CD PRO 129 -39.691 31.851 -77.113 1.00 85.77 HI -C ATOM 5720 CA PRO 129 -41.121 30.890 -75.387 1.00 85.80 HI c ATOM 5721 CB PRO 129 -41.604 32.293 -75.747 1.00 85.81 HI c ATOM 5722 CG PRO 129 -41.019 32.555 -77.094 1.00 86.05 HI c ATOM 5723 C PRO 129 -42.175 29.827 -75.697 1.00 86.17 HI c ATOM 5724 O PRO 129 -42.318 29.391 -76.840 1.00 85.88 HI 0 ATOM 5725 N SER 130 -42.911 29.421 -74.667 1.00 86.84 HI N ATOM 5726 CA SER 130 -43.963 28.421 -74.816 1.00 87.43 HI c ATOM 5727 CB SER 130 -44.385 27.890 -73.441 1.00 87.92 HI c ATOM 5728 OG SER 130 -43.298 27.275 -72.771 1.00 88.97 HI 0 ATOM 5729 C SER 130 -45.175 29.014 -75.531 1.00 87.44 HI c ATOM 5730 O SER 130 -45.780 28.371 -76.391 1.00 87.06 HI 0 ATOM 5731 N GLY 136 -50.193 34.409 -68.488 1.00 99.67 HI N ATOM 5732 CA GLY 136 -51.016 34.123 -69.648 1.00 99.80 HI c ATOM 5733 C GLY 136 -51.050 35.272 -70.638 1.00100.02 HI c ATOM 5734 0 GLY 136 -51.114 35.055 -71.850 1.00100.03 HI 0 ATOM 5735 N GLY 137 -51.007 36.498 -70.123 1.00 99.85 HI N ATOM 5736 CA GLY 137 -50.995 37.666 -70.986 1.00 99.13 HI c ATOM 5737 C GLY 137 -49.608 37.961 -71.527 1.00 98.66 HI c ATOM 5738 0 GLY 137 -49.456 38.642 -72.542 1.00 98.56 HI 0 ATOM 5739 N THR 138 -48.591 37.446 -70.842 1.00 98.05 HI N ATOM 5740 CA THR 138 -47.209 37.602 -71.282 1.00 96.71 HI c ATOM 5741 CB THR 138 -46.393 38.445 -70.280 1.00 96.65 HI c ATOM 5742 OG1 THR 138 -46.424 37.817 -68.991 1.00 96.53 HI 0 ATOM 5743 CG2 THR 138 -46.967 39.851 -70.175 1.00 95.98 HI c ATOM 5744 C THR 138 -46.526 36.247 -71.444 1.00 95.56 HI c ATOM 5745 O THR 138 -46.947 35.250 -70.853 1.00 95.36 HI 0 ATOM 5746 N ALA 139 -45.472 36.220 -72.253 1.00 94.21 HI N ATOM 5747 CA ALA 139 -44.659 35.022 -72.418 1.00 92.92 HI c ATOM 5748 CB ALA 139 -44.780 34.497 -73.846 1.00 93.04 HI c ATOM 5749 C ALA 139 -43.202 35.339 -72.095 1.00 91.71 HI c ATOM 5750 O ALA 139 -42.713 36.430 -72.395 1.00 91.15 HI 0 ATOM 5751 N ALA 140 -42.513 34.383 -71.480 1.00 90.37 HI N ATOM 5752 CA ALA 140 -41.123 34.582 -71.092 1.00 88.70 HI c ATOM 5753 CB ALA 140 -40.928 34.187 -69.634 1.00 89.09 HI c ATOM 5754 C ALA 140 -40.178 33.783 -71.982 1.00 87.42 HI c ATOM 5755 O ALA 140 -40.491 32.667 -72.400 1.00 86.82 HI 0 ATOM 5756 N LEU 141 -39.020 34.368 -72.267 1.00 86.13 HI N ATOM 5757 CA LEU 141 -38.002 33.722 -73.084 1.00 85.33 HI c ATOM 5758 CB LEU 141 -38.303 33.941 -74.572 1.00 85.25 HI c ATOM 5759 CG LEU 141 -38.499 35.376 -75.081 1.00 85.32 HI c ATOM 5760 CDl LEU 141 -37.162 36.103 -75.165 1.00 84.61 HI c ATOM 5761 CD2 LEU 141 -39.154 35.334 -76.453 1.00 85.35 HI c ATOM 5762 C LEU 141 -36.621 34.275 -72.741 1.00 85.01 HI c ATOM 5763 O LEU 141 -36.496 35.396 -72.247 1.00 85.36 HI 0 ATOM 5764 N GLY 142 -35.587 33.484 -73.001 1.00 83.90 HI N ATOM 5765 CA GLY 142 -34.233 33.941 -72.752 1.00 83.19 HI c ATOM 5766 C GLY 142 -33.231 33.175 -73.589 1.00 82.79 HI c ATOM 5767 0 GLY 142 -33.609 32.491 -74.539 1.00 83.09 HI 0 ATOM 5768 N CYS 143 -31.952 33.289 -73.248 1.00 82.17 HI N ATOM 5769 CA CYS 143 -30.940 32..4 65 -73.890 1.00 81.85 HI c ATOM 5770 C CYS 143 -29.954 31.864 -72.882 1.00 80.13 HI c ATOM 5771 0 CYS 143 -29.537 32.518 -71.925 1.00 79.94 HI 0 ATOM 5772 CB CYS 143 -30.204 33.270 -74.974 1.00 83.41 HI c ATOM 5773 SG CYS 143 -28.939 34.449 -74.400 1.00 87.73 HI s ATOM 5774 N LEU 144 -29.601 30.602 -73.109 1.00 78.24 HI N ATOM 5775 CA LEU 144 -28.826 29.808 -72.161 1.00 75.92 HI c ATOM 5776 CB LEU 144 -29.286 28.349 -72.233 1.00 75.88 HI c ATOM 5777 CG LEU 144 -28.506 27.285 -71.462 1.00 76.15 HI c ATOM 5778 CDl LEU 144 -28.543 27.594 -69.977 1.00 76.40 HI c ATOM 5779 CD2 LEU 144 -29.115 25.915 -71.739 1.00 75.59 HI c ATOM 5780 C LEU 144 -27.329 29.895 -72.449 1.00 74.33 HI c ATOM 5781 O LEU 144 -26.890 29.633 -73.566 1.00 74.67 HI 0 ATOM 5782 N VAL 145 -26.549 30.260 -71.436 1.00 72.28 HI N ATOM 5783 CA VAL 145 -25.103 30.401 -71.591 1.00 70.90 HI c ATOM 5784 CB VAL 145 -24.623 31.746 -71.003 1.00 69.27 HI c ATOM 5785 CGI VAL 145 -23.127 31.873 -71.147 1.00 69.00 HI c ATOM 5786 CG2 VAL 145 -25.319 32.894 -71.705 1.00 68.74 HI c ATOM 5787 C VAL 145 -24.358 29.254 -70.899 1.00 71.16 HI c ATOM 5788 O VAL 145 -24.173 29.269 -69.680 1.00 71.43 HI 0 ATOM 5789 N LYS 146 -23.927 28 .266 -71.684 1.00 7 0.62 HI N 497 WO 2009/026558 PCT/US2008/074097 ATOM 5790 CA LYS 146 -23.358 27 ATOM 5791 CB LYS 146 -23.870 25 ATOM 5792 CG LYS 146 -25.286 25 ATOM 5793 CD LYS 146 -25.822 24 ATOM 5794 CE LYS 146 -24.948 23 ATOM 5795 NZ LYS 146 -25.126 22 ATOM 5796 C LYS 146 -21.831 26 ATOM 5797 0 LYS 146 -21.173 27 ATOM 5798 N ASP 147 -21.286 26 ATOM 5799 CA ASP 147 -19.906 25 ATOM 5800 CB ASP 147 -19.759 24 ATOM 5801 CG ASP 147 -20.730 23 ATOM 5802 OD1 ASP 147 -20.976 23 ATOM 5803 OD2 ASP 147 -21.250 23 ATOM 5804 C ASP 147 -18.857 26 ATOM 5805 O ASP 147 -18.121 26 ATOM 5806 N TYR 148 -18.775 27 ATOM 5807 CA TYR 148 -17.760 28 ATOM 5808 CB TYR 148 -18.411 30 ATOM 5809 CG TYR 148 -19.292 30 ATOM 5810 CDl TYR 148 -18.787 31 ATOM 5811 CEl TYR 148 -19.594 32 ATOM 5812 CD2 TYR 148 -20.632 30 ATOM 5813 CE2 TYR 148 -21.448 31 ATOM 5814 CZ TYR 148 -20.923 32 ATOM 5815 OH TYR 148 -21.731 32 ATOM 5816 C TYR 148 -16.920 29 ATOM 5817 O TYR 148 -17.296 28 ATOM 5818 N PHE 149 -15.777 29 ATOM 5819 CA PHE 149 -14.897 30 ATOM 5820 CB PHE 149 -14.209 28 ATOM 5821 CG PHE 149 -13.335 28 ATOM 5822 CDl PHE 149 -12.012 29 ATOM 5823 CD2 PHE 149 -13.843 28 ATOM 5824 CEl PHE 149 -11.210 29 ATOM 5825 CE2 PHE 149 -13.047 28 ATOM 5826 CZ PHE 149 -11.727 29 ATOM 5827 C PHE 149 -13.844 31 ATOM 5828 O PHE 149 -13.365 31 ATOM 5829 N PRO 150 -13.473 32 ATOM 5830 CD PRO 150 -12.274 32 ATOM 5831 CA PRO 150 -14.104 32 ATOM 5832 CB PRO 150 -13.037 32 ATOM 5833 CG PRO 150 -12.295 33 ATOM 5834 C PRO 150 -15.389 33 ATOM 5835 O PRO 150 -16.077 32 ATOM 5836 N GLU 151 -15.700 33 ATOM 5837 CA GLU 151 -16.743 34 ATOM 5838 CB GLU 151 -17.550 34 ATOM 5839 CG GLU 151 -18.290 33 ATOM 5840 CD GLU 151 -19.458 33 ATOM 5841 OE1 GLU 151 -20.618 33 ATOM 5842 OE2 GLU 151 -19.216 33 ATOM 5843 C GLU 151 -16.079 36 ATOM 5844 0 GLU 151 -14.868 36 ATOM 5845 N PRO 152 -16.867 37 ATOM 5846 CD PRO 152 -16.420 38 ATOM 5847 CA PRO 152 -18.292 37 ATOM 5848 CB PRO 152 -18.849 38 ATOM 5849 CG PRO 152 -17.712 39 ATOM 5850 C PRO 152 -18.556 36 ATOM 5851 O PRO 152 -17.630 36 ATOM 5852 N VAL 153 -19.830 36 ATOM 5853 CA VAL 153 -20.266 37 ATOM 5854 CB VAL 153 -20.722 35 ATOM 5855 CGI VAL 153 -19.573 34 ATOM 5856 CG2 VAL 153 -21.909 35 ATOM 5857 C VAL 153 -21.428 38 ATOM 5858 O VAL 153 -22.353 37 ATOM 5859 N THR 154 -21.367 39 ATOM 5860 CA THR 154 -22.408 40 ATOM 5861 CB THR 154 -21.808 41 ATOM 5862 OG1 THR 154 -21.139 41 ATOM 5863 CG2 THR 154 -20.811 41 ATOM 5864 C THR 154 -23.417 39 ATOM 5865 O THR 154 -23.034 39 -71.141 1.00 70.17 HI c -71.925 1.00 71.40 HI c -71.583 1.00 74.93 HI c -72.605 1.00 78.01 HI c -72.701 1.00 79.46 HI c -71.534 1.00 80.50 HI N -71.127 1.00 68.82 HI C -72. Oil 1.00 68.87 HI O -70.106 1.00 66.87 HI N -70.110 1.00 64.95 HI C -71.129 1.00 64.08 HI C -70.877 1.00 65.39 HI c -69.697 1.00 64.41 HI 0 -71.8 62 1.00 66.30 HI 0 -70.390 1.00 64.29 HI c -71.368 1.00 64.65 HI 0 -69.527 1.00 63.41 HI N -69.687 1.00 63.64 HI c -70.061 1.00 63.45 HI c -68.984 1.00 62.08 HI c -68.081 1.00 61.94 HI c -67.112 1.00 61.63 HI c -68.887 1.00 62.19 HI c -67.920 1.00 62.61 HI c -67.037 1.00 61.07 HI c -66.082 1.00 61.02 HI 0 -68.425 1.00 64.03 HI c -67.348 1.00 63.78 HI 0 -68.572 1.00 64.42 HI N -67.446 1.00 65.06 HI c -66.972 1.00 63.77 HI c -65.765 1.00 62.58 Hi c -65.904 1.00 61.56 HI c -64.489 1.00 62.08 HI c -64.795 1.00 60.99 HI c -63.373 1.00 62.34 HI c -63.527 1.00 61.88 HI c -67.865 1.00 66.30 HI c -68.998 1.00 67.25 HI 0 - 66.955 1.00 67.74 HI N -67.107 1.00 67.53 HI c -65.645 1.00 68.63 HI c -64.841 1.00 67.62 HI c -65.866 1.00 67.46 HI c -65.742 1.00 70.45 HI c -66.764 1.00 71.47 HI 0 -64.663 1.00 71.80 HI N -64.676 1.00 72.52 HI c -63.378 1.00 72.76 HI c -63.155 1.00 74.07 HI c -62.204 1.00 74.56 HI c -62.665 1.00 74.92 Hi 0 -60.997 1.00 73.75 HI 0 -64.806 1.00 73.24 HI c -64.624 1.00 72.62 HI 0 -65.113 1.00 74.62 HI N -64.959 1.00 74.59 HI c -65.452 1.00 75.10 HI c -64.867 1.00 75.76 HI c -65.029 1.00 75.41 HI c -66.952 1.00 75.76 HI c -67.761 1.00 75.62 HI 0 -67.312 1.00 76.74 HI N -68.676 1.00 78.44 HI c -69.410 1.00 78.41 HI c -69.489 1.00 78.22 Hi c -68.700 1.00 78.16 HI c -68.651 1.00 79.27 HI c -67.848 1.00 79.85 HI 0 -69.528 1.00 7 9.67 HI N -69.613 1.00 79.68 HI c -69.963 1.00 79.51 HI c -71.228 1.00 79.48 . HI 0 -68.897 1.00 78.20 HI c -70.693 1.00 80.21 HI c -71.812 1.00 80.43 HI 0 498 WO 2009/026558 PCT/US2008/074097 ATOM 58 66 N VAL 155 -24.703 39 ATOM 5867 CA VAL 155 -25.752 39 ATOM 5868 CB VAL 155 -26.580 38 ATOM 5869 CGI VAL 155 -27.614 37 ATOM 5870 CG2 VAL 155 -25.666 37 ATOM 5871 C VAL 155 -26.701 40 ATOM 5872 O VAL 155 -27.351 41 ATOM 5873 N SER 156 -26.772 41 ATOM 5874 CA SER 156 -27.654 42 ATOM 5875 CB SER 156 -26.847 43 ATOM 5876 OG SER 156 -27.652 44 ATOM 5877 C SER 156 -28.739 41 ATOM 5878 O SER 156 -28.596 40 ATOM 5879 N TRP 157 -29.825 42 ATOM 5880 CA TRP 157 -30.919 42 ATOM 5881 CB TRP 157 -32.180 41 ATOM 5882 CG TRP 157 -32.120 40 ATOM 5883 CD2 TRP 157 -32.489 39 ATOM 5884 CE2 TRP 157 -32.248 38 ATOM 5885 CE3 TRP 157 -33.000 38 ATOM 5886 CDl TRP 157 -31.684 40 ATOM 5887 NEl TRP 157 -31.757 39 ATOM 5888 CZ2 TRP 157 -32.498 37 ATOM 5889 CZ3 TRP 157 -33.247 37 ATOM 5890 CH2 TRP 157 -32.997 36 ATOM 5891 C TRP 157 -31.219 43 ATOM 5892 O TRP 157 -31.410 44 ATOM 5893 N ASN 158 -31.260 42 ATOM 5894 CA ASN 158 -31.495 43 ATOM 5895 CB ASN 158 -32.946 44 ATOM 5896 CG ASN 158 -33.946 43 ATOM 5897 OD1 ASN 158 -33.691 42 ATOM 5898 ND2 ASN 158 -35.091 43 ATOM 5899 C ASN 158 -30.536 45 ATOM 5900 0 ASN 158 -30.939 46 ATOM 5901 N SER 159 -29.264 44 ATOM 5902 CA SER 159 -28.203 45 ATOM 5903 CB SER 159 -27.970 46 ATOM 5904 OG SER 159 -27.479 45 ATOM 5905 C SER 159 -28.471 46 ATOM 5906 O SER 159 -27.791 47 ATOM 5907 N GLY 160 -29.459 46 ATOM 5908 CA GLY 160 -29.716 47 ATOM 5909 C GLY 160 -31.108 48 ATOM 5910 0 GLY 160 -31.570 48 ATOM 5911 N ALA 161 -31.779 48 ATOM 5912 CA ALA 161 -33.105 48 ATOM 5913 CB ALA 161 -33.569 48 ATOM 5914 C ALA 161 -34.112 47 ATOM 5915 O ALA 161 -35.083 48 ATOM 5916 N LEU 162 -33.874 46 ATOM 5917 CA LEU 162 -34.769 46 ATOM 5918 CB LEU 162 -35.189 44 ATOM 5919 CG LEU 162 -36.018 43 ATOM 5920 CDl LEU 162 -37.267 44 ATOM 5921 CD2 LEU 162 -36.384 42 ATOM 5922 C LEU 162 -34.106 45 ATOM 5923 O LEU 162 -33.176 44 ATOM 5924 N THR 163 -34.591 46 ATOM 5925 CA THR 163 -34.069 46 ATOM 5926 CB THR 163 -33.414 47 ATOM 5927 OG1 THR 163 -34.374 48 ATOM 5928 CG2 THR 163 -32.218 47 ATOM 5929 C THR 163 -35.194 45 ATOM 5930 O THR 163 -34.957 45 ATOM 5931 N SER 164 -36.420 46 ATOM 5932 CA SER 164 -37.584 45 ATOM 5933 CB SER 164 -38.737 46 ATOM 5934 OG SER 164 -39.855 46 ATOM 5935 C SER 164 -38.016 44 ATOM 5936 O SER 164 -38.185 43 ATOM 5937 N GLY 165 -38.193 43 ATOM 5938 CA GLY 165 -38.616 42 ATOM 5939 C GLY 165 -37.452 41 ATOM 5940 0 GLY 165 -37.651 40 ATOM 5941 N VAL 166 -36.233 42
-70.359 1.00 80.71 HI N -71.330 1.00 81.00 HI C -70.910 1.00 80.93 HI C -71.979 1.00 8 0.65 HI c -70.689 1.00 81.15 HI c -71.503 1.00 81.78 HI c -70.551 1.00 81.71 HI 0 -72.727 1.00 82.68 HI N -73.046 1.00 83.16 HI c -73.674 1.00 83.30 HI c -73.878 1.00 84.63 HI 0 -74.014 1.00 83.16 HI c -74.658 1.00 82.89 HI 0 -74.110 1.00 83.58 HI N -75.001 1.00 84 . 15 HI c -74.188 1.00 83.42 HI c -73.494 1.00 83.40 HI c -74.042 1.00 83.53 HI c -73.047 1.00 83.19 HI c -75.277 1.00 83.42 HI c -72.224 1.00 83.06 HI c -71.947 1.00 82.93 HI N -73.250 1.00 83.39 HI c -75.476 1.00 83.62 HI c -74.468 1.00 83.34 HI c -76.041 1.00 84.76 HI c -75.706 1.00 84.03 HI 0 -77.306 1.00 85.58 HI N -78.411 1.00 8 6.37 HI c -78.389 1.00 86.40 HI c -78.553 1.00 87.21 HI c -79.268 1.00 86.86 HI 0 -77.889 1.00 8 6.97 HI N -78.315 1.00 86.98 HI c -78.439 1.00 86.86 HI 0 -78.077 1.00 87.36 HI N -78.013 1.00 87.62 HI c -79.398 1.00 87.30 HI c -80.297 1.00 86.83 HI 0 -76.999 1.00 87.96 HI c -76.998 1.00 87.94 HI 0 -76.136 1.00 88.50 HI N -75.062 1.00 88.84 HI c -75.103 1.00 88.98 HI c -74.120 1.00 88.61 HI 0 -76.242 1.00 89.24 HI N -76.430 1.00 89.63 HI c -77.868 1.00 89.23 HI c -75.461 1.00 89.76 HI c -75.067 1.00 89.81 HI 0 -75.084 1.00 89.21 HI N -74.182 1.00 88.42 HI c -74.806 1.00 87.77 HI c -73.923 1.00 87.40 HI c -73.439 1.00 86.87 HI c -74.710 1.00 86.79 HI c -72.833 1.00 88.21 HI c -72.727 1.00 88.43 HI 0 -71.804 1.00 87.73 HI N -70.453 1.00 87.13 HI c -69.937 1.00 87.76 HI c -69.962 1.00 88.69 HI 0 -70.804 1.00 87.58 HI c -69.503 1.00 86.16 HI c -68.449 1.00 85.76 HI 0 -69.888 1.00 84.83 HI N -69.052 1.00 83.71 HI c -69.475 1.00 84 . 14 HI c -68.616 1.00 84 . 04 HI 0 -69.149 1.00 82.36 HI c -70.244 1.00 82.47 HI 0 -67.995 1.00 80.97 HI N -67.972 1.00 79.30 . HI c -68.016 1.00 78.12 HI c -68.120 1.00 77.82 HI 0 -67.935 1.00 76.72 HI N 499 WO 2009/026558 PCT/US2008/074097 ATOM 5942 CA VAL 166 -35.037 41 ATOM 5943 CB VAL 166 -33.905 41 ATOM 5944 CGI VAL 166 -32.673 41 ATOM 5945 CG2 VAL 166 -34.365 42 ATOM 5946 C VAL 166 -34.526 40 ATOM 5947 O VAL 166 -34.253 41 ATOM 5948 N HIS 167 -34.396 39 ATOM 5949 CA HIS 167 -33.935 38 ATOM 5950 CB HIS 167 -35.057 38 ATOM 5951 CG HIS 167 -34.777 37 ATOM 5952 CD2 HIS 167 -33.696 37 ATOM 5953 NDl HIS 167 -35.684 36 ATOM 5954 CEl HIS 167 -35.176 36 ATOM 5955 NE2 HIS 167 -33.971 37 ATOM 5956 C HIS 167 -32.708 38 ATOM 5957 0 HIS 167 -32.783 37 ATOM 5958 N THR 168 -31.581 38 ATOM 5959 CA THR 168 -30.335 37 ATOM 5960 CB THR 168 -29.156 38 ATOM 5961 OG1 THR 168 -29.449 39 ATOM 5962 CG2 THR 168 -27.878 37 ATOM 5963 C THR 168 -30.026 36 ATOM 5964 O THR 168 -29.731 37 ATOM 5965 N PHE 169 -30.093 35 ATOM 5966 CA PHE 169 -29.878 34 ATOM 5967 CB PHE 169 -30.615 33 ATOM 5968 CG PHE 169 -32.108 33 ATOM 5969 CDl PHE 169 -32.748 33 ATOM 5970 CD2 PHE 169 -32.877 32 ATOM 5971 CEl PHE 169 -34.128 34 ATOM 5972 CE2 PHE 169 -34.257 33 ATOM 5973 CZ PHE 169 -34.884 33 ATOM 5974 C PHE 169 -28.398 34 ATOM 5975 O PHE 169 -27.663 34 ATOM 5976 N PRO 170 -27.942 34 ATOM 5977 CD PRO 170 -28.702 34 ATOM 5978 CA PRO 170 -26.555 33 ATOM 5979 CB PRO 170 -26.526 34 ATOM 5980 CG PRO 170 -27.618 35 ATOM 5981 C PRO 170 -26.132 32 ATOM 5982 O PRO 170 -26.948 31 ATOM 5983 N ALA 171 -24.847 32 ATOM 5984 CA ALA 171 -24.329 31 ATOM 5985 CB ALA 171 -22.955 31 ATOM 5986 C ALA 171 -24.243 30 ATOM 5987 O ALA 171 -24.030 30 ATOM 5988 N VAL 172 -24.415 28 ATOM 5989 CA VAL 172 -24.118 27 ATOM 5990 CB VAL 172 -25.148 26 ATOM 5991 CGI VAL 172 -25.070 26 ATOM 5992 CG2 VAL 172 -24.898 25 ATOM 5993 C VAL 172 -22.721 27 ATOM 5994 O VAL 172 -22.304 27 ATOM 5995 N LEU 173 -21.990 26 ATOM 5996 CA LEU 173 -20.688 26 ATOM 5997 CB LEU 173 -19.698 26, ATOM 5998 CG LEU 173 -18.205 26 ATOM 5999 CDl LEU 173 -17.376 26 ATOM 6000 CD2 LEU 173 -17.858 25 ATOM 6001 C LEU 173 -20.879 24 ATOM 6002 O LEU 173 -21.379 23 ATOM 6003 N GLN 174 -20.482 23 ATOM 6004 CA GLN 174 -20.744 22 ATOM 6005 CB GLN 174 -21.044 22 ATOM 6006 CG GLN 174 -22.139 23 ATOM 6007 CD GLN 174 -22.385 23 ATOM 6008 OE1 GLN 174 -23.070 22 ATOM 6009 NE2 GLN 174 -21.823 23 ATOM 6010 C GLN 174 -19.565 21 ATOM 6011 0 GLN 174 -18.445 22 ATOM 6012 N SER 175 -19.820 20 ATOM 6013 CA SER 175 -18.777 19 ATOM 6014 CB SER 175 -19.346 18 ATOM 6015 OG SER 175 -19.975 17 ATOM 6016 C SER 175 -17.610 19 ATOM 6017 O SER 175 -16.541 18 -68.040 1.00 75.81 HI c -68.770 1.00 75.90 HI c -68.856 1.00 75.62 HI c -70.161 1.00 75.64 HI c -66.670 1.00 75.14 HI c -65.809 1.00 75.37 HI D -66.480 1.00 73.47 HI N -65.214 1.00 72.00 HI C -64.569 1.00 72.27 HI C -63.155 1.00 72.47 HI c -62.363 1.00 72.15 HI c -62.390 1.00 71.80 HI N -61.189 1.00 71.72 HI c -61.147 1.00 72.50 HI N -65.438 1.00 70.88 HI C -66.121 1.00 69.91 HI 0 -64.855 1.00 70.00 HI N -65.027 1.00 68.86 HI C -65.269 1.00 69.61 HI c -66.394 1.00 7 0.62 HI 0 -65.548 1.00 69.75 HI c -63.803 1.00 67.17 HI c -62.727 1.00 67.02 HI 0 -63.979 1.00 64.86 HI N -62.881 1.00 62.90 HI c -63.150 1.00 62.05 HI c -63.176 1.00 62.68 HI c -64.266 1.00 62.88 HI c -62.118 1.00 62.49 HI c -64.299 1.00 62.61 HI c -62.144 1.00 62.55 HI c -63.237 1.00 62.31 HI c -62.683 1.00 61.96 HI c -63.645 1.00 61.82 HI 0 -61.421 1.00 60.72 HI N -60.244 1.00 60.03 HI c -61.078 1.00 59.89 HI c -59.554 1.00 59.29 HI c -59.246 1.00 59.11 HI c -61.561 1.00 59.02 HI c -61.647 1.00 57.43 HI 0 -61.873 1.00 58.34 HI N -62.496 1.00 58.50 HI c -63.094 1.00 57.77 HI c -61.517 1.00 58.57 HI c -60.320 1.00 57.67 HI 0 -62.035 1.00 58.56 HI N -61.268 1.00 59.16 HI c -61.553 1.00 58.86 HI c -63. Oil 1.00 59.09 HI c -60.632 1.00 60.06 HI c -61.641 1.00 59.63 HI c -62.796 1.00 59.35 HI 0 -60.663 1.00 59.79 HI N -60.937 1.00 60.87 HI c -59.811 1.00 59.98 HI c -60.167 1.00 60.10 HI c -58.905 1.00 57.51 HI c -61.201 1.00 58.71 HI c -61.041 1.00 61.60 HI c -60.110 1.00 62.78 HI 0 -62.172 1.00 62.51 HI N -62.446 1.00 63.92 HI c -63.929 1.00 65.18 HI c -64.450 1.00 67.24 HI c -65.928 1.00 69.04 HI c -66.337 1.00 70.60 HI 0 -66.741 1.00 68.01 HI N -62.050 1.00 63.96 HI c -61.895 1.00 64.54 HI 0 -61.896 1.00 63.64 HI N -61.501 1.00 63.62 HI c -61.407 1.00 64.57 . HI c -62.616 1.00 66.59 HI 0 -62.481 1.00 63.00 HI c -62.197 1.00 64.06 HI 0 500 WO 2009/026558 PCT/US2008/074097 ATOM 6018 N SER 176 -17.816 20 ATOM 6019 CA SER 176 -16.776 20 ATOM 6020 CB SER 176 -17.399 20 ATOM 6021 OG SER 176 -17.863 21 ATOM 6022 C SER 176 -15.806 21 ATOM 6023 O SER 176 -14.733 21 ATOM 6024 N GLY 177 -16.191 22 ATOM 6025 CA GLY 177 -15.384 23 ATOM 6026 C GLY 177 -15.778 24 ATOM 6027 0 GLY 177 -15.157 25 ATOM 6028 N LEU 178 -16.822 24 ATOM 6029 CA LEU 178 -17.298 25 ATOM 6030 CB LEU 178 -17.436 24 ATOM 6031 CG LEU 178 -16.115 24 ATOM 6032 CD1 LEU 178 -16.387 23 ATOM 6033 CD2 LEU 178 -15.268 25 ATOM 6034 C LEU 178 -18.631 25 ATOM 6035 O LEU 178 -19.428 25 ATOM 6036 N TYR 179 -18.864 27 ATOM 6037 CA TYR 179 -20.064 27 ATOM 6038 CB TYR 179 -19.725 29 ATOM 6039 CG TYR 179 -18.831 29 ATOM 6040 CD1 TYR 179 -19.346 29 ATOM 6041 CEl TYR 179 -18.540 29 ATOM 6042 CD2 TYR 179 -17.482 29 ATOM 6043 CE2 TYR 179 -16.667 30 ATOM 6044 CZ TYR 179 -17.200 29 ATOM 6045 OH TYR 179 -16.394 30 ATOM 6046 C TYR 179 -21.174 27 ATOM 6047 O TYR 179 -20.914 27 ATOM 6048 N SER 180 -22.413 27 ATOM 6049 CA SER 180 -23.589 27 ATOM 6050 CB SER 180 -24.290 26 ATOM 6051 OG SER 180 -23.501 25 ATOM 6052 C SER 180 -24.554 28 ATOM 6053 O SER 180 -24.671 28 ATOM 6054 N HIS 181 -25.242 29 ATOM 6055 CA HIS 181 -26.293 30 ATOM 6056 CB HIS 181 -25.689 31 ATOM 6057 CG HIS 181 -25.466 33 ATOM 6058 CD2 HIS 181 -24.413 33 ATOM 6059 ND1 HIS 181 -26.387 34 ATOM 6060 CEl HIS 181 -25.909 34 ATOM 6061 NE2 HIS 181 -24.713 34 ATOM 6062 C HIS 181 -27.264 31 ATOM 6063 0 HIS 181 -26.990 30 ATOM 6064 N SER 182 -28.402 31 ATOM 6065 CA SER 182 -29.458 32 ATOM 6066 CB SER 182 -30.702 31 ATOM 6067 OG SER 182 -30.418 29 ATOM 6068 C SER 182 -29.827 33 ATOM 6069 O SER 182 -29.763 34 ATOM 6070 N SER 183 -30.205 34 ATOM 6071 CA SER 183 -30.900 35 ATOM 6072 CB SER 183 -30.Ill 36 ATOM 6073 OG SER 183 -30.820 37, ATOM 6074 C SER 183 -32.276 35 ATOM 6075 O SER 183 -32.414 34 ATOM 6076 N VAL 184 -33.294 35 ATOM 6077 CA VAL 184 -34.658 35 ATOM 6078 CB VAL 184 -35.491 34 ATOM 6079 CGI VAL 184 -36.949 34 ATOM 6080 CG2 VAL 184 -34.941 33 ATOM 6081 C VAL 184 -35.378 37 ATOM 6082 O VAL 184 -35.375 37 ATOM 6083 N VAL 185 -35.992 37 ATOM 6084 CA VAL 185 -36.816 38 ATOM 6085 CB VAL 185 -36.362 39 ATOM 6086 CGI VAL 185 -36.360 38 ATOM 6087 CG2 VAL 185 -37.281 40 ATOM 6088 C VAL 185 -38.281 38 ATOM 6089 O VAL 185 -38.632 37 ATOM 6090 N THR 186 -39.132 38 ATOM 6091 CA THR 186 -40.571 38 ATOM 6092 CB THR 186 -41.244 38 ATOM 6093 OG1 THR 186 -40.924 39 -63.632 1.00 61.79 HI N -64.650 1.00 60.10 HI C -66.025 1.00 59.94 HI C -66.150 1.00 60.80 HI 0 -64.355 1.00 59.39 HI c -64.951 1.00 59.39 HI 0 -63.443 1.00 57.70 HI N -63.176 1.00 56.90 HI c -64.068 1.00 56.87 HI c -64.043 1.00 56.89 HI 0 -64.860 1.00 5 6.63 HI N -65.778 1.00 57.28 HI c -67.188 1.00 57.13 HI c -67.872 1.00 56.25 HI c -69.230 1.00 55.52 HI c -68.017 1.00 56.22 HI c -65.328 1.00 57.07 HI c -64.665 1.00 55.79 HI 0 -65.697 1.00 57.71 HI N -65.280 1.00 59.38 HI c -64.961 1.00 58.68 HI c -63.754 1.00 58.53 HI c -62.465 1.00 58.26 HI c -61.356 1.00 58.61 HI c -63.904 1.00 57.93 HI c -62.803 1.00 58.41 HI c -61.531 1.00 58.60 HI c -60.438 1.00 56.00 HI 0 -66.328 1.00 60.05 HI c -67.531 1.00 59.38 HI 0 -65.852 1.00 61.78 HI N -66.698 1.00 64.17 HI c -66.917 1.00 63.61 HI c -67.708 1.00 65.69 HI 0 -66.024 1.00 65.91 HI c -64.797 1.00 65.96 HI 0 -66.823 1.00 67.43 HI N -66.290 1.00 69.34 HI c -65.606 1.00 70.05 HI c -66.524 1.00 70.38 HI c -67.309 1.00 70.89 HI c -66.676 1.00 70.55 HI N -67.513 1.00 71.32 HI c -67.911 1.00 71.85 HI N -67.371 1.00 70.14 HI C -68.564 1.00 69.87 HI 0 -66.941 1.00 71.10 HI N -67.859 1.00 70.94 HI C -67.636 1.00 70.38 HI c -67.830 1.00 68.38 HI 0 -67.688 1.00 71.53 HI c -66.584 1.00 71.22 HI 0 -68.794 1.00 72.30 HI N -68.757 1.00 72.41 HI c -69.525 1.00 71.36 HI c -69.569 1.00 69.72 HI 0 -69.388 1.00 73.63 HI c -70.421 1.00 73.54 HI 0 -68.762 1.00 75.17 HI N -69.269 1.00 76.46 HI c -68.424 1.00 76.29 HI c -68.852 1.00 76.19 HI c -68.594 1.00 76.69 HI c -69.300 1.00 77.45 HI c -68.320 1.00 77.46 HI 0 -70.439 1.00 78.31 HI N -70.572 1.00 78.79 HI c -71.778 1.00 78.96 HI c -73.049 1.00 78.89 HI c -71.931 1.00 79.45 HI c -70.743 1.00 78.60 HI c -71.624 1.00 77.83 HI 0 -69.880 1.00 79.19 . HI N -69.998 1.00 80.16 HI c -68.609 1.00 80.16 HI c -67.907 1.00 80.54 HI 0 501 WO 2009/026558 PCT/US2008/074097 ATOM 6094 CG2 THR 186 -40.761 37 ATOM 6095 C THR 186 -41.172 39 ATOM 6096 O THR 186 -41.107 40 ATOM 6097 N VAL 187 -41.750 39 ATOM 6098 CA VAL 187 -42.248 40 ATOM 6099 CB VAL 187 -41.451 40 ATOM 6100 CGI VAL 187 -39.975 40 ATOM 6101 CG2 VAL 187 -41.662 38 ATOM 6102 C VAL 187 -43.726 40 ATOM 6103 O VAL 187 -44.303 39 ATOM 6104 N PRO 188 -44.357 41 ATOM 6105 CD PRO 188 -43.802 42 ATOM 6106 CA PRO 188 -45.756 40 ATOM 6107 CB PRO 188 -46.050 42 ATOM 6108 CG PRO 188 -45.028 43 ATOM 6109 C PRO 188 -45.950 39 ATOM 6110 O PRO 188 -45.245 39 ATOM 6111 N SER 189 -46.908 38 ATOM 6112 CA SER 189 -47.239 37 ATOM 6113 CB SER 189 -48.429 37 ATOM 6114 OG SER 189 -48.108 36 ATOM 6115 C SER 189 -47.584 38 ATOM 6116 O SER 189 -47.261 37 ATOM 6117 N SER 190 -48.233 39 ATOM 6118 CA SER 190 -48.654 40 ATOM 6119 CB SER 190 -49.228 41 ATOM 6120 OG SER 190 -50.258 41 ATOM 6121 C SER 190 -47.498 40 ATOM 6122 O SER 190 -47.679 40 ATOM 6123 N SER 191 -46.311 40 ATOM 6124 CA SER 191 -45.161 41 ATOM 6125 CB SER 191 -44.210 42 ATOM 6126 OG SER 191 -44.862 43 ATOM 6127 C SER 191 -44.405 39 ATOM 6128 O SER 191 -43.393 40 ATOM 6129 N LEU 192 -44.895 38 ATOM 6130 CA LEU 192 -44.297 37 ATOM 6131 CB LEU 192 -44.718 36 ATOM 6132 CG LEU 192 -44.246 36 ATOM 6133 CD1 LEU 192 -44.734 35 ATOM 6134 CD2 LEU 192 -42.727 36 ATOM 6135 C LEU 192 -44.719 37 ATOM 6136 O LEU 192 -45.907 37 ATOM 6137 N GLY 193 -43.738 37 ATOM 6138 CA GLY 193 -44.034 37 ATOM 6139 C GLY 193 -43.844 38 ATOM 6140 0 GLY 193 -43.566 38 ATOM 6141 N THR 194 -43.995 39 ATOM 6142 CA THR 194 -43.785 40 ATOM 6143 CB THR 194 -45.009 41 ATOM 6144 OG1 THR 194 -45.217 41 ATOM 6145 CG2 THR 194 -46.257 41 ATOM 6146 C THR 194 -42.556 41 ATOM 6147 O THR 194 -42.136 42 ATOM 6148 N GLN 195 -41.986 40 ATOM 6149 CA GLN 195 -40.809 41. ATOM 6150 CB GLN 195 -41.181 42 ATOM 6151 CG GLN 195 -40.009 42 ATOM 6152 CD GLN 195 -39.320 43 ATOM 6153 OE1 GLN 195 -38.732 43 ATOM 6154 NE2 GLN 195 -39.387 44 ATOM 6155 C GLN 195 -39.694 40 ATOM 6156 0 GLN 195 -39.919 39 ATOM 6157 N THR 196 -38.493 40 ATOM 6158 CA THR 196 -37.335 39 ATOM 6159 CB THR 196 -36.406 40 ATOM 6160 OG1 THR 196 -35.943 41 ATOM 6161 CG2 THR 196 -37.146 39 ATOM 6162 C THR 196 -36.526 40 ATOM 6163 O THR 196 -36.262 41 ATOM 6164 N TYR 197 -36.137 39 ATOM 6165 CA TYR 197 -35.347 39 ATOM 6166 CB TYR 197 -36.104 38 ATOM 6167 CG TYR 197 -37.457 39 ATOM 6168 CD1 TYR 197 -38.628 38 ATOM 6169 CEl TYR 197 -39.867 39 -67.796 1.00 80.44 HI c -70.833 1.00 80.74 HI c -70.455 1.00 79.91 HI 0 -71.975 1.00 82.12 HI N -72.923 1.00 83.45 HI c -74.246 1.00 83.13 HI c -73.975 1.00 82.39 HI c -74.933 1.00 82.96 HI c -73.239 1.00 84.60 HI c -72.906 1.00 83.97 HI 0 -73.886 1.00 86.10 HI N -74.148 1.00 86.23 HI c -74.316 1.00 87.32 HI c -74.919 1.00 87.01 HI c -74.315 1.00 86.99 HI c -75.339 1.00 88.92 HI c -76.347 1.00 89.36 HI 0 -75.080 1.00 90.12 HI N -76.033 1.00 91.74 HI c -75.529 1.00 91.44 HI c -74.333 1.00 91.54 HI 0 -77.382 1.00 93.06 HI c -78.436 1.00 93.63 HI 0 -77.334 1.00 94.02 HI N -78.536 1.00 94.90 HI c -78.159 1.00 94 .23 HI c -77.192 1.00 94.02 HI 0 -79.512 1.00 95.63 HI c -80.727 1.00 95.93 HI 0 -78.974 1.00 96.22 HI N -79.796 1.00 96.93 HI c -79.002 1.00 97.27 HI c -78.596 1.00 97.43 HI 0 -80.314 1.00 97.19 HI c -81.003 1.00 96.64 HI 0 -79.982 1.00 97.72 HI N -80.489 1.00 98.54 HI c -79.626 1.00 98.53 HI c -78.170 1.00 98.25 HI c -77.483 1.00 98.23 HI c -78.118 1.00 97.62 HI c -81.935 1.00 98.79 HI c -82.232 1.00 98.91 HI 0 -82.831 1.00 98.91 HI N -84.241 1.00 99.03 HI c -85.037 1.00 98.92 HI c -86.236 1.00 98.95 HI 0 -84.373 1.00 98.94 HI N -85.018 1.00 98.85 HI c -84.838 1.00 98.60 Hi c -83.444 1.00 98.43 HI 0 -85.424 1.00 98.49 HI c -84.446 1.00 98.74 HI c -84.944 1.00 98.84 HI 0 -83.394 1.00 98.32 HI N -82.750 1.00 97.95 HI c -81.368 1.00 97.62 HI c -80.572 1.00 97.74 HI c -81.265 1.00 98.15 HI c -82.335 1.00 98.48 HI 0 -80.656 1.00 97.92 HI N -82.615 1.00 97.59 HI c -82.127 1.00 97.42 HI 0 -83.052 1.00 96.87 HI N -82.936 1.00 96.09 HI c -84.167 1.00 96.10 HI c -84.292 1.00 96.22 HI 0 -85.434 1.00 95.59 HI c -81.681 1.00 95.48 HI c -81.375 1.00 95.11 HI 0 -80.958 1.00 94.60 HI N -79.745 1.00 93.36 HI c -78.545 1.00 93.41 . HI c -78.317 1.00 92.83 HI c -78.621 1.00 92.54 ' HI c -78.419 1.00 92.56 HI c 502 WO 2009/026558 PCT/US2008/074097 ATOM 6170 CD2 TYR 197 -37.561 40 ATOM 6171 CE2 TYR 197 -38.794 41 ATOM 6172 CZ TYR 197 -39.945 40 ATOM 6173 OH TYR 197 -41.175 41 ATOM 6174 C TYR 197 -34.000 38 ATOM 6175 O TYR 197 -33.937 37 ATOM 6176 N ILE 198 -32.925 39 ATOM 6177 CA ILE 198 -31.577 38 ATOM 6178 CB ILE 198 -30.846 39 ATOM 6179 CG2 ILE 198 -29.408 38 ATOM 6180 CGI ILE 198 -31.579 39 ATOM 6181 CDl ILE 198 -30.918 39 ATOM 6182 C ILE 198 -30.760 39 ATOM 6183 0 ILE 198 -30.556 40 ATOM 6184 N CYS 199 -30.292 38 ATOM 6185 CA CYS 199 -29.523 38 ATOM 6186 C CYS 199 -28.039 38 ATOM 6187 0 CYS 199 -27.521 37 ATOM 6188 CB CYS 199 -29.752 37 ATOM 6189 SG CYS 199 -28.628 35 ATOM 6190 N ASN 200 -27.363 39 ATOM 6191 CA ASN 200 -26.000 39 ATOM 6192 CB ASN 200 -25.917 41 ATOM 6193 CG ASN 200 -27.051 41 ATOM 6194 OD1 ASN 200 -27.673 42 ATOM 6195 ND2 ASN 200 -27.326 41 ATOM 6196 C ASN 200 -24.999 39 ATOM 6197 0 ASN 200 -24.758 39 ATOM 6198 N VAL 201 -24.408 38 ATOM 6199 CA VAL 201 -23.438 37 ATOM 6200 CB VAL 201 -23.413 35 ATOM 62 01 CGI VAL 201 -22.441 35 ATOM 6202 CG2 VAL 201 -24.809 35 ATOM 6203 C VAL 201 -22.038 38 ATOM 6204 O VAL 201 -21.636 38 ATOM 6205 N ASN 202 -21.302 38 ATOM 6206 CA ASN 202 -19.929 38 ATOM 6207 CB ASN 202 -19.897 40 ATOM 6208 CG ASN 202 -18.503 40 ATOM 6209 OD1 ASN 202 -17.597 40 ATOM 6210 ND2 ASN 202 -18.327 42 ATOM 6211 C ASN 202 -19.063 38 ATOM 6212 0 ASN 202 -19.273 38 ATOM 6213 N HIS 203 -18.089 37 ATOM 6214 CA HIS 203 -17.166 36 ATOM 6215 CB HIS 203 -17.108 35 ATOM 6216 CG HIS 203 -16.304 34 ATOM 6217 CD2 HIS 203 -16.174 35 ATOM 6218 NDl HIS 203 -15.509 33 ATOM 6219 CEl HIS 203 -14.923 33 ATOM 6220 NE2 HIS 203 -15.310 34 ATOM 6221 C HIS 203 -15.772 37 ATOM 6222 0 HIS 203 -14.946 36 ATOM 6223 N LYS 204 -15.517 38 ATOM 6224 CA LYS 204 -14.282 39 ATOM 6225 CB LYS 204 -14.296 4 0, ATOM 6226 CG LYS 204 -15.279 41 ATOM 6227 CD LYS 204 -15.674 42 ATOM 6228 CE LYS 204 -14.453 43 ATOM 6229 NZ LYS 204 -14.820 44 ATOM 6230 C LYS 204 -12.996 38 ATOM 6231 0 LYS 204 -11.983 38 ATOM 6232 N PRO 205 -13.013 37 ATOM 6233 CD PRO 205 -14.006 37 ATOM 6234 CA PRO 205 -11.854 36 ATOM 6235 CB PRO 205 -12.254 35 ATOM 6236 CG PRO 205 -13.239 36 ATOM 6237 C PRO 205 -11.542 35 ATOM 6238 O PRO 205 -10.378 35 ATOM 6239 N SER 206 -12.589 35 ATOM 6240 CA SER 206 -12.432 34 ATOM 62 41 CB SER 206 -13.477 33 ATOM 6242 OG SER 206 -13.303 32 ATOM 6243 C SER 206 -12.559 35 ATOM 6244 O SER 206 -12.301 34 ATOM 6245 N ASN 207 -12.955 36
-77 .801 1 . 00 92 .54 HI c -77 .596 1 . 00 92 . 67 HI c -77 .907 1 . 00 92 .86 HI c -77 .710 1 . 00 92 .25 HI 0 -79 .888 1 . 00 92 .48 HI c -80 . 190 1 . 00 92 . 42 HI 0 -79 . 670 1 . 00 91 .09 HI N -79 .783 1 .00 89 . 67 HI c -81 .011 1, . 00 89 .35 HI c -81 .045 1, . 00 89, .56 HI c -82 .295 1, . 00 88 .73 HI c -83 . 560 1, . 00 87 .61 HI c -78 . 530 1, . 00 89 .23 HI c -78 . 170 1, . 00 88 . 50 HI 0 -77 . 870 1, . 00 88 .78 HI N -76 . 640 1, . 00 87 .96 HI c -76 .971 1, . 00 87 . 57 HI c -77 . 868 1, . 00 87 . 15 HI 0 -75 .731 1 , . 00 87 .80 HI c -76 . 005 1 , . 00 86 .80 HI s -76 .247 1 , . 00 87 .80 HI N -76 .593 1. .00 87 .93 HI c -76 .743 1. .00 CO CO .63 HI c -77 . 577 1 , . 00 89 .36 HI c -77 .201 1 , . 00 89 .44 HI 0 -78 .716 1. , 00 89 .25 HI N -75 .539 1 , . 00 87 .45 HI c -74 .550 1 , . 00 87 . 13 HI 0 -75 .766 1. ,00 86 .80 HI N -74 .835 1. ,00 85, .93 HI c -74 .92 6 1. , 00 85 .26 HI c -73 .907 1. ,00 85 , .22 HI c -74 .698 1. , 00 84 , .35 HI c -75 . 121 1. , 00 85 , .88 HI c -76 .277 1. , 00 85 , . 83 HI 0 -74 .0 62 1. , 00 86, . 08 HI N -74 .196 1. , 00 86, .41 HI c -74 . .196 1. , 00 86, . 12 HI c -74 .437 1. , 00 86, .38 HI c -74 .860 1 . , 00 86, . 49 HI 0 -74 .168 1. , 00 86, .34 HI N -73, . 056 1 . , 00 86, .59 HI c -71, . 893 1 . , 00 86, .68 HI 0 -73, . 397 1 . , 00 87 , . 00 HI N -72 , .409 1 . , 00 87 , .34 HI c -72 , . 537 1 . , 00 CO CO . 04 HI c -71, .465 1. .00 89, .65 HI c -70 , . 145 1 . , 00 90 , .06 HI c -71, .707 1 . , 00 89. .81 HI N -70 , . 583 1. 00 89, .71 HI c -69, . 620 1 . , 00 90 , . 14 HI N -72 , . 603 1. .00 87 , .37 HI C -73 , .318 1. 00 87 , .61 HI 0 -71 , .953 1. 00 87 , .39 HI N -72 , . 154 1. 00 87 , . 67 HI C -71 , .281 1. 00 87 , .25 HI c -71 , .759 1. 00 CO CO , 05 HI c -70 , . 637 1. 00 CO CO .66 HI c -69, .965 1. 00 89. , 19 HI c -68 , .736 1. 00 90. , 12 HI N -71. .903 1. 00 87 . , 80 HI c -72 . .566 1. 00 88 . , 12 HI 0 -70 . , 940 1. 00 87 . , 81 HI N -69, .868 1. 00 87 . ,68 HI c -70 , .763 1. 00 87 . , 47 HI c -69. , 583 1 . 00 87 . ,20 HI c -68. , 825 1. .00 86. ,89 HI c -72 , .012 1 . 00 87 . ,26 HI c -72 , .369 1 . 00 86. , 44 HI 0 -72 , .673 1 . 00 87 . , 15 HI N -73 . , 812 1 . 00 87 . ,33 HI c -73 . ,738 1 . 00 86. , 84 HI c -74 . ,781 1 . 00 87 . ,39 . HI 0 -75. , 150 1 . 00 87 . ,95 HI c -76. ,209 1 . 00 87 . ,21 HI 0 -75. , 095 1 . 00 CO CO .68 HI N 503 WO 2009/026558 PCT/US2008/074097 ATOM 62 4 6 CA ASN 207 -13.253 ATOM 6247 CB ASN 207 '-11.971 ATOM 6248 CG ASN 207 -11.180 ATOM 62 4 9 OD1 ASN 207 -10.011 ATOM 6250 ND2 ASN 207 -11.816 ATOM 6251 C ASN 207 -14.260 ATOM 6252 0 ASN 207 -14.192 ATOM 6253 N THR 208 -15.189 ATOM 6254 CA THR 208 -16.290 ATOM 6255 CB THR 208 -16.700 ATOM 6256 OG1 THR 208 -15.581 ATOM 6257 CG2 THR 208 -17.850 ATOM 6258 C THR 208 -17.492 ATOM 6259 O THR 208 -18.310 ATOM 6260 N LYS 209 -17.586 ATOM 6261 CA LYS 209 -18.681 ATOM 62 62 CB LYS 209 -18.158 ATOM 6263 CG LYS 209 -18.875 ATOM 6264 CD LYS 209 -20.221 ATOM 62 65 CE LYS 209 -20.057 ATOM 6266 NZ LYS 209 -21.372 ATOM 62 67 C LYS 209 -19.748 ATOM 6268 0 LYS 209 -19.498 ATOM 62 69 N VAL 210 -20.934 ATOM 6270 CA VAL 210 -21.966 ATOM 6271 CB VAL 210 -22.164 ATOM 6272 CGI VAL 210 -23.304 ATOM 6273 CG2 VAL 210 -20.880 ATOM 6274 C VAL 210 -23.311 ATOM 6275 O VAL 210 -23.579 ATOM 6276 N ASP 211 -24.146 ATOM 6277 CA ASP 211 -25.536 ATOM 6278 CB ASP 211 -25.698 ATOM 6279 CG ASP 211 -24.793 ATOM 6280 OD1 ASP 211 -25.173 ATOM 62 81 OD2 ASP 211 -23.699 ATOM 6282 C ASP 211 -26.416 ATOM 6283 O ASP 211 -26.143 ATOM 6284 N LYS 212 -27.466 ATOM 6285 CA LYS 212 -28.407 ATOM 62 8 6 CB LYS 212 -28.410 ATOM 6287 CG LYS 212 -29.376 ATOM 6288 CD LYS 212 -29.021 ATOM 6289 CE LYS 212 -27.672 ATOM 6290 NZ LYS 212 -27.417 ATOM 6291 C LYS 212 -29.810 ATOM 6292 0 LYS 212 -30.237 ATOM 6293 N LYS 213 -30.523 ATOM 6294 CA LYS 213 -31.861 ATOM 6295 CB LYS 213 -32.032 ATOM 6296 CG LYS 213 -33.204 ATOM 6297 CD LYS 213 -33.200 ATOM 6298 CE LYS 213 -34.314 ATOM 6299 NZ LYS 213 -34.365 ATOM 6300 C LYS 213 -32.893 ATOM 6301 0 LYS 213 -32.933 ATOM 6302 N VAL 214 -33.723 ATOM 6303 CA VAL 214 -34.723 ATOM 6304 CB VAL 214 -34.883 ATOM 6305 CGI VAL 214 -35.835 ATOM 6306 CG2 VAL 214 -33.524 ATOM 6307 C VAL 214 -36.075 ATOM 6308 O VAL 214 -36.666 ATOM 6309 N GLU 215 -36.556 ATOM 6310 CA GLU 215 -37.829 ATOM 6311 CB GLU 215 -37.591 ATOM 6312 CG GLU 215 -36.659 ATOM 6313 CD GLU 215 -36.464 ATOM 6314 OE1 GLU 215 -35.937 ATOM 6315 OE2 GLU 215 -36.841 ATOM 6316 C GLU 215 -38.735 ATOM 6317 O GLU 215 -38.263 ATOM 6318 N PRO 216 -40.053 ATOM 6319 CD PRO 216 -40.692 ATOM 6320 CA PRO 216 -41.045 ATOM 6321 CB PRO 216 -42.376 -76.299 1.00 88.90 HI c -77.088 1.00 89.10 HI c -76.515 1.00 89.83 HI c -76.850 1.00 90.22 HI 0 -75.645 1.00 90.17 HI N -77.185 1.00 88.67 HI c -78.411 1.00 88.61 HI 0 -76.551 1.00 88.73 HI N -77.264 1.00 88.95 HI c -76.593 1.00 88.70 HI c -76.577 1.00 88.37 HI 0 -77.350 1.00 87.89 HI c -77.271 1.00 89.54 HI c -76.352 1.00 89.28 HI 0 -78.312 1.00 90.21 HI N -78.445 1.00 90.36 HI c -79.049 1.00 90.46 HI c -78.568 1.00 91.30 HI c -79.256 1.00 92.32 HI c -80.713 1.00 92.31 HI c -81.382 1.00 91.57 HI N -79.347 1.00 90.48 HI c -80.523 1.00 91.28 HI 0 -78.790 1.00 90.31 HI N -79.474 1.00 90.33 HI c -78.792 1.00 90.01 HI c -79.450 1.00 88.87 HI c -78.879 1.00 89.86 HI c -79.519 1.00 90.85 HI c -78.715 1.00 90.85 HI 0 -80.477 1.00 91.03 HI N -80.526 1.00 91.23 HI c -81.532 1.00 91.67 HI c -81.228 1.00 92.43 HI c -80.391 1.00 92.57 HI 0 -81.828 1.00 92.96 HI 0 -80.940 1.00 91.08 HI c -81.935 1.00 91.24 HI 0 -80.168 1.00 90.73 HI N -80.501 1.00 90.77 HI c -79.410 1.00 90.14 HI c -79.673 1.00 8 9.67 HI c -80.949 1.00 89.85 HI c -80.831 1.00 89.83 HI c -81.967 1.00 89.22 HI N -80.668 1.00 91.33 HI c -79.902 1.00 91.11 HI 0 -81.674 1.00 91.62 HI N -81.977 1.00 92.18 HI c -83.494 1.00 92.88 HI c -83.933 1.00 93.56 HI c -85.446 1.00 93.60 HI c -85.896 1.00 93.91 HI c -87.380 1.00 92.57 HI N -81.415 1.00 92.17 HI c -81.799 1.00 92.12 HI 0 -80.501 1.00 92.74 HI N -79.869 1.00 93.76 HI c -78.370 1.00 93.57 HI c -77.709 1.00 92.68 HI c -77.684 1.00 93.40 HI c -80.557 1.00 94.58 HI c -80.559 1.00 94.67 HI 0 -81.141 1.00 95.50 HI N -81.850 1.00 96.61 HI c -83.347 1.00 97.66 HI c -83.970 1.00 99.30 HI c -85.458 1.00100.39 HI c -86.128 1.00100.64 HI 0 -85.956 1.00101.04 HI 0 -81.313 1.00 96.73 HI c -80.717 1.00 96.90 HI 0 -81.519 1.00 97.02 . HI N -82.139 1.00 96.97 HI c -81.032 1.00 97.59 HI c -81.507 1.00 97.22 HI c 504 WO 2009/026558 PCT/US2008/074097
ATOM 6322 CG PRO 216 -42.109 33 ATOM 6323 C PRO 216 -40.819 29 ATOM 6324 O PRO 216 -40.189 29 ATOM 6325 N LYS 217 -41.343 28 ATOM 6326 CA LYS 217 -41.133 27 ATOM 6327 CB LYS 217 -41.567 26 ATOM 6328 CG LYS 217 -40.832 26 ATOM 6329 CD LYS 217 -41.398 25 ATOM 6330 CE LYS 217 -40.737 26 ATOM 6331 NZ LYS 217 -41.369 25 ATOM 6332 C LYS 217 -41.892 26 ATOM 6333 0 LYS 217 -42.770 25 ATOM 6334 OXT LYS 217 -41.600 27 TER 6335 LYS 217 END
-81.652 1.00 97.02 HI c -81.553 1.00 98.15 HI c -82.591 1.00 97.93 HI 0 -80.821 1.00 99.25 HI N -81.137 1.00100.54 HI c -79.954 1.00100.87 HI c -78.652 1.00101.66 HI c -77.496 1.00101.93 HI c -76.173 1.00102.31 HI c -75.006 1.00101.76 HI N -82.392 1.00100.93 HI c -82.277 1.00101.08 HI 0 -83.476 1.00101.13 HI 0 HI 505

Claims (30)

  1. WHAT IS CLAIMED IS
    1. An isolated monoclonal antibody that binds to human PCSK9 and is neutralizing in that an excess of said antibody reduces the quantity of human PCSK9 bound to LDLR in an in vitro competitive binding assay, wherein said monoclonal antibody competes for binding to PCSK9 with an antibody that comprises: a heavy chain variable region of the amino acid sequence in SEQ ID NO: 49; and a light chain variable region of the amino acid sequence in SEQ ID NO: 23.
  2. 2. The isolated monoclonal antibody according to claim 1, wherein said monoclonal antibody is a human or a humanized monoclonal antibody.
  3. 3. The isolated monoclonal antibody according to claim 1, wherein said monoclonal antibody is an IgG.
  4. 4. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises an intact immunoglobulin, a fragment of an intact immunoglobulin.
  5. 5. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a heavy chain that comprises the amino acid sequence of SEQ ID NO: 154.
  6. 6. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a heavy chain that comprises the amino acid sequence of SEQ ID NO: 155.
  7. 7. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a human kappa light chain.
  8. 8. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a human lambda light chain.
  9. 9. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a light chain that comprises the amino acid sequence of SEQ ID NO: 156.
  10. 10. The isolated monoclonal antibody according to claim 1, wherein the monoclonal antibody comprises a light chain that comprises the amino acid sequence of SEQ ID NO: 157.
  11. 11. An isolated nucleic acid encoding the monoclonal antibody according to any one of claims 1-10.
  12. 12. A recombinant expression vector comprising the nucleic acid molecule according to claim 11.
  13. 13. A host cell comprising the vector according to claim 12.
  14. 14. A hybridoma which produces the antibody according to claim 11.
  15. 15. A method of making the isolated monoclonal antibody according to any one of claims 1-10, comprising the step of preparing said antigen binding protein from a host cell that secretes the antibody.
  16. 16. A method of producing an isolated monoclonal antibody, the method comprising the steps of introducing the expression vector according to claim 12 into an isolated host cell, growing the cell under conditions permitting production of the monoclonal antibody, and recovering the antibody so produced.
  17. 17. An isolated monoclonal antibody produced by the expression of recombinant DNA in the host cell according to claim 13 or the hybridoma according to claim 14.
  18. 18. The method according to claim 16 or the isolated monoclonal antibody according to claim 17, wherein the host cell is selected from the group consisting of Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells, and human epithelial kidney 293 cells.
  19. 19. A pharmaceutical composition comprising at least one monoclonal antibody according to any one of claims 1 to 10 and a pharmaceutically acceptable excipient.
  20. 20. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is for use prior to, concurrent with, or subsequent to, the use of at least one other therapeutic agent.
  21. 21. The pharmaceutical composition according to claim 20, wherein the at least one other therapeutic agent is selected from the group comprising: a statin, nictotimic acid, fibric acid, bile acid sequestrants, cholesterol absorption inhibitors, combinations of nicotinic acid and statin, combinations of a statin with an absorption inhibitor, lipid modifying agents, PPAR gamma agonists, PPAR alpha/gamma agonists, squalene synthase inhibitors, CETP inhibitors, anti-hypertensives, anti-diabetic agents, insulin, ApoB modulators, MTP inhibitors, and arteriosclerosis obliterans treatments.
  22. 22. A kit for the treatment of cholesterol related disorders comprising the composition according to any one of claims 19 to 21.
  23. 23. Use of the isolated monoclonal antibody according to any one of claims 1 to 10 in the manufacture of a medicament for treating or preventing a condition associated with an elevated serum cholesterol level in a subject.
  24. 24. Use of the monoclonal antibody according to any one of claims 1 to 10 in the treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject.
  25. 25. A method when used in the treatment or prevention of a condition associated with an elevated serum cholesterol level in a subject, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of an isolated monoclonal antibody according to any one of claims 1 to 10 or a pharmaceutical composition according to any one of claims 19 to 21.
  26. 26. The use according to claim 23 or 24, wherein the condition is selected from the group comprising: hypercholesterolemia, heart disease, cardiovascular diseases, metabolic syndrome, coronary heart disease, atherosclerotic diseases, diabetes, stroke, Alzheimers disease, hyperlipidemia, dyslipidemia, familial hypertriglyceridemia, familial hypercholesterolemia, heterozygous hypercholesterolemia, hypothyroidism, chronic renal failure, Cushing’s syndrome, primary biliary cirrhosis, glycogen storage diseases, hepatoma, cholestasis, acromegaly, insulinoma, isolated growth hormone deficiency, alcohol-induce hypertriglyceridemia.
  27. 27. The use according to 26, wherein the condition is hypercholesterolemia, hyperlipidemia, dyslipidemia, familial hypertriglyceridemia, familial hypercholesterolemia, or heterozygous hypercholesterolemia.
  28. 28. The use according to 26, wherein the condition is heart disease, cardiovascular diseases, coronary heart disease, or atherosclerotic diseases.
  29. 29. The use according to claim 26, wherein the condition is metabolic syndrome or diabetes.
  30. 30. The isolated monoclonal antibody according to any one of claim 1, or the method according to claim 15 or 16, substantially as herein before described with reference to the Examples.
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AU2013203751B2 (en) 2016-09-22
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