CA2324060A1 - Methods and compounds for modulating nuclear receptor activity - Google Patents

Abstract

The present invention relates to methods and agonist/antagonist compounds for modulating nuclear receptor activity, and nuclear receptor ligand binding. The invention includes a method for identifying residues comprising a ligand binding domain for a nuclear receptor of interest. Also included in a method of identifying agonists and/or antagonists that bind to the ligand binding domain of the nuclear receptors, and the estrogen receptor in particular. The invention is exemplified by identification and manipulation of the ligand binding domain of the estrogen receptor and compounds that bind to this site.
The methods can be applied to other nuclear receptors including TR, GR and PR.

Description

METHODS AND COMPOUNDS FOR MODULATING NUCLEAR RECEPTOR ACTIVITY
This invention was support in part by grants from the U.S. Army Medical and Research Material Command grant DAMD 17-94-J-4228, the National Cancer Institute Cancer Center Support grant P30 CA-14599, NIGMS grant GM31627, American Cancer Society grant BE61, and the National Institutes of Health grant DK51083. The U.S. Government may have rights in this invention.
' The present invention relates to improved methods and compounds for modulating nuclear receptor activity. In particular, the present invention relates to improved methods and compounds for modulating estrogen receptor activity.
Cells contain receptors that can elicit a biological response by binding various molecules including proteins, hormones and/or drugs. Nuclear receptors represent a super family of proteins that are hormone/ligand-activated transcription factors that enhance or repress transcription in a cell type-, ligand- and promoter-dependent manner. A
classic nuclear receptor, the estrogen receptor a (ERa) is a key factor in regulating the differentiation and maintenance of neural, skeletal, cardiovascular and reproductive tissues (Korach, science 266:1524-1527 (1994); Smith, et al., j~ ~,gl. ,[. ~. 331:1056-1061 ( 1994)). The nuclear receptor family also includes receptors for glucocorticoids, androgens, mineralocorticoids, progestins, thyroid horrnones, vitamin D, retinoids, peroxisome proliferators and eicosanoids. A
subset of the nuclear receptor family are the steroid receptors, which include the estrogen, glucocorticoid and progestin receptors.
Overall sequence conservation between nuclear receptors varies between different families of receptors; however, sequence conservation between functional regions, or modules, of the receptors is high. For example, nuclear receptors can be organized into functional modules comprising an N-terminal transcriptional activation domain, a central DNA binding domain (DBD), and a C-terminal ligand binding domain (LBD). The LBD of nuclear receptors represents a hormone/ligand-dependent molecular switch, and recognizes a variety of compounds diverse in their size, shape and chemical propenies. Accordingly, the estrogen hormones exert their physiological effects by binding to the estrogen receptor (Beato, et al., ~

WO 99/SOb58 PCTNS99/06937 83(6):81-857 (1995); Tsai, et al.. Annu. Rev. Biochem. 63:451-86 (1994)).
Binding of a hormone to a nuclear receptor's LBD also changes its ability to modulate transcription of DNA, although they may have transcription-indepeindent actions..
All ERa ligands bind exclusively to the C-terminal LBD. Some of these ligands, including the endogenous estrogen. 17(3-estradiol (E2), and the synthetic nonsteroidal estrogen, diethylstilbestrol (DES), function as pure agonists whereas others such as ICI-164,384 function as pure antagonists. Synthetic ligands such as tamoxifen and raloxifene (RAL) belong to a growing class of molecules known as selective estrogen receptor modulators (SERMs), which function as antagonists in specific tissue and promoter contexts (Grese, et al., Proc. Natl. Acad.
Sci. USA 94:14105-10 (1997)). The remarkable tissue-specific behavior of tamoxifen was recently demonstrated in a breast cancer prevention trial, reported in Smigel, J. Natl. Cancer _Inst.
90:647-8 ( 1998), where a group of women at high risk for breast cancer who received tamoxifen treatment over a six year period, e.~chibited an increased incidence of endometrial cancer but a reduced occurrence of certain bone fractures and a dramatic 45% reduction in breast cancer incidence. The rational design of new SERMs and the optimization of existing ones require an understanding of the effects of different ligand chemistries and structures upon ERa transcriptional activity.
Nuclear receptors also bind proteins, such as chaperone complexes, corepressors, or coactivators, that are involved in receptor function. In particular, ligand-dependent activation of transcription by nuclear receptors is mediated by interactions with coactivators. Receptor agonists promote coactivator binding and antagonists block coactivator binding. Hormone binding by a nuclear receptor can increase or decrease binding affinity to these proteins, and can influence or mediate the multiple actions of the nuclear receptors on transcription.
Transcriptional activation by ERa is mediated by at least two separate activation functions (AFs) located within different domains of the protein, AF-1 in the N-terminus, and AF-2 in the LBD. These AFs can act independently or cooperatively, depending on the cell type and the promoter context. The activity of AF-1 is regulated by growth factors acting through the MAP kinase pathway (Kato, et al., Science 270:1491-1494 (1995)) and is generally believed to be activated in a ligand-independent manner, while AF-2 activity ("transcriptional activity") is responsive to ligand binding (Kumar. et al., Cell 51 (6):941-951 ( 1987)). The binding of agonists triggers transcriptional activity whereas the binding of antagonists does not (Berry, et al., EMBO
J. 9:2811-8 (1990)). In addition, coactivators mediate transcriptional activity. The structural and functional nature of the site to which coactivators bind has only recently been defined. Apriletti, et al., US Provisional No. 60/079,956, filed March 30. 1998, the disclosure of which is incorporated herein by reference.
Recent structural studies suggest that ligands regulate transcriptional activity by directly affecting the structure of the LBD. Comparison of the structure of the unliganded human retinoid X receptor a LBD (Bourguet, et al., Nature 375:377-82 ( 1995)) with the structures of the liganded LBDs of the human retinoic acid receptor y (RARy) (Renaud, et al.. Nature 378:681-689 (1995) and Wurtz, et al., Nat. Struct. Biol. 3:87-94(1996)}, the thyroid hormone receptor a (TRa) (Wagner, et al., Nature 378:690-697 (1995)), the progesterone receptor (Williams, et al., Nature 393:392-395 (1998)) and the ERa (Brzozowski, et al., Nature 389:753-758 (1997); Tanenbaum, et al., Proc. Natl. Acad. Sci. USA 95:5998-6003 (1998)) suggests that an agonist-induced conformational change involving the repositioning of helix 12, the most C-terminal helix of the LBD, is essential for transcriptional activity. Because certain point mutations in helices 3, 5 and 12 abolish transcriptional activity but have no effect on ligand or I 5 DNA binding, these regions of the LBD have been predicted to form part of a recognition surface, created in the presence of agonist, for molecules that link the receptor to the general transcriptional machinery (Danielian, et al., EMBO J. 11:1025-33(1992); Feng, et al., Science 280:1747-9 (1998); Henttu, et al., Mol. Cell. Biol. 17:1832-9 (1997); Wrenn, et al., J. Biol.
Chem. 268:24089-24098 (1993)). The structures of the LBD complexed with E2 and RAL show that although both ligands bind at the same site within the core of the LBD
(Brzozowski, et al., supra), each of these ligands induces a different conformation of helix 12.
Whereas helix 12 in the E2-LBD complex packs against the helices 3, 5/6 and 11 in a conformation that has been observed for the corresponding helix in other agonist-bound NR LBD structures, helix 12 in the RAL-LBD complex is bound in a hydrophobic groove composed of residues from helices 3 and 5. This alternative orientation of helix 12 partially buries residues in the groove that are necessary for transcriptional activity, suggesting that RAL and possibly other antagonists block transcriptional activity by disrupting the topography of the coactivator binding site surface.
Biochemical and genetic approaches have led to the identification of several proteins that associate in a ligand-dependent manner with ERa (Horwitz, et al., Mol.
Endocrinol. 10:1167-1177 (1996)) including SRC-1/N-CoAI (Onate, et al., Science 270:1354-1357 (1995)), GRIP1/TIF2/SRC-2 (Hong, et al., Proc. Natl. Acad. Sci. USA 93(10):4948-4952 (1996) and Voegel, et al. EMBO J. 15:3667-3675 (1996)), p/CIP/R.AC3/ACTRIAIBI/SRC-3 (Anzick. et al., Science 277:965-968( 1997), Chen. et al., Cell 90(3):569-80 ( 1997). Li, et al., Proc. Natl. Acad.
Sci. USA 94:8479-84 ( 1997) and Torchia. et al.. Nature 387:677-684 ( 1997)) and CBP/p300 (Hanstein, et al., Proc. Natl. Acad. Sci. USA 93:11540-11545 (1996)). These proteins have been classified as transcriptional coactivators because they enhance ligand-dependent transcriptional activation by ERa as well as by several other NRs (Glass, et al., Curr. Opin.
Cell Biol. 9:222-32 ( 1997); Torchia, et al., supra). The observation of partial hormone resistance in mice with a disrupted SRC-1 gene (Xu, et al., Science 279:1922-1925( 1998)) provides compelling evidence that coactivators are required for NR function in vivo. Consistent with its proposed role in AF-2 directed transcriptional activation, SRC-1 possesses histone acetylase activity and the ability to interact not only with agonist-bound receptors but also with other coactivators and several general transcription factors (Kamei, et al., Cell 85(3):403-14 (1996); Onate, et al., supra;
Spencer, et al., Nature 389:194-8 (1997); Takeshita, et al., Endocrinolosv 137:3594-7 (1996)).
SRC-1 and GRIP1 also bind to the agonist-bound LBDs of both the human TR~i and human ERa using the putative coactivator binding site (Feng, et al., supra).
Members of the p160 family of coactivators such as SRC-1, GRIP1/TIF2/SRC-2, and p/CIP/RAC3/ACTR/AIB 1 /SRC-3 as well as other coactivators recognize agonist-bound NR
LBDs through a short signature sequence motif, LXXLL (SEQ ID NO:1 ) (where L
is leucine and X is any amino acid), known as the NR box (Ding, et al., Mol. Endocrinol.
12:302-313 (1998);
Heery, et al., Nature 387:733-736 (1997); Le Douarin, et al., EMBO J. 15:6701-15 (1996);
Torchia, et al., su ra . Mutagenesis studies indicate that the affinity of coactivators for NR
LBDs is determined principally, if not exclusively, by these NR boxes (Ding, et al., supra);
Heery, et al., Nature 387:733-736 (1997); Le Douarin, et al., EMBO J. 15:6701-15 (1996);
Torchia, et al., supra). Each of the p 160 coactivators contains several NR
boxes. The NR boxes within SRC-1, GRIP1 and TIF2 have been demonstrated to recognize different NRs with different affinities (Ding, et al., supra; Kalkhoven, et al., EMBO J. 17:232-43 (1998); Voegel, et al., EMBO J. 17:507-19 ( 1998)), but the reasons for these binding preferences are unknown.
Darimont, et al:, "Structure and specificity of nuclear receptor-coactivator interactions"
Genes Dev. 12:3343-3356 ( 1998) describes structural studies of the complex between TRø and the GRIP1 NR Box II peptide and biochemical studies of GRIP1 binding to TR(3 and GR. The PPARy/SRC-1 peptide complex is described in Nolte, et al., Nature 395:137-143 ( 1998).
The medical importance of nuclear receptors is significant. They have been implicated in breast cancer, prostate cancer. cardiac arrhythmia. infertility, osteoporosis, hyperthyroidism, hypercholesterolemia, obesity and other conditions. For example, compounds that modulate ERa transcriptionai activity are currently being used to treat osteoporosis, cardiovascular disease and breast cancer (Gradishar, et al., J. Clin. Oncol. 15:840-52 ( 1997) and Jordan. J. Natl. Cancer Inst. 90:967-71 (1998)).
A need continues to exist for further identification and characterization of the key residues within the ligand binding domains of the nuclear receptors, and molecules that affect the receptor by binding to these sites. Understanding these interactions provides a basis for iterative drug design, synthesis, and selection. It also would be advantageous to devise methods and compositions for reducing the time required to discover compounds that target these binding sites and administer them to organisms to modulate physiological processes regulated by the nuclear receptors, and the estrogen receptor in particular.
SUMMARY OF THE INVENTION
The present invention relates to the further identification and manipulation of the ligand binding domain (LBD) of nuclear receptors, which facilitates the design of compounds that bind I S to the LBD and modulate nuclear receptor activity, and the estrogen receptor in particular. The compounds include agonists and antagonists that modulate nuclear receptor activity, and can be receptor-, cell- and/or tissue-specific. In particular, the compounds modulate nuclear receptor activity by affecting coactivator-coactivator binding site interactions.
The present invention also includes protein cocrystals of the nuclear receptors with an agonist bound to the LBD and a peptide bound to the coactivator binding site and methods for making them. Similarly, the invention also includes protein cocrystals of the nuclear receptors with an antagonist bound to the LBD and methods for making them. The cocrystals provide means to obtain atomic modeling information of the specific amino acids and their atoms forming the LBD and coactivator binding sites and that interact with molecules that bind to the sites. The cocrystals also provide modeling information regarding the ligand:nuclear receptor and coactivator:nuclear receptor interactions, as well the structure of ligands bound thereto.
The present invention further provides methods for identifying and designing molecules that modulate ligand binding to a nuclear receptor using atomic models of nuclear receptors.
The method involves modeling test compounds that fit spacialiy into a nuclear receptor LBD
using an atomic structural model comprising a nuclear receptor LBD or portion thereof, screening the test compounds in an assay, such as a biological assay, characterized by binding of a test compound to the nuclear receptor LBD. and identifying a test compound that modulates ligand binding to the receptor.
The invention also includes compositions and methods for identifying key residues within the LBDs of nuclear receptors. The methods involve examining the surface of a nuclear receptor of interest to identify residues that modulate ligand and/or coactivator binding. The residues can be identified by homology to the key residues within the LBD of human ERa described herein. Overlays and superpositioning with a three dimensional model of a nuclear receptor's LBD, and/or a portion thereof, also can be used for this purpose.
Additionally, alignment and/or modeling can be used as a guide for the placement of mutations on the LBD
surface to characterize the nature of the site in the context of a cell.
Also provided is a method of modulating the activity of a nuclear receptor.
The method can be in vitro or in vivo. The method comprises administering in vitro or in vivo a sufficient amount of a compound that binds to the ligand binding domain and acts either as an agonist or an antagonist. Preferred compounds bind to the site with greater affinity than ligands found in a cell of interest.
The invention further includes a method for identifying an agonist or antagonist of ligand binding to a nuclear receptor. The method comprises providing the atomic coordinates comprising a nuclear receptor ligand binding domain or portion thereof to a computerized modeling system; modeling compounds which fit spatially into the nuclear receptor ligand binding domain; and identifying in an assay, for example a biological assay, for nuclear receptor activity a compound that increases or decreases activity of the nuclear receptor through binding the ligand binding domain.
Also provided is a machine-readable data storage medium with information for constructing and manipulating an atomic model comprising the ligand binding domain or portions thereof. The medium comprises a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex for a nuclear receptor ligand binding domain.
Also provided is a method of identifying a compound that selectively modulates the activity of one type of nuclear receptor compared to other nuclear receptors.
The method is exemplified by modeling test compounds that fit spatially and preferentially into a nuclear receptor ligand binding domain of interest using an atomic structural model of a nuclear receptor LBD, selecting a compound that interacts with one or more residues of the LBD
unique in the context of that site. and identifying in an assay, for example a biological assay, for ligand binding activity a compound that selectively binds to the LBD compared to other nuclear receptors. The unique features involved in receptor-selective ligand binding can be identified by comparing atomic models of different nuclear receptors or isoforms of the same type of receptor.
The invention finds use in the selection and characterization of peptide.
peptidomimetic, as well as other compounds, such as small organic molecules, identified by the methods of the invention, particularly new lead compounds useful in treating nuclear receptor-based disorders, in particular steroid receptor-based disorders, and more specifically estrogen receptor-based disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 provides a stereo view of the electron density of the complexes, where Figure lA is a stereo view of the electron density of the DES-ERa LBD-GRIP1 NR Box II
peptide complex and Figure 1 B is a stereo view of the electron density of the OHT-ERa LBD complex.
1 S Figure 1 is a black and white graphical representation of a figure that was generated using BOBSCRIPT (Esnouf, J. Mol. Grayh. Model. 15, 132-4, 112-3 (1997)) and rendered using Raster3D (Merritt, et al., Acta CrystalloQr. D 50:869-873 (1994)).
Figure 2 was generated using BOBSCRIPT and rendered using Raster3D as described above. Figure 2A shows the overall structure of the DES-ERa LBD-GRIP1 NR Box II peptide complex in two orthogonal views. Figure 2B shows the overall structure of the OHT-ERa LBD
complex in two orthogonal views similar to those of the agonist complex in Figure 2A.
Figures 3A and 3B were generated using BOBSCRIPT and rendered using Raster3D
as described above. Figures 3C and 3D were created using GRASP (Nicholls. GRASP
Manual (New York: Columbia University, 1992)). Figure 3A shows a close-up view of the coactivator peptide bound to the LBD, i.e., the NR Box II peptide/LBD interface. The regions of the LBD
that do not interact with the peptide have been omitted for clarity. Helices 3. 4 and 5 are labeled H3, H4 and HS respectively. The side chains of receptor residues which interact with the peptide are depicted, except for Lys 362 (blue) and Glu 542 (red), the side chains are colored by atom type (carbon and sulfur atoms are colored green, oxygen atoms are colored red and nitrogen atoms are colored blue). Helix 12 is colored magenta. The peptide. colored gold. is depicted as a Ca worm; only the side chains of Ile 689 and the three motif leucines (Leu 690, Leu 693 and Leu 694) are drawn (Figure 3C). Figure 3B shows the helix 12/LBD interface as a close-up view of the OHT-LBD complex showing helix 12 bound to part of the coactivator binding site. Only the side chains of residues that interact with helix 12 are drawn (with the exception of side chain of His 373 which is omitted for clarity). Except for Lys 362 (blue) and Glu 380 (red), the side chains are colored by atom type as specified for Figure 3A. Residues 630-551 are depicted as a Ca worm; residues 636-644 are colored magenta. The side chains of Leu 536, Tyr 637, Leu 540, Met 543 and Leu 544 are shown. Figure 3C is a molecular surface representation showing the electrostatic surface of the ERa LBD bound to the NR Box II peptide as positive (blue) and negative (red) regions. as calculated in GRASP. The coactivator peptide is depicted as in Figure 3A and the view is equivalent to that in Figure 3A. The side chains of Leu 690 and Leu 694 are bound in a hydrophobic groove and those of Ile 689 and Leu 693 rest against the edge of this groove. Figure 3D shows the electrostatic surface of the ERa LBD complexed with OHT, showing positive (blue) and negative (red) regions as in Figure 3C. Residues 530-S 11 are depicted as in Figure 3B and the view is equivalent to that in Figure 3B.
Whereas the side chains of Leu 540 and Leu 544 are embedded in the hydrophobic groove, that of Met 543 lies along the I 5 edge of this groove.
Figure 4 was generated using LIGPLOT (Wallace, et al., Protein Eng. 8:127-34 (1995)) and provides schematic diagrams illustrating the DES interactions with the LBD
(Figure 4A) and OHT interactions with the ligand binding pocket (Figure 4B). Residues that interact with the ligands are drawn at approximately their true positions. The residues that form van der Waals contacts with ligand are depicted as labeled arcs with radial spokes that face towards the ligand atoms with which they interact. The residues that hydrogen bond to ligand are shown in ball-and-stick representation. Hydrogen bonds are represented as dashed cyan lines and the distance of each bond is given. The ligand rings and the individual ligand atoms are labeled.
Figure 5 was generated using BOBSCRIPT and rendered using Raster3D as described above, and shows a comparison of helix 12 from the OHT complex and the NR Box II peptide.
Figure 6A and Figure 6B are stereo views. The structures of the OHT-LBD
complex and the DES-LBD-NR Box II peptide complex were overlapped using the Ca coordinates of residues 306-626 of the LBD. Helix 12 from the DES-LBD-coactivator peptide complex is omitted for clarity. Residues 636-661 (helix 12=residues 536-544) from the OHT-LBD complex are colored magenta and the peptide is colored gold. The hydrogen bonds between the E-amino group of Lys 362 and the backbone carbonyls of residues 543 and 544 of helix 12 are illustrated as dashed magenta lines. The hydroeen bonds between the e-amino group of Lys 362 and the backbone carbonyls of residues 693 and 696 of the coactivator peptide are depicted as dashed orange lines.
The following abbreviations are used on helix 12: L540=Leu 540, M543=Met X43, and L544=Leu X44. The following abbreviations are used on the peptide: L690=Leu 690, L693=Leu 693 and L694=Leu 694.
Figures 6A and 6D were generated using BOBSCRIPT and rendered using Raster3D
as described above. Figures 6B and 6C were created using MidasPlus (Huang, et al., J. Mol. Graph.
9:230-6. 242 ( 1991 )). Figure 6A shows that agonists and antagonists promote different LBD
conformations, as ribbon representations of the DES complex (without the coactivator peptide), the OHT complex and the EZ complex such as is described in Tanenbaum, et al., supra. The hormones are shown in space-filling representation. In each complex, helix 12 is colored magenta and the main chain of residues 339 to 341, 421 to 423, and 527 to 530 is indicated in red. Helices 3, 8 and 11 (H3, H8 and HI 1 respectively) are labeled in the DES
complex. Figure 6B shows DES bound in the ligand binding cavity. A cross-section of a space-filling model of the LBD bound to DES (green) showing the ligand completely embedded in the ligand binding cavity. The A' ring of DES (A'), Phe 404 (404), Met 421 (421 ) and Phe 425 (425) are labeled.
The carbon atoms of side chain of Met 421 are colored magenta, and the sulfur atom is colored yellow. Figure 6C is a cross-section of a space-filling model of OHT (red) bound in the ligand binding pocket. The view is equivalent to that in Figure 6B. The B ring of OHT
(B), Phe 404 (404), Met 421 (421 ) and Phe 425 {425) are labeled. The side chain of Met 421 is colored as in Figure 6B. The conformation of the B ring forces Met 421 to adopt a different conformation than in the one it adopts in the DES complex (compare with Figure 6B). Figure 6D provides a comparison of the ligand binding pocket bound to DES (green) and to OHT (red).
The structures of the OHT complex and the DES complex were overlapped as in Figure S. The A
rings of both ligands point out of the page; the B ring of OHT and the A' ring of DES point into the page. The LBD bound to OHT is colored blue and the LBD bound to DES is colored light blue-grey. The side chains of some of the residues whose conformations are dramatically different between the two complexes are drawn; Met 342 (342), Met 343 (343), Phe 404 (404), Met 421 (421), Ile 424 (424), Phe 425 (425), His 524 (524), Leu 525 (525), Met 528 (528). The sulfur atom of Met 421 is colored yellow in both structures.
Figure 7 illustrates a model of antagonist action. Agonist (white triangle) binding stabilizes a conformation of the LBD that promotes coactivator (yellow) binding. Residues 527-530 (red) are part of helix 11 (blue) and the length of the interhelical loop prevents helix 12 (magenta) from binding to the static region of the surface involved in transcriptional activity.
Antagonist {white cross) side chains preclude helix 12 from being positioned over the ligand binding pocket. Residues 527-530 (red) adopt an extended conformation as a result of antagonist-driven structural perturbations in and around the ligand binding pocket. The length of the loop between helices 11 and 12 allows helix 12 to bind the static region of this surface and inhibit coactivator recognition.
Figure 8 shows alignment of amino acid sequences (single letter amino acid designations) containing residues that form the coactivator binding sites of several nuclear receptors: human and recombinant thyroid hormones (hTR~i and rTRa) (SEQ ID NO:S and 6 and SEQ
ID N0:7 and 8), retinoids (hRARy and hRXRa) (SEQ ID N0:9 and 10 and SEQ ID NO:11 and 12), peroxisome (hPPARr) (SEQ ID N0:13 and 14), vitamin D (hVDR) (SEQ ID NO:15 and 16), estrogen (hERa) (SEQ ID N0:17 and 18), glucocorticoid (hGR) (SEQ ID N0:19 and 20), progestin (hPR) (SEQ ID N0:21 and 22), mineralocorticoid (hMR) (SEQ ID N0:23 and 24) and androgen (hAR) (SEQ ID N0:25 and 26). The boxes represent residues of alpha-helix (H3, H4, 1 S H5, H6 and H 12); lower case letters "h" and "q" represent hydrophobic and polar residues, respectively. The numbered positions at the top of the table, 280, 281, etc., correspond to hTR(3 residues.
DESCRIPTION OF SPECIFIC EMBODIMENTS
The present invention provides methods and compositions for identifying compounds that modulate nuclear receptor activity, in particular steroid receptor activity, and more particularly estrogen receptor activity. The compounds are nuclear receptor agonists or antagonists that bind to the ligand binding domain. Compounds that bind to the LBD also are provided. The compounds can be natural or synthetic. Preferred compounds are small organic molecules, peptides and peptidomimetics (e.g., cyclic peptides, peptide analogs, or constrained peptides).
Certain residues within the ERa LBD have been identified that are of particular importance:Met343, Leu346, A1a350, GIu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, G1y521, His524, Leu525 and Met528 (See Figure 4A). Of these, some have been found to directly or indirectly effect the positioning of helix 12:
Met343. Met421, His524, Leu525 and Met528. Interactions with these particular residues, such as occurs when DES binds to the receptor stabilizes a conformation of the LBD that promotes coactivator binding.
Modifications to a ligand that enhance binding or interaction with these residues would provide for an improved agonist of receptor activity. Similarly, modifications to a ligand that adversely affects the binding or interaction with these residues would provide for an improved antagonist.
In addition, it is believed that the ERa Tyr537 residue plays a role in stabilizing the unliganded receptor so that helix 12 is free to interact with the coactivator binding site. The ER
is quite unique in having a tyrosine at this position as hTR(3, rTRa, hRARy, hGR, hPR. hMR and hAR all have a proline residue. hRXRa has as aspartic acid residue, hPPARY has a histidine residue and hVDR has a threonine residue at positions con esponding to the Tyr 537 residue of hERa. Therefore, selective agonists and antagonists can be designed for the estrogen receptor that interact with Tyr 537.
Traditional antagonists such as OHT or RAL have side chains that directly block helix 12 positioning as it is in the agonist complexes (DES or EZ). In addition, it is expected that iigand-induced perturbations are required to allow helix 12 to reach into the coactivator helix binding site, thereby blocking coactivator binding and inhibiting transcriptional activity. Such perturbations or interference with proper interactions with one or more of these LBD residues, has been found to relax the receptor, disassembling the receptor's secondary structure and resulting in unwinding of helix 11. The unwinding of helix 11 increases the length of the loop between helices 11 and 12, allowing helix 12 to move away from the ligand binding pocket and towards the coactivator binding site, where it occludes the coactivator recognition groove by mimicking the interactions of the coactivator, and thus inhibits coactivator recognition (see Figure 7). Modifications to a ligand that interfere with binding or interaction with one or more of the amino acids positions indicated, would cause receptor relaxation, affecting the receptor's secondary structure and cause the unwinding of helix i2. Compounds based upon such modified ligands would act as antagonists.
Accordingly, one aspect of the invention is a method of identifying a compound that modulates (i.e., increases or decreases) nuclear receptor activity, comprising: modeling test compounds that fit spatially into a nuclear receptor ligand binding domain of interest using an atomic structural model of the estrogen receptor a ligand binding domain or portion thereof, screening the test compounds in an assay, for example a biological assay, characterized by binding of a test compound to the ligand binding domain, and identifying a test compound that modulates nuclear receptor activity, wherein the atomic structural model comprises atomic coordinates of amino acid residues corresponding to residues of human estrogen receptor a Met343, Leu346. A1a350. G1u353, Leu384, Leu387, Leu391, Arg394, Phe404.
Met421, Leu428.

G1y~21. His524, Leu525 and Met528. preferably Met343, Met421, His524, Leu~25 and Met528.
In a preferred embodiment. the nuclear receptor is the ER. The test compound can be an agonist and nuclear receptor activity is measured by binding of a coactivator or a compound that mimics a coactivator, to the coactivator binding site. as defined below. On the other hand, the test compound can be an antagonist and nuclear receptor activity is measured by the unwinding of helix 12 and/or the blocking of coactivator binding to the coactivator binding site. The screening is typically in vitro, and high throughput screening is preferable. Suitable test compounds can be designed, as is described later, or can be obtained from a library of compounds, and include, by means of illustration and not limitation, small organic molecules, peptides and peptidomimetics.
The method described above may also include the step of providing the atomic coordinates of the estrogen receptor a ligand binding domain or portion thereof to a computerized modeling system, prior to said modeling step.
As used herein, the term "portion thereof' is intended to mean the atomic coordinates corresponding to a sufficient number of residues or their atoms of the LBD
that interact with a IS compound capable of binding to the site. This includes receptor residues having an atom within 4.SA of a bound compound or fragment thereof. Thus, for example, the atomic coordinates provided to the modeling system can contain atoms of the nuclear receptor LBD, part of the LBD
such as atoms corresponding to the LBD or a subset of atoms useful in the modeling and design of compounds that bind to a LBD.
The atomic coordinates of a compound that fits into the ligand binding domain also can be used for modeling to identify compounds or fragments that bind the site. By "modeling" is intended quantitative and qualitative analysis of molecular structure/function based on atomic structural infonmation and receptor-ligand agonists/antagonists interaction models. This includes conventional numeric-based molecular dynamic and energy minimization models, interactive computer graphic models, modified molecular mechanics models, distance geometry and other structure-based constraint models. Modeling is preferably performed using a computer and may be further optimized using known methods. By "fits spatially" is intended that the three-dimensional structure of a compound is accommodated geometrically by a cavity or pocket of a nuclear receptor LBD.
It is expected that targeting the corresponding amino acids on other nuclear receptors will have the same effect. Accordingly, one embodiment of the invention pertains to methods of designing antagonists that bind the LBD of a nuclear receptor but do not interact with one of more residues within the LBD that correspond to (i.e.. the same as or equivalent to) human ERa residues Met343. Leu346. A1a350, G1u353, Leu384. Leu387. Leu391, Arg394, Phe404, Met421, Leu428, G1y521. His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu~25 and Met528. Similarly, another embodiment of the invemion pertains to methods of designing agonists that bind the LBD of a nuclear receptor and have enhanced interaction with one or more residues within the LBD that correspond to the human ERa residues Met343, Leu346, A1a350, G1u353, Leu384. Leu387, Leu391, Arg394, Phe404. Met421, Leu428, G1y521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu~25 and Met528. An example of enhanced interaction is where the agonist has a greater binding affinity for one or more of said residues, as compared to an endogenous ligand. Such corresponding positions for other members of the nuclear receptor family are shown in Table 1, which provides an aiignment of amino acid sequences (one letter amino acid designations) containing residues from the ligand binding domains of several nuclear receptors that correspond to the designated positions on the human estrogen receptor (hERa): recombinant thyroid hormone (rTRa), retinoids (hRARy and hRXRa), glucocorticoid (hGRa), progestin (hPR), mineralocorticoid (hMR) and androgen (hARa). It is understood that Table 1 is merely illustrative of the invention and is not intended to be limiting in any manner. Accordingly, it is understood that corresponding amino acid residues of other nuclear receptors such as other estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors. may also be used in the methods of the invention.
Table hERa M343 M421 F425 H524 L525 M528 hPR L715 F794 I798 Y890 C891 T894 hARa L701 M780 Q784 F876 T877 L881 hGRa M560 M639 Q643 Y735 C736 T740 hMR L766 M845 L849 F941 C942 T946 hRARy W227 F304 L308 8396 A397 L401 hRXRa V265 6343 F346 H435 L436 F440 rTRa F215 L292 V296 8384 F385 M389 The term "coactivator binding site" is used herein to mean a structural segment or segments of the nuclear receptor polypeptide chain folded in such a way so as to give the proper geometry and amino acid residue conformation for binding coactivator. This is the physical arrangement of protein atoms in three-dimensional space forming a coactivator binding site pocket or cavity. As described by Apriletti. et al., supra, residues forming the coactivator binding site on nuclear receptors are amino acids that correspond to (i.e., the same as or equivalent to) human TR residues of C-terminal heiix 3 (I1e280. Thr281, Va1283, Va1284, A1a287, and Lys288), helix 4 (Phe293). helix S (G1n301, I1e302. Leu305.
Lys306), helix 6 (Cys309), and helix 12 (Pro453. Leu4~4. G1u457, Va1458 and Phe459), as shown in Figure 8.
The coactivator binding site is highly conserved among the nuclear receptor super family. Thus, this site corresponds to a surprisingly small cluster of residues on the surface of the LBD that form a prominent hydrophobic cleft. The hydrophobic cleft is formed by hydrophobic residues corresponding to human TR residues of C-terminal helix 3 (I1e280, Va1283, Va1284, and A1a287), helix 4 (Phe293), helix ~ (I1e302 and Leu305), helix 6 (Cys309), and helix 12 (Leu454, Va1458 and Phe459). This hydrophobic cleft of the coactivator binding site is also highly conserved among the nuclear receptor super family.
Based upon the Examples set forth herein, residues forming the coactivator binding site on the estrogen receptor were found to correspond to those positions described above for the human TR. Accordingly, the residues forming the coactivator binding site on ERa are the human ERa residues of C-terminal helix 3 (Leu354, Va1355, Met357, I1e358, A1a361, and Lys362), helix 4 (Phe367), helix 5 (G1n375, Va1376, Leu379, G1u380), helix 6 (Trp383), and helix 12 (Asp538, Leu539, G1u542, Met543 and Leu544), as shown in Figure 8. As noted above for the nuclear receptor family in general, this site corresponds to residues on the surface of the LBD that form a prominent hydrophobic cleft, formed by hydrophobic residues corresponding to human ERa residues of C-terminal helix 3 (Leu354, Met357, I1e358 and A1a361 ), helix 4 (Phe367), helix 5 (Va1376, Leu379), helix 6 (Trp383), and helix 12 (Leu~39, Met543 and Leu544). This corroborates the data presented by Apriletti, et al., supra, for the nuclear receptor family.
Structural analysis has revealed the mechanisms by which tamoxifen and other SERMs bind the ligand binding domain and block coactivator binding and hence transcriptional activity.
By this, an understanding of ligand and coactivator binding has also been achieved. Therefore, the coactivator binding site residues described above are useful in designing coactivator mimics that have broad application in the methods of the instant invention. Such "coactivator mimics"
are peptides or poiypeptides that mimic the coactivator binding site recognition area on the surface of a coactivator such that a "coactivator mimic" acts as a competitive inhibitor of coactivator binding to the coactivator binding site. Coactivator mimics can be used in an assay to determine receptor activity and hence the agonist or antagonist nature of a test compound, in that an agonist will permit a coactivator mimic to bind to the coactivator binding site. while an antagonist will prevent such binding. In addition. such coactivator mimics may have therapeutic utility when administered in combination with an agonist compound of the invention.
Another embodiment of the invention pertains to a method of identifying a compound that modulates ligand binding to a nuclear receptor, typically by binding to the ligand binding domain. This method comprises the steps of modeling test compounds that fit spatially into a nuclear receptor Iigand binding domain of interest using an atomic structural model of the estrogen receptor a ligand binding domain or portion thereof, screening the test compounds in an assay characterized by binding of a test compound to the binding domain, and identifying a test compound that modulates ligand binding to said nuclear receptor, wherein said atomic structural model comprises atomic coordinates of amino acid residues corresponding to residues of human estrogen receptor a Met343, Leu346, A1a350, GIu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, G1y521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528. In the preferred method, the nuclear receptor is ER, TR, GR or PR. The screening is typically in vitro such as by high throughput screening.
Suitable test compounds can be designed or obtained from a library of compounds, and include, by means of illustration and not limitation, small organic molecules, peptides and peptidomimetics. The test compounds can be either agonists or antagonists of ligand binding.
The invention also includes compositions and methods for identifying key residues within the ligand binding domains of nuclear receptors. The methods involve examining the surface of a nuclear receptor of interest to identify residues that modulate ligand and/or coactivator binding. The residues can be identified by homology to the key residues on the LBD
of human ERa described herein. A preferred method is alignment with the residues of any nuclear receptor corresponding to (i.e., equivalent to) human ERa residues of Met343, Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, G1y521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528.
Overlays and superpositioning with a three-dimensional model of a nuclear receptor LBD, or a portion thereof that contains these or corresponding residues, also can be used for this purpose. For example, three-dimensional structures of TR, GR and PR LBDs can be used for this purpose. For example, nuclear receptors identifiable by homology alignment include normal nuclear receptors or proteins structurally related to nuclear receptors found in humans. natural mutants of nuclear 1~

WO 99/50658 PCT/US99/0693'7 receptors found in humans. normal or mutant receptors found in animals, as well as non-mammalian organisms such as pests or infectious organisms, or viruses.
Alignment and/or modeling also can be used as a guide for the placement of mutations on the LBD surface to characterize the nature of the site in the context of a cell. Selected residues ~ are mutated to preserve global receptor structure and solubility in the case of an agonist, or to disassemble such structure and permit helix 12 to unwind, as is the case with an antagonist.
Mutants can be tested for ligand binding as well as the relative change in strength of the binding interaction. Ligand-dependent coactivator interaction assays also can be tested for this purpose, such as those described herein.
In particular, the present invention relates to the structural and functional effects on the estrogen receptor's LBD. of the binding of two chemically-related compounds, the agonist, diethylstilbestrol (DES), and the selective antagonist 4-hydroxytamoxifen (OHT), the active metabolite of tamoxifen. As described in the Examples, mutagenesis and binding studies, coupled with analysis of atomic models derived from cocrystals, reveals the structure of the human estrogen receptor a ligand binding domain (ERa LBD) co-crystallized with a peptide molecule comprising a GRIP1 NR Box II peptide sequence (SEQ ID N0:4) (i.e., a peptide derived from the NR Box II region of the p 160 coactivator GRIP 1 ) bound to the coactivator binding site and the agonist, DES. Also revealed is the structure of the ERa LBD co-crystallized with the antagonist, OHT. The Examples provide the 2.03 resolution crystal structure of the hERa LBD bound to DES and the coactivator and the 1.9t~ x-ray crystal structure of the hERa LBD bound to OHT, i.e., the crystals defract with at least 2.03 or 1.9A
resolution, respectively.
In yet another aspect of the invention. compounds of interest are discovered, i.e., agonists or antagonists of ligand binding are identified, by a method for identifying an agonist or antagonist of ligand binding to a nuclear receptor. The method comprises the steps of providing the atomic coordinates of the ERa LBD or portion thereof to a computerized modeling system.
modeling compounds which fit spatially into the LBD, and identifying in an assay for nuclear receptor activity a compound which increases or decreases the activity of the nuclear receptor by binding the LBD of the nuclear receptor. Preferably, the atomic coordinates are of the amino acid residues corresponding to residues of human estrogen receptor a Met343.
Leu346, AIa350, G1u353, Leu384. Leu387. Leu391. Arg394, Phe404, Met421, Leu428, G1y521.
His524, Leu525 and Met528, preferably Met343, Met421, His~24, Leu52~ and Met528.

Compounds of particular interest fit spatially and preferentially into the ligand binding domain. By "its spatially and preferentially" is intended that a compound possesses a three-dimensional structure and conformation for selectively interacting with a nuclear receptor LBD.
Compounds that fit spatially and preferentially into the LBD interact with amino acid residues forming the hydrophobic cleft of this site. The present invention also includes a method for identifying a compound capable of selectively modulating nuclear receptor activity. The method comprises the steps of modeling test compounds that fit spatially and preferentially into the LBD
of a nuclear receptor of interest using an atomic structural model of a nuclear receptor, screening the test compounds in an assay for nuclear receptor activity characterized by preferential binding of a test compound to the LBD of a nuclear receptor, and identifying a test compound that selectively modulates the activity of a nuclear receptor. Such receptor-specific compounds are selected that exploit differences between the LBDs of one type of nuclear receptor versus a second type of nuclear receptor.
The invention also is applicable to generating new compounds that distinguish nuclear receptor isoforms. This can facilitate generation of either tissue-specific or function-specific compounds. For instance, GR subfamily members have usually one receptor encoded by a single gene, although there are exceptions. For example, there are two PR
isoforms, A and B, translated from the same mRNA by alternate initiation from different AUG
codons. There are two GR forms, one of which does not bind ligand. This method is especially applicable to the ER subfamily which usually has several receptors that are encoded by at least two (ER: a, Vii) genes or have alternate RNA splicing.
The receptor-specific compounds of the invention preferably interact with conformationally constrained residues of the LBD that are conserved among one type of nuclear receptor compared to a second type of nuclear receptor. "Conformationally constrained" is intended to refer to the three-dimensional structure of a chemical or moiety thereof having certain rotations about its bonds fixed by various local geometric and physical-chemical constraints. Conformationally constrained structural features of a LBD include residues that have their natural flexible conformations fixed by various geometric and physical-chemical constraints, such as local backbone, local side chain, and topological constraints. These types of constraints are exploited to restrict positioning of atoms involved in receptor-coactivator recognition and binding.

The present invention also provides for a computational method using three dimensional models of nuclear receptors based on crystals of nuclear receptors. Generally, the computational method of designing a nuclear receptor ligand determines which amino acid or amino acids of a nuclear receptor LBD interact with a chemical moiety (at least one) of the ligand using a three dimensional model of a crystallized protein comprising a nuclear receptor LBD
with a bound ligand, and selecting a chemical modification (at least one) of the chemical moiety to produce a second chemical moiety with a structure that either decreases or increases an interaction between the interacting amino acid and the second chemical moiety compared to the interaction between the interacting amino acid and the chemical moiety. In the instant invention, crystal structures of the hERa with DES/peptide and with OHT, have shown that amino acid residues that correspond to hERoc Met343. Leu346, A1a350, G1u353, Leu384. Leu387. Leu391, Arg394, Phe404, Met421, Leu428, GIy521. His524, Leu525 and Met528, preferably Met343, Met421, His524.
Leu525 and/or Met528, interact with at least one chemical moiety on the ligand.
Accordingly, one embodiment of the invention is a computational method of designing a nuclear receptor ligand where at least one amino acid residue of a nuclear receptor LBD that corresponds to human estrogen receptor a Met343, Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, GIy521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528, interacts with at least one first chemical moiety of the ligand, comprising the step of selecting at least one chemical modification of the first chemical moiety to produce a second chemical moiety with a structure to either decrease or increase an interaction between the interacting amino acid and the second chemical moiety as compared to the interaction between the interacting amino acid and the first chemical moiety.
This computational method may further comprise determining a change in interaction between the interacting amino acid and the ligand after chemical modification of the first chemical moiety. The chemical modification can either enhance or reduce hydrogen bonding interaction, charge interaction, hydrophobic interaction. Van Der Waals interaction or dipole interaction between the second chemical moiety and the interacting amino acid as compared to the interaction between the first chemical moiety and the interacting amino acid.
Chemical modifications will often enhance or reduce interactions an atom of a LBD
amino acid and an atom of an LBD ligand. Steric hindrance will be a common means of changing the interaction of the LBD binding cavity with the activation domain.
Chemical modifications are preferably introduced at C-H, C- and C-OH position in ligands, where the carbon is part of the ligand structure which remains the same after modification is complete. In the case of C-H, C could have 1. ? or 3 hydrogens, but usually only one hydrogen will be replace. The H or OH are removed after modification is complete and replaced with the desired chemical moiety.
S Such chemical modifications would preferably involve the addition of substituents, onto any of the free carbons of the A' ring of DES positioning these substituents to collide or bind preferentially with one or more residues that correspond to hERa Met343.
Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, G1y521, His524, Leu525 and Met528, preferably Met343, Met421. His524, Leu525 or Met528. Typical substituents are hydrophobic groups, including by way of example and not limitation. alkyl groups such as ethyl, propyl, isopropyl, etc., and aromatic groups such as benzyl, etc.
In practice, one would start with a known ligand for the nuclear receptor of interest as the chemical backbone, upon which to base agonist/antagonist design. The known ligand would be modified as described above. For example 17(3-estradiol is an endogenous ligand for the hERa.
In the case of estradiol, positions of interest are C6a, C7a, C 12a, C 1 Sa, C
16a and C 17a.
Modifications at one or more of these free carbons on 17~i-estradiol's backbone would affect the ligand's interactions with one or more of the Met343, Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, G1y521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528 residues, either providing for enhancing interaction, which would be the basis for agonist design, or reduced interaction, which would be the basis for antagonist design.
Other chemical backbones of other known ligands could be used in a similar manner.
For example, other known agonists include diethylstilbestrol (synthetic), moxestrol (synthetic), mesohexestrol (synthetic), coumestrol (clover), D9-THC (cannabis), o,p-DDT
(insecticide), zearalenone (fungal) and kepone (insecticide). Known estrogen receptor antagonists include the ICI series of modified steroids such as ICI 164,384 and EM800. Known SERM's include tamoxifen, raloxifene and GW5638.
Alternatively known agonists could be positioned in the ligand binding pocket through computational or manual docking. Positions for substitution would then be selected based on the predicted binding orientation of these compounds. In addition, hybrid molecules could be generated that also possessed side chains that prevented helix 12 from adopting the agonist-bound position. Novel SERMs can be produced by varying the strength of two different effects:
the helix 12 displacement and the secondary structure disorganization.
Previous efforts to make antagonists have involved attachment of large bulky substituents to agonists. typically through trial and error, and the drug design methods described herein provide an alternative strategy of ligand design that may be critical for developing new potential antagonists.
For modeling, docking algorithms and computer programs that employ them can be used to identify compounds that fit into the ligand binding domain. For example, docking programs can be used to predict how a molecule of interest can interact with the nuclear receptor LBD.
Fragment-based docking also can be used in building molecules de novo inside the LBD, by placing chemical fragments that complement the site to optimize intermolecular interactions.
The techniques can be used to optimize the geometry of the binding interactions. This design approach has been made possible by identification of the LBD structure thus, the principles of molecular recognition can now be used to design a compound which is complementary to the structure of this site. Compounds fitting the LBD serve as a starting point for an iterative design, synthesis and test cycle in which new compounds are selected and optimized for desired properties including affinity, efficacy, and selectivity. For example, the compounds can be subjected to addition modification, such as replacement and/or addition of R-group substituents of a core structure identified for a particular class of binding compounds, modeling and/or activity screening if desired, and then subjected to additional rounds of testing.
Computationally small molecule databases can be screened for chemical entities or compounds that can bind in whole, or in part, to a nuclear receptor ligand binding domain of interest. In this screening, the quality of fit of such entities or compounds to the binding site may be judged either by shape cornplementarity (DesJalais, et al., J. Med. Chem.
31:722-729 ( 1988)) or by estimated interaction energy (Meng, et al., J. Comn. Chem. 13:505-524 {
1992)). The molecule databases include any virtual or physical database, such as electronic and physical compound library databases, and are preferably used in developing compounds that modulate coactivator binding.
Compounds can be designed intelligently by exploiting available structural and functional information by gaining an understanding of the quantitative structure-activity relationship (QSAR), using that understanding to design new compound libraries, particularly focused libraries having chemical diversity of one or more particular groups of a core structure, ?0 and incorporating any structural data into that iterative design process. For example, one skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with the ligand binding domain of a nuclear receptor of interest. This process may begin by visual inspection of. for example, the LBD on the computer screen. Selected fragments or chemical entities may then be positioned into all or part of the site. Docking may be accomplished using software such as Quanta and Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics force-fields, such as CHARMM and AMBER.
Specialized computer programs may also assist in the process of selecting chemical entity fragments or whole compounds. These include: GRID (Goodford. J. Med. Chem.
28:849-857 (1985), available from Oxford University, Oxford, UK); MCSS (Miranker, et al., "Proteins:
Structure, Function and Genetics" 11:29-34 ( 1991 ), available from Molecular Simulations, Burlington. MA); AUTODOCK (Goodsell, et al., "Proteins: Structure. Function and Genetics"
8:195-202 (1990), available from Scripps Research Institute, La Jolla, CA);
and DOCK (Kuntz, et al, J. Mol. Biol. 161:269-288 (1982), available from University of California, San Francisco, CA).
Additional commercially available computer databases for small molecular compounds include Cambridge Structural Database and Fine Chemical Database (Rusinko, Chem. Des.
Auto. News 8:44-47 (1993)).
Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound. Assembly may be proceeded by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of a nuclear receptor. This can be followed by manual model building using software such as Quanta or Sybyl.
Useful programs to aid one of skill in the art in connecting the individual chemical entities or fragments include: CAVEAT (Bartlett, et al., "CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules", in Molecular Recognition in Chemical and Biological Problems, Special Pub., Royal Chem. Soc. 78:182-196 ( 1989), available from the University of California, Berkeley, CA); 3D Database systems such as MACCS- -3D (MDL Information Systems. San Leandro. CA. reviewed in Martin. J.
Med. Chem.
35:2145-21 ~4 ( 1992)); and HOOK (available from Molecular Simulations.
Burlington. MA).

In addition to building a compound in a step-wise fashion. one fragment or chemical entity at a time as described above. compounds that bind to a ligand binding domain of interest also may be designed as a whole or de novo using either an empty LBD or optionally including some portions) of a molecule known to bind to the site, such as a known ligand. These methods include: LUDI (Bohm, J. C_ omv. Aid. Molec. Desi n 6:61-78 (1992), available tcom Biosm Technologies, San Diego, CA); LEGEND (Nishibata, et al., Tetrahedron 47:8985 ( 1991 ), available from Molecular Simulations, Burlington, MA); and LeapFrog (available from Tripos Associates, St. Louis, MO).
Other molecular modeling techniques may also be employed in accordance with this invention. See, for example, Cohen, et al., J. Med. Chem. 33:883-894 ( 1990) and Navia, et al., Current Opinions in Structural Biology 2:202-210 (1992). For example, where the structures of test compounds are known, a model of the test compound may be superimposed over the model of the structure of the invention. Numerous methods and techniques are known in the art for performing this step, any of which may be used. See, for example, Farmer, "Drug Design"
10:119-143, Ariens, ed., Academic Press, New York (1980); U.S. Patent No.

5,331,573; U.S.
Patent No. x,500,807; Verlinde, Structure 2:577-587 (1994); and Kuntz, et al., Science 257:1078-1082 (1992). The model building techniques and computer evaluation systems described herein are not a limitation on the present invention.
Using these computer modeling systems a large number of compounds may be quickly and easily examined and expensive and lengthy biochemical testing avoided.
Moreover, the need for actual synthesis of many compounds can be substantially reduced and/or effectively eliminated.
Compounds identified through modeling can be screened in assays such as are well known in the art. Such assays, which include biological assays, are characterized by binding of the compound to a Iigand binding domain of interest for ligand binding activity. Screening can be, for example, in vitro, in cell culture, and/or in vivo. Biological screening preferably centers on activity-based response models, binding assays (which measure how well a compound binds to the receptor), and bacterial, yeast and animal cell lines (which measure the biological effect of a compound in a cell). The assays can be automated for high capacity-high throughput screening (HTS) in which large numbers of compounds can be tested to identify compounds with the desired activity.

As an example. in vitro binding assays can be performed in which compounds are tested for their ability to block the binding of a ligand. fragment. fusion or peptide thereof, to a ligand binding domain of interest. For cell and tissue culture assays, they may be performed to assess a compound's ability to block function of cellular coactivators. such as members of the p 160 family of coactivator proteins, such as SRC-1, AIB1, RAC3, p/CIP, and GRIPI
and its homologues TIF 2 and NcoA-2, and those that exhibit receptor and/or isoform-specific binding affinity. In a preferred embodiment, compounds of the invention bind to a ligand binding domain with greater affinity than the endogenous ligands. Tissue profiling and appropriate animal models also can be used to select compounds. Different cell types and tissues also can be used for these biological screening assays. Suitable assays for such screening are described herein and in Shibata. et al., Recent Proe. Horm. Res. 52:141-164 (1997);
Tagami, et al., Mol.
Cell. Biol. 17(5):2642-2648 (1997); Zhu, et al., J. Biol. Chem. 272(14):9048-9054 (1997); Lin, et al., _Mol. Cell. Biol. 17(10):6131-6138 (1997); Kakizawa, et al., J. Biol.
Chem. 272(38):23799-23804 (1997); and Chang, et al., Proc. Natl. Acad. Sci. USA 94(17):9040-9045 (1997), which references are incorporated herein in their entirety by reference.
The compounds selected can have agonist and/or antagonistic properties. The compounds also include those that exhibit new properties with varying mixtures of agonist and antagonist activities, depending on the effects of altering ligand binding in the context of different activities of nuclear receptors, either hormone-dependent or honmone-independent, which are mediated by proteins other than coactivators, and which interact with the receptors at locations other than the coactivator binding site. The compounds also include those, which through their binding to receptor locations that are conformationally sensitive to hormone binding, have allosteric effects on the receptor by stabilizing or destabilizing the hormone-bound conformation of the receptor, or by directly inducing the same, similar, or different conformational changes induced in the receptor by the binding of hormone.
Of particular interest is use of such compounds in a method of modulating nuclear receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a compound that fits spatially and preferentially into a ligand binding domain of a nuclear receptor of interest. By "modulating" is intended increasing or decreasing activity of a nuclear receptor. For example. pre-clinical candidate compounds can be tested in appropriate animal models in order to measure efficacy, absorption, pharmacokinetics and toxicity following standard techniques known in the art. Compounds exhibiting desired properties are then tested in clinical trials for use in treatment of various nuclear receptor-based disorders. These include ER-based disorders, such as postmenopausal symptoms and cancer resulting from loss of estrogen production, and osteoporosis and cardiovascular disease stemming tiom traditional estrogen replacement therapy. Others include GR-based disorders including Type II diabetes and inflammatory conditions such as rheumatic diseases.
Although for many nuclear receptors. the goal is to discover novel synthetic agonists or antagonists, it is important to realize the value for some nuclear receptors.
especially the estrogen receptor, of developing compounds that have the desired agonist and antagonist effects in target tissues. Such compounds can be discovered and/or designed by the methods described herein, then screened for tissue specificity by methods that are well known in the art. For example, there is a great need for the improvement of existing therapies and the development of new agonists that act like estrogen in cardiovascular and brain tissue and bone, and new antagonists that act upon the estrogen receptor in uterine and breast tissue. Ideally, a compound will have more than one of these traits, i.e., a compound will act as an agonist in one tissue, while acting as an I S antagonist in another tissue. While the tissue-selective antagonism of SERMs such as OHT and RAL is the result of numerous factors (Grainger, et al., Nature Medicine 2(4):381-385 (1996);
Grese, et al., supra; and Jordan, J. Natl. Cancer Inst. 90:967-71 ( 1998)), dissection of the mechanisms of action of these ligands requires a comprehensive understanding of how they act on the LBD and regulate its interactions with other cellular factors. The instant invention shows, unexpectedly, that ligand-mediated structural perturbations in and around the ligand binding pocket, and not simply side chain effects, contribute to receptor antagonism.
Accordingly, by adjusting the balance between these two effects provides a novel strategy for the design of improved SERMs.
With this knowledge, it is of particular interest to design therapeutic compounds that will distort at least one amino acid residue corresponding to residues of human estrogen receptor a Met343, Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394. Phe404, Met421, Leu428, G1y521. His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528.
Accordingly, one aspect of the invention is a method of modulating nuclear receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a ligand that fits spatially and preferentially into a ligand binding domain of a nuclear receptor of interest, wherein the ligand is designed by a computational method where at least one amino acid residue of a nuclear receptor LBD that corresponds to hERa Met343, Leu346. A1a3~0.
G1u353, Leu384, Leu387. Leu391. Arg394. Phe404, Met421, Leu428, G1y~21. His524, Leu~25 and Met528.
preferably Met343, Met421, His524, Leu525 and Met~~B. interacts with at least one first chemical moiety of the ligand. Such a method involves selecting at least one chemical modification of the first chemical moiety to produce a second chemical moiety with a structure that either decreases or increases an interaction between the interacting amino acid and the second chemical moiety as compared to the interaction between the interacting amino acid and the first chemical moiety.
Compounds designed by this method can be either agonists or antagonists and the method of modulating nuclear receptor activity can comprise administering an antagonist atone. an agonist alone or an agonist in combination with a coactivator or a compound that mimics a coactivator by binding to the coactivator binding site.
The coactivator can be a known coactivator. The coactivator mimic can be designed by a computational method where at least one amino acid residue of a nuclear receptor coactivator binding site that corresponds to hERa helix 3 residues Leu354, Va1355, Met357, I1e358, A1a361 I S and Lys362, helix 4 residue Phe367, helix 5 residues G1n375, Va1376, Leu379 and G1u380, helix 6 residue Trp383. and helix 12 residues Asp538, Leu539, G1u542, Met543 and Leu544, interacts with at least one first chemical moiety of the coactivator mimic. The method involves selecting at least one chemical modification of the first chemical moiety to produce a second chemical moiety with a structure that either decreases or increases an interaction between the interacting amino acid and the second chemical moiety as compared to the interaction between the interacting amino acid and the first chemical moiety.
Use of an agonist in combination with a coactivator or coactivator mimic also provides a unique strategy for delivering therapeutics that have novel tissue-specific effects. For example, coactivator mimics can be designed to bind into the site involved in transcriptional activity only when helix-12 is in its agonist bound state. If such coactivator mimics are specific for this site of a particular receptor, it is possible to selectively inhibit that receptor only in the presence of agonist. This could lead to novel, tissue specific antagonism based on the levels of endogenous agonists. Agonists designed by the methods of the instant invention could be used in assay to determine the specificity of coactivator mimics. Alternatively, the effective levels in a given tissue could be modulated by giving known antagonists or antagonists designed by the methods of the instant invention. The crystal structure of the LBD/DES/GRIP1 peptide complex.
described herein, precisely defines the binding site that would need to be targeted.

As noted above and as exemplified in the Examples, ER LBDs are co-crystallized with a peptide molecule comprising a coactivator GRIP1 NR Box II peptide sequence (SEQ ID N0:4) bound to the coactivator binding site and DES with-the cocrystal structure refined to a resolution of 2.03 and co-crystallized with OHT with the cocrystal structure refined to a resolution of 1.9A. Accordingly, the invention also provides for cocrystals made from nuclear receptor ligand binding domains with a ligand bound to the ligand binding domain and a molecule bound to the coactivator binding site. Preferably the cocrystal structure is refined to a resolution greater than 3.6A, i.e.. having a resolution value less than 3.6A. More preferably the cocrystal structure is refined to greater than 3.4A, 3.2~, 3.0~. 2.8t~, 2.6A, 2.4~, 2.2t~, even more preferably to a resolution greater than 2.03A. The invention further provides for cocrystals made from nuclear receptor ligand binding domains with a ligand bound to the ligand binding domain. Preferably the cocrystal structure is refined to a resolution greater than 3.6A, i.e., having a resolution value less than 3.6t~. More preferably the cocrystal structure is refined to greater than 3.4~, 3.2A, 3.Ot~, 2.8~, 2.6~,, 2.4A, 2.2~, 2.Ot~, even more preferably to a resolution greater than 1.9~.
1 S Crystals are made from purified nuclear receptor LBDs that are usually expressed by a cell culture, such as E. colt. E. colt is often a preferred expression system.
The thyroid receptor was successfully expressed in E. colt in Apriletti, et al., supra. However. it has long been believed that a human heat shock protein was required for successful recombinant expression of the estrogen receptor. Therefore, it was quite unexpected to find that the estrogen receptor could be expressed as an active protein in E. colt.
Preferably, different crystals (cocrystals) for the same nuclear receptor are separately made using different coactivators-type molecules, such as protein fragments, fusions or small peptides. The coactivator-type molecules preferably contain NR-box sequences necessary for binding to the coactivator binding site, or derivatives of NR-box sequences.
Other molecules can be used in co-crystallization, such as small organics that bind to the coactivator or honmone binding site(s). Heavy atom substitutions can be included in the LBD and/or a co-crystallizing molecule.
After the three dimensional structure of the cocrystal is determined, the structural information can be used in computational methods to design synthetic compounds for the nuclear receptor, and further structure-activity relationships can be determined through routine testing using the assays described herein and known in the art.

Since nuclear receptor LBDs may crystallize in more than one crystal form the structure coordinates of such receptors or portions thereof: as provided in Appendices 1 and 2, are particularly useful to solve the structure of those other crystal forms of nuclear receptors. They may also be used to solve the structure of mutants or co-complexes of nuclear receptors having sufficient homology.
One method that may be employed for this purpose is molecular replacement. In this method, the unknown crystal structure, may be determined using the structure coordinates of this invention as provided in Appendices 1 and 2. The Appendix 1 coordinates for the DES-ERa LBD-GRIP1 NR Box II peptide complex and for the Appendix 2 coordinates for the OHT-ERa LBD complex have been deposited with the Brookhaven National Laboratory Protein Data Bank, and have been assigned Brookhaven Protein Data Bank Accession Numbers 2erd and 2ert, respectively. This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.
Atomic coordinate information gleaned from the crystals of the invention can be stored.
In a preferred embodiment, the information is provided in the form of a machine-readable data storage medium. This medium contains information for constructing and/or manipulating an atomic model of a ligand binding domain or portion thereof. For example, the machine readable data for the iigand binding domain comprises structure coordinates of amino acids corresponding to hERa Met343, Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394.
Phe404, Met421, Leu428, GIy52I, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528, or a homologue of the molecule or molecular complex comprising the site. The homologues comprise a LBD that has a root mean square deviation from the backbone atoms of the amino acids of not more than 1.5~. A preferred molecule or complex represents a compound bound to the LBD.
The machine-readable data storage medium can be used for interactive drug design and molecular replacement studies. For example, a data storage material is encoded with a first set of machine-readable data that can be combined with a second set of machine-readable data. For molecular replacement, the first set of data can comprise a Fourier transform of at least a portion of the structural coordinates of the nuclear receptor or portion thereof of interest. and the second data set comprises an X-ray diffraction pattern of the molecule or molecular complex of interest.
Using a machine programmed with instructions for using the first and second data sets a portion or all of the structure coordinates corresponding to the second data can be determined.
?7 Protein for crystals and assays described herein can be produced using expression and purification techniques described herein and known in the art. For example, high level expression of nuclear receptor LBDs can be obtained in suitable expression hosts such as E. coli.
Expression of LBDs in E. toll, for example, includes the ERa LBD and other nuclear receptors, including GR and PR. Yeast and other eukaryotic expression systems can be used with nuclear receptors that bind heat shock proteins as these nuclear receptors are generally more difficult to express in bacteria, with the exception of ER, which can be expressed in bacteria.
Representative nuclear receptors or their ligand binding domains have been cloned and sequenced: human ER (as described in Seielstad, et al., Molecular EndocrinoloQV 9(6):647-658 (1995), incorporated herein by reference), human GR, and human PR. The LBD for each of these receptors has been identified.
Coactivator proteins can be expressed using techniques known in the art, particularly members of the p160 family of coactivator proteins that have been cloned and/or expressed previously, such as SRC-1, AIB1, RAC3, p/CIP, and GRIP1 and its homologues TIF
2 and 1 S NcoA-2. A preferred method for expression of coactivator protein is to express a fragment that retains transcriptional activation activity using the "Song and Fields" method (also referred to as the "yeast 2-hybrid" method) as described in publications by Hong, et al., Mol. Celt. Biol.
17:2735-44 (1997) and Proc. Natl. Acad. Sci. USA 93(10):4948-52 (1996)), for expression, which references are incorporated herein by reference.
The proteins can be expressed alone, as fragments of the mature or full-length sequence, or as fusions to heterologous sequences. For example, ERa can be expressed without any portion of the DBD or amino-terminal domain. Portions of the DBD or amino-terminus can be included if further structural information with amino acids adjacent the LBD
is desired.
Generally, for the ERa the LBD used for crystals will be less than 320 amino acids in length.
Preferably, the ERa LBD will be at least 220 amino acids in length and most preferably at least 250 amino acids in length. For example the LBD used for crystallization can comprise amino acids spanning from 297 to X54 of the ERa.
Typically the LBDs are purified to homogeneity for crystallization. Purity of LBDs can be measured with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).
mass spectrometry (MS) and hydrophobic high performance liquid chromatography (HPLC).
The purified LBD for crystallization should be at least 97.5 % pure, preferably at least 99.0%
pure, and more preferably at least 99.5% pure.

Initially, purification of the unliganded receptor can be obtained by conventional techniques, such as hydrophobic interaction chromatography (HPLC), ion exchange chromatography (HPLC), and heparin affinity chromatography. To achieve higher purification for improved crystals of nuclear receptors, especially the estrogen receptor.
the receptors can be ligand-shift-purified using a column that separates the receptor according to charge, such as an ion exchange or hydrophobic interaction column, and then bind the eluted receptor with a ligand, especially an agonist. The ligand induces a change in the receptor's surface charge such that the liganded receptor elutes at a different position than the unliganded receptor.
Usually saturating concentrations of ligand are used in the column and the protein can be preincubated with the ligand prior to passing it over the column. The structural studies detailed herein indicate the general applicability of this technique for obtaining super-pure nuclear receptor LBDs for crystallization.
Purification can also be accomplished by use of a purification handle or "tag," such as with a histidine amino acid engineered to reside on the end of the protein, such as on the N-terminus, and then using a nickel or cobalt chelation column for purification.
(Janknecht, Proc.
Natl. Acad. Sci. USA, 88:8972-8976 ( 1991 )) incorporated by reference.
Typically purified LBD, such as ERa LBD, is equilibrated at a saturating concentration of ligand at a temperature that preserves the integrity of the protein. Ligand equilibration can be established between 2 and 37°C, although the receptor tends to be more stable in the 2-20°C range. Preferably crystals are made with the hanging drop methods detailed herein. Regulated temperature control is desirable to improve crystal stability and quality. Temperatures between 4 and 25°C are generally used and it is often preferable to test crystallization over a range of temperatures. The crystals are then subjected to vapor diffusion and bombarded with x-rays to obtain x-ray diffraction pattern following standard procedures.
For co-crystallization with a ligand that binds the ligand binding domain, alone or in conjunction with a peptide that binds to the coactivator binding site, various concentrations of ligands and peptides containing a sequence that binds to a coactivator binding site of a nuclear receptor of interest can be used in microcrystallization trials, and the appropriate compounds selected for further crystallization. Ligands and peptides can be assayed for binding to the ligand binding domain and coactivator binding sites of a nuclear receptor of interest by any number of techniques. including those assays described herein. For crystallization trials with the ERa LBD. the hanging drop vapor diffusion method is preferred. Conditions of pH, solvent and solute components and concentrations and temperature can be adjusted, for instance. as described in the Examples. In the handing drop method, to obtain suitable crystals for x-ray diffraction analysis, seeding of prepared drops with microcrystals of the complex can be used.
Collection of structural information can be determined by molecular replacement using the structure of the ERa LBD determined herein. The structure is refined following standard techniques known in the art.
There are many uses and advantages provided by the present invention. For example. the methods and compositions described herein are useful for identifying peptides, peptidomimetics or small natural or synthetic organic molecules that modulate nuclear receptor activity. The compounds are useful in treating nuclear receptor-based disorders. Methods and compositions of the invention also find use in characterizing structure/function relationships of natural and synthetic ligands.
The following discussion of provides an understanding of the basis for the examples, along with the results obtained and/or the conclusions reached.
As described above, many coactivators recognize agonist bound nuclear receptor LBDs through the sequence LXXLL (SEQ ID NO:1), where L is leucine and X is any amino acid (the NR box). The structure of the DES-hERa LBD-GRIP 1 peptide complex reveals that the LXXLL motif (SEQ ID NO:1 ) forms the core of a short amphipathic a helix which is recognized by a highly complementary hydrophobic groove on the surface of the receptor.
In agreement with the conclusions of other mutational and structural studies (Brzozowski, et al., supra and Feng, et al., supra), it is believed that this peptide binding groove formed by residues from helices 3, 4, 5 and 12 and the turn between helices 3 and 4 is the surface of ERa involved with transcriptional activity, i.e., the coactivator binding site. Further, structural studies of the complex between TR(3 and the GRIP 1 NR box II peptide and biochemical studies of GRIP 1 binding to TR~i and GR (Darimont, et al., supra) and study of the general features of the PPARy/SRC-1 peptide complex (Nolte, et al., supra) are similar to those of the ERa/GRIP1 NR
box II peptide complex described herein, suggesting that the mechanisms of NR
box recognition are conserved across the nuclear receptor family.
Of the eleven AF-2 residues whose side chains interact with the coactivator helix (Figure 3A), only four (Lys 362, Leu 379. Gln 375 and Glu X42) are highly conserved across the nuclear receptor family (Wurtz, et al., supra). The side chains of Gln 375 and Leu 379 are predominantly buried even in the absence of GRIPI binding and appear to form integral parts of the architecture of the surface involved in transcriptional activity. In contrast. the side chains of Lys 362 and Glu 542 are largely solvent exposed in the absence of coactivator and make both nonpolar contacts and the only receptor-mediated polar interactions with the coactivator helix.
These two capping interaction residues are perfectly positioned at opposite ends of the coactivator binding site groove not only to stabilize the main chain conformation of the coactivator but also to function as a molecular caliper; the 15~ distance between Lys 362 and Glu 542 is well suited to measure off the --I 1 ~ axial length of the short, two-turn coactivator a helix (Figure 3C). Similar receptor-mediated capping interactions have also been observed in a complex between the TR~3 LBD and the NR box II peptide (Darimont, et al., supra). Mutation of either of these two residues severely cripples coactivator binding by ERa as well as by TR(3 (see the Examples, Apriletti, et al., supra and Feng, et al., supra and Henttu, et al., supra). Hence, the formation of helix capping interactions may be a general feature of coactivator recognition by nuclear receptors.
The side chains of six hydrophobic AF-2 residues (Ile 358, Leu 372, Val 376, Leu 379, Leu 539 and Met 543) form a large part of the highly cooperative network of van der Waals contacts made by the receptor with the hydrophobic face of the coactivator helix (Figures 3A and 3C). Mutations in Ile 358, Val 376 and Leu 539 abrogate GRIpI binding (see the Examples and Feng, et al., supra). Although these residues are, in general, more poorly conserved across nuclear receptors than either Lys 362 or Glu 542, their hydrophobic character, with the exception of Leu 372, is conserved. Since the different NR LBDs adopt the same overall fold (Moras, et al., Curr. Onin. Cell Biol. 10:384-91 ( 1998)), it follows that the hydrophobic regions of different nuclear receptor coactivator binding site surfaces are distinctly textured. In support of this hypothesis, the NR box II peptide used in crystallization inhibited binding of GRIP1 to the LBDs of the ERa, the TR(i and the glucocorticoid receptor (GR) with very different efficiencies (Ding, et al., supra).
The hydrophobic face of the NR box helix is formed by the side chains of the three motif leucines and the isoleucine preceding the motif (Ile 689). The functional importance of the conserved leucines in receptor binding has been demonstrated by numerous in vitro and in vivo studies. In contrast, the role of the residue preceding the motif in receptor binding has been poorly characterized. Both biochemical and structural data implicate Ile 689 as a key receptor binding determinant. In the crystal, only the side chains of the motif leucines and Ile 689 extensively contact the LBD in both noncrystallographic symmetry related peptides. Mutation of Ile 689 to alanine reduces the ability of the peptide to inhibit the binding of GRIP1 to ERa by ~30 fold in a competition assay (data not shown). The side chain of Ile 689 lies in a rather chemically distinct environment; this residue forms van der Waals contacts with the aliphatic portion of the Asp 538 side chain. the side chain of Leu 539 and the y-carboxylate of GIu 542 (Figures i A and 3A). The proximity of this negatively charged moiety of Giu 542 to the hydrophobic side chain of Ile 689 should enhance the electrostatic potential of the side chain carboxylate and strengthen its stabilizing interactions with the N-terminus of the coactivator helix. Despite its apparently crucial role in receptor recognition, the identity of the residue immediately preceding known NR boxes is poorly conserved. This sequence variability should have effects not only on packing interactions with ERa but also on both the chemical environment and the critically important orientation of Glu 542. This should in turn translate into variations in affinity for the receptor. Indeed, the three NR boxes from GRIP1, which each contain a different residue preceding the LXXLL motif (SEQ ID NO:1 ), have differing affinities for ERa (Ding, et al., supra; Voegel, et al., EMBO J. 17:507-19 ( 1998)).
The NR boxes of TIF2, the human homologue of GRIP1, have been found to be partially functionally redundant despite their individual differences in receptor binding affinities. All three of NR boxes of TIF2 must be mutated to completely eliminate interaction with the ERa (Voegel, et al., EMBO J. 17:507-19 (1998)). Our data indicate that a single NR
box peptide is sufficient to form a tight complex with a single ERa LBD. Yet p160 coactivators possess multiple NR boxes. A possible explanation for the presence of multiple NR
boxes is that they provide coactivators with broad specificity. Receptor binding relies upon the intricate formation of multiple van der WaaIs interactions yet the various nuclear receptors appear to have different coactivator binding site surfaces. The different amino acids in the position immediately preceding the LXXLL motif (SEQ ID NO:1 ) might allow some degree of adaptability to these distinct surfaces; however, there may be no NR box sequence that is capable of efficiently binding to all nuclear receptors. Multiple NR boxes may therefore provide coactivators the diversity of interfaces necessary to recognize a variety of targets.
ERa transcriptional activity is blocked by antagonists such as OHT and RAL.
The most striking feature of the structures of the OHT and RAL liganded ERa LBDs is that helix 12 is bound to the static region of the coactivator recognition groove (Figure 3B
and (Brzozowski. et al., supra). A comparison of these two structures with the structure of the coactivator/LBD
complex reveals that in the antagonist complexes, the region of helix 12 with an NR box-like sequence (LXXML versus LXXLL) (SEQ ID N0:2 versus SEQ ID NO:1 ) functions as an intramolecular mimic of the coactivator helix (Figure ~ and Brzozowski. et al., supra).
Consistent with the proposals of others (Brzozowski, et al., supra and Darimont, et al., supra), this disposition of helix 12 directly affects the structure and function of the surface responsible for transcriptional activity in two ways. First, because helix 12 residues form an integral part of the coactivator binding site surface, the surface is incomplete when helix 12 is in the antagonist-bound conformation. In particular, Leu 539, Glu 542 and Met 543 are incorrectly oriented for coactivator recognition. Second, residues from the static region of this surface are bound to helix 12 and are prevented from interacting with coactivator (Figures 3A and 3B).
The sequence similarity of helix 12 of the ERa LBD to the LXXLL motif (SEQ ID
NO:1 ) appears to be unique among nuclear receptors. The identities of the residues in this region of helix 12 in other nuclear receptors, although generally hydrophobic in character, do not as closely resemble the sequence of an NR box as those of ERa (Wurtz, et al., supra). However, it is possible that an intramolecular inhibitor with a suboptimal recognition sequence would compete for coactivator binding given its extremely high local concentration.
The binding of OHT to the ERa promotes a helix 12 conformation that inhibits binding of the coactivator. OHT does not directly interact with any helix 12 residues (Figure 4B).
Moreover, the structure of the LBD in the region of the coactivator binding site groove that interacts with helix 12 in the OHT complex is the same in the DES and E2 complexes (Figures 3A, 3B and 5).
Numerous studies have demonstrated the importance of the OHT side chain in receptor antagonism (Jordan, et al., supra and Robertson, et al., J. Med. Chem. 25:167-71 ( 1982)). A
comparison of the structures of the OHT and DES complexes reveals that the binding mode of the OHT side chain precludes the agonist-induced conformation of helix 12. The OHT side chain projects out of the ligand binding pocket between helices 3 and 11 (Figures 2B, 6B and 6C). As a result, the positioning of helix I2 over the ligand binding pocket, as it is in the agonist-bound conformation, would bury the positively charged dimethylamino group of the OHT side chain within a hydrophobic cavity and produce steric clashes between the dimethylaminoethyl region of side chain and the side chain of Leu X40.
In functional terms, OHT is not, however. simply "an agonist with a side chain". OHT
binding promotes a conformation of the LBD that is distinct from that stabilized by either DES

or E~ binding. These different conformations impose different restrictions on the positioning of helix 12.
Helices 3, 8 and 11 in the DES and Ea complexes are between one to two turns longer than they are in the OHT complex (Figure 6A and (Brzozowski, et al., supra).
Helix 11 ends at Cys 530 in the DES and E~ complexes and it ends at Tyr 526 in the OHT complex.
Helix I2 begins at Leu 536 in the OHT complex. This appears to be necessary; in the antagonist complex, Leu 536 forms a cooperative network of nonpolar contacts and hydrogen bonds with Glu 380 and Tyr X37 that stabilizes the N-terminus of helix 12 (Figure 1 B).
Therefore, if helix 12 were to bind the static region of the coactivator binding site in the presence of agonist, the loop connecting helices 11 and 12 would be required to span ~17~ over five residues. Although theoretically possible, this conformation would be highly strained and hence unlikely. In contrast, the longer loop connecting helices 11 and 12 in the OHT complex allows helix 12 to extend to the static region of the coactivator binding groove.
In the DES and E2 complexes, helix 12 and the loop connecting helices 11 and 12 pack 1 S against helices 3 and 11, whereas they do not in the OHT complex (Figures 2A and 2B and (Brzozowski, et al., s-unra). A recently described structure of the Ez-LBD
complex suggests that the longer helices in the DES and EZ complexes are not dependent upon the interactions helix 12 forms in the agonist-bound conformation (Tanenbaum, et al., supra). In this structure, a crystal packing artifact forces helix 12 to contact a symmetry-related molecule. Helix 12 is clearly not positioned over the ligand binding pocket in this structure. Nevertheless.
helices 3, 8 and 11 are longer than they are in the OHT complex (Figure 6A). Hence the longer helices of the agonist complexes occur independently of the positioning of helix 12 over the ligand binding pocket and are instead a direct result of agonist binding.
The secondary structure differences between the agonist complexes and the OHT
complex arise from distinct arrangements of packing interactions induced by the different ligands. A cooperative network of van der Waals contacts, organized around DES
or E2, between various hydrophobic residues from helices 3, 7, 8 and 1 l and the ~i hairpin appears to stabilize the longer helices in the agonist complexes (Figure 4A and 6D). The placement of the OHT B ring forces many of ligand binding pocket residues that surround it to adopt conformations that are dramatically different from those they adopt in either the DES or E2 structures. As a result, many of the interresidue packing interactions present in the DES and E
structures are either absent or altered in the OHT structure (Figure 6D).
These structural distortions apparently force the main chain from residues 339 to 341, 421 to 423. and X27 to X30 (which form parts of helices 3, 8 and I 1 respectively in the agonist structures ) to adopt an extended conformation in the OHT structure (Figures 6A-D).
Therefore the binding of OHT has two distinct effects on the positioning of helix 12. each of which contributes to antagonism (Figure 7). Helix 12 is prevented from being positioned over the ligand binding pocket by the OHT side chain. In addition. the alternative packing arrangement of ligand binding pocket residues around OHT stabilizes a conformation of the LBD that permits helix I2 to reach the static region of the coactivator binding site and mimic bound coactivator.
These mechanisms do not appear to be specific to OHT. The side chain of RAL, like that of OHT, sterically hinders the agonist-bound conformation of helix 12 (Brzozowski, et al..
supra). In addition, helix 11 appears to end at Met X28 in the RAL complex.
This may result from the distortions in the binding pocket in the vicinity of His 524 directed by RAL binding (Brzozowski, et al., supra).
These results are supported by the experimental data provided in the examples below, which are also intended to illustrate various aspects of this invention. These examples do not limit the scope of this invention.
EXAMPLES
Example 1 Experimental Procedures Protein Expression and Purification The human ERa-LBD 297-554 was overexpressed as described previously (Seielstad, et al., Mol. Endocrinol. 9:647-658 (1995)) in BL21(DE3)pLysS cells transformed with a modified pET-23d-ERG vector that contained the sequence Met-Asp-Pro fused to residues 297 through 554 of the hERa (provided by Paul Sigler of Yale University). Clarified bacterial lysates were adjusted to 3 M in urea and 0.7 M in NaCI and then applied to a 10-ml column of estradiol-Sepharose (Greene, et al., Proc. Natl. Acad. Sci. USA 77:511 S-5119 ( 1980);
Landel. et al., Mol.
Endocrinol. 8:1407-1419 (1994); Landel, et al., J. Steroid Biochem. Molec.
Biol. 63:59-73 ( 1997)).
To carboxymethylate the solvent-accessible cysteines, the bound hERa-LBD was treated with 5 mM iodoacetic acid in 10 mM Tris, pH 8.1. ?~0 mM NaSCN (Hegy, et al..
Steroids 61:367-373 (1996)). Protein was eluted with 3 x 10-~ M ligand (either DES or OHT) in 30-100 ml of ~0 mM Tris. l mM EDTA. 1 mM DTT and 250 mM NaSCN. pH 8.~. The yield of hERa-LBD was typically close to 100% (Seielstad, et al., Biochemistry 34:12605-12615 (1995)). The affinity-purified material was concentrated and exchanged into 20 mM Tris, 1 mM EDTA, 4 mM
DTT, pH 8.1 by ultrafiltration. The protein was bound to a Resource Q column (Pharmacia) and then eluted with a linear gradient of 25-350 mM NaCI in 20 mM Tris, pH 8.1. 1 mM DTT. The hERa-LBD-ligand complexes eluted at 150-200 mM NaCI. Pooled fractions were concentrated by ultrafiltration and analyzed by SDS-PAGE, native PAGE, and electrospray ionization mass spectrometry.
GST-pulldown Assays A fusion between giutathione-S-transferase (GST) and amino acids 282-595 of hERa was constructed by subcloning the EcoRI fragment from pSGS ERa-LBD (Lopez et al., submitted manuscript) into pGEX-3X (Pharmacia). The Ile 358-> Arg, Lys 362->Ala, and Leu 539->Arg mutations were introduced into the GST-LBD construct using the QuikChange Kit (Stratagene) according to the manufacturer's instructions. The Val 376->Arg and Glu 542->Lys mutations were created in the GST-LBD construct by subcloning the BsmI/HindIII
fragments of derivatives of pSGS-ER-HEGO (Tora. et al., EMBO J. 8:1981-6 ( 1989)) into which these mutations had already been introduced. All constructs were verified by automated sequencing (University of Chicago Cancer Research Center DNA Sequencing Facility).
The wild-type and mutant GST-LBDs were expressed in BL21(DE3) cells. Total ligand binding activity was determined by a controlled pore glass bead assay (Greene, et al., Mol.
Endocrinol. 2:714-726 ( 1988)) and protein levels were monitored by western blotting with a monoclonal antibody to hERa (H222). Cleared extracts containing the GST-LBDs were incubated in buffer alone (50 mM Tris, pH 7.4, 150 mM NaCI, 2 mM EDTA, 1 mM
DTT, 0.5%
NP-40 and a protease inhibitor cocktail) or with 1 1tM of either DES or OHT
for 1 hour at 4°C.
Extract samples containing thirty pmol of GST-LBD were then incubated with 10 ~1 glutathione-Sepharose-4B beads (Pharmacia) for 1 hour at 4°C. Beads were washed five times with 20 mM
HEPES, pH 7.4, 400 mM NaCI, and 0.05% NP-40. 35S-labeled GRIP i was synthesized by in vitro transcription and translation using the TNT Coupled Reticulocyte Lysate System (Promega}
according to the manufacturer's instructions and pSGS-GRIP1 (provided by Michael Stallcup of the University of Southern California) as the template. Immobilized GST-LBDs were incubated for 2.~ hours with 2.5 ~l aliquots of crude translation reaction mixture diluted in 300 pl of Tris-buffered saline (TBS). After five washes in TBS containing 0.05% NP-40.
proteins were eluted by boiling the beads for 10 minutes in sample buffer. Bound 3'S-GRIPI was quantitated by fluorography following SDS-PAGE.
Crystallization and Data Collection Crystals of the DES-hERa LBD-GRIPI NR Box II peptide complex were obtained by hanging drop vapor diffusion. Prior to crystallization, the DES-hERa LBD
(residues 297-554) complex was incubated with a 2-4 fold molar excess of the GRIP1 NR Box II
peptide (SEQ ID
N0:4) for 7-16 hr. Two pL samples of this solution were mixed with equal volume samples of reservoir buffer consisting of 25-27% (w/v) PEG 4000, 90 mM Tris (pH 8.75-9.0) and 180 mM
Na Acetate and suspended over wells containing 800 pL of the reservoir buffer.
After 4-7 days at 19-21 °C. rod-like crystals were obtained. The coactivator complex crystals lie in the spacegroup P2, with cell dimensions a=54.09, b=82.22. c=58.04 and (3=111.34.
Two molecules each of the DES-LBD and the coactivator peptide form the asymmetric unit. A
200 ~m x 40 pm x 40 pm crystal was transferred to a cryosolvent solution containing 25% (w/v) PEG 4000, 10%
(w/v) ethylene glycol, 100 mM Tris (pH 8.5), 200 mM Na Acetate and 10 p.M
peptide and frozen in an N~ stream at -170°C in a rayon loop. Diffraction data from this crystal were measured at -170°C using a 300 mm MAR image plate at the Stanford Synchrotron Radiation Laboratory (SSRL) at beamline 7-1 at a wavelength of 1.08.
Crystals of the hERa LBD complexed to OHT were obtained by the hanging drop vapor diffusion method. Equal volume aliquots (2 pL) of a solution containing 3.9 mg/mL protein-ligand complex and the reservoir solution containing 9% (w/v) PEG 8000, 6%
(w/v) ethylene glycol, 50 mM HEPES (pH 6.7) and 200 mM NaCI were mixed and suspended over 800 pL of the reservoir solution. Hexagonal plate-like crystals formed after 4-7 days at 21-23°C. Both crystal size and quality were improved through microseeding techniques. These crystals belong to the space group P6s22 with cell parameters a=b=~8.24A and c=277.47A. The asymmetric unit consists of a single LBD monomer; the dimer axis lies along a crystallographic two-fold. A
single crystal {400 pm x 250 pm x 40 Pm} was briefly incubated in a cryoprotectant solution consisting of 10% (w/v) PEG 8000, 25% (w/v) ethylene glycol, 50 mM HEPES (pH

7.0) and 200 mM NaCI and then flash frozen in liquid N2 suspended in a rayon loop.
Diffraction data were measured at -170°C using a 345 mm MAR image plate at SSRL at beamline 9-1 and at a wavelength of 0.98.

The images of both data sets were processed with DENZO and scaled with SCALEPACK (Otwinowski. et al.. Methods Enzvmol. 276:307-326 ( 1997)) using the default -3a cutoff, Structure Determination and Refinement Initial efforts to determine the structure of the DES-LBD-GRIP1 NR Box II
peptide complex utilized a low resolution (3.1A) data set (data not shown). A self rotation search implemented with POLARRFN ("The CCP4 suite: programs for protein crystallography", Acta Crvstall~. D 50:760-763 ( 1994)) indicated the presence of a noncrystallographic dyad. The two LBDs in the asymmetric were located by molecular replacement in AMoRe (CCP4, 1994) using a partial polyalanine model of the human'RARy LBD (Renaud, et al., supra) as the search probe (R=58.2%, CC=35.6% after placement of both monomers). Given that the model at this point was both inaccurate (r.m.s.d. 1.7A between this model and the final model based on Ca positions) and incomplete (accounting for only ~45% of the total scattering matter in the asymmetric unit), an aggressive density modification protocol was undertaken.
Iterative cycles of two-fold NCS averaging in DM (CCP4, 1994) interspersed with model building in MOLOC
(Muller, et al., Bull. Soc: Chim. Bel~. 97:655-667 (1988)) and model refinement in REFMAC
(Murshudov, et al., Acta Crystallo~r. D 53:240-255 (1997)) (using tight NCS
restraints) were used to quickly build a model of the LBD alone. For this procedure, MAMA
(Kleywegt, et al., "Halloween...masks and bones. In From First Map to Final Model", Bailey, et al, eds., Warrington, England, SERC Daresbury Laboratory, 1994) was used for all mask manipulations and PHASES (Furey, et al.. PA33 Am. Crust. Assoc. Mtg. Abstr. 18:73 (1990)) and the CCP4 suite (CCP4, 1994) were used for the generation of structure factors and the calculation of weights.
However, although the DES-LBD-GRIP1 NR Box II peptide complex model accounted for ~90% of the scattering matter in the asymmetric unit, refinement was being hampered by severe model bias. The OHT complex data set was then collected. Starting with one of the monomers of the preliminary DES-LBD model as the search probe, molecular replacement in AMoRe was used to search for the location of LBD in this crystal form in both P6,22 and P6s22.
A translation search in P6;22 yielded the correct solution (R=X3.8%, CC=38.2%). In order to reduce model bias, DMMULTI (CCP4. 1994) was then used to project averaged density from the DES complex cell into the OHT complex cell. Using MOLOC. a model of the LBD
was built into the resulting density. The model was refined initially in REFMAC and later with the simulated annealing, positional and B-factor refinement protocols in X-PLOR
(Brunger, X-PLOR Version 3.843. New Haven. Connecticut: Yale University, 1996) using a maximum-likelihood target (Adams, et al., Proc. Natl. Acad. Sci. USA 94:5018-23 ( 1997)). Anisotropic scaling and a bulk solvent con ection were used and all B-factors were refined isotropically.
Except for the Rf«< set (a random sampling consisting of 8% of the data set), all data between 41 and 1.9A (with no a cutoff) were included. The final model consisted of residues 306-SS 1, the ligand and 79 waters. According to PROCHECK (CCP4, 1994), 91.6% of all residues in the model were in the core regions of the Ramachandran plot and none were in the disallowed regions.
The high resolution data set of the DES-LBD-GRIP1 NR Box II peptide complex became available when the R~~~ of the OHT-LBD model was ~31 %. Both monomers in the asymmetric unit of the DES complex crystal were relocated using AMoRe and the incompletely refined OHT-LBD model (with helix 12 and the loop between helices 11 and 12 removed) as the search model. The missing parts of the model were built and the rest of the model was corrected using 1 S MOLOC and two-fold averaged maps generated in DM. Initially, refinement was carried out with REFMAC using tight NCS restraints. At later stages, the model was refined without NCS
restraints using the simulated annealing, positional and B-factor refinement protocols in X-PLOR and a maximum-likelihood target. All B-factors were refined isotropically and anisotropic scaling and a bulk solvent correction were used. The Rfrce set contained a random sample of 6.S% of all data. In refinement, all data between 27 and 2.03 (with no a cutoff) were used. The final model was composed of residues 305-549 of monomer A, residues 305-461 and 470-SS4 of monomer B, residues 687-697 of peptide A, residues 686-696 of peptide B, two ligand molecules, 147 waters, two carboxymethyl groups and a chloride ion.
According to PROCHECK, 93.7% of all residues in the model were in the core regions of the Ramachandran 2S plot and none were in the disallowed regions.
Figure lA provides a view of a 2Fo-Fc electron density map calculated at 2.03 resolution and contoured at 1.0 a showing the GRIP 1 NR box II interaction with the LBD. The GRIP1 NR Box II peptide (SEQ ID N0:4) was omitted from the model prior to map calculation.
Ile 689 from the peptide and two of the three receptor residues with which it interacts (Glu 542 and Leu 539) are labeled. Asp 538 has been omitted for clarity. The hydrogen bonds between the y-carboxylate of Glu 542 and the amides of residues 689 and 690 of the peptide are depicted as dashed orange bonds. Figure 1 B provides a view of a 2Fo-Fc electron density map calculated WO 99!50658 PCTNS99/06937 at 1.90A resolution and contoured at 1.0 a showing the N-terminal region of helix 12. The dashed orange bonds depict the water-mediated hydrogen bond network between the imidazole ring of His 377, the y-carboxylate of Glu 380. and the amide of Tyr 537. The three labeled residues (Glu 380. Leu X36 and Tyr 537) interact with each other through van der Waals contacts and/or hydrogen bonds. Intriguingly, mutations in each these three residues dramatically increase the transcriptional activity of unliganded ERa LBD (Eng, et al., Mol.
Cell. B- iol.
17:4644-4653 (1997); Lazennec, et al., Mol. Endocrinol. 11:1375-86 (1997);
White, et al., EMBO J. 16:1427-35 (1997)).
Example 2 Structure Determination GRIP1, a mouse p160 coactivator, interacts both in vivo and in vitro with the ERa LBD
bound to agonise (Ding, et al., su ra), but not with the LBD bound to antagonist (Morris, et al., J.
Biol. Chem. 273:6679-88 ( 1998)). Mutational studies of GRIP l and its human homologue TIF2 suggest that of the three NR boxes from GRIP1, NR box II (residues 690 to 694) binds most tightly to the ERa LBD (Ding, et al., supra and Voegel, et al., su ra .
Competition assays indicate that a 13 residue GRIP1 NR Box II peptide, NH2-KHKILHRLLQDSS-C02H (SEQ ID N0:4), corresponding to residues 686-698 of GRIP1 (Ding, et al., suQra), synthesized by standard solid phase methods, binds specifically to the agonist-bound ERa LBD (ICSO<0.4p.M; Kushner, unpublished) and to other agonist-bound NR LBDs (Ding, et al., supra and Darimont, at al, supra).
An electrophoretic mobility shift assay was used to demonstrate that the GRIP1 NR Box II peptide (SEQ ID N0:4) bound the ERa LBD in the presence of the agonist, DES, but not the antagonist, OHT. Eight microgram samples of purified hERa-LBD bound to either DES or OHT were incubated in the absence of the GRIP 1 NR Box II peptide (SEQ ID
N0:4), i.e.. buffer alone, or in the presence of either a 2-fold or 10-fold molar excess of the GRIP 1 NR Box II
peptide. The binding reactions were performed on ice for 45 minutes in 10 pl of buffer containing 20mM Tris, pH 8.1, 1mM DTT, and 200mM NaCI and then subjected to 6%
native PAGE. Gels were stained with GELCODE Blue Stain reagent (Pierce).
In the presence of the NR box II peptide, the migration of the DES-LBD complex was retarded. In contrast, peptide addition had no effect on the mobility of the OHT-LBD complex.
Hence, this peptide fragment of GRIP1 possesses the ligand-dependent receptor binding activity characteristic of the full-length protein. These observations suggest that the GRIP1 NR Box II
peptide is a valid model for studying the interaction between GRIP1 and the ERa LBD.
In order to characterize structwally the interaction between the GRIP 1 NR Box II peptide and the ERa LBD, recombinant human ERa LBD (residues 297-554) was crystallized bound to both DES and the GRIP1 NR Box II peptide. The ERa LBD bound to OHT was also crystallized in order to determine the mechanism by which this antagonist blocks coactivator/ERa interaction. X-ray diffraction data from these crystals were measured and the structures were determined by a combination of molecular replacement (using a modified version of the coordinates of the human retinoic acid receptor y (RARy) LBD.
Renaud, et al., supra, as the search model) and aggressive density modification.
The structure of the DES-ERa LBD-GRIP1 NR Box II peptide complex has been refined to a crystallographic R-factor of 19.9% (R~~ee=25.0%) using data to 2.03 resolution. as shown in Figure 1 A and Table 2. The structure of the OHT-ERa LBD complex has been refined using data to 1.904 to a crystallographic R-factor of 23.0% (Rs~ee 26.2%), as shown in Figure 1 B and Table 2.
Table 2 Summary of Crystallographic Statist ics Li~~and Data Collection DES OHT

Space group P2~ P6522 Resolution 2.03 1.90 Observations 104189 269253 Unique 30265 23064 Completeness (%) 98.4 99.1 Rsy,t,(%)8 7.8 7.0 Average I/aI 9.8 16.1 Refinement Number of non-hydrogen atoms 4180 2070 Rcryst (%)b~frce (%) 19.9/25.0 23.0/26.1 Bond r.m.s. deviation (A) 0.006 0.006 Angle r.m.s. deviation () 1.05 1.05 Average B factor (AZ) 34.0 40.4 Rsym =E; ~ I;- <I;> ~ / E;I; where <I;> is the average intensity over symmetry equivalents b ~ryst=~~F-F~E/~~Fo~

Example 3 Overall Structure of the DES-LBD-GRIP1 NR Box II Peptide Complex The asymmetric unit of the DES-LBD-GRIP1 NR Box II peptide complex crystals contains the same noncn~stallographic dimer of LBDs that has been observed in the previously determined structures of the LBD bound to both E~ and RAL (Brzozowski. et al..
supra and Tanenbaum, et al.. supra). Beyond the flexible loops between helices 2 and 3 and helices 9 and 10, the two LBDs of the dimer adopt similar structures (r.m.s.d. 0.47 based on Ca positions).
The conformation of each LBD complexed with DES closely resembles that of the LBD bound to EZ (Brzozowski, et al.. supra); each monomer is a wedge shaped molecule consisting of three layers of eleven to twelve helices and a single beta hairpin (Figure 2A). In each LBD, the hydrophobic face of helix 12 is packed against helices 3. S/6 and 11 covering the ligand binding pocket (Figure 2A). One GRIP 1 NR Box II peptide is bound to each LBD in a hydrophobic cleft composed of residues from helices 3, 4, 5 and 12 and the turn between 3 and 4 (Figures 2A and 3A). The density for both peptides in the asymmetric unit is continuous and unambiguous (Figure lA). Residues 687 to 697 from the GRIPI NR Box II peptide, designated peptide A. and residues 686 to 696 from the GRIP 1 NR Box II peptide, designated peptide B, have been modeled; the remaining residues are disordered. Given that each peptide lies within a different environment within the crystal, it is striking that from residues Ile 689 to Gln 695 each peptide forms a two turn, amphipathic a helix (Figures 2A and 3A). Flanking this region of common secondary structure, the peptides adopt dissimilar random coil conformations.
The overall structures of the DES-ERa LBD-GRIP 1 NR Box II peptide complex and the OHT-ERa LBD complex are illustrated in Figure 2. In Figure 2A, the coactivator peptide and the LBD are shown as ribbon drawings. The peptide is colored gold and helix 12 (residues ~38-546) is colored magenta. Helices 3, 4 and 5 (labeled H3. H4 and HS
respectively) are colored blue. DES, colored green. is shown in space-filling representation. In Figure 2B. the LBD is depicted as a ribbon drawing. As in Figure 2A, helix 12 (residues 536-544) is colored in magenta and helices 3, 4 and 5 are colored blue. OHT, in red, is shown in space-filling representation.
Example 4 The NR Box II Peptide-LBD Interface The binding of the GRIPI NR Box II peptide to the ERa LBD buries 1000'' of predominantly hydrophobic surface area from both molecules. The GRIP 1 NR Box II peptide binding site is a shallow groove composed of residues Leu 35-t. Val 36~. Ile 3~8. Ala 361 and 4~

Lys 362 from helix 3: Phe 367 and Val 368 from helix 4: Leu 372 from the turn between helices 3 and 4; Gln 375, Val 376, Leu 379 and Glu 380 from helix ~: and Asp X38. Leu X39, Glu 542 and Met 543 from helix I? (Figure 3A). The floor and sides of this groove are completely nonpolar, but the ends of this groove are charged (Figure 3C).
The LBD interacts primarily with the hydrophobic face of the GRIP 1 NR Box II
peptide a helix formed by the side chains of Ile 689 and the three LXXLL motif (SEQ ID
NO:1) leucines (Leu 690, Leu 693 and Leu 694). The side chain of Leu 690 is deeply embedded within the groove and forms van der Waals contacts with the side chains of Ile 358, Val 376, Leu 379, Glu 380 and Met 543 (Figure 3A and 3C). The side chain of Leu 694 is similarly isolated within the groove and makes van der Waals contacts with the side chains of Ile 358, Lys 362, Leu 372, Gln 375, Val 376 and Leu 379 (Figure 3A and 3C). In contrast, the side chains of both Ile 689 and the second NR box leucine. Leu 693. rest against the rim of the groove (Figure 3A and 3C).
The side chain of Ile 689 lies in a shallow depression formed by the side chains of Asp 538, Leu 539 and Glu 542. The side chain of Leu 693 makes nonpolar contacts with the side chains of Ile 358 and Leu 539.
The charged and polar side chains which form the hydrophilic face of the peptide helix project away from the receptor and either interact predominantly with solvent or form symmetry contacts (Figure IA). None of the side chains of the polar and charged residues outside the helical region of either peptide in the asymmetric unit, with the exception of Lys 688 of peptide B, is involved in hydrogen bonds or salt bridges with its associated LBD
monomer. The s-amino group of Lys 688 of peptide B hydrogen bonds to the side chain carboxylate of Glu 380 of monomer B. This interaction is presumably a crystal artifact; the main chain atoms of the N-terminal three residues of peptide B are displaced from monomer B and interact extensively with a symmetry-related LBD.
In addition to interacting with the hydrophobic face of the peptide helix, the LBD
stabilizes the main chain conformation of the NR box peptide by forming capping interactions with both ends of the peptide helix. Glu 542 and Lys 362 are positioned at opposite ends of the peptide binding site (Figure 3A). The side chains of Glu 542 and Lys 362 form van der Waals contacts with main chain and side chain atoms at the N- and C-terminal turns of the peptide helix respectively . These interactions position the stabilizing charges of the y-carboxvlate of Glu 542 and s-amino group of Lys 362 near the ends of the GRIPI NR Box II peptide helix (Figure 3C).
The side chain carboxylate (y-carboxylate) of Glu ~4? hydrogen bonds to the amides of the residues of N-terminal turn of the peptide helix residues 688 and 689 of peptide A; residues 689 and 690 of peptide B) (Figure 1 A). Similarly. the ~-amino group of Lys 362 hydrogen bonds to the carbonyls of the residues of the C-terminal turn of the peptide helix (residue 693 of peptide A; residues 693 and 694 of peptide B) (Figure ~).
To test the importance of the GRIP1 NR Box II peptide/LBD interface observed in the crystal, a series of site-directed mutations were introduced into the ERa LBD.
These mutations were designed either to simultaneously perturb the structural integrity and the nonpolar character of the floor of the binding groove (Ile 358->Arg, Val 376->Arg and Leu 539->Arg) or to prevent the formation of the capping interactions (Lys 362->Ala and Glu 542->Lys).
Fusions of glutathione-S-transferase (GST) to the wild-type and mutant LBDs were analyzed for their ability to bind 35S-labeled GRIP1 in the absence of ligand or in the presence of DES or OHT.
3'S-labeled GRIPI was incubated with either immobilized GST, immobilized wild type GST-hERa LBD, or immobilized mutant GST-LBDs in the absence of ligand or in the presence of DES or OHT. The bound GRIPI was quantitated after SDS-PAGE. I358R, mutant LBD
containing a Ile->Arg substitution at residue 3~8; K362A, mutant LBD
containing a Lys->Ala substitution at residue 362; V376R, mutant LBD containing a Val->Arg substitution at residue 376; L539R, mutant LBD containing a Leu->Arg substitution at residue 539;
E542K, mutant LBD containing a Glu->Lys substitution at residue 542.
In the absence of ligand or in the presence of OHT, fusions to the wild-type protein and all of the mutant LBDs showed no detectable binding to GRIP1. The Ile 358->Arg, Val 376->Arg and Leu 539->Arg mutants were all unable to interact with coactivator in the presence of agonist, confirming the importance of the packing interactions observed in the crystal.
Disruption of either the N- or C-terminal capping interaction also compromised GRIP I binding in the presence of agonist. Only the wild-type GST-LBD was able to recognize the coactivator in the presence of DES.
Example 5 A~onist Recosnition Despite its different shape and larger molecular volume, DES (273t~3) is accommodated within the same binding pocket that recognizes E~ (2523). In its receptor complex. DES is completely encased within the nan;ower half of the LBD in a predominantly hydrophobic cavity composed of residues from helices 3. 6, 7, 8. 1 1, and 12 as well as the S I
/S2 hairpin (Figures 2A
and 4A).
-t.I

The interaction of DES with ERa resembles that of E,. One of the phenolic rings of DES
lies in the same position as the E~ A ring near helices 3 and 6. Like the aromatic ring of the E~, the DES A ring (Figure 4A) is engaged by the side chains of Phe 404. Ala 350, Leu 387 and Leu 391 with its phenolic hydroxyl forming hydrogen bonds to the y-carboxylate of Glu 353, to the guanidinium group of Arg 394, and to a structurally conserved water molecule.
The A' ring of DES (Figwe 4A) is bound near helices 7, 8 and 11 adjacent to the location of the E2 C and D
rings. This ring forms van der Waals contacts not only with Gly 521 and Leu 525, like the D
ring of E~, but also with Met 343, Leu 346 and Met 421 (Figure 4A). Even though it is located 1.7A from the position of the D ring hydroxyl, the DES A' ring phenolic hydroxyl is still able to hydrogen bond to the imidazole ring of His 524 (Figure 4A).
DES also forms contacts with the LBD that EZ does not. There are unoccupied cavities adjacent to the a face of the B ring and the (3 face of the C ring of the EZ
(Brcozowski, et al..
supra and Tanenbaum, et al., supra). The ethyl groups of DES, which project perpendicularly from the plane of the phenolic rings, fit snugly into these spaces. The resulting additional 1 S nonpolar contacts with the side chains of Ala 350, Leu 384, Phe 404, and Leu 428 (Figure 4A) may account for the higher affinity of DES for the receptor (Kuiper, et al., Endocrinoloszv 138:863-70 ( 1997)).
Except for Met 421 and Met 528 (both of which contact only DES) and Met 388 and Ile 424 (both of which contact only E2), the ER is able to use the same residues to form all of the observed hydrogen bonds and van der Waals contacts with both agonists (Figure 4A, Brzozowski, et al., s_~ra, and Tanenbaum, et al., supra). This remarkable adaptability is presumably the result of both relatively large molecular volume of the binding pocket (~500~3 in both complexes) and its apparent structural plasticity. In particular, at the DES A' ring/steroid D
ring end of the binding pocket, Met 343, Met 421, His 524 and Met 528 adopt different packing configwations in response to each ligand (data not shown). This plasticity may be necessary to allow the receptor to recognize endogenous estrogens such as estrone and estriol, which differ structurally from EZ at the D ring.
Example 6 Structure of the OHT-LBD Complex The binding of OHT induces a conformation of the LBD that differs in both secondary and tertiary structural organization from that driven by DES binding. In the DES complex. the main chain from residues 339 to 341, 421 to 423, and 5?7 to X30 form parts of helices 3. 8 and 1 I respectively. .In contrast. these regions adopt an extended conformation in the OHT complex (Figures 2 A. 2B and 6A). In addition. the composition and orientation of helix 12 are different in the two structures. Helix 12 in the DES complex consists of residues X38 to X46 whereas helix 1? in the OHT complex consists of residues X36 to 544. Most dramatically, rather than covering the ligand binding pocket as it does in the DES complex, helix 12 in the OHT complex occupies the part of the coactivator binding groove formed by residues from helices 3, 4, and 5, and the turn connecting helices 3 and 4 {Figures 2A, 2B and 3B). This alternative conformation of helix 12 appears to be similar to that observed in the RAL complex (Brzozowski, et al., supra).
Example 7 Helix 12-LBD Interface Except for the orientation of helix 12, the structure of the peptide binding groove is almost identical in the DES and OHT complexes (Figures 3A and 3B). The region of this groove outside of helix 12 is referred to herein as the "static region" of the NR box binding site. Helix 12 in the OHT complex and the NR box peptide helix in the DES complex interact with the static region of the coactivator recognition groove in strikingly similar ways.
Helix 12 mimics the hydrophobic interactions of the NR box peptide with the static region of the groove with a stretch of residues (residues 540 to 544) that resembles an NR box (LLEML instead of LXXLL) (SEQ ID N0:3 instead of SEQ ID NO:1 ). The side chains of Leu 540 and Met 543 lie in approximately the same locations as those of the first and second motif leucines (Leu 690 and Leu 693) in the peptide complex (Figure S). Leu 540 is inserted into the groove and makes van der Waals contacts with Leu 354, Val 376 and Glu 380 (Figures 3B and 3D). Met 543 lies along the edge of the groove and forms van der Waals contacts with the side chains of Leu 354, VaI 355 and Ile 358 (Figures 3B and 3D). The side chain position of Leu 544 almost exactly overlaps that of the third NR box leucine, Leu 694 (Figure ~).
Deep within the groove, the Leu 544 side chain makes van der Waals contacts with the side chains of Ile 358, Lys 362, Leu 372, Gln 375, Val 376 and Leu 379 (Figures 3B and 3D).
Helix 12 in the OHT complex is also stabilized by N- and C-terminal capping interactions. Lys 362 interacts with the C-terminal turn of helix 12 much as it does with the equivalent turn of the peptide helix (Figures 3A and 3B). The Lys 362 side chain packs against the C-terminal turn of the helix 12 with its s-amino group hydrogen bonding to the carbonyls of residues X43 and X44 (Figure ~). Given that the capping interaction at the N-terminal turn coactivator helix is formed by a helix 1? residue (Glu 542), the N-terminal turn of helix 12 in the antagonist complex is forced to interact with another residue. Glu 380 (Figures 3B and 3D). The Glu 380 y-carboxylate forms van der Waals contacts with Tyr X37 and interacts with the amide of Tyr 537 through a series of water-mediated hydrogen bonds (Figure I B).
In addition to forming these "NR box-like" interactions, helix 12 also forms van der Waals contacts with areas of the LBD outside of the coactivator recognition groove. The side chain of Leu X36 forms van der Waals contacts with Glu 380 and Trp 383 and that of Tyr X37 forms van der Waals contacts with His 373, Val 376 and Glu 380 (Figures 1B. 3B
and 3D). As a result of these contacts, helix 12 in the OHT complex buries more solvent accessible surface area (--12002) than the NR box peptide in the DES complex.
Example 8 OHT Recoenition OHT is bound within the same pocket that recognizes DES, E2 and RAL. The orientation of OHT within the binding pocket appears to be dictated by the positioning of two structural features of this ligand, the phenolic A ring and the bulky side chain (Figures 4B and 6C). The A
ring of OHT is bound in approximately the same location as the A ring of DES
near helices 3 and 6 with its phenolic hydroxyl hydrogen bonding to a structurally conserved water and to the side chains of Glu 353 and Arg 394 (Figure 4B). Like the bulky side chain of RAL, the side chain of OHT exits the binding pocket between helices 3 and 11 (Figures 2B and 4B). The OHT
C ring (Figure 4B) forms van der Waals contacts with the side chains of Met 343, Leu 346, Thr 347, Ala 350, Trp 383. Leu 384, Leu 387 and Leu 525. The positioning of the flexible dimethylaminoethyl region of the side chain is stabilized by van der Waals contacts with Thr 347, Ala 350 and Trp 383 and by a salt-bridge between the dimethylamino group of the side chain and the /3-carboxylate of Asp 351, which lies 3.8A away (Figure 4B). The positions of the A ring and the side chain in the context of the rigid triphenylethylene framework of OHT
requires that the ethylene group of OHT lie in an orientation nearly orthogonal to that of the ethylene group of DES (Figures 4A, 4B and 6D). As a result, the B ring of OHT
is driven more deeply into the binding pocket than the A' ring of DES (Figures 6B and 6C).
This location of the OHT B ring apparently cannot be accommodated by the same mechanisms that allow the DES A' ring/E~ D ring end of the binding pocket to adapt to the different structural features of DES and E~. Instead, the residues that contact the B ring (Met 343, Leu 346, Met 421. Ile 424, Gly 521. His X24 and Leu ~?S), most of which also interact with the A' ring of DES, adopt conformations distinct from the ones they adopt in the DES structure (Figure 6D). In fact, the location of the B ring actualiv_ precludes the side chain of one residue.
:l7 Met 421, from adopting the same conformation that it adopts in the DES
structure (Figures 6B
and 6C). As a consequence of these B ring-induced side chain conformations.
many interresidue van der Waals contacts present in the DES complex are absent in the OHT
complex. For example. whereas Met 421 packs against His X24 from helix I 1 and against Met 343 from helix 3 in the agonist complexes, it is precluded by the location of the OHT B ring from interacting with either of these residues in the antagonist complex (Figure 6D).
The structural effects of the placement of the B ring are not limited to the residues that contact the B ring; the conformations of these residues force other residues throughout the binding pocket to, in turn, adopt alternative conformations. For instance. the conformation adopted by Met 421 in the OHT complex prevents the side chains of Phe 404 and Phe 425 from occupying the positions they take in the DES complex (Figure 6B and 6C). As a consequence, Phe 404 does not make van der Waals contacts with the OHT A ring as it does with the A rings of DES or E2 (Figure 6C). In fact, Phe 404 only contacts the ethyl group of OHT (Figures 6C
and 6D). The alternative conformations of the side chains of both the residues that directly I S contact the B ring and those that are indirectly affected by it, force the main chain throughout the binding pocket to adopt a different conformation as well (Figure 6D).
Identification and characterization of key residues within ligand binding domain of the ERa and extension of this information to other nuclear receptors shows that these residues are common for all nuclear receptors identified to date. Thus, the Examples presented herein demonstrate that information derived from the structure and function of the ERa ligand binding domain can be applied in design and selection of compounds that modulate binding of compounds to nuclear receptors for all members of the nuclear receptor family.
All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Appendix 1 Atomic Coordinates for Human ERa Complexed With DES and a GRIP1 NR Box II
Peptide CRYST1 54.094 82.217 58.041 90.00 111.33 90.00 P 21 ?
ORIGX 1.000000 0.000000 0.000000 1 0.00000 ORIGX2 0.000000 1.000000 0.000000 0.00000 ORIGX3 0.000000 0.000000 1.000000 0.00000 SCALE1 0.018486 0.000000 0.007221 0.00000 SCALE2 0.000000 0.0121630.000000 0.00000 SCALE3 0.000000 0.000000 0.018497 0.00000 ATOM 1 CB SER A 305 35.230 -14.787-1.1631.00 73.26 ATOM 2 C SER A 305 35.331 -14.3031.289 1.00 72.95 ATOM 3 O SER A 305 34.146 -13.9841.186 1.00 72.46 ATOM 4 N SER A 305 36.797 -16.0330.285 1.00 74.06 ATOM ~ CA SER A 305 36.138 -14.7130.061 1.00 73.59 ATOM 6 N LEU A 306 35.982 -14.3132.449 1.00 72.21 ATOM 7 CA LEU A 306 35.329 -13.9503.702 1.00 71.05 ATOM 8 CB LEU A 306 36.251 -14.2564.878 1.00 70.19 ATOM 9 C LEU A 306 34.929 -12.4783.719 1.00 69.57 ATOM 10 O LEU A 306 35.580 -11.6383.100 1.00 69.96 ATOM 11 N ALA A 307 33.851 -12.1764.434 1.00 68.06 ATOM 12 CA ALA A 307 33.358 -10.8104.541 1.00 64.88 ATOM 13 CB ALA A 307 31.841 -10.7954.436 1.00 65.83 ATOM 14 C ALA A 307 33.792 -10.2045.866 1.00 63.36 ATOM 15 O ALA A 307 33.878 -8.984 6.005 1.00 62.73 ATOM 16 N LEU A 308 34.064 -11.0626.842 1.00 62.52 ATOM 17 CA LEU A 308 34.487 -10.5988.156 1.00 62.57 ATOM 18 CB LEU A 308 34.423 -11.7459.171 1.00 62.81 ATOM 19 CG LEU A 308 33.214 -12.6889.130 1.00 64.21 ATOM 20 CD1 LEU A 308 33.188 -13.51310.4061.00 66.28 ATOM 21 CD2 LEU A 308 31.919 -11.8988.989 1.00 63.80 ATOM 22 C LEU A 308 35.903 -10.0378.100 1.00 61.61 ATOM 23 O LEU A 308 36.385 -9.445 9.066 1.00 62.92 ATOM 24 N SER A 309 36.561 -10.2196.959 1.00 60.50 ATOM 25 CA SER A 309 37.928 -9;743 6.771 1.00 58.73 ATOM 26 CB SER A 309 38.720 -10.7505.934 1.00 59.53 ATOM '_'7OG SER A 309 38.889 -10.2834.606 1.00 59.47 ATOM ?8 C SER A 309 37.986 -8.373 6.099 1.00 57.05 ATOM ?9 O SER A 309 38.965 -7.637 6.249 1.00 56.70 ATOM 30 N LEU A 310 36.940 -8.038 5.352 1.00 52.69 ATOM 31 CA LEU A 310 36.877 -6.759 4.658 1.00 -18.20 ATOM 32 CB LEU A 310 35.516 -6.596 3.974 1.00 48.32 ATOM 33 CG LEU A 310 35.301 -7.188 2.583 1.00 44.94 ATOM 3.1 CDl LEU A 3I0 33.951 -6.728 2.055 1.00 -16.45 ATOM 35 CD2 LEU A 310 36.417 -6.755 1.650 i.00 13.19 ATOM 36 C LEU A 310 37.086 -5.589 5.609 1.00 46.44 ATOM 37 O LEU :'~310 36.605 -5.607 6.741 1.00 46.78 ATOM 38 N THR A 311 37.812 -4.576 5.148 1.00 44.36 ATOM 39 CA THR A 311 38.034 -3.380 5.949 1.00 .12.88 ATOM 40 CB THR A 311 39.313 -2.633 5.532 1.00 42.31 ATOM 41 OGI THR A 311 39.079 -1.936 -1.3031.00 42.50 ATOM 42 CG2 THR A 311 40.464 -3.606 5.350 1.00 46.02 ATOM 43 C THR A 311 36.834 -2.475 5.674 1.00 43.21 ATOM 44 O THR A 311 36.021 -2.776 4.800 1.00 42.12 ATOM 45 N ALA A 312 36.726 -1.372 6.409 1.00 42.16 ATOM 46 CA ALA A 312 35.616 -0.444 6.228 1.00 40.10 ATOM 47 CB ALA A 312 35.741 0.709 7.205 1.00 40.07 ATOM 48 C ALA A 312 35.561 0.090 4.799 1.00 41.80 ATOM 49 O ALA A 312 34.510 0.074 4.154 1.00 37.81 I ATOM 50 N ASP A 313 36.698 0.564 4.304 1.00 42.35 S

ATOM 51 CA ASP A 313 36.752 1.104 2.953 1.00 42.27 ATOM 52 CB ASP A 313 38.133 1.703 2.680 1.00 43.74 ATOM 53 CG ASP A 313 38.323 3.054 3.348 I.00 46.62 ATOM 54 OD ASP A 313 39.414 3.645 3.205 1.00 51.01 ATOM 55 OD2 ASP A 313 37.380 3.529 4.015 1.00 48.89 ATOM 56 C ASP A 313 36.422 0.027 1.926 1.00 38.68 ATOM 57 O ASP A 313 35.704 0.281 0.959 1.00 38.75 ATOM 58 N GLN A 314 36.931 -1.179 2.145 1.00 34.76 ATOM 59 CA GLN A 314 36.666 -2.277 1.229 1.00 33.55 ATOM 60 CB GLN A 314 37.462 -3.512 1.643 1.00 36.90 ATOM 61 CG GLN A 314 38.963 -3.384 1.436 1.00 40.45 ATOM 62 CD GLN A 314 39.700 -4.610 1.905 1.00 43.13 ATOM 63 OE GLN A 314 39.394 -5.196 2.935 1.00 43.60 ATOM 64 NE2 GLN A 314 40.701 -5.032 1.117 1.00 44.03 ATOM 65 C GLN A 314 35.176 -2.595 1.201 1.00 34.95 ATOM 66 O GLN A 314 34.605 -2.860 0.140 1.00 32.89 ATOM 67 N MET A 315 34.542 -2.564 2.374 1.00 32.54 ATOM 68 CA MET A 315 33.115 -2.848 2.470 1.00 35.46 ATOM 69 CB MET A 315 32.650 -2.794 3.926 1.00 37.09 ATOM 70 CG MET A 315 31.137 -2.777 4.097 1.00 39.42 ATOM 71 SD MET A 315 30.443 -4.426 4.053 1.00 46.55 ATOM 72 CE MET A 315 31.351 -5.205 5.397 1.00 45.29 ATOM 73 C MET A 315 32.311 -1.859 1.640 1.00 31.83 ATOM 74 O MET A 315 31.453 -2.247 0.852 1.00 32.10 ATOM 75 N VAL A 316 32.587 -0.560 1.830 1.00 32.62 ATOM 76 CA VAL A 316 31.882 0.470 1.079 1.00 31.09 ATOM 77 CB VAL A 316 32.395 1.888 1.425 1.00 34.77 ATOM ?8 CG VAL A 316 31.786 2.899 0.461 1.00 34.10 ATOM 79 CG2 VAL A 316 32.021 2.246 2.862 1.00 34.40 ATOM 80 C VAL A 316 32.092 0.232 -0.4141.00 33.48 ATOM 81 O VAL A 316 31.145 0.266 -1.200I.00 32.49 ATOM 82 N SER A 317 33.337 -0.027 -0.7951.00 33.49 ATOM 83 CA SER A 317 33.682 -0.280 -2.1871.00 32.88 ATOM 84 CB SER A 317 35.165 -0.635-?.297 1.00 35.77 ATOM 85 OG SER A 317 35.825 0.277 -3.154 1.00 -12.70 ATOM 86 C SER A 317 32.849 -1.396-2.801 1.00 30.71 ATOM 87 O SER A 317 32.279 -1.238-,.880 1.00 31.14 ATOM 88 N ALA A 318 32.792 -2.529-2.111 1.00 29.51 ATOM 89 CA ALA A 318 32.035 -3.676''.580 1.00 29.93 ATOM 90 CB ALA A 318 32.156 -4.811-1.579 1.00 28.56 ATOM 91 C ALA A 318 30.565 -3.305'.771 1.00 31.55 ATOM 92 O ALA A 318 29.961 -3.642-3.784 1.00 30.64 ATOM 93 N LEU A 319 29.997 -2.614-1.79 1.00 34.13 I

ATOM 94 CA LEU A 319 28.597 -2.212-1.861 1.00 32.93 ATOM 95 CB LEU A 319 28.170 -1.576-0.540 1.00 31.15 ATOM 96 CG LEU A 319 28.076 -2.5550.632 1.00 32.27 ATOM 97 CD1 LEU A 319 27.523 -1.8401.852 1.00 32.14 ATOM 98 CD2 LEU A 319 27.194 -3.7330.243 1.00 31.82 ATOM 99 C LEU A 319 28.340 -1.257-3.020 1.00 34.41 ATOM 100 O LEU A 319 27.430 -1.475-3.818 1.00 35.23 ATOM 101 N LEU A 320 29.140 -0.195-3.120 1.00 32.53 ATOM 102 CA LEU A 320 28.972 0.756 -=1.2121.00 35.33 ATOM 103 CB LEU A 320 30.052 1.839 -:x.1551.00 33.52 ATOM 104 CG LEU A 320 29.974 2.899 -3.054 1.00 34.60 ATOM 105 CD1 LEU A 320 31.060 3.940 -3.292 1.00 33.69 ATOM 106 CD2 LEU A 320 28.611 3.562 -3.044 1.00 31.05 ATOM 107 C LEU A 320 29.052 0.040 -5.561 1.00 35.41 ATOM 108 O LEU A 320 28.230 0.271 -b.446 1.00 39.16 ATOM 109 N AASP A 321 30.042 -0.833-5.720 0.50 36.33 ATOM 110 N BASP A 321 30.041 -0.839-5.695 0.50 35.76 ATOM 111 CA AASP A 321 30.214 -1.559-6.977 0.50 37.71 ATOM 112 CA BASP A 321 30.258 -1.595-6.925 0.50 37.11 ATOM 113 CB AASP A 321 31.537 -2.334-6.973 0.50 40.01 ATOM 114 CB BASP A 321 31.573 -2.374-6.826 0.50 39.41 ATOM 115 CG AASP A 321 31.694 -3.230-8.195 0.50 41.93 ATOM 116 CG BASP A 321 32.770 -1.562-7.284 0.50 39.96 ATOM 117 OD1 AASP A 321 31.523 -2.733-9.329 0.50 42.11 ATOM 118 OD1 BASP A 321 33.312 -1.868-8.366 0.50 43.41 ATOM 119 OD2 AASP A 321 31.988 -4.432-8.022 0.50 42.69 ATOM 120 OD2 BASP A 321 33.170 -0.622-6.564 0.50 41.33 ATOM 121 C AASP A 321 29.069 -2.524-7.275 0.50 37.19 ATOM 122 C BASP A 321 29.123 -2.565-7.253 0.50 36.68 ATOM 123 O AASP A 321 28.820 -2.861-8.434 0.50 36.87 ATOM 124 O BASP A 321 28.934 -2.942-8.411 0.50 36.08 ATOM 125 N ALA A 322 28.374 -2.968-6.235 1.00 35.35 ATOM 126 CA ALA A 322 27.268 -3.902-6.4I7 1.00 31.59 ATOM 127 CB ALA A 322 27.124 -4.781-x.175 1.00 30.73 ATOM 128 C ALA A 322 25.946 -3.20-1-6.709 1.00 30.07 ATOM 129 O ALA A 322 24.955 -3.857-7.036 1.00 26.53 ATOM 130 N GLU A 323 25.932 -1.880-6.596 1.00 27.98 ATOM 131 CA GLU A 323 24.713 -1.117-6.827 1.00 29.88 ATOM 132 CB GLU A 323 25.027 0.380 -6.855 1.00 30.98 ATOM 133 CG GLU A 323 24.870 1.068 -x.509 1.00 31.62 ATOM 134 CD GLU A 323 ?3.463 0.940 --1.9601.00 31.98 ATOM 135 OE1 GLU A 323 ?3.183 -0.056-.L257 1.00 33.10 ATOM 136 OE2 GLU A 323 22.640 1.836 -5.233 1.00 30.01 ATOM 137 C GLU A 323 24.010 -ISIS -8.123 1.00 30.86 ATOM 138 O GLU A 323 24.6>j -1.705-9.151 1.00 '_'8.86 ATOM 139 N PRO A 324 22.674 -1.659-8.083 1.00 30.66 ATOM 140 CD PRO A 324 21.77.1 -1.466-6.935 1.00 31.01 ATOM 141 CA PRO A 324 21.935 -2.032-9.290 1.00 30.29 ATOM 142 CB PRO A 324 20.613 -2.598-8.760 1.00 31.42 ATOM 143 CG PRO A 324 20.626 -2.363-7.258 1.00 33.66 ATOM 144 C PRO A 324 21.717 -0.785-10.1381.00 27.46 ATOM 145 O PRO A 324 21.893 0.332 -9.668 1.00 26.19 ATOM 146 N PRO A 325 21.335 -0.959-11.4031.00 27.80 ATOM 147 CD PRO A 325 21.082 -2.198-12.1611.00 27.35 ATOM 148 CA PRO A 325 21.12 0.242 -12.2111.00 25.59 ATOM 149 CB PRO A 325 21.258 -0.266-13.6371.00 ?4.02 ATOM 150 CG PRO A 325 20.773 -1.695-13.5591.00 26.00 ATOM 151 C PRO A 325 19.749 0.830 -11.9541.00 23.73 ATOM 152 O PRO A 325 18.873 0.165 -11.4021.00 24.83 ATOM 153 N ILE A 326 19.571 2.081 -12.3521.00 22.11 ATOM 154 CA ILE A 326 18.296 2.762 -12.2121.00 24.01 ATOM 155 CB ILE A 326 18.502 4.282 -12.1331.00 25.97 ATOM 156 CG2 ILE A 326 17.168 4.992 -12.2861.00 20.75 ATOM I CG ILE A 326 19.189 4.632 -10.8051.00 29.31 ATOM 158 CD1 ILE A 326 19.301 6.120 -10.5251.00 32.91 ATOM 159 C ILE A 326 17.506 2.408 -13.4711.00 25.72 ATOM 160 O ILE A 326 17.906 2.758 -14.5811.00 25.55 ATOM 161 N LEU A 327 16.392 1.703 -13.3011.00 25.57 ATOM 162 CA LEU A 327 15.59 1.279 -14.4391.00 23.80 ATOM 163 CB LEU A 327 14.872 -0.029-14.1041.00 X3.96 ATOM 164 CG LEU A 327 15.778 -1.210-13.7281.00 19.89 ATOM 165 CDI LEU A 327 14.944 -2.462-13.5831.00 21.19 ATOM 166 CD2 LEU A 327 16.850 -1.415-14.8051.00 17.53 ATOM 167 C LEU A 327 14.598 2.317 -14.9351.00 27.16 ATOM 168 O LEU A 327 14.161 3.202 -14.1941.00 25.98 ATOM 169 N TYR A 328 14.251 2.207 -16.2101.00 X6.56 ATOM 170 CA TYR A 328 13.303 3.I23 -16.8141.00 24.4 ATOM 1.71 CB TYR A 328 13.724 3.46 -18.2451.00 26.7?

ATOM 172 CG TYR A 328 14.587 4.693 -18.3141.00 X7.73 ATOM 173 CD1 TYR A 328 14.021 5.949 -18.5181.00 28.56 ATOM 174 CE1 TYR A 328 14.798 7.092 -18.5091.00 X9.10 ATOM 175 CD2 TYR A 328 15.96? 4.612 -18.1101.00 X6.01 ATOM 176 CE? TYR A 328 16.70 x.753 -18.0981.00 30.63 ATOM 177 CZ TYR A 328 16.1 6.988 -18.2971.00 30.07 ~7 ATOM 178 O)-I TYR A 328 16.917 8.130 -18.26 1.00 37.94 ATOM 179 C TYR A 328 11.923 2.501 -16.8271.00 ?4.9~

:'ATOM 180 O TYR :~ 328 11.774 1.27-1- t 1.00 27.02 6.8.16 ATOM 181 N SER :1 329 10.912 3.358 -16.8001.00 25.60 ATOM 182 CA SER :~ 329 9.533 2.908 -16.8371.00 29.45 ATOM 183 CB SER :~ 329 8.661 3.858 -16.0201.00 30.80 :ATOM 184 OG SER :~ 329 7.297 3.721 -16.3641.00 33.74 ATOM 185 C SER :'~329 9.129 2.947 -18.3131.00 31.30 ATOM 186 O SER A 329 9.908 3.397 -19.1511.00 27.35 ATOM 187 N GLU A 330 7.930 2.469 -18.6291.00 32.98 ATOM 188 CA GLU A 330 7.459 2.482 -20.0071.00 35.10 ATOM 189 CB GLU A 330 6.031 1.968 -20.0741.00 34.67 ATOM 190 C GLU A 330 7.532 3.924 -20.5051.00 40.06 ATOM 191 O GLU A 330 7.068 4.841 -19.8261.00 42.65 ATOM 192 N TYR A 331 8.124 4.126 -21.6811.00 41.16 ATOM 193 CA TYR A 331 8.263 5.470 -22.2341.00 42.66 ATOM 194 CB TYR A 331 9.323 5.482 -23.3501.00 42.54 ATOM 195 CG TYR A 331 9.202 4.347 -24.3451.00 38.67 ATOM 196 CDI TYR .A 331 10.105 3.284 -24.3341.00 34.66 ATOM 197 CEI TYR A 331 9.985 2.228 -25.2331.00 34.89 ATOM 198 CD2 TYR A 331 8.174 4.327 -25.2871.00 37.88 ATOM 199 CE2 TYR A 331 8.045 3.276 -26.1931.00 34.65 ATOM 200 CZ TYR A 331 8.950 2.232 -26.1591.00 30.73 ATOM 201 OH TYR A 331 8.814 1.191 -27.0421.00 30.97 ATOM 202 C TYR A 331 6.943 6.043 -22.7541.00 46.24 ATOM 203 O TYR A 331 6.018 5.301 -23.0961.00 45.38 ATUM 204 N ASP A 332 6.868 7.372 -22.7921.00 49.11 ATOM 205 CA ASP A 332 5.684 8.092 -23.2621.00 52.40 ATOM 206 CB ASP A 332 5.781 8.321 -24.7721.00 52.86 ATOM 207 C ASP A 332 4.356 7.410 -22.9261.00 52.90 ATOM 208 O ASP A 332 3.561 7.116 -23.8181.00 53.94 ATOM 209 N PRO A 333 4.103 7.144 -21.6321.00 53.63 ATOM 210 CD PRO A 333 4.962 7.418 -20.4651.00 53.63 ATOM 211 CA PRO A 333 2.840 6.497 -21.2531.00 53.55 ATOM 212 CB PRO A 333 3.070 6.076 -19.8021.00 53.78 ATOM 213 CG PRO A 333 4.101 7.028 -19.2901.00 53.42 ATOM 214 C PRO A 333 1.673 7.478 -21.3981.00 52.17 ATOM 215 O PRO A 333 1.879 8.690 -21.3951.00 51.19 ATOM 216 N THR A 334 0.457 6.956 -21.5321.00 52.26 ATOM 217 CA THR A 334 -0.724 7.802 -21.6871.00 54.21 ATOM 218 CB THR A 334 -1.997 6.949 -21.8131.00 53.90 ATOM '19 OG1 THR A 334 -1.971 6.256 -23.0651.00 53.92 ATOM X20 CG2 THR A 334 -3.237 7.821 -21.7611.00 54.15 ATOM 221 C THR A 334 -0.864 8.782 -20.5251.00 56.34 ATOM '2~ O THR A 334 -1.389 8.443 -19.4611.00 56.44 ATOM 223 N ARG A 335 -0.386 10.002-20.7661.00 58.24 ATOM ~~4 CA ARG A 335 -0.377 11.099-19.8011.00 57.96 ATOM "5 CB ARG A 335 -0.569 12.427-20.5311.00 60.22 ATOM 226 C ARG A 335 -1.349 10.996-18.6271.00 56.61 ATOM '27 O ARG r~ 335 -0.919 10.908-17.4751.00 60.70 ATOM ''28 N PRO A 336 -2.667 11.015-18.8891.00 62.43 ATOM ?29 CD PRO A 336 -3.389 11.117-20.1651.00 .19.06 ATOM ?30 CA PRO A 336 -3.587 10.915-17.7521.00 -19.58 ATOM 231 CB PRO A 336 -4.911 11.456-18.3021.00 -18.66 ATOM 232 CG PRO A 336 -4.645 11.809-19.7601.00 ~
1.33 ATOM 233 C PRO A 336 -3.698 9.468 -17.2791.00 -19.25 ATOM 234 O PRO A 336 -4.340 8.644 -17.9291.00 -18.06 ATOM 235 N PHE A 337 -3.063 9.170 -16.1471.00 .17.90 ATOM 236 CA PHE A 337 -3.055 7.821 -15.5821.00 :16.61 ATOM 237 CB PHE A 337 -2.063 7.732 -14.4211.00 -17.73 ATOM 238 CG PHE A 337 -0.649 8.011 -14.8051.00 16.27 ATOM 239 CDI PHE A 337 -0.017 9.168 -14.3681.00 46.55 ATOM 240 CD2 PHE A 337 0.061 7.113 -15.5911.00 48.12 ATOM 241 CEI PHE A 337 1.305 9.429 -14.7071.00 48.09 ATOM 242 CE2 PHE A 337 1.386 7.364 -15.9381.00 47.57 ATOM 243 CZ PHE A 337 2.009 8.525 -15.4951.00 48.40 ATOM 244 C PHE A 337 -4.401 7.338 -15.0711.00 46.1 S

ATOM 245 O PHE A 337 -5.250 8.127 -14.6711.00 48.34 ATOM 246 N SER A 338 -4.573 6.022 -15.0801.00 45.06 ATOM 247 CA SER A 338 -5:781 5.385 -14.5781.00 45.12 ATOM 248 CB SER A 338 -6.477 4.594 -15.6841.00 44.49 ATOM 249 OG SER A 338 -6.227 3.206 -15.5541.00 45.78 ATOM 250 C SER A 338 -5.292 4.439 -13.4881.00 47.04 ATOM 251 O SER A 338 -4.090 4.186 -13.3871.00 44.08 ATOM 252 N GLU A 339 -6.206 3.916 -12.676i.00 45.63 ATOM 253 CA GLU A 339 -5.802 3.012 -11.6081.00 15.40 ATOM 254 CB GLU A 339 -7.015 2.521 -10.8141.00 45.66 ATOM 255 CG GLU A 339 -6.637 1.680 -9.600 1.00 46.81 ATOM 256 CD GLU A 339 -7.717 1.652 -8.535 1.00 47.56 ATOM 257 OEI GLU A 339 -8.471 0.656 -8.477 1.00 47.37 ATOM 258 OE2 GLU A 339 -7.810 2.625 -7.754 1.00 49.29 ATOM 259 C GLU A 339 -5.040 1.821 -12.1701.00 15.23 ATOM 260 O GLU A 339 -3.862 1.641 -11.8721.00 46.51 ATOM 261 N ALA A 340 -5.712 1.010 -12.9821.00 42.87 ATOM 262 CA ALA A 340 -5.078 -0.158-13.5741.00 40.24 ATOM 263 CB ALA A 340 -6.055 -0.871-14.4961.00 41.40 ATOM 264 C ALA A 340 -3.837 0.273 -14.3501.00 38.83 ATOM 265 O ALA A 340 -2.909 -0.515-14.5431.00 35.58 ATOM 266 N SER A 341 -3.836 1.535 -14.7731.00 35.79 ATOM 267 CA SER A 341 -2.742 2.133 -15.5371.00 36.58 ATOM 268 CB SER A 341 -3.231 3.454 -16.1541.00 39.01 ATOM 269 OG SER A 341 -2.211 4.130 -16.8641.00 36.09 ATOM 270 C SER A 341 -1.480 2.376 -14.6911.00 3.63 ATOM 271 O SER A 341 -0.389 1.913 -15.0381.00 33.20 ATOM 272 N MET A 342 -1.626 3.115 -13.59 1.00 3.92 ATOM 273 CA MET A 342 -0.498 3.396 -12.7081.00 3.88 ATOM 274 CB MET A 342 -0.912 1.396 -11.6231.00 3.96 ATOM 275 CG MET A 342 0.241 x.218 -11.0591.00 38.02 ~~4 ATOM 276 SD MET A 342 -0.308 6.374 -9.780 1.00 44.73 ATOM 277 CE MET A 342 0.626 7.815 -10.2051.00 12.49 ATOM 278 C MET A 342 -0.011 ?.100 -12.0591.00 34.17 ATOM 279 O MET A 342 1.195 1.880 -11.9091.00 33.40 ATOM 280 N MET A 343 -0.957 1.243 -i 1.6871.00 29.95 ATOM 281 CA MET A 343 -0.640 -0.034 -11.0621.00 31.96 ATOM 282 CB MET A 343 -1.921 -0.810 -10.7511.00 31.70 ATOM 283 CG MET A 343 -2.667 -0.337 -9.502 1.00 37.13 ATOM 284 SD MET A 343 -1.749 -0.507 -7.940 1.00 36.00 l0 ATOM 285 CE MET A 343 -1.468 -2.299 -7.886 1.00 32.14 ATOM 286 C MET A 343 0.234 -0.875 -11.9791.00 31.72 ATOM 287 O MET A 343 1.159 -1.558 -11.5271.00 30.26 ATOM 288 N GLY A 344 -0.069 -0.823 -13.2721.00 29.04 ATOM 289 CA GLY A 344 0.688 -1.591 -14.2421.00 24.94 15 ATOM 290 C GLY A 344 2.104 -1.085 -14.3961.00 26.01 ATOM 291 O GLY A 344 3.046 -1.873 -14.4631.00 28.72 ATOM 292 N LEU A 345 2.257 0.232 -14.4711.00 26.97 ATOM 293 CA LEU A 345 3.576 0.839 -14.6081.00 31.15 ATOM 294 CB LEU A 345 3.459 2.361 -14.7531.00 30.06 20 ATOM 295 CG LEU A 345 2.765 2.924 -15.9951.00 33.50 ATOM 296 CD1 LEU A 345 2.901 4.439 -15.9991.00 33.52 ATOM 297 CD2 LEU A 345 3.379 2.324 -17.2571.00 33.22 ATOM 298 C LEU A 345 4.433 0.534 -13.3831.00 30.31 ATOM 299 O LEU A 345 5.564 0.061 -13.5051.00 32.80 25 ATOM 300 N LEU A 346 3.884 0.813 -12.2051.00 27.83 ATOM 301 CA LEU A 346 4.595 0.596 -10.9471.00 26.19 ATOM 302 CB LEU A 346 3.729 1.063 -9.783 1.00 24.51 ATOM 303 CG LEU A 346 3.483 2.569 -9.682 1.00 26.33 ATOM 304 CDI LEU A 346 2.623 2.844 -8.463 1.00 27.33 30 ATOM 305 CD2 LEU A 346 4.809 3.317 -9.587 1.00 24.89 ATOM 306 C LEU A 346 5.032 -0.848 -10.7071.00 25.72 ATOM 307 O LEU A 346 6.181 -1.102 -10.3451.00 29.86 ATOM 308 N THR A 347 4.117 -1.793 -10.8911.00 23.80 ATOM 309 CA THR A 347 4.436 -3.196 -10.6741.00 23.91 35 ATOM 310 CB THR A 347 3.164 -4.058 -10.6411.00 26.39 ATOM 311 OG1 THR A 347 2.421 -3.860 -11.8491.00 24.57 ATOM 312 CG2 THR A 347 2.301 -3.682 -9.444 1.00 23.98 ATOM 313 C THR A 347 5.36b -3.734 -11.7561.00 26.17 ATOM 314 O THR A 347 6.176 -4.622 -11.4961.00 27.44 40 ATOM 315 N ASN A 348 5.242 -3.197 -12.9701.00 25.48 ATOM 316 CA ASN A 348 6.092 -3.617 -14.0821.00 23.77 ATOM 317 CB ASN A 348 5.657 -2.926 -15.3851.00 24.59 ATOM 318 CG ASN A 348 6.522 -3.302 -16.5711.00 29.93 ATOM 319 ODI ASN A 348 7.616 -2.799 -16.7711.00 24.81 45 ATOM 320 ND2 ASN A 348 6.010 -=1.236-17.3911.00 32.61 ATOM 321 C ASN A 348 7.532 -3.229 -13.7411:00 22.82 ATOM 322 O ASN A 348 8.453 --1.027-13.8701.00 18.83 ATOM 323 N LEU A 349 7.711 -1.993 -13.2881.00 22.58 >j ATOM 324 CA LEU A 349 9.030 -1.507-12.9141.00 21.85 ATOM 325 CB LEU A 349 8.929 -0.028-12.5361.00 22.00 ATOM 326 CG LEU A 349 10.155 0.673 -11.9531.00 23.64 ATOM 327 CD1 LEU A 349 11.224 0.826 -13.0171.00 19.35 S ATOM 328 CD2 LEU A 349 9.726 2.040 -1 I I 21.97 .41 .00 ~

ATOM 329 C LEU A 349 9.564 -2.335-11.7341.00 ?2.94 ATOM 330 O LEU A 349 10.724 -2.749-11.7171.00 23.97 ATOM 331 N ALA A 350 8.705 -2.591-10.7561.00 21.67 ATOM 332 CA ALA A 350 9.113 -3.356-9.586 1.00 21.83 ATOM 333 CB ALA A 350 7.963 -3.441-8.593 1.00 18.95 ATOM 334 C ALA A 350 9.568 -4.757-9.985 1.00 21.90 ATOM 335 O ALA A 350 10.625 -5.221-9.554 1.00 24.15 ATOM 336 N ASP A 351 8.767 -5.423-10.8101.00 23.24 ATOM 337 CA ASP A 351 9.093 -6.772-11.2591.00 25.87 i5 ATOM 338 CB ASP A 351 8.028 -7.274-12.2391.00 27.03 ATOM 339 CG ASP A 351 8.103 -8.772-12.4581.00 31.64 ATOM 340 ODl ASP A 351 8.217 -9.196-13.6281.00 35.06 ATOM 341 OD2 ASP A 351 8.049 -9.525-11.4641.00 36.86 ATOM 342 C ASP A 351 10.469 -6.825-11.9121.00 22.36 ATOM 343 O ASP A 351 11.219 -7.773-11.7021.00 25.15 ATOM 344 N ARG A 352 10.810 -5.808-12.6971.00 23.58 ATOM 345 CA ARG A 352 12.115 -5.787-13.3471.00 21.07 ATOM 346 CB ARG A 352 12.120 -4.785-14.5071.00 21.02 ATOM 347 CG ARG A 352 11.539 -5.352-15.7971.00 20.44 ATOM 348 CD ARG A 352 11.554 -4.319-16.9151.00 20.43 ATOM 349 NE ARG A 352 10.592 -3.245-16.6871.00 19.85 ATOM 350 CZ ARG A 352 10.910 -1.954-16.6411.00 19.69 ATOM 351 NH1 ARG A 352 12.172 -1.564-16.8131.00 17.36 ATOM 352 NH2 ARG A 352 9.962 -1.049-16.4411.00 21.88 ATOM 353 C ARG A 352 13.223 -5.442-12.3501.00 22.1 i ATOM 354 O ARG A 352 14.346 -5.945-12.4541.00 24.13 ATOM 355 N GLU A 353 12.909 -4.587-11.3831.00 18.66 ATOM 356 CA GLU A 353 13.888 -4.206-10.3761.00 19.08 ATOM 357 CB GLU A 353 13.317 -3.102-9.483 1.00 21.62 ATOM 358 CG GLU A 353 13.295 -1.718-10.1141.00 20.97 ATOM 359 CD GLU A 353 12.832 -0.648-9.129 1.00 23.84 ATOM 360 OE1 GLU A 353 11:611 -0.531-8.926 1.00 24.76 ATOM 361 OE2 GLU A 353 13.686 0.066 -8.557 1.00 24.95 ATOM 362 C GLU A 353 14.246 -5.423-9.512 1.00 20.14 ATOM 363 O GLU A 353 15.398 -5.600-9.104 1.00 19.40 ATOM 364 N LEU A 354 13.246 -6.257-9.235 1.00 19.54 ATOM 365 CA LEU A 354 13.434 -7.452-8.415 1.00 21.77 ATOM 366 CB LEU A 354 12.107 -8.209-8.270 1.00 23.09 ATOM 367 CG LEU A 354 11.160 -7.606-7.223 1.00 25.00 ATOM 368 CD LEU A 354 9.720 -8.013-7.510 I 23.49 1 .00 ATOM 369 CD2 LEU A 354 11.584 -8.069-x.839 1.00 23.31 ATOM 370 C LEU A 354 14.500 -8.386-8.981 1.00 23.21 ATOM 371 O LEU A 354 15.255 -9.007-8.234 1.00 22.44 ATOM 372 N VAL A 355 14.560 -8.490-10.3021.00 ?x.52 ATOM 373 CA VAL A 355 15.551 -9.343-10.9351.00 X1.66 ATOM 374 CB VAL A 355 15.353 -9.365-12.4661.00 24.35 ATOM 375 CG1 VAL A 355 16.435 -10.214-13.1191.00 ''8.16 ATOM 376 CG2 VAL A 355 13.957 -9.886-12.798I '' .00 1.59 ATOM 377 C VAL A 355 16.944 -8.811-10.6061.00 X3.74 ATOM 378 O VAL A 355 17.857 -9.581-10.2911.00 X3.51 ATOM 379 N HIS A 356 17.105 -7.489-I0.6691.00 ~ 1.27 ATOM 380 CA HIS A 356 18.392 -6.861-10.369I ~ 1.31 .00 ATOM 381 CB HIS A 356 18.384 -5.390-10.8111.00 19.87 ATOM 382 CG HIS A 356 18.494 -5.205-12.2951.00 '' 1.77 ATOM 383 CD2 HIS A 356 17.543 -5.048-13.2481.00 21.66 ATOM 384 ND1 HIS A 356 19.704 -5.177-12.9551.00 21.11 ATOM 385 CE1 HIS A 356 19.496 -5.011-14.2491.00 24.96 ATOM 386 NE2 HIS A 356 18.192 -4.931-14.4551.00 18.37 ATOM 387 C HIS A 356 18.702 -6.947-8.875 1.00 21.41 ATOM 388 O HIS A 356 19.864 -7.111-8.465 1.00 ~ 1.88 ATOM 389 N MET A 357 17.660 -6.843-8.058 1.00 21.84 ATOM 390 CA MET A 357 17.837 -6.906-6.610 1.00 ?'1.51 ATOM 391 CB MET A 357 16.503 -6.668-5.898 1.00 17.60 ATOM 392 CG MET A 357 16.629 -6.579-4.369 1.00 19.36 ATOM 393 SD MET A 357 15.051 -6.755-3.531 1.00 23.64 ATOM 394 CE MET A 357 14.189 -5.332-4.163 1.00 23.13 ATOM 395 C MET A 357 18.411 -8.259-6.192 1.00 23.69 ATOM 396 O MET A 357 19.337 -8.328-5.389 1.00 24.41 ATOM 397 N ILE A 358 17.856 -9.331-6.746 1.00 27.14 ATOM 398 CA ILE A 358 18.314 -10.672-6.425 1.00 28.79 ATOM 399 CB ILE A 358 17.529 -11.725-7.232 1.00 32.42 ATOM 400 CG2 ILE A 358 18.267 -13.064-7.220 1.00 32.77 ATOM 401 CG1 ILE A 358 16.125 -11.880-6.644 1.00 31.94 ATOM 402 CDI ILE A 358 15.062 -12.196-7.680 1.00 34.85 ATOM 403 C ILE A 358 19.801 -10.802-6.728 1.00 28.75 ATOM 404 O ILE A 358 20.569 -11.305-5.912 1.00 31.60 ATOM 405 N ASN A 359 20.207 -10.325-7.897 1.00 27.91 ATOM 406 CA ASN A 359 21.601 -10.401-8.293 1.00 29.16 ATOM 407 CB ASN A 359 21.721 -10.172-9.801 1.00 31.88 ATOM 408 CG ASN A 359 21.253 -11.381-10.5991.00 39.34 ATOM 409 OD1 ASN A 359 21.916 -12.422-10.6121.00 41.27 ATOM 410 ND2 ASN A 359 20.102 -11.255-11.2531.00 38.58 ATOM 411 C ASN A 359 22.476 -9.436-7.510 1.00 30.75 ATOM 412 O ASN A 359 23.686 -9.629-7.412 1.00 33.35 ATOM 413 N TRP A 360 21.872 -8.400-6.940 1.00 30.07 ATOM 414 CA TRP A 360 22.634 -7.451-6.132 1.00 27.87 ATOM 415 CB TRP A 360 21.849 -6.150-5.948 1.00 24.80 ATOM 416 CG TRP A 360 22.196 -5.392-4.691 1.00 X3.04 ATOM 417 CD2 TRP A 360 21.501 -5.443-3.438 1.00 19.83 ATOM 418 CE2 TRP A 360 22.147 -4.543-2.564 1.00 ~~.31 ATOM 419 CE3 TRP A 360 20.392 -6.165-2.972 1.00 X0.09 ATOM -120 CD1 TRP A 360 23.212 -4.488-.x.5291.00 18.99 ATOM 421 NE1 TRP A 360 23.187 -3.974-3.255 1.00 21.17 ATOM 422 CZ2 TRP .~ 360 21.721 -4.340-1.243 1.00 20.43 ATOM :123 CZ3 TRP A 360 19.968 -5.965-1.661 1.00 X0.12 ATOM .124 CH2 TRP A 360 20.635 -5.057-0.812 1.00 18.54 ATOM 425 C TRP A 360 22.892 -8.099-.1.7661.00 24.88 ATOM 426 O TRP A 360 23.978 -7.980--1.1981.00 ?5.00 ATOM 427 N ALA A 361 21.879 -8.789-.1.2521.00 24.08 ATOM 428 CA ALA A 361 21.972 -9.462-2.958 1.00 26.06 ATOM 429 CB ALA A 361 20.676 -10.203-2.672 1.00 20.27 ATOM 430 C ALA A 361 23.161 -10.433-2.897 1.00 28.44 ATOM 431 O ALA A 361 23.843 -10.531-1.876 1.00 28.95 ATOM 432 N LYS A 362 23.414 -11.144-3.992 1.00 31.41 ATOM 433 CA LYS A 362 24.530 -12.097-4.047 1.00 33.33 ATOM 434 CB LYS A 362 24.564 -12.824-x.390 1.00 34.81 ATOM 435 CG LYS A 362 23.319 -13.608-x.756 1.00 36.27 ATOM 436 CD LYS A 362 23.458 -14.178-7.167 1.00 38.30 ATOM 437 CE LYS A 362 22.369 -15.193-7.472 1.00 40.94 ATOM 438 NZ LYS A 362 22.111 -15.322-8.937 1.00 42.49 ATOM 439 C LYS A 362 25.854 -11.351-3.893 1.00 34.17 ATOM 440 O LYS A 362 26.880 -11.977-3.595 1.00 35.40 ATOM 441 N AARG 363 25.826 -10.059-4.095 0.50 34.23 A

ATOM 442 N BARG 363 25.826 -10.059-4.095 0.50 34.03 A

ATOM 443 CA AARG 363 27.035 -9.254-3.987 0.50 33.25 A

ATOM 444 CA BARG 363 27.035 -9.254-3.987 0.50 32.83 A

ATOM 445 CB AARG 363 27.031 -8.153-5.044 0.50 34.67 A

ATOM 446 CB BARG 363 27.031 -8.153-5.045 0.50 34.20 A

ATOM 447 CG AARG 363 26.933 -8.654-6.478 0.50 36.32 A

ATOM 448 CG BARG 363 26.930 -8.654-6.480 0.50 35.56 A

ATOM 449 CD AARG 363 27.745 -7.775-7.415 0.50 38.39 A

ATOM 450 CD BARG 363 27.752 -7.781-7.414 0.50 37.18 A

ATOM 451 NE AARG 363 29.171 -7.793-7.091 0.50 39.98 A

ATOM 452 NE BARG 363 27.195 -7.725-8.762 0.50 37.39 A

ATOM 453 CZ AARG 363 30.086 -7.038-7.692 0.50 40.54 A

ATOM 454 CZ BARG 363 27.905 -7.457-9.855 0.50 40.02 A

ATOM 455 NH1AARG 363 29.735 -6.218-8.675 0.50 38.13 A

ATOM 456 NH1BARG 363 29.205 -7.191-9.761 0.50 40.42 A

ATOM 457 NH2AARG 363 31.358 -7.123-7.326 0.50 43.19 A

ATOM 458 NH2BARG 363 27.311 -7.436-11.0410.50 38.91 A

ATOM 459 C AARG 363 27.207 -8.630-2.610 0.50 33.28 A

ATOM 460 C BARG 363 27.207 -8.630-2.610 0.50 32.81 A

ATOM 461 O AARG 363 28.223 -7.992-2.344 0.50 34.18 A

ATOM 462 O BARG 363 28.223 -7.992-2.345 0.50 33.43 A

ATOM 463 N VAL A 364 26.215 -8.798-1.740 1.00 33.12 ATOM 464 CA VAL A 364 26.288 -8.240-0.389 1.00 33.63 ATOM 465 CB VAL A 364 24.898 -8.1780.29? 1.00 34.97 ATOM 466 CG1 VAL A 364 25.036 -7.6081.700 1.00 35.44 ATOM 467 CG2 VAL A 364 23.946 -7.328-0.53? 1.00 36.69 ~8 ATOM :168 C VAL A 364 '_'7.184-9.157 0.428 1.00 34.27 ATOM 469 O VAL A 364 '6.878 -10.3410.603 1.00 34.95 ATOM 470 N PRO A 365 28.306 -8.626 0.935 1.00 36.08 ATOM .171 CD PRO A 365 ''8.775 -7.235 0.793 1.00 34.84 ATOM d72 CA PRO A 365 ?9.231 -9.442 1.733 1.00 37.82 ATOM 473 CB PRO A 365 30.110 -8.408 2.430 1.00 34.31 ATOM 474 CG PRO A 365 30.127 -7.247 1.475 1.00 37.77 ATOM 475 C PRO A 365 28.538 -10.3732.720 1.00 37.61 ATOM 476 O PRO A 365 27.692 -9.945 3.507 1.00 37.74 ATOM 477 N GLY A 366 28.890 -11.6542.654 1.00 39.04 ATOM 478 CA GLY A 366 28.307 -12.6353.554 1.00 38.27 ATOM 479 C GLY A 366 26.991 -13.2643.138 1.00 39.32 ATOM 480 O GLY A 366 26.638 -14.3363.635 1.00 39.53 ATOM 481 N PHE A 367 26.246 -12.6152.236 1.00 38.60 ATOM 482 CA PHE A 367 24.960 -13.1481.783 1.00 36.36 ATOM 483 CB PHE A 367 24.281 -12.1780.808 1.00 32.10 ATOM 484 CG PHE A 367 22.827 -12.4730.581 1.00 30.12 ATOM 485 CD1 PHE A 367 22.401 -13.083-0.5961.00 28.95 ATOM 486 CD2 PHE A 367 21.882 -12.1761.563 1.00 X6.18 ATOM 487 CE1 PHE A 367 21.050 -13.400-0.7921.00 29.42 ATOM 488 CE2 PHE A 367 20.535 -12.4911.373 1.00 27.60 ATOM 489 CZ PHE A 367 20.118 -13.1030.196 1.00 26.81 ATOM 490 C PHE A 367 25.072 -14.5191.117 1.00 36.82 ATOM 491 O PHE A 367 24.244 -15.3981.359 1.00 36.55 ATOM 492 N VAL A 368 26.088 -14.6940.276 1.00 38.28 ATOM 493 CA VAL A 368 26.289 -15.965-0.4201.00 42.34 ATOM 494 CB VAL A 368 27.386 -15.850-1.5041.00 41.78 ATOM 495 CG1 VAL A 368 26.972 -14.831-2.5501.00 44.60 ATOM 496 CG2 VAL A 368 28.707 -15.457-0.8731.00 42.23 ATOM 497 C VAL A 368 26.664 -17.1000.533 1.00 43.85 ATOM 498 O VAL A 368 26.469 -18.2740.216 1.00 44.85 ATOM 499 N ASP A 369 27.199 -16.7501.699 1.00 44.93 ATOM 500 CA ASP A 369 27.579 -17.7552.688 1.00 44.96 ATOM 501 CB ASP A 369 28.336 -17.1063.849 1.00 43.76 ATOM 502 CG ASP A 369 29.608 -16.4133.404 1.00 13.04 ATOM 503 OD1 ASP A 369 30.121 -15.5704.167 1.00 44.32 ATOM 504 OD2 ASP A 369 30.097 -16.7092.293 1.00 46.76 ATOM 505 C ASP A 369 26.340 -18.4653.228 1.00 45.89 ATOM 506 O ASP A 369 26.360 -19.6713.475 1.00 48.61 ATOM 507 N LEU A 370 25.261 -17.7143.407 1.00 -13.59 ATOM 508 CA LEU A 370 24.020 -18.2793.924 1.00 44.24 ATOM 509 CB LEU A 370 22.980 -17.1734.110 1.00 -11.42 ATOM 510 CG LEU A 370 23.404 -16.0155.014 1.00 -11.45 ATOM 511 CDI LEU A 370 22.219 -15.0955.245 1.00 -12.25 ATOM 512 CD2 LEU A 370 23.931 -16.5526.332 1.00 ;8.35 ATOM X13 C LEU A 370 ?3.449 -19.3603.013 1.00 .14.03 ATOM 514 O LEU A 370 23.773 -19.4231.829 1.00 -13.63 ATOM 515 N THR A 371 ?2.593 -20.2063.575 1.00 -14.29 .ATOM ~ CA THR .1 371 21.968 -21.272x.806 1.00 44.84 .ATOM ~ CB THR A 371 21.293 -22.3023.730 1.00 45.65 ATOM 518 OG1 THR .4 371 20.262 -21.663-1.4951.00 46.43 ATOM 519 CG2 THR A 371 22.314 -22.903.1.6771.00 46.48 3 :ATOM 520 C THR A 371 20.923 -20.6841.864 1.00 44.93 .ATOM 521 O THR A 371 20.418 -19.585?.092 1.00 44.36 ATOM 522 N LEU A 372 20.607 -21.4180.804 1.00 43.83 ATOM 523 CA LEU A 372 19.624 -20.971-0.1661.00 44.62 .ATOM 524 CB LEU A 372 19.407 -22.043-1.2371.00 47.17 ATOM 525 CG LEU A 372 18.512 -21.690'.429 1.00 46.91 ATOM 526 CD1 LEU A 372 19.005 -20.417-3.0981.00 48.73 ATOM 527 CD2 LEU A 372 18.521 -22.844-3.4201.00 51.12 ATOM 528 C LEU A 372 18.307 -20.6440.512 1.00 44.84 ATOM 529 O LEU A 372 17.705 -19.6020.261 1.00 43.25 ATOM 530 N HIS A 373 17.849 -21.5581.382 1.00 43.14 ATOM 531 CA HIS A 373 16.599 -21.3532.100 1.00 42.23 ATOM 532 CB HIS A 373 16.318 -22.5253.062 1.00 45.38 ATOM 533 CG HIS A 373 15.114 -22.3153.934 1.00 51.43 ATOM 534 CD2 HIS A 373 13.808 -22.6213.743 1.00 54.99 ATOM 535 NDI HIS A 373 15.187 -21.7165.174 1.00 54.26 ATOM 536 CE1 HIS A 373 13.979 -21.6635.709 1.00 53.77 ATOM 537 NE2 HIS A 373 13.124 -22.2064.861 1.00 55.27 ATOM 538 C HIS A 373 16.665 -20.0472.885 1.00 39.78 ATOM 539 O HIS A 373 15.677 -19.3242.971 1.00 37.71 ATOM 540 N ASP A 374 17.839 -19.7383.440 1.00 36.38 ATOM 541 CA ASP A 374 18.020 -18.5164.219 1.00 37.21 ATOM 542 CB ASP A 374 19.287 -18.6205.073 1.00 38.17 ATOM 543 CG ASP A 374 19.064 -19.4256.344 1.00 41.47 ATOM 544 OD1 ASP A 374 17.896 -19.5436.772 1.00 37.09 ATOM 545 OD2 ASP A 374 20.052 -19.9406.912 1.00 44.40 ATOM 546 C ASP A 374 18.083 -17.2773.326 1.00 37.19 ATOM 547 O ASP A 374 17.598 -16.2083.696 1.00 38.13 ATOM 548 N GLN A 375 18.688 -17.4312.152 1.00 33.13 ATOM 549 CA GLN A 375 18.788 -16.3391.198 1.00 31.94 ATOM 550 CB GLN A 375 19.634 -16.756-0.0011.00 28.81 ATOM 551 CG GLN A 375 21.125 -16.5700.189 1.00 3I.71 ATOM 552 CD GLN A 375 21.920 -17.222-0.9221.00 34.49 ATOM 553 OEl GLN A 375 21.478 -17.267-2.0671.00 36.09 ATOM 554 NE2 GLN A 375 23.097 -17.736-0.5881.00 40.32 ATOM 555 C GLN A 375 17.379 -16.0090.730 1.00 31.50 ATOM 556 O GLN A 375 16.990 -14.8400.653 1.00 27.42 ATOM 557 N VAL A 376 16.617 -17.0560.429 1.00 30.38 ATOM 558 CA VAL A 3?6 15.242 -16.907-0.0271.00 33.50 ATOM 559 CB VAL A 376 14.588 -18.286-0.2861.00 30.57 ATOM 560 CG1 VAL A 376 13.093 -18.1?'_'-0.5161.00 33.14 rITOM 561 CG2 VAL A 376 15.232 -18.95?-1.4851.00 30.79 :'ATOM 562 C VAL .A 376 14.393 -16.1591.002 1.00 33.80 ATOM 563 O VAL A 376 13.653 -15.2370.661 1.00 34.89 ATOM X64 V HIS A 377 1-L500 -16.568?.261 1.00 33.3 ATOM 565 CA HIS A 377 13.730 -15.9413.329 1.00 32.81 ATOM X66 CB HIS A 377 13.966 -16.694-1.6441.00 35.24 ATOM X67 CG HIS A 377 13.429 -15.9895.851 1.00 40.15 ATOM 568 CD2 HIS A 377 14.054 -15.4956.946 1.00 40.86 ATOM X69 NDI HIS A 377 12.090 -15.7036.012 1.00 43.08 ATOM ~ CE HIS A 377 11.913 -15.0627. 1.00 42.44 ATOM 571 NE2 HIS A 377 13.089 -14.9227.740 1.00 44.85 ATOM 572 C HIS A 377 14.058 -14.4543.507 1.00 28.63 ATOM 573 O HIS A 377 13.158 -13.6193.613 1.00 X9.20 ATOM 374 N LEU A 378 15.343 -14.1253.544 1.00 24.41 ATOM 575 CA LEU A 378 15.759 -12.7383.721 1.00 23.21 ATOM 576 CB LEU A 378 17.289 -12.6503.743 1.00 20.98 ATOM ~ CG LEU A 378 17.960 - I 5.016 1.00 24.22 77 3.190 IS ATOM 578 CD1 LEU A 378 19.471 -13.0414.924 1.00 21.07 ATOM 579 CD2 LEU A 378 17.431 -12.4466.221 1.00 20.24 ATOM 580 C LEU A 378 15.190 -11.8272.630 1.00 24.78 ATOM 581 O LEU A 378 14.638 -10.7662.922 1.00 '2.09 ATOM 582 N LEU A 379 15.321 -12.2421.374 1.00 24.13 ATOM 583 CA LEU A 379 14.812 -11.4470.262 1.00 25.02 ATOM 584 CB LEU A 379 15.307 -12.025-1.0621.00 27.12 ATOM 585 CG LEU A 379 16.724 -11.600-1.4371.00 24.39 ATOM 586 CDI LEU A 379 17.299 -12.557-2.4701.00 27.58 ATOM 587 CD2 LEU A 379 16.679 -10.178-1.9831.00 29.05 ATOM 588 C LEU A 379 13.287 -11.3550.246 1.00 27.61 ATOM 589 O LEU A 379 12.726 -10.301-0.0621.00 26.16 ATOM 590 N GLU A 380 12.616 -12.4540.576 1.00 25.65 ATOM 591 CA GLU A 380 11.154 -12.4710.592 1.00 26.85 ATOM 592 CB GLU A 380 10.640 -13.8820.871 1.00 29.38 ATOM 593 CG GLU A 380 10.718 -14.796-0.3311.00 35.58 ATOM 594 CD GLU A 380 10.228 -16.194-0.0251.00 39.31 ATOM 595 OEI GLU A 380 10.142 -17.008-0.9671.00 42.89 ATOM 596 OE2 GLU A 380 9.927 -16.4781.153 1.00 39.45 ATOM 597 C GLU A 380 10.604 -11.5261.649 1.00 25.43 ATOM 598 O GLU A 380 9.551 -10.9251.469 1.00 27.75 ATOM 599 N CYS A 381 11.324 -11.4002.753 1.00 25.57 ATOM 600 CA CYS A 381 10.907 -10.5303.843 1.00 26.46 ATOM 601 CB CYS A 381 11.570 -11.0005.149 1.00 31.46 ATOM 602 SG CYS A 381 11.305 -9.946 6.623 1.00 45.32 ATOM 603 C CYS A 381 11.262 -9.059 3.589 1.00 24.77 ATOM 604 O CYS A 381 10.516 -8.166 3.975 1.00 25.01 ATOM 605 N ALA A 382 12.377 -8.815 2.903 1.00 X2.23 ATOM 606 CA ALA A 382 12.855 -7.449 2.681 I ~ 1.83 .00 ATOM 607 CB ALA A 382 14.319 -7.383 3.095 1.00 21.56 ATOM 608 C ALA A 382 12.705 -6.778 1.311 1.00 19.78 ATOM 609 O ALA A 382 12.996 -5.587 1.182 1.00 17.01 ATOM 610 N TRP A 383 12.261 -7.507 0.294 1.00 17.61 ATOM 611 CA TRP A 383 12.164 -6.915 -1.0361.00 18.06 ATOM 612 CB TRP :~ 383 11.580 -7.928 2.03 1.00 X0.28 ATOM 613 CG TRP A 383 10.105 -8.201 -1.9191.00 X0.50 ATOM 614 CD2 TRP A 383 9.049 -7.509 -?.5991.00 X2.48 ATOM 615 CE2 TRP A 383 7.836 -8.138 -2.2381.00 X0.41 ATOM 616 CE3 TRP A 383 9.012 -6.420 -3.4821.00 ?x.06 ATOM 617 CD1 TRP A 383 9.506 -9.189 -1.1901.00 ?3.38 ATOM 618 NE1 TRP A 383 8.142 -9.159 -1.3771.00 '_2.59 ATOM 619 CZ2 TRP A 383 6.598 -7.713 -2.7241.00 ?
1.98 ATOM 620 CZ3 TRP A 383 7.780 -x.998 -3.9681.00 ~~.50 ATOM 621 CH2 TRP A 383 6.589 -b.647 -3.5871.00 23.11 ATOM 622 C TRP A 383 11.448 -x.564 -1.1701.00 19.18 ATOM 623 O TRP A 383 11.972 -4.663 -1.8241.00 19.27 ATOM 624 N LEU A 384 10.273 -5.396 -0.5671.00 18.32 ATOM 625 CA LEU A 384 9.586 -4.118 -0.7191.00 16.38 ATOM 626 CB LEU A 384 8.125 -4.218 -0.2581.00 16.79 ATOM 627 CG LEU A 384 7.211 -3.013 -0.5771.00 18.39 ATOM 628 CD1 LEU A 384 7.464 -2.485 -1.9951.00 13.91 ATOM 629 CD2 LEU A 384 5.750 -3.432 -0.4101.00 18.38 ATOM 630 C LEU A 384 10.324 -3.027 0.051 1.00 18.80 ATOM 631 O LEU A 384 10.334 -1.870 -0.3571.00 20.90 ATOM 632 N GLU A 385 10.949 -3.404 1.163 1.00 18.61 ATOM 633 CA GLU A 385 11.718 -2.462 1.970 1.00 19.58 ATOM 634 CB GLU A 385 12.274 -3.154 3.213 1.00 17.43 ATOM 635 CG GLU A 385 11.292 -3.237 4.357 1.00 22.92 ATOM 636 CD GLU A 385 11.963 -3.676 5.640 1.00 25.83 ATOM 637 OE1 GLU A 385 12.431 -2.799 6.391 1.00 23.69 ATOM 638 OE2 GLU A 385 12.027 -4.897 5.889 1.00 27.64 ATOM 639 C GLU A 385 12.890 -1.934 1.156 1.00 19.46 ATOM 640 O GLU A 385 13.206 -0.743 1.196 1.00 15.04 ATOM 641 N ILE A 386 13.539 -2.842 0.431 1.00 13.32 ATOM 642 CA ILE A 386 14.685 -2.484 -0.3881.00 15.01 ATOM 643 CB ILE A 386 15.475 -3.763 -0.8071.00 17.43 ATOM 644 CG2 ILE A 386 16.544 -3.424 -1.8491.00 17.99 ATOM 645 CG1 ILE A 386 16.185 -4.338 0.432 1.00 20.31 ATOM 646 CD1 ILE A 386 16.682 -5.766 0.284 1.00 23.97 ATOM 647 C ILE A 386 14.273 -1.645 -1.5981.00 16.10 ATOM 648 O ILE A 386 14.993 -0.724 -2.0041.00 17.42 ATOM 649 N LEU A 387 13.112 -1.944 -2.1671.00 17.61 ATOM 650 CA LEU A 387 12.620 -1.173 -3.3041.00 18.20 ATOM 651 CB LEU A 387 11.359 -1.814 -3.8821.00 17.51 ATOM 652 CG LEU A 387 11.519 -3.064 -4.7471.00 X6.37 ATOM 653 CD1 LEU A 387 10.173 -3.406 -5.3951.00 24.63 ATOM 654 CD2 LEU A 387 12.589 -2.824 -x.8081.00 21.58 ATOM 65~ C LEU A 387 12.283 0.249 -2.8381.00 17.60 4~ ATOM 656 O LEU A 387 12.571 1.224 -3.5301.00 17.1 ATOM 657 N MET A 388 11.677 0.37 -1.6601.00 17.6 ATOM 658 CA MET A 388 11.286 1.66 -1.1211.00 18.49 ATOM 659 CB MET A 388 10.302 1.460 0.034 1.00 19.6 ATOM 660 CG MET A 388 8.893 1.105 -0.4351.00 15.12 ATOM 66 SD MET :~ 388 7.744 0.769 0.910 t 18.73 i .00 ATOM 662 CE MET :~ 388 6.163 0.908 0.048 1.00 18.34 ATOM 663 C MET .~ 388 12.451 2.553 -0.6911.00 ?2.62 ATOM 664 O MET A 388 12.417 3.767 -0.928i.00 22.49 A'rOM 665 N ILE .A 389 13.482 1.988 -0.0641.00 21.45 ATOM 666 CA ILE A 389 14.604 2.831 0.331 1.00 18.54 ATOM 667 CB ILE A 389 15.590 2.108 1.299 1.00 19.35 ATOM 668 CG2 ILE A 389 16.362 0.998 0.578 1.00 15.50 ATOM 669 CG1 ILE A 389 16.556 3.142 1.889 1.00 21.95 ATOM 670 CD1 ILE A 389 17.373 2.658 3.080 1.00 15.86 ATOM 671 C ILE A 389 15.333 3.322 -0.9221.00 18.67 ATOM 672 O ILE A 389 15.813 4.453 -0.9701.00 19.75 ATOM 673 N GLY A 390 15.410 2.477 -1.9431.00 20.58 I ATOM 674 CA GLY A 390 16.049 2.895 -3.1831.00 19.33 S

ATOM 675 C GLY A 390 15.243 4.021 -3.8191.00 17.48 ATOM 676 O GLY A 390 15.801 4.994 --1.3181.00 21.87 ATOM 677 N LEU A 391 13.920 3.888 -3.7871.00 19.17 ATOM 678 CA LEU A 391 13.018 4.887 -4.3431.00 21.50 ATOM 679 CB LEU A 391 11.561 4.420 -4.1941.00 18.25 ATOM 680 CG LEU A 391 10.480 5.497 -4.3421.00 21.98 ATOM 681 CD1 LEU A 391 10.579 6.156 -5.7251.00 21.39 ATOM 682 CD2 LEU A 391 9.115 4.868 -4.1481.00 17.15 ATOM 683 C LEU A 391 13.208 6.216 -3.6201.00 23.27 ATOM 684 O LEU A 391 13.440 7.255 -4.2431.00 23.60 ATOM 685 N VAL A 392 13.122 6.170 -2.2951.00 23.04 ATOM 686 CA VAL A 392 13.282 7.357 -1.4691.00 24.42 ATOM 687 CB VAL A 392 13.186 6.993 0.042 1.00 27.38 ATOM 688 CG1 VAL A 392 13.733 8.129 0.897 1.00 30.37 ATOM 689 CG2 VAL A 392 11.739 6.712 0.414 1.00 23.48 ATOM 690 C VAL A 392 14.626 8.014 -1.7541.00 27.55 ATOM 691 O VAL A 392 14.728 9.242 -1.8321.00 27.50 ATOM 692 N TRP A 393 15.652 7.186 -1.9241.00 23.65 ATOM 693 CA TRP A 393 16.999 7.670 -2.2041.00 24.76 ATOM 694 CB TRP A 393 17.977 6.491 -2.1991.00 22.86 ATOM 695 CG TRP A 393 19.287 6.784 -2.8571.00 25.90 ATOM 696 CD2 TRP A 393 20.341 7.605 -2.3391.00 28.09 ATOM 697 CE2 TRP A 393 21.375 7.612 -3.3021.00 29.94 ATOM 698 CE3 TRP A 393 20.512 8.335 -1.1541.00 30.20 ATOM 699 CD1 TRP A 393 19.710 6.339 -4.0771.00 26.55 ATOM 700 NE1 TRP A 393 20.963 6.833 -4.3511.00 30.64 ATOM 701 CZ2 TRP A 393 22.566 8.323 -3.1201.00 32.43 ATOM 702 CZ3 TRP ,A 393 21.698 9.044 -0.9711.00 34.58 ATOM 703 CH2 TRP A 393 22.709 9.030 -1.9501.00 36.54 ATOM 704 C TRP A 393 17.082 8.414 -3.5471.00 25.02 ATOM 705 O TRP A 393 17.767 9.435 -3.6501.00 20.97 ATOM 706 N ARG A 394 16.399 7.897 --4.5681.00 23.06 ATOM 707 CA ARG A 394 16.412 8.531 -5.8901.00 25.97 ATOM 708 CB ARG A 394 15.776 7.633 -6.9651.00 ?4.05 ATOM 709 CG ARG A 394 16.213 6.195 -7.0241.00 '6.05 ATOM 710 CD ARG A 394 15.830 ~.~~I -8.3521.00 ''x.70 ATOM 711 NE ARG A 394 I-1.443 5.071 -8.3631.00 ?0.71 ATOM 712 CZ ARG A 394 1:1.053 3.912 -7.8411.00 '_' I
.26 ATOM 713 NH ARG A 394 14.914 3.108 -7.2671.00 ?0.09 ATOM 714 NH2 ARG A 394 12.783 3.544 -7.9071.00 ? 1.26 ATOM 715 C ARG A 394 15.622 9.833 -5.8791.00 ?3.40 ATOM 7I6 O ARG A 394 15.889 10.729 -6.6771.00 '8.61 ATOM 717 N SER A 395 14.638 9.924 -4.9881.00 ~6.6~

ATOM 718 CA SER A 395 13.776 i 1.104-4.9021.00 ''7.46 ATOM 719 CB SER A 395 12.395 10.696 -4.3821.00 ?6.70 ATOM 720 OG SER A 395 11.916 9.530 -5.0291.00 ?2.95 ATOM 721 C SER A 395 14.316 12.240 -4.0331.00 31.45 ATOM 722 O SER A 395 13.726 13.324 -3.9771.00 28.11 ATOM 723 N MET A 396 15.437 11.986 -3.3681.00 33.83 ATOM 724 CA MET A 396 16.061 12.954 -2.4751.00 38.83 ATOM 725 CB MET A 396 17.466 12.483 -2.1121.00 39.47 ATOM 726 CG MET A 396 17.585 11.919 -0.7151.00 41.37 ATOM 727 SD MET A 396 19.192 12.262 0.004 1.00 42.20 ATOM 728 CE MET A 396 20.263 11.996 -1.4041.00 42.84 ATOM 729 C MET A 396 16.143 14.376 -3.0181.00 40.69 ATOM 730 O MET A 396 15.637 15.316 -2.4031.00 38.85 ATOM 731 N GLU A 397 16.794 14.526 -4.1661.00 42.19 ATOM 732 CA GLU A 397 16.971 15.831 -4.7901.00 44.80 ATOM 733 CB GLU A 397 18.184 15.785 -5.7291.00 46.02 ATOM 734 CG GLU A 397 17.883 15.189 -7.0961.00 54.42 ATOM 735 CD GLU A 397 19.117 14.665 -7.8101.00 59.40 ATOM 736 OE1 GLU A 397 19.219 13.430 -7.9901.00 60.63 ATOM 737 OE2 GLU A 397 19.980 15.485 -8.1961.00 62.71 ATOM 738 C GLU A 397 15.735 16.322 -5.5541.00 42.94 ATOM 739 O GLU A 397 15.830 17.229 -6.3761.00 44.68 ATOM 740 N HIS A 398 14.579 15.728 -5.2801.00 40.82 ATOM 741 CA HIS A 398 13.342 16.118 -5.9501.00 39.21 ATOM 742 CB HIS A 398 12.924 15.043 -6.9561.00 39.05 ATOM 743 CG HIS A 398 13.870 14.886 -8.1041.00 41.57 ATOM 744 CD2 HIS A 398 13.904 15.484 -9.3181.00 39.28 ATOM 745 ND1 HIS A 398 14.940 14.017 -8.0741.00 41.85 ATOM 746 CE1 HIS A 398 15.592 14.086 -9.2201.00 40.88 ATOM 747 NE2 HIS A 398 14.985 14.969 -9.9931.00 42.30 ATOM 748 C HIS A 398 12.216 16.332 -4.9441.00 37.04 ATOM 749 O HIS A 398 11.282 15.535 -4.8641.00 36.51 ATOM 750 N PRO A 399 12.283 17.427 -4.1711.00 39.19 ATOM 751 CD PRO A 399 13.328 18.467 -4.1981.00 35.36 ATOM 75? CA PRO A 399 11.2-13 17.709 -3.1731.00 37.10 ATOM 753 CB PRO A 399 11.603 19.101 -2.6541.00 37.86 ATOM 754 CG PRO A 399 13.050 19.267 -2.9631.00 35.83 ATOM 755 C PRO A 399 9.828 17.663 -3.7441.00 37.02 .ATOM 756 O PRO :~ 399 9.554 18.249--1.7891.00 38.52 ATOM 757 N GLY :~ 400 8.938 16.954-;.057 1.00 33.58 ATOM 758 CA GLY .-~400 7.559 16.866-:.503 1.00 32.12 ATOM 759 C GLY :~ 400 7.230 1 x.706--1.-1281.00 32.43 ATOM 760 O GLY .-~400 6.063 15.344--1.5741.00 33.21 ATOM 761 N LYS :~ 401 8.237 15.11?-x.055 1.00 31.35 ATOM 762 CA LYS .-~401 7.972 14.007-x.966 1.00 30.75 ATOM 763 CB LYS .~~401 8.235 14.430-7.415 1.00 35.43 ATOM 764 CG LYS ~1 401 8.130 15.927-7.675 1.00 35.15 ATOM 765 CD LYS :~ 401 9.096 16.353-8.774 1.00 36.88 ATOM 766 CE LYS r1 401 8.733 17.7? -9.331 1.00 36.71 ATOM 767 NZ LYS A 401 7.295 18.027-9.116 1.00 34.22 ATOM 768 C LYS A 401 8.768 12.746-5.677 1.00 30.97 ATOM 769 O LYS A 401 9.809 12.776-5.006 1.00 27.60 ATOM 770 N LEU A 402 8.256 11.635-6.197 1.00 27.28 ATOM 771 CA LEU A 402 8.889 10.334-6.050 1.00 29.07 ATOM 772 CB LEU A 402 7.866 9.294 -,.590 1.00 22.55 ATOM 773 CG LEU r1 402 7.265 9.555 -.x.2071.00 24.94 ATOM 774 CD1 LEU A 402 6.126 8.583 -3.937 1.00 19.32 ATOM 775 CD2 LEU A 402 8.355 9.416 -3.157 1.00 21.54 ATOM 776 C LEU A 402 9.448 9.948 -7.414 1.00 28.78 ATOM 777 O LEU A 402 8.704 9.836 -8.389 1.00 29.98 ATOM 778 N LEU A 403 10.761 9.770 -7.487 1.00 27.57 ATOM 779 CA LEU A 403 11.393 9.400 -8.744 1.00 27.17 ATOM 780 CB LEU A 403 12.825 9.937 -8.816 1.00 26.95 ATOM 781 CG LEU A 403 13.401 10.027-10.2381.00 30.42 ATOM 782 CD1 LEU A 403 14.519 11.046-10.2881.00 30.76 ATOM 783 CD2 LEU A 403 13.915 8.665 -10.6761.00 33.11 ATOM 784 C LEU A 403 11.419 7.891 -8.901 1.00 24.78 ATOM 785 O LEU A 403 12.428 7.257 -8.619 1.00 24.68 ATOM 786 N PHE A 404 10.306 7.319 -9.344 1.00 23.11 ATOM 787 CA PHE :1 404 10.239 5.881 -9.546 1.00 26.93 ATOM 788 CB PHE A 404 8.826 5.470 -9.946 1.00 27.04 ATOM 789 CG PHE A 404 7.850 5.513 -8.816 1.00 27.89 ATOM 790 CD1 PHE A 404 7.028 6.623 -8.631 1.00 26.20 ATOM 791 CD2 PHE r'1404 7.750 4.444 -7.925 1.00 23.10 ATOM 792 CE1 PHE A 404 6.116 6.668 -7.573 1.00 25.29 ATOM 793 CE2 PHE A 404 6.845 4.481 -6.870 1.00 21.01 ATOM 794 CZ PHE ~'1404 6.026 5.595 -6.693 1.00 22.91 ATOM 795 C PHE .~ 404 11.232 5.507 -10.6371.00 26.04 ATOM 796 O PHE r~ 404 11.882 4.464 -10.5781.00 27.27 ATOM 797 N ALA .-~405 11.348 6.383 -11.6261.00 28.80 ATOM 798 CA ALA r1 405 12.271 6.195 -1 ?.7401.00 29.21 ATOM 799 CB ALA .-~405 11.650 5.287 -13.8061.00 26.89 ATOM 800 C ALA :~ 405 12.549 7.578 -13.3171.00 30.23 ATOM 801 O ALA .-~405 11.770 8.508 -13.109I 27.38 .00 ATOM 802 N PRO :~ 406 13.672 7.737 -1.1.03?1.00 30.05 .ATOM 803 CD PRO .~ 406 14.712 6.746 -1-L35~1.00 X6.31 ATOM 804 CA PRO A 406 13.977 9.053 -14.604i.00 32.10 ATOM 805 CB PRO A 406 1.232 8.800 -15.4381.00 31.28 ATOM 806 CG PRO A 406 1 ~.86~ 7.602 -14.7761.00 31.44 ATOM 807 C PRO A 406 12.820 9.589 -15.4361.00 32.58 ATOM 808 O PRO A 406 12.605 10.796-15.5071.00 32.58 ATOM 809 N ASN A 407 12.063 8.690 -16.0531.00 32.86 ATOM 810 CA ASN A 407 10.93 9.119 -16.8651.00 32.78 ATOM 811 CB ASN A 407 10.950 8.418 -18.2281.00 34.73 ATOM 812 CG ASN A 407 10.884 6.907 -18.1211.00 35.37 ATOM 8I3 OD1 ASN A 407 11.189 6.317 -17.0771.00 30.24 ATOM 814 ND2 ASN A 407 10.486 6.268 -19.2151.00 34.08 ATOM 81 C ASN A 407 9.605 8.901 -16.166I 34.90 S .00 ATOM 816 O ASN A 407 8.549 8.897 -16.7981.00 36.09 ATOM 817 N LEU A 408 9.660 8.724 -14.8511.00 33.56 1 ATOM 818 CA LEU A 408 8.452 8.544 -14.0611.00 35.59 S

ATOM 819 CB LEU A 408 8.141 7.062 -13.8511.00 33.81 ATOM 820 CG LEU A 408 6.696 6.823 -13.3971.00 36.44 ATOM 821 CD1 LEU A 408 x.746 7.479 -14.3901.00 34.14 ATOM 822 CD2 LEU A 408 6.406 5.334 -13.2871.00 32.96 ATOM 823 C LEU A 408 8.607 9.245 -12.7171.00 38.03 ATOM 824 O LEU A 408 8.880 8.614 -11.6951.00 36.38 ATOM 825 N LEU A 409 8.441 10.563-12.7411.00 37.87 ATOM 826 CA LEU A 409 8.548 11.395-11.5531.00 37.95 ATOM 827 CB LEU A 409 9.373 12.636-11.8771.00 39.52 ATOM 828 CG LEU A 409 10.023 13.399-10.7281.00 42.46 ATOM 829 CD1 LEU A 409 11.100 12.547-10.0821.00 43.24 ATOM 830 CD2 LEU A 409 10.614 14.691-11.2661.00 46.05 ATOM 831 C LEU A 409 7.132 11.792-11.1631.00 37.13 ATOM 832 O LEU A 409 6.482 12.546-11.8821.00 35.70 ATOM 833 N LEU A 410 6.654 11.284-10.0301.00 35.29 ATOM 834 CA LEU A 410 5.297 11.576-9.583 1.00 33.33 ATOM 835 CB LEU A 410 4.503 10.277-9.449 1.00 29.37 ATOM 836 CG LEU A 410 4.645 9.238 -10.5601.00 32.75 ATOM 837 CDl LEU A 410 4.026 7.925 -10.1041.00 29.16 ATOM 838 CD2 LEU A 410 3.958 9.744 -11.8191.00 30.70 ATOM 839 C LEU A 410 5.207 12.332-8.261 1.00 35.14 ATOM 840 O LEU A 410 6.078 12.214-7.400 1.00 36.94 ATOM 841 N ASP A 411 4.141 13.108-8.105 1.00 34.76 ATOM 842 CA ASP A 411 3.933 13.843-6.873 1.00 35.40 ATOM 843 CB ASP A 411 3.733 15.341-7.144 1.00 ~i0.02 ATOM 844 CG ASP A 411 2.471 15.645-7.928 1.00 41.32 ATOM 845 OD ASP A 411 1.570 14.785-8.001 1.00 45.03 ATOM 846 OD2 ASP A 411 2.383 16.764-8.474 1.00 45.01 ATOM 847 C ASP A 411 2.727 13.234-6.179 1.00 36.10 ATOM 848 O ASP A 411 2.033 12.395-6.762 1.00 34.08 ATOM 849 N ARG A 412 2.480 13.647-4.940 1.00 3.99 ATOM 850 CA ARG A 4I2 1.37 13.099-4.169 1.00 39.37 ATOM 851 CB ARG A 412 1.260 13.824-2.825 1.00 39.7 ATOM 852 CG ARG A 412 0.562 15.168 -2.8701.00 40.49 ATOM 853 CD ARG A 412 0.454 15.736 -1.465I 40.65 .00 ATOM 854 NE ARG A 112 -0.261 14.826 -0.5771.00 37.48 ATOM 855 CZ ARG A 412 -1.574 1-x.855-0.3841.00 =12.84 ATOM 856 NH ARG A 412 -2.316 15.75:1-1.0241.00 40.82 I

ATOM 857 NH2 ARG A 412 -2.150 13.986 0.438 1.00 38.32 ATOM 858 C ARG A 412 0.034 13.108 --1.8891.00 39.80 ATOM 859 O ARG A 412 -0.775 12.201 -4.7061.00 39.92 ATOM 860 N ASN A 4 i -0.198 14.1 -5.7171.00 41.64 ATOM 861 CA ASN A 413 -1.458 14.215 -6.4401.00 43.19 ATOM 862 CB ASN A 413 -1.518 15.533 -7.2101.00 46.44 ATOM 863 CG ASN A 413 -1.739 16.718 -6.2991.00 47.86 ATOM 864 OD1 ASN A 413 -2.376 16.594 -5.2491.00 48.05 ATOM 865 ND2 ASN A 413 -1.213 17.876 -6.6871.00 49.43 ATOM 866 C ASN A 413 -1.673 13.044 -7.3851.00 41.48 ATOM 867 O ASN A 413 -2.792 12.567 -7.5461.00 40.50 ATOM 868 N GLN A 414 -0.600 12.577 -8.0101.00 42.82 ATOM 869 CA GLN A 414 -0.703 11.448 -8.9251.00 44.73 ATOM 870 CB GLN A 414 0.585 11.307 -9.7411.00 47 ATOM 871 CG GLN A 414 0.572 12.088 -11.0491.00 .
50.47 ATOM 872 CD GLN A 414 1.914 12.713 -11.3751.00 53.91 ATOM 873 OEI GLN A 414 2.591 13.257 -10.5011.00 53.68 ATOM 874 NE2 GLN A 414 2.309 12.637 -12.6411.00 56.91 ATOM 875 C GLN A 414 -0.970 10.163 -8.1411.00 43.21 ATOM 876 O GLN A 414 -1.491 9.193 -8.6821.00 42.33 ATOM 877 N GLY A 415 -0.618 10.168 -6.8601.00 41.97 ATOM 878 CA GLY A 4 i -0.836 8.992 -6.0401.00 40.43 ATOM 879 C GLY A 415 -2.306 8.720 -5.8041.00 40.80 ATOM 880 O GLY A 415 -2.696 7.601 -5.4721.00 37.83 ATOM 881 N LYS A 416 -3.129 9.748 -5.9781.00 42.16 ATOM 882 CA LYS A 416 -4.566 9.613 -5.7791.00 44.34 ATOM 883 CB LYS A 416 -5.212 10.996 -5.7041.00 45.65 ATOM 884 CG LYS A 416 -4.761 11.819 -4.5101.00 47.42 ATOM 885 CD LYS A 416 -4.910 I3.309 -4.7771.00 50.97 ATOM 886 CE LYS A 416 -5.992 13.924 -3.8981.00 53.25 ATOM 887 NZ LYS A 416 -5.416 14.764 -2.8091.00 56.95 ATOM 888 C LYS A 416 -5.227 8.793 -6.8861.00 45.33 ATOM 889 O LYS A 416 -6.339 8.299 -6.7141.00 46.50 ATOM 890 N CYS A 417 -4.540 8.648 -8.0151.00 45.18 ATOM 891 CA CYS A 417 -5.066 7.890 -9.1481.00 46.25 ATOM 892 CB CYS A 417 -4.062 7.902 -10.3051.00 49.29 ATOM 893 SG CYS A 417 -3.91b 9.493 -11.1681.00 49.59 ATOM 894 C CYS A 417 -5.373 6.452 -8.7521.00 47.18 ATOM 895 O CYS A 417 -6.220 5.794 -9.3591.00 46.50 ATOM 896 N VAL A 418 -4.671 5.968 -7.7311.00 45.07 ATOM 897 CA VAL A 418 -4.866 4.61? -7.2321.00 42.75 ATOM 898 CB VAL A 418 -3.525 3.841 -7.2061.00 42.45 ATOM 899 CGI VAL r1 418 -3.670 2.563 -6.4101.00 40.22 ATOM 900 CG2 VAL A -118 -3.071 3.538 -8.634 1.00 38.03 ATOM 901 C VAL A -118 -5.441 4.714 -5.818 1.00 41.46 .ATOM 902 O VAL A -118 -4.883 5.400 --1.9631.00 -12.08 ATOM 903 N GLU A -119 -6.559 -1.036-5.579 1.00 -10.95 ATOM 904 CA GLU A -119 -7.223 4.073 -.1.2751.00 42.51 ATOM 905 CB GLU A 419 -8.536 3.282 -.1.33;1.00 44.52 ATOM 906 CG GLU A 419 -9.010 2.751 -?.984 1.00 50.42 ATOM 907 CD GLU A 419 -10.413 2.168 -3.035 1.00 54.38 ATOM 908 OEI GLU A 419 -10.582 1.059 -3.590 1.00 54.09 ATOM 909 OE2 GLU A 419 -11.347 2.820 -?.516 1.00 57.90 ATOM 910 C GLU A 419 -6.370 3.552 -3.121 1.00 41.11 ATOM 911 O GLU A 419 -5.955 2.393 -3.116 1.00 39.42 ATOM 912 N GLY A 420 -6.129 4.419 -2.140 1.00 40.53 ATOM 913 CA GLY A 420 -5.346 4.049 -0.973 1.00 37.61 ATOM 914 C GLY A 420 -3.854 4.258 -1.140 1.00 37.01 ATOM 915 O GLY A 420 -3.088 4.105 -0.190 1.00 32.59 ATOM 916 N MET A 421 -3.444 4.623 -2.350 1.00 36.21 ATOM 917 CA MET A 421 -2.035 4.825 -2.65b 1.00 36.02 ATOM 918 CB MET A 421 -1.799 4.607 -4.160 1.00 32.84 ATOM 919 CG MET A 421 -0.351 4.754 -4.617 1.00 35.82 ATOM 920 SD MET A 421 0.806 3.611 -3.812 1.00 35.57 ATOM 921 CE MET A 421 0.881 2.294 -5.005 1.00 32.51 ATOM 922 C MET A 421 -1.474 6.180 -2.226 1.00 34.93 ATOM 923 O MET A 421 -0.275 6.294 -1.985 1.00 35.17 ATOM 924 N VAL A 422 -2.319 7.205 -2.118 1.00 33.97 ATOM 925 CA VAL A 422 -1.823 8.520 -1.708 1.00 31.29 ATOM 926 CB VAL A 422 -2.927 9.607 -1.766 1.00 33.14 ATOM 927 CGI VAL A 422 -3.823 9.535 -0.533 1.00 30.10 ATOM 928 CG2 VAL A 422 -2.279 10.982-1.854 1.00 30.08 ATOM 929 C VAL A 422 -1.231 8.498 -0.296 1.00 32.64 ATOM 930 O VAL A 422 -0.274 9.220 0.002 1.00 28.41 ATOM 931 N GLU A 423 -1.803 7.670 0.571 1.00 31.53 ATOM 932 CA GLU A 423 -1.311 7.558 1.935 1.00 35.99 ATOM 933 CB GLU A 423 -2.190 6.594 2.737 1.00 40.37 ATOM 934 CG GLU A 423 -3.588 7.129 3.043 1.00 49.41 ATOM 935 CD GLU A 423 -4.438 7.336 1.795 1.00 52.38 ATOM 936 OE1 GLU A 423 -5.349 8.188 1.835 1.00 56.91 ATOM 937 OE2 GLU A 423 -4.200 6.652 0.776 1.00 54.53 ATOM 938 C GLU A 423 0.127 7.043 1.886 1.00 34.83 ATOM 939 O GLU A 423 1.007 7.552 2.581 1.00 31.85 ATOM 940 N ILE A 424 0.369 6.038 1.050 1.00 30.17 ATOM 941 CA ILE A 424 1.711 5.488 0.929 1.00 28.99 ATOM 942 CB ILE A 424 1.696 4.195 0.109 1.00 30.96 ATOM 943 CG2 ILE A 424 3.108 3.588 0.068 1.00 27.20 ATOM 944 CG ILE A 424 0.671 3.230 0.725 1.00 30.77 ATOM 945 CD1 1LE A 424 0.810 1.787 0.291 1.00 34.69 ATOM 946 C ILE A 424 2.700 6.483 0.312 1.00 28.21 ATOM 947 O ILE A 424 3.856 6.551 0.735 1.00 28.48 ATOM 948 V PHE .~ 425 2.253 7.260 -0.6751.00 '_'7.68 ATOM 949 CA PHE :~ 425 3.119 8.253 -1.3151.00 ?7.30 ATOM 960 CB PHE A 425 2.381 8.958 -2.4581.00 ?6.36 ATOM 951 CG PHE :~ 425 ?.638 8.289 -3.7981.00 ?7.22 ~ ATOM 952 CD1 PHE A 425 ?.619 9.050 -4.9581.00 ?7.36 ATOM 953 CD2 PHE .~ 425 ?.666 6.900 -3.9051.00 ?7.89 ATOM 964 CE PHE A 425 2.721 8.443 -6.2071.00 29.63 ATOM 956 CE2 PHE :~ 425 2.668 6.282 -5.1491.00 ?7.28 ATOM 956 CZ PHE A 425 2.745 7.056 -6.3031.00 27.63 ATOM 957 C PHE A 425 3.591 9.306 -0.3121.00 ?6.66 ATOM 958 O PHE A 425 4.757 9.713 -0.3281.00 26.33 ATOM 969 N ASP A 426 2.680 9.746 0.552 1.00 27.92 ATOM 960 CA ASP A 426 2.984 10.759 1.570 1.00 28.88 ATOM 961 CB ASP A 426 1.721 11.102 2.369 1.00 32.58 ATOM 962 CG ASP A 426 0.781 12.034 1.613 1.00 37.47 ATOM 963 ODI ASP A 426 -0.432 12.039 1.925 1.00 37.72 ATOM 964 OD2 ASP A 426 1.253 12.758 0.710 1.00 36.35 ATOM 965 C ASP a 426 4.071 10.278 2.532 1.00 26.96 ATOM 966 O ASP A 426 4.974 11.030 2.900 1.00 ?7.20 ATOM 967 N MET A 427 3.978 9.022 2.947 1.00 25.76 ATOM 968 CA MET A 427 4.981 8.468 3.856 1.00 25.89 ATOM 969 CB MET A 427 4.567 7.070 4.309 1.00 21.17 ATOM 970 CG MET A 427 3.385 7.072 5.257 1.00 24.38 ATOM 971 SD MET A 427 3.153 5.489 6.080 1.00 34.32 ATOM 972 CE MET A 427 2.173 4.637 4.910 1.00 21.03 ATOM 973 C MET A 427 6.321 8.410 3.128 1.00 22.29 ATOM 974 O MET A 427 7.363 8.760 3.689 1.00 22.19 ATOM 975 N LEU A 428 6.285 7.985 1.868 1.00 21.75 ATOM 976 CA LEU A 428 7.506 7.892 1.075 1.00 ?2.91 ATOM 977 CB LEU A 428 7.202 7.252 -0.2871.00 18.47 ATOM 978 CG LEU A 428 6.910 5.747 -0.1761.00 19.24 ATOM 979 CDI LEU A 428 6.278 5.222 -1.4681.00 16.82 ATOM 980 CD2 LEU A 428 8.204 5.010 0.131 1.00 t 6.23 ATOM 981 C LEU A 428 8.148 9.269 0.902 1.00 23.98 ATOM 982 O LEU A 428 9.366 9.416 1.034 1.00 23.06 ATOM 983 N LEU A 429 7.328 10.281 0.628 1.00 23.91 ATOM 984 CA LEU A 429 7.837 11.642 0.462 1.00 26.29 ATOM 985 CB LEU A 429 6.714 12.571 -0.0031.00 27.47 ATOM 986 CG LEU A 429 6.331 12.411 -I.4761.00 30.78 ATOM 987 CD1 LEU A 429 6.022 13.139 -1.7511.00 34.75 ATOM 988 CD2 LEU A 429 7.449 12.952 -2.3501.00 31.96 ATOM 989 C LEU :~ 429 8.426 12.166 1.776 1.00 ?6.83 ATOM 990 O LEU A 429 9.482 12.808 1.793 1.00 26.42 ATOM 991 N ALA A 430 7.734 11.890 2.877 1.00 26.46 ATOM 992 CA ALA :~ 430 8.201 12.333 4.186 1.00 '?6.11 ATOM 993 CB ALA A 430 7.211 11.909 6.265 1.00 '_'3.13 ATOM 994 C ALA A 430 9.577 11.742 4.462 1.00 ~~.01 ATOM 996 O ALA A 430 10.466 12.409 6.006 1.00 24.31 ATOM 996 N THR :1 431 9.767 10.486 .1.0741.00 X5 ATOM 997 CA THR :~ 431 11.046 9.825 -1.2941.00 .

ATOM 998 CB THR :1 43 10.973 8.323 3.962 1.00 .
i 21 ATOM 999 OGI THR A :131 9.924 7.727 .1.7271.00 .

ATOM 1000 CG2 THR :A 431 12.291 7.633 .1.2991.00 .

ATOM 1001 C THR r~ 431 12.103 10.477 3.429 1.00 .

ATOM 1002 O THR r~ 431 13.234 10.667 3.868 1.00 .

ATOM 1003 N SER .\ 432 11.736 10.819 2.197 1.00 .

ATOM 1004 CA SER t1 :132 12.676 11.479 1.301 1.00 .

ATOM 1005 CB SER .a 432 12.067 11.650 -0.0931.00 .

ATOM 1006 OG SER A :132 13.084 11.930 -1.0391.00 .

ATOM 1007 C SER A 432 13.033 12.850 1.876 1.00 .

ATOM 1008 O SER .4 432 14.176 13.294 1.779 1.00 .

ATOM 1009 N SER A 433 12.045 13.521 2.459 1.00 .

ATOM 1010 CA SER A 433 12.269 14.824 3.076 1.00 .

ATOM 1011 CB SER A 433 10.957 15.387 3.623 1.00 .

ATOM 1012 OG SER A 433 10.175 15.961 2.591 1.00 .

ATOM 1013 C SER A 433 13.263 14.644 =1.2231.00 .

ATOM 1014 O SER A 433 14.152 15.473 4.429 1.00 .

ATOM 1015 N ARG A 434 13.105 13.545 4.959 1.00 .

ATOM 1016 CA ARG A 434 13.980 13.236 6.086 1.00 .

ATOM 1017 CB ARG A 434 13.468 11.994 6.819 1.00 .

ATOM 1018 CG ARG A 434 14.331 11.541 7.983 1.00 .
32.17 ATOM 1019 CD ARG A 434 14.626 12.672 8.958 1.00 37 ATOM 1020 NE ARG A 434 15.321 12.169 10.1401.00 .

ATOM 1021 CZ ARG A 434 15.935 12.935 11.0341.00 .

ATOM 1022 NHI ARG A 434 15.949 14.255 10.8851.00 .
45.52 ATOM 1023 NH2 ARG A 434 16.528 12.381 12.0841.00 45.01 ATOM 1024 C ARG A 434 15.413 13.014 5.605 1.00 29 ATOM 1025 O ARG A 434 16.352 13.563 6.173 1.00 .

ATOM 1026 N PHE A 435 15.577 12.206 4.561 1.00 .

ATOM 1027 CA PHE A 435 16.901 11.935 4.000 1.00 .
30.59 ATOM 1028 CB PHE A 435 16.777 11.045 2.758 1.00 32 ATOM 1029 CG PHE A 435 16.795 9.563 3.051 1.00 .

ATOM 1030 CDI PHE A 435 16.758 9.084 4.359 1.00 .

ATOM 1031 CD2 PHE A 435 16.847 8.643 ?.009 1.00 .

ATOM 1032 CE1 PHE A 435 16.771 7.709 4.622 1.00 .

ATOM 1033 CE2 PHE A 435 16.860 7.271 2.262 1.00 .

ATOM 1034 CZ PHE A 435 16.821 6.807 3.570 1.00 .

ATOM 1035 C PHE :1 435 17.576 13.253 3.607 1.00 .

ATOM 1036 O PHE :1 435 18.763 13.464 3.871 1.00 .

ATOM 1037 N ARG A -136 16.812 14.137 ?.975 1.00 .

ATOM 1038 CA ARG .~ 436 17.341 15.429 x.549 1.00 .

ATOM 1039 CB ARG :~ 436 16.282 16.206 1.756 1.00 .

ATOM 1040 CG ARG :~ :136 16.846 17.317 0.877 1.00 .

ATOM 1041 CD ARG : -136 15.750 17.960 0.040 I .
~ .00 44 ATOM 1042 NE ARG r1 436 14.826 16.955 -0.47?1.00 .

ATOM 1043 CZ ARG A 436 13.530 16.913 -0.1841.00 .
48.81 ATOM 1044 NH ARG A 436 12.997 17.823 0.619 1.00 -17.80 I

ATOM 1045 NH2 ARG A -136 12.769 15.950 -0.6871.00 49.53 ATOM 1046 C ARG A -136 17.792 16.250 3.753 1.00 38.10 ATOM 1047 O ARG A :1:36 18.896 16.789 3.764 1.00 :1.00 ATOM 1048 N MET A 437 16.936 16.334 =1.7661.00 39.47 ATOM 1049 CA MET A 437 i 7.257 17.087 5.975 1.00 38.20 ATOM 1050 CB MET A 437 16.102 16.998 6.965 1.00 39.79 ATOM 1 OS C MET A 437 I 8.550 16.594 6.626 i =~
I .00 1.
I

ATOM 1052 O MET A 437 19.303 17.378 7.201 1.00 40 ATOM 1053 N MET A 438 18.804 15.285 6.538 1.00 .
39.65 ATOM 1054 CA MET A 438 20.011 14.693 7.117 1.00 39.70 ATOM 1055 CB MET A 438 19.787 13.221 7.463 1.00 39.90 ATOM 1056 CG MET A 438 18.694 12.938 8.460 1.00 41.94 ATOM 1057 SD MET A 438 18.747 11.188 8.880 1.00 43.12 ATOM 1058 CE MET A 438 20.374 11.064 9.619 1.00 43.73 ATOM 1059 C MET A 438 21.176 14.756 6.142 1.00 38.03 ATOM 1060 O MET A 438 22.321 14.503 6.522 1.00 38.39 ATOM 1061 N ASN A 439 20.886 15.070 4.895 1.00 37.64 ATOM 1062 CA ASN A 439 21.924 15.118 3.895 1.00 35 ATOM 1063 CB ASN A 439 23.019 16.125 4.243 1.00 .
40.98 ATOM 1064 CG ASN A 439 23.933 16.407 3.090 1.00 45.09 ATOM 1065 OD ASN A 439 23.528 16.295 1.934 1.00 47.16 ATOM 1066 ND2 ASN A 439 25.197 16.733 3.372 1.00 46.87 ATOM 1067 C ASN A 439 22.552 13.732 3.739 1.00 31.06 ATOM 1068 O ASN A 439 23.764 13.581 3.649 1.00 29.54 ATOM 1069 N LEU A 440 21.692 12.698 3.704 1.00 31.47 ATOM 1070 CA LEU A 440 22.161 11.326 3.579 1.00 31.63 ATOM 1071 CB LEU A 440 20.991 10.344 3.380 1.00 33.05 ATOM 1072 CG LEU A 440 21.451 8.886 3.209 1.00 37 ATOM 1073 CDI LEU A 440 21.957 8.353 4.546 1.00 .
36.18 ATOM 1074 CD2 LEU A 440 20.318 8.032 2.682 1.00 32.33 ATOM 1075 C LEU A 440 23.146 11.161 2.435 1.00 32.10 ATOM 1076 O LEU A 440 22.925 11.671 1.333 1.00 32.76 ATOM 1077 N GLN A 441 24.225 10.450 2.702 1.00 32.54 ATOM 1078 CA GLN A 441 25.255 10.220 1.699 1.00 31.97 ATOM 1079 CB GLN A 441 26.632 10.320 2.345 1.00 31.75 ATOM 1080 CG GLN A 441 26.896 11.669 2.979 1.00 35.56 ATOM 1081 CD GLN A 441 27.040 12.748 1.939 1.00 34.97 ATOM 1082 OE1 GLN A 441 27.985 12.782 1.167 1.00 35.51 ATOM 1083 NE2 GLN A 441 26.053 13.659 1.899 1.00 35.41 ATOM 1084 C GLN A 441 25.100 8.860 1.038 1.00 ;4.08 ATOM 1085 O GLN A 441 24.540 7.931 1.625 1.00 30.73 ATOM 1086 N GLY A 442 25.608 8.752 -0.1871.00 32.78 ATOM 1087 CA GLY A 442 25.528 7.503 -0.9211.00 32.91 ATOM 1088 C GLY A 442 26.181 6.350 -0.1841.00 31.87 ATOM 1089 O GLY A 442 25.642 5.245 -0.1541.00 33.18 ATOM 1090 N GLU A 443 27.340 6.603 0.416 1.00 30.60 ATOM 1091 CA GLU A :143 X8.057 x.567 1.150 1.00 30.8 AT01~1 1092 GLU A .1-13 29.376 6. i 1.704 1.00 32 CB l I 74 ATOM 1093 GLU A .1-13 30.425 6.378 0.646 1.00 .

ATOM 1094 GLU A -143 30.310 7.770 0.066 1.00 .

ATOM 1095 OE1 GLU A -143 29.677 8.630 0.716 1 .

ATOM 1096 GLU A :143 30.853 8.003 -1.038. .
OE2 1.00 46 ATOM 1097 C GLU A -1.~3 ?7.206 5.048 '' 1.00 .

ATOM 1098 O GLU A .143 27.21 3.854 x.595 i .00 .

I

ATOM 1099 N GLU A :144 26.482 5.955 x.948 1.00 .

ATOM II00 CA GLU A 444 25.619 5.589 -1.0671 .

ATOM 1101 CB GLU A 444 25.147 6.843 4.797 . .
1.00 26 ATOM 1102 CG GLU A 444 26.250 7.633 5.463 1.00 .

ATOM 1103 CD GLU A 444 25.748 8.944 6.023 1.00 .

ATOM 1104 OE1 GLU A 444 25.006 9.652 5.304 1.00 .

ATOM 1105 OE2 GLU A 444 26.088 9.268 7.182 1 .

ATOM 1106 C GLU A 444 24.403 4.813 3.572 . .
1.00 26 ATOM 1107 O GLU A 444 23.970 3.841 1.191 1.00 .

ATOM 1108 N PHE A 445 23.861 5.256 x.443 1.00 .

ATOM 1109 CA PHE A :145 22.688 4.633 1.853 1.00 .

ATOM 1110 CB PHE A 445 22.254 5.416 0.610 1 .

ATOM 1111 CG PHE A 445 21.372 4.634 -0.316. .

ATOM 1112 CD1 PHE A 445 20.034 4.419 -0.004. .
1.00 23 ATOM 1113 CD2 PHE A 445 21.885 4.094 -1.4891.00 .

ATOM 1114 CEI PHE A 445 19.215 3.670 -0.8551.00 .

ATOM 1115 CE2 PHE A 445 21.079 3.349 -2.3421 .

ATOM 1116 CZ PHE A 445 19.741 3.138 -2.023. .
1.00 22 ATOM IlI7 C PHE A 445 22.913 3.169 1.489 1.00 .

ATOM 1118 O PHE A 445 22.083 2.316 1.796 1 .

ATOM 1119 N VAL A 446 24.019 2.868 0.822 . .
1.00 22 ATOM 1120 CA VAL A 446 24.278 1.481 0.447 1 .

ATOM 1121 CB VAL A 446 25.522 1.360 -0.465. .
1.00 22 ATOM 1122 CG1 VAL A 446 25.251 2.046 -1.7991 .

ATOM 1123 CG2 VAL A 446 26.735 1.968 0.217 . .

ATOM 1124 C VAL A 446 24.467 0.614 1.694 . .

ATOM 1125 O VAL A 446 24.177 -0.586 1.680 . .

ATOM 1126 N CYS A 447 24.962 1.223 2.770 . .

ATOM 1127 CA CYS A 447 25.155 0.503 4.025 . .

ATOM 1128 CB CYS A 447 25.953 1.359 5.011 . .

ATOM 1129 SG CYS A 447 27.738 1.324 4.731 . .

ATOM 1130 C CYS A 447 23.781 0.178 1.618 . .

ATOM 1131 O CYS A 447 23.512 -0.960 5.002 . .

ATOM 1132 N LEU A 448 22.915 1.186 4.680 . .

ATOM 1133 CA LEU A 448 21.568 1.002 5.219 . .

ATOM 1134 CB LEU A 448 20.803 2.324 5.207 . .

ATOM 1135 CG LEU A 448 21.142 3.337 6.303 . .

ATOM 1136 CDl LEU A -148 20.328 4.594 6.07? . .

ATOM 1137 CD2 LEU A :148 20.827 x.760 7.67 . .

ATOM 1138 C LEU A 448 20.766 -0.038 -1.442. .

ATOM 1139 LEU A 448 20.006 -0.803 5.030 . .
O 1.00 X0.87 7?

ATOM 1140 N LYS A 449 20.929 -0.055 3.119 I ? 1.42 .00 ATOM 1141 CA LYS a 449 20.205 -0.997 x.269 1.00 X0.98 ATOM 1142 CB LYS A 449 20.440 -0.659 0.788 1.00 21.55 ATOM 1143 CG LYS A 449 19.438 -1.297 -0.1731.00 24.82 ATOM 1144 CD LYS A 449 19.456 -0.613 -1.5421.00 X3.33 ATOM 1145 CE LYS :~ 449 20.816 -0.754 -2.2291.00 23.58 ATOM 1146 NZ LYS A 449 20.741 -0.482 -3.6981.00 28.77 ATOM 1147 C LYS A 449 20.629 -2.436 2.548 1.00 20.33 ATOM 1148 O LYS A 449 i 9.800 -3.345 2.552 1.00 20 ATOM 1149 N SER A 450 21.924 -2.637 2.777 1.00 .
19.25 ATOM ~ CA SER A 450 22.451 -3.965 3.074 1.00 21.84 ATOM 1151 CB SER A 450 23.982 -3.953 3.041 1.00 20.59 ATOM 1152 OG SER A 450 24.460 -3.975 1.702 1.00 29.78 ATOM 1153 C SER A 450 21.975 -4.408 4.454 1.00 21.58 ATOM 1154 O SER A 450 21.728 -5.590 4.682 1.00 20.06 ATOM 1155 N ILE A 451 21.853 -3.449 5.369 1.00 22.20 ATOM 1156 CA ILE A 451 21.385 -3.741 6.726 1.00 22.82 ATOM 1157 CB ILE A 451 21.452 -2.476 7.616 1.00 19.62 ATOM 1158 CG2 ILE A 451 20.593 -2.658 8.886 1.00 21 ATOM 1159 CG ILE A 451 22.909 -2.210 7.999 1.00 .
1 22.20 ATOM 1160 CD ILE A 451 23.115 -0.960 8.850 1.00 24.48 ATOM 1161 C ILE A 451 19.952 -4.250 6.662 1.00 21.82 ATOM 1162 O ILE A 451 19.575 -5.184 7.369 1.00 21.72 ATOM 1163 N ILE A 452 19.152 -3.642 5.795 1.00 20.18 ATOM 1164 CA ILE A 452 17.763 -4.058 5.649 1.00 18.13 ATOM 1165 CB ILE A 452 17.024 -3.145 4.627 1.00 19.72 ATOM 1166 CG2 ILE A 452 15.720 -3.792 4.169 1.00 18.99 ATOM 1167 CG1 ILE A 452 16.725 -1.788 5.282 1.00 18.33 ATOM 1168 CD1 ILE A 452 16.284 -0.707 4.306 1.00 23.25 ATOM 1169 C ILE A 452 17.725 -5.517 5.191 1.00 19.50 ATOM 1170 O ILE A 452 16.980 -6.340 5.737 1.00 17.60 ATOM 1171 N LEU A 453 18.555 -5.844 4.209 1.00 19.23 ATOM 1172 CA LEU A 453 18.589 -7.205 3.679 1.00 21.60 ATOM 1173 CB LEU A 453 19.624 -7.316 2.554 1.00 21 ATOM 1174 CG LEU A 453 19.835 -8.729 1.989 1.00 .
25.06 ATOM 1175 CD LEU A 453 18.550 -9.250 I .3641.00 25.27 ATOM 1176 CD2 LEU A 453 20.948 -8.694 0.953 1.00 24.73 ATOM 1177 C LEU A 453 18.906 -8.245 4.746 i 19.4 .00 I

ATOM 1178 O LEU A 453 18.198 -9.241 4.891 1.00 20.75 ATOM 1179 N LEU A 454 19.966 -7.997 5.499 1.00 2I.35 ATOM 1180 CA LEU A 454 20.410 -8.925 6.530 1.00 23.67 ATOM 1181 CB LEU A 454 2I.870 -8.625 6.878 1.00 20.69 ATOM 1182 CG LEU A 454 22.816 -8.584 5.673 1.00 24.92 ATOM 1183 CD LEU A 454 24.222 -8.268 6.132 1.00 24 =1~ATOM 1184 CD2 LEU A 454 22.785 -9.913 4.952 1.00 .
X2.8:1 ATOM 1185 C LEU A 454 19.572 -8.945 7.807 1.00 ?6.06 ATOM 1186 O LEU A 454 19.413 -9.997 8.438 1.00 27.44 ATOM 1187 N ASN .-~455 19.011 -7.795 8.167 1.00 ?5.01 WO 99/50658 . PCTNS99/06937 ATOM 1188 ASN -155 18.240 -7.681 9.400 1 26 ATOM 1189 ASN -155 18.439 -6.295 10.002. .
CB A 1.00 22 ATOM 1190 CG ASN -155 17.627 -6.109 11.2641.00 .

ATOM 1191 ODi ASN -i55 17.899 -6.751 1'?.2701.00 .

ATOM 1192 ND2 ASN -155 16.615 -5.246 11.2121.00 .

ATOM 1193 C ASN -15~ 16.739 -7.957 9.418 1.00 .

ATOM 1194 O ASN .155 16.230 -8.516 10.3801.00 .

ATOM I N SER A .156 16.027 -7.549 8.381 1.00 .
i95 28 ATOM 1196 CA SER A -156 14.578 -7.704 8.371 1 .

ATOM 1197 CB SER A .156 14.019 -7.213 7.033 . .
1.00 35 ATOM 1198 OG SER A -156 14.266 -5.818 6.897 1.00 .

ATOM 1199 C SER A 456 14.033 -9.086 8.711 1.00 .

ATOM 1200 O SER A -156 13.112 -9.202 9.523 1 .

ATOM I201 N GLY A 457 14.597 -10.1308.117 . .

ATOM 1202 CA GLY A -t57 14.115 -11.4648.413 . .
1.00 36 ATOM 1203 C GLY A :157 15.055 -12.2899.277 1.00 .

ATOM 1204 O GLY A .157 14.831 -13.4869.456 1 .

ATOM 1205 N VAL A :158 16.095 -11.6579.820 . .
1.00 44 ATOM 1206 CA VAL A 458 17.079 -12.35610.6471 .

ATOM 1207 CB VAL A =158 18.214 -11.39911.095. .
1.00 51 ATOM 1208 CGi VAL A 458 17.688 -10.39012.1041.00 .

ATOM 1209 CG2 VAL A 458 19.365 -12.19911.6921.00 .

ATOM 1210 C VAL A 458 16.513 -13.06011.8851 .

ATOM 1211 O VAL A 458 17.085 -14.04512.356. .

ATOM 1212 N TYR A 459 15.401 -12.56012.416. .
1.00 62 ATOM 1213 CA TYR A 459 14.793 -13.17713.5921.00 .

ATOM 1214 CB TYR A 459 14.293 -12.10014.5601.00 .

ATOM I215 CG TYR A 459 15.396 -11.19615.0691.00 .

ATOM 1216 CDi TYR A 459 15.127 -9.888 15.4621 .

ATOM 1217 CE TYR A 459 16.147 -9.045 15.898. .

.00 60 ATOM 1218 CD2 TYR A :159 16.716 -11.64415.1281.00 .

ATOM 1219 CE2 TYR A 459 17.741 -10.81215.5601.00 .

ATOM 1220 CZ TYR A 459 17.450 -9.514 15.9411.00 .

ATOM 1221 OH TYR A 459 18.467 -8.687 16.3511 .

ATOM 1222 C TYR A 459 13.649 -14.09713.187. .
1.00 71 ATOM 1223 O TYR A 459 13.380 -15.09913.8521.00 .

ATOM I N THR A 460 12.981 -13.75612.0901 .

ATOM 1225 CA THR A 460 11.881 -14.56711.589. .
1.00 77 ATOM 1226 CB THR A 460 11.246 -13.90010.3731 .

ATOM 1227 C THR A 460 12.436 -15.93811.212. .
1.00 80 ATOM 1228 O THR A 460 11.684 -16.86610.912I .
.00 80 ATOM 1229 N PHE A 461 13.762 -16.05111.2311.00 .

ATOM 1230 CA PHE A 161 14.440 -17.29910.9051.00 .

ATOM 1231 CB PHE A :161 15.920 -17.03410.6301 .

ATOM 1232 C PHE A :161 14.284 -18.28812.059. .
1.00 87 ATOM 1233 PHE A -161 14.493 -17.94013.22=11.00 .

ATOM 1234 LEU A -162 13.914 -19.520 I .
N 11.72:1 .00 89 ATOM 1235 LEU A .162 13.711 -20.568 1.00 .
CA 1'_'.718 91.34 ATOM 1236 CB LEU A 462 12.961 -? 1.74112.0871.00 91.23 ATOM 1237 C LEU A 462 15.016 -21.06013.3401.00 92.05 ATOM 1238 O LEU A 462 16.042 -21.16512.6641.00 91.91 ATOM 1239 N SER A 463 14.966 -21.35714.6351.00 92.53 ATOM 1240 CA SER A 463 16.131 -21.85515.3581.00 92.96 ATOM 1241 CB SER A 463 16.033 -21.48316.8331.00 91.67 ATOM 1242 C SER A 463 16.189 -23.37115.2001.00 93.39 ATOM 1243 O SER A 463 15.156 -24.03415.1021.00 93.44 ATOM 1244 N SER A 464 17.399 -23.91715.1671.00 93.82 ATOM 1245 CA SER A 464 17.577 -25.35515.0151.00 93.85 ATOM 1246 CB SER A 464 17.284 -?5.76913.5771.00 93.74 ATOM 1247 C SER A 464 18.997 -25.74315.3961.00 93.96 ATOM 1248 O SER A 464 19.815 -26.07414.5351.00 93.65 ATOM 1249 N THR A 465 19.279 -25.69916.6941.00 93.91 ATOM 1250 CA THR A 465 20.600 -26.03617.2121.00 93.79 ATOM 1251 CB THR A 465 20.952 -27.48316.8631.00 93.38 ATOM I C THR A 465 ? 1.640 -25.08516.6341.00 93.27 ATOM 1253 O THR A 465 21.302 -24.01716.1211.00 93.03 ATOM 1254 N LEU A 466 22.907 -25.47916.7231.00 93.26 ATOM 1255 CA LEU A 466 23.999 -24.66516.2071.00 92.34 ATOM 1256 CB LEU A 466 25.335 -25.33816.4981.00 91.59 ATOM 1257 C LEU A 466 23.829 -24.46114.7061.00 92.18 ATOM 1258 O LEU A 466 24.411 -23.54514.1251.00 92.67 ATOM 1259 N LYS A 467 23.028 -25.32314.0861.00 91.28 ATOM 1260 CA LYS A 467 22.772 -25.23812.6531.00 90.02 ATOM 1261 CB LYS A 467 21.740 -26.28712.2401.00 89.93 ATOM 1262 C LYS A 467 22.269 -23.84112.3081.00 88.35 ATOM 1263 O LYS A 467 23.032 -22.99011.8491.00 88.50 ATOM 1264 N SER A 468 20.981 -23.61012.5361.00 86.02 ATOM 1265 CA SER A 468 20.384 -22.31 12.2521.00 84.10 S

ATOM 1266 CB SER A 468 18.901 -22.33312.6201.00 84.08 ATOM 1267 OG SER A 468 18.229 -23.37811.9371.00 83.03 ATOM 1268 C SER A 468 21.109 -21.23013.0401.00 83.39 ATOM i O SER A 468 21.264 -20.1 12.5651.00 83.48 ATOM 1270 N LEU A 469 21.558 -21.57914.2421.00 82.04 ATOM 1271 CA LEU A 469 22.276 -20.64015.0981.00 80.28 ATOM 1272 CB LEU A 469 22.595 -21.29416.4361.00 79.81 ATOM 1273 C LEU A 469 23.564 -20.17414.4191.00 79.18 ATOM 1274 O LEU A 469 24.111 -19.12214.7561.00 78.61 ATOM 1275 N GLU A 470 24.044 -20.96913.4661.00 76.69 ATOM 1276 CA GLU A 470 25.256 -20.63812.7261.00 74.84 ATOM 1277 CB GLU A 470 25.803 -21.88012.0321.00 74.12 ATOM I C GLU A 470 24.920 -19.5651 i 1.00 73.77 278 .697 ATOM 1279 O GLU A 470 ?5.617 -18.55611.5811.00 72.94 :ISATOM 1280 N GLU A 471 ?3.842 -19.79?10.9531.00 72.08 ATOM 1281 CA GLU A 471 23.396 -18.8429.945 1.00 70.05 ATOM 1282 CB GLU A 471 ?2.461 -19.5268.944 i.00 71.52 ATOM 1283 CG GLU A 471 23.150 -19.9767.668 1.00 7?.90 7;

ATOM 1284 CD GLU A 471 24.512 -?0.5867.932 1.00 74.01 ATOM 1285 OE1 GLU A 471 25.469 -20.2587.198 1.00 74.22 ATOM 1286 OE2 GLU A 471 24.626 ? 1.3958.878 1.00 75.18 ATOM 1287 C GLU A 471 22.667 - l 10.630 1.00 67.33 7.692 ATOM 1288 O GLU ,A 471 21.685 -17.16510.107 1.00 67.77 ATOM 1289 N LYS A 472 23.152 -17.31911.811 1.00 62.63 ATOM 1290 CA LYS A 472 22.564 -16.22912.578 1.00 57.41 ATOM 1291 CB LYS A 472 21.697 -16.77713.713 1.00 58.74 ATOM 1292 CG LYS A 472 20.683 -15.77614.243 1.00 60.32 ATOM 1293 CD LYS A 472 19.271 -16.34?14.219 1.00 60.73 ATOM 1294 CE LYS A 472 18.485 -15.90915.449 1.00 61.78 ATOM 1295 NZ LYS A 472 19.352 -15.78816.658 1.00 60.09 ATOM 1296 C LYS A 472 23.662 -15.33913.150 1.00 53.42 ATOM 1297 O LYS A 472 23.631 -14.12012.978 1.00 50.87 ATOM 1298 N ASP A 473 24.628 -15.94913.830 1.00 47.52 ATOM 1299 CA ASP A 473 25.73? -15.19414.405 1.00 45.55 ATOM 1300 CB ASP A 473 26.613 -16.09415.269 1.00 50.48 ATOM 1301 CG ASP A 473 26.380 -15.88516.749 1.00 55.50 ATOM 1302 OD1 ASP A 473 25.272 -15.43617.118 1.00 58.06 ATOM 1303 OD2 ASP A 473 27.304 -16.17017.541 1.00 59.81 ATOM 1304 C ASP A 473 26.557 -14.61113.269 1.00 42.62 ATOM 1305 O ASP A 473 27.087 -13.50613.373 1.00 42.10 ATOM 1306 N HIS A 474 26.663 -15.36412.180 1.00 38.05 ATOM 1307 CA HIS A 474 27.416 -14.90411.026 1.00 37.25 ATOM 1308 CB HIS A 474 27.429 -15.9789.941 1.00 35.07 ATOM 1309 CG HIS A 474 28.036 -15.5238.653 1.00 37.36 ATOM 1310 CD2 HIS A 474 29.292 -15.1138.355 1.00 38.86 ATOM 1311 NDI HIS A 474 27.322 -15.4527.476 T.00 41.31 ATOM 1312 CE1 HIS A 474 28.110 -15.0206.509 1.00 40.86 ATOM 1313 NE2 HIS A 474 29.311 -14.8077.016 1.00 44.49 ATOM 1314 C HIS A 474 26.749 -13.64010.493 1.00 36.68 ATOM 1315 O HIS A 474 27.417 -12.67610.132 1.00 36.48 ATOM 1316 N ILE A 475 25.422 -13.65210.447 1.00 35.93 ATOM 1317 CA ILE A 475 24.683 -12.4999.963 1.00 36.21 ATOM 1318 CB ILE A 475 23.174 -12.79?9.868 i.00 36.31 ATOM 1319 CG2 ILE A 475 22.411 -11.5279.513 1.00 38.19 ATOM 1320 CGI ILE A 475 22.922 -13.8748.813 1.00 36.97 ATOM 1321 CDI ILE A 475 21.528 -14.4548.869 1.00 35.59 ATOM 1322 C ILE A 475 24.893 -11.32210.907 1.00 35.34 ATOM 1323 O ILE A 475 25.092 -10.18910.471 1.00 33.20 ATOM 1324 N HIS A 476 24.857 -11.59612.206 1.00 35.95 ATOM 1325 CA HIS A 476 25.031 -10.54013.193 1.00 35.06 ATOM 1326 CB HIS A 476 24.681 -11.06214.585 1.00 37.30 ATOM 1327 CG HIS :~ 476 23.210 -11.06814.860 1.00 43.06 ATOM 1328 CD2 HIS A 476 ''2.3?9-10.05115.017 1.00 43.93 ATOM 1329 ND1 HiS A 476 22.476 -1?.2301-1.9681.00 45.60 ATOM I330 CE1 HiS :1 476 21.207 -11.92815.177 1.00 -17.56 ATOM I331 NE? HIS :~ 476 21.091 -10.61315.211 1.00 46.21 ATOM 1332 C HIS A 476 26.438 -9.966 13.1701.00 35.40 ATOM 1333 O HIS A 476 26.634 -8.774 13.41 1.00 35.45 S

ATOM 1334 N ARG A 477 27.420 -10.80512.8621.00 34.07 ATOM 1335 CA ARG A 477 28.796 -10.33112.7951.00 34.18 ATOM 1336 CB ARG A 477 29.757 -11.50612.6051.00 41.04 ATOM 1337 CG ARG A 477 29.800 -12.45913.7881.00 47.61 ATOM 1338 CD ARG A 477 30.782 -13.59913.5571.00 55.67 ATOM 1339 NE ARG A 477 31.780 -13.67514.6221.00 60.17 ATOM 1340 CZ ARG A 477 32.780 -12.81114.7701.00 61.98 ATOM 1341 NH1 ARG A 477 32.918 -11.80313.9181.00 64.29 ATOM 1342 NH2 ARG A 477 33.643 -12.95515.7661.00 62.79 ATOM 1343 C ARG A 477 28.906 -9.361 11.6211.00 30.77 ATOM 1344 O ARG A 477 29.462 -8.268 11.7531.00 33.59 ATOM 1345 N VAL A 478 28.369 -9.766 10.4751.00 27.65 1 ATOM 1346 CA VAL A 478 28.389 -8.930 9.280 1.00 27.07 S

ATOM 1347 CB VAL A 478 27.658 -9.605 8.100 1.00 28.00 ATOM 1348 CG1 VAL A 478 27.672 -8.678 6.890 1.00 25.83 ATOM 1349 CG2 VAL A 478 28.319 -10.9337.761 1.00 31.66 ATOM 1350 C VAL A 478 27.689 -7.610 9.584 1.00 26.92 ATOM 1351 O VAL A 478 28.216 -6.536 9.294 1.00 26.97 ATOM 1352 N LEU A 479 26.499 -7.702 10.1711.00 25.74 ATOM 1353 CA LEU A 479 25.727 -6.516 10.5301.00 27.97 ATOM 1354 CB LEU A 479 24.474 -6.912 11.3241.00 25.55 ATOM 1355 CG LEU A 479 23.211 -7.229 10.5171.00 29.01 ATOM 1356 CDI LEU A 479 22.056 -7.503 11.4811.00 27.05 ATOM 1357 CD2 LEU A 479 22.864 -6.063 9.584 1.00 24.92 ATOM 1358 C LEU A 479 26.592 -5.582 11.3691.00 25.39 ATOM 1359 O LEU A 479 26.595 -4.370 11.1581.00 27.39 ATOM 1360 N ASP A 480 27.324 -6.158 12.3201.00 26.04 ATOM 1361 CA ASP A 480 28.206 -5.388 13.1931.00 27.32 ATOM 1362 CB ASP A 480 28.878 -6.305 14.2221.00 26.67 ATOM 1363 CG ASP A 480 27.990 -6.602 15.4171.00 31.02 ATOM 1364 OD1 ASP A 480 28.355 -7.505 16.1981.00 31.50 ATOM 1365 OD2 ASP A 480 26.935 -5.944 15.5801.00 32.21 ATOM 1366 C ASP A 480 29.283 -4.699 12.3611.00 25.59 ATOM 1367 O ASP A 480 29.672 -3.562 12.6361.00 27.15 ATOM 1368 N LYS A 481 29.767 -5.394 11.3401.00 25.17 ATOM 1369 CA LYS A 481 30.794 -4.830 10.4771.00 24.93 ATOM 1370 CB LYS A 481 31.30b -5.890 9.512 1.00 28.42 ATOM 1371 CG LYS A 481 32.158 -6.953 10.1881.00 35.59 ATOM 1372 CD LYS A 481 32.894 -7.799 9.157 1.00 41.21 ATOM 1373 CE LYS A 481 33.883 -6.963 8.350 1.00 41.48 ATOM 1374 NZ LYS A 481 34.954 -6.388 9.21 1.00 43.22 ~

ATOM 1375 C LYS A 481 30.260 -3.635 9.696 1.00 26.12 ATOM 1376 O LYS A 481 30.979 -2.657 9.463 1.00 23.73 ATOM1 1377 N ILE A 482 28.996 -3.705 9.291 1.00 25.44 ATOM 1378 CA ILE A 482 28.421 -2.598 8.545 1.00 27.69 ATOM 1379 CB ILE A 482 27.066 -2.983 7.915 1.00 27.59 ATOM 1380 CG2 ILE A 482 26.470 -1.788 7.183 1.00 X5.97 ATOM 1381 CG ILE A 482 27.274 -4.131 6.922 1.00 23.80 I

ATOM 1382 CD1 ILE A 482 26.000 -4.838 6.533 1.00 X1.30 ATOM 1383 C ILE A 482 28.253 -1.408 9.481 1.00 27.33 S ATOM 1384 O ILE A 482 28.312 -0.256 9.045 1.00 28.55 ATOM 1385 N THR A 483 28.046 -1.690 10.7681.00 25.03 ATOM 1386 CA THR A 483 27.905 -0.632 11.7601.00 23.62 ATOM 1387 CB THR A 483 27.535 -1.192 13.1541.00 22.18 ATOM 1388 OG1 THR A 483 26.181 -1.658 13.1331.00 25.39 ATOM 1389 CG2 THR A 483 27.673 -0.111 14.2261.00 25.84 ATOM 1390 C THR A 483 29.257 0.074 11.8581.00 23.04 ATOM 1391 O THR A 483 29.331 1.306 11.84b1.00 23.55 ATOM 1392 N ASP A 484 30.324 -0.714 11.9601.00 22.24 ATOM 1393 CA ASP A 484 31.674 -0.152 12.0391.00 25.48 ATOM 1394 CB ASP A 484 32.718 -1.273 12.1071.00 26.88 ATOM 1395 CG ASP A 484 32.629 -2.083 13.3941.00 32.52 ATOM 1396 OD1 ASP A 484 32.002 -1.608 14.3661.00 33.68 ATOM 1397 OD2 ASP A 484 33.185 -3.198 13.4341.00 34.63 ATOM 1398 C ASP A 484 31.930 0.715 10.8.071.00 25.16 ATOM 1399 O ASP A 484 32.481 1.812 10.9051.00 26.05 ATOM 1400 N THR A 485 31.505 0.226 9.645 1.00 28.96 ATOM 1401 CA THR A 485 31.689 0.960 8.394 1.00 26.63 ATOM 1402 CB THR A 485 31.124 0.166 7.197 1.00 26.12 ATOM 1403 OGI THR A 485 31.753 -1.123 7.132 1.00 24.30 ATOM 1404 CG2 THR A 485 31.381 0.907 5.898 1.00 23.31 ATOM 1405 C THR A 485 30.994 2.318 8.468 1.00 28.90 ~

ATOM 1406 O THR A 485 31.583 3.354 8.137 1.00 27.26 ATOM 1407 N LEU A 486 29.743 2.310 8.915 1.00 24.76 ATOM 1408 CA LEU A 486 28.973 3.537 9.027 1.00 26.19 ATOM 1409 CB LEU A 486 27.567 3.233 9.547 1.00 27.27 ATOM 1410 CG LEU A 486 26.508 2.921 8.486 1.00 23.50 ATOM 1411 CD1 LEU A 486 25.210 2.550 9.183 1.00 22.03 ATOM 1412 CD2 LEU A 486 26.309 4.128 7.577 1.00 21.35 ATOM 1413 C LEU A 486 29.662 4.519 9.960 1.00 27.36 ATOM 1414 O LEU A 486 29.745 5.710 9.669 1.00 25.87 ATOM 1415 N ILE A 487 30.151 4.015 11.0881.00 27.88 ATOM 1416 CA ILE A 487 30.843 4.857 12.0551.00 28.40 ATOM 1417 CB ILE A 487 31.203 4.054 13.3321.00 26.74 ATOM 1418 CG2 ILE A 487 32.255 4.803 14.1541.00 27.54 ATOM 1419 CG1 ILE A 487 29.937 3.813 14.1631.00 25.93 ATOM 1420 CDI ILE A 487 29.237 5.088 14.6241.00 23.42 ATOM 1421 C ILE A 487 32.125 5.393 11.4121.00 28.89 ATOM 1422 O ILE A 487 32.497 6.554 11.6021.00 29.85 ATOM 1423 N HIS A 488 32.791 4.533 10.6491.00 29.71 ATOM 1424 CA HIS A 488 34.031 4.898 9.967 1.00 34.12 ATOM 1425 CB HIS A 488 34.58 3.691 9.207 1.00 36.61 ATOM 1426 CG HIS A 488 35.799 3.997 8.385 1.00 42.74 ATOM 1427 CD2 HIS A 488 35.970 4.089 7.045 1.00 43.12 ATOM 1428 A 188 37.034 4.239 1.00 43 ND1 8.946 13 HIS

ATOM 1429 HIS A 488 37.913 4.466 1.00 .
CE1 7.987 43 ATOM 1430 NE2 HIS A 488 37.293 4.381 6.825 1.00 .

ATOM 1431 C HIS A 488 33.799 6.OS 8.998 I .

S ATOM 1432 O HIS A 488 34.577 7.004 8.955 . .
1.00 31 ATOM 1433 N LEU A 489 32.721 S.9S8 8.223 1.00 .

ATOM 1434 CA LEU A 489 32.384 6.992 7.258 1.00 .

ATOM 1435 CB LEU A 489 31.145 6.S87 6.464 1.00 .

ATOM 1436 CG LEU A 489 31.310 S.3S3 S.S74 1 .

ATOM 1437 CDI LEU A 489 29.945 4.856 S.12S . .
1.00 33 ATOM 1438 CD2 LEU A 489 32.183 5.701 -1.3781.00 .

ATOM 1439 C LEU A 489 32.124 8.320 7.954 1.00 .

ATOM 1440 O LEU A 489 32.587 9.365 7.507 1.00 .

ATOM 1441 N MET A 490 31.387 8.274 9.058 1 .

1 ATOM 1442 CA MET A 490 31.056 9.482 9.801 . .
S 1.00 30 ATOM 1443 CB MET A 490 30.000 9.161 10.8621.00 .

ATOM 1444 CG MET A 490 28.607 8.940 10.2891.00 .

ATOM I44S SD MET A 490 27.457 8.247 11.4961.00 .

ATOM 1446 CE MET A 490 26.321 7.408 10.4181 .

ATOM 1447 C MET A 490 32.287 10.108 10.455. .
1.00 32 ATOM 1448 O MET A 490 32.412 11.330 10.5171.00 .

ATOM 1449 N ALA A 491 33.184 9.262 10.9491.00 .

ATOM 1450 CA ALA A 491 34.407 9.730 I1.S8S1.00 .

ATOM 1451 CB ALA A 491 35.168 8.554 12.1851 .

2S ATOM 1452 C ALA A 491 35.275 10.445 10.550. .
1.00 42 ATOM 1453 O ALA A 491 35.865 11.487 10.8381 .

ATOM 1454 N LYS A 492 35.339 9.876 9.347 . .
1.00 44 ATOM 1455 CA LYS A 492 36.122 10.440 8.248 1.00 .

ATOM 1456 CB LYS A 492 36.136 9.477 7.052 1 .

ATOM 1457 ~ LYS A 492 37.490 8.840 6.744 . .
CG 1.00 47 ATOM 1458 CD LYS A 492 37.390 7.830 ~.S9S 1.00 .

ATOM 1459 CE LYS A 492 38.631 6.937 ~.S 1.00 .

ATOM 1460 NZ LYS A 492 38.357 S.S77 4.948 1 .

ATOM 1461 C LYS A 492 35.534 11.780 7.809 . .

3S ATOM 1462 O LYS A 492 36.227 12.604 7.21 . .

ATOM 1463 N ALA A 493 34.254 11.992 8.100 . .
1.00 43 ATOM 1464 CA ALA A 493 33.590 13.238 7.728 1.00 .

ATOM 1465 CB ALA A 493 32.097 13.001 7.528 1.00 .

ATOM 1466 C ALA A 493 33.816 14.305 8.796 1 .

ATOM 1467 O ALA A 493 33.277 15.410 8.707 . .
1.00 40 ATOM 1468 N GLY A 494 34.604 13.960 9.811 1 .

ATOM 1469 CA GLY A 494 34.903 14.904 10.873. .
1.00 41 ATOM 1470 C GLY A 494 33.857 15.060 11.9651 .

ATOM 1471 O GLY A 494 33.916 16.011 1?.747. .

4S ATOM 1472 LEU A 495 32.905 14.138 12.04;. .
N 1.00 39 ATOM 1473 LEU A 495 31.876 14.248 13.0681 .

ATOM 1474 LEU A 495 ;0.713 13.304 1 x.769. .

.00 20 ATOM 1475 LEU A 495 29.540 13.901 11.9881.00 .
CG 40.73 ATOM 1476 CD1 LEU A 495 29.976 14.17010.553 1.00 37.80 ATOM 1477 CD2 LEU A 495 28.349 12.94312.026 1.00 40.94 ATOM 1478 C LEU A 495 32.461 13.92314.431 1.00 36.01 ATOM 1479 O LEU A 495 33.347 13.07414.544 1.00 34.85 ATOM 1480 N THR A 496 31.979 14.60415.459 1.00 37.52 ATOM 1481 CA THR A 496 32.462 14.35016.812 1.00 35.45 ATOM 1482 CB THR A 496 31.925 15.37517.829 1.00 37.55 ATOM 1483 OG THR A 496 30.498 15.26317.908 1.00 32.93 ATOM 1484 CG2 THR A 496 32.315 16.79717.434 1.00 36.16 ATOM 1485 C THR A 496 31.933 12.98717.210 I.00 35.67 ATOM 1486 O THR A 496 31.081 12.42716.521 1.00 34.34 ATOM 1487 N LEU A 497 32.429 12.45218.319 1.00 34.88 ATOM 1488 CA LEU A 497 31.965 11.15118.786 1.00 35.67 ATOM 1489 CB LEU A 497 32.689 10.76020.074 1.00 41.10 ATOM 1490 CG LEU A 497 33.714 9.640 19.896 1.00 45.27 ATOM 1491 CD1 LEU A 497 34.755 9.692 21.008 1.00 45.09 ATOM 1492 CD2 LEU A 497 32.988 8.305 19.884 1.00 47.77 ATOM 1493 C LEU A 497 30.455 l1.i9819.026 1.00 33.72 ATOM 1494 O LEU A 497 29.712 10.35018.534 1.00 33.20 ATOM 1495 N GLN A 498 30.006 12.20219.773 1.00 30.82 ATOM 1496 CA GLN A 498 28.586 12.34820.062 1.00 31.47 ATOM 1497 CB GLN A 498 28.344 13.56620.951 1.00 30.51 ATOM 1498 CG GLN A 498 26.894 13.79621.341 1.00 34.38 ATOM 1499 CD GLN A 498 26.712 15.13022.015 1.00 38.60 ATOM 1500 OE GLN A 498 27.363 16.1 21.686 I 42.92 l I .00 ATOM 1501 NE2 GLN A 498 25.809 15.17623.008 1.00 40.02 ATOM 1502 C GLN A 498 27.776 12.47618.773 1.00 30.47 ATOM 1503 O GLN A 498 26.682 11.92718.665 1.00 30.85 ATOM 1504 N GLN A 499 28.311 13.19617.793 1.00 29.52 ATOM 1 CA GLN A 499 27.603 13.36216.524 1.00 30.24 SOS

ATOM 1506 CB GLN A 499 28.292 14.42015.661 1.00 30.20 ATOM 1507 CG GLN A 499 28.135 15.84016.191 1.00 31.60 ATOM 1508 CD GLN A 499 28.930 16.84915.389 1.00 31.61 ATOM 1509 OE GLN A 499 29.956 16.51814.795 1.00 30.66 ATOM 1510 NE2 GLN A 499 28.457 18.08915.364 1.00 34.17 ATOM 1511 C GLN A 499 27.529 12.04715.753 1.00 29.40 ATOM 1512 O GLN A 499 26.567 11.79315.032 1.00 30.04 ATOM 1513 N GLN A 500 28.550 11.21415.903 1.00 25.67 ATOM 1514 CA GLN A 500 28.577 9.937 15.216 1.00 29.30 ATOM 1515 CB GLN A 500 29.933 9.276 15.406 1.00 31.52 ATOM 1516 CG GLN A 500 31.012 9.839 14.508 1.00 33.05 ATOM 1517 CD GLN A 500 32.371 9.370 14.930 1.00 34.84 ATOM 1518 OE1 GLN A 500 32.612 8.194 15.141 1.00 36.47 ATOM 1519 NE2 GLN A 500 33.301 10.32415.082 1.00 38.25 ATOM 1520 C GLN A 500 27.459 9.017 15.711 1.00 ?7.98 ATOM 1521 O GLN A 500 26.700 8.469 14.908 1.00 X4.84 ATOM 1522 N HIS A 501 27.357 8.864 17.029 1.00 X6.20 ATOM I523 CA HIS A 501 26.327 8.021 17.631 1.00 X7.63 ATOM 1524 CB HIS A 501 26.535 7.919 19.145 1.00 27.97 ATOM 1525 CG HIS A 501 27.892 7.420 19.535 1.00 34.27 ATOM 1526 CD2 HIS A 501 28.726 6.540 18.931 1.00 36.10 ATOM 1527 ND1 HIS A 501 28.541 7.844 20.676 1.00 31.81 ATOM 1528 CE1 HIS A 501 29.716 7.244 20.758 1.00 34.89 ATOM 1529 NE2 HIS A 501 29.854 6.448 19.712 1.00 37.46 ATOM 1530 C HiS A 501 24.935 8.572 17.348 1.00 24.93 ATOM 1531 O HIS A 501 23.998 7.81 17.107 1.00 26.73 S

ATOM 1532 N GLN A 502 24.796 9.892 17.379 1.00 22.79 ATOM 1533 CA GLN A 502 23.504 10.498 17.119 1.00 26.14 ATOM 1534 CB GLN A 502 23.554 12.006 17.371 1.00 22.36 ATOM 1535 CG GLN A 502 23.460 12.378 18.848 1.00 26.19 ATOM 1536 CD GLN A 502 23.589 13.875 19.089 1.00 28.67 ATOM 1537 OE1 GLN A 502 23.632 14.663 18.149 I.00 28.40 ATOM 1538 NE2 GLN A 502 23.65 14.268 20.355 I 24.72 i .00 ATOM 1539 C GLN A 502 23.056 10.221 15.685 1.00 26.19 ATOM 1540 O GLN A 502 21.913 9.822 15.453 1.00 24.09 ATOM 1541 N ARG A 503 23.955 10.429 14.727 1.00 24.88 ATOM 1542 CA ARG A 503 23.630 10.196 13.326 1.00 25.25 ATOM 1543 CB ARG A 503 24.772 10.668 12.418 1.00 27.63 ATOM 1544 CG ARG A 503 24.432 10.563 10.932 1.00 28.75 ATOM 1545 CD ARG A 503 25.479 11.222 10.056 1.00 27.72 ATOM 1546 NE ARG A 503 25.072 11.214 8.654 1.00 29.35 ATOM 1547 CZ ARG A 503 24.279 12.126 8.105 1.00 25.84 ATOM 1548 NHi ARG A 503 23.804 13.120 8.840 1.00 27.35 ATOM 1549 NH2 ARG A 503 23.962 12.044 6.820 1.00 30.63 ATOM 1550 C ARG A 503 23.347 8.716 13.065 1.00 24.53 ATOM 1551 O ARG A 503 22.425 8.375 12.321 1.00 25.90 ATOM 1552 N LEU A 504 24.143 7.841 13.672 1.00 23.00 ATOM 1553 CA LEU A 504 23.953 6.406 13.496 1.00 22.60 ATOM 1554 CB LEU A 504 24.971 5.621 14.323 1.00 25.43 ATOM 1555 CG LEU A 504 24.781 4.100 14.344 1.00 25.23 ATOM 1556 CD LEU A 504 25.166 3.505 12.991 1.00 28.52 ATOM 1557 CD2 LEU A 504 25.627 3.495 15.444 1.00 22.14 ATOM 1558 C LEU A 504 22.541 6.030 13.934 1.00 22.84 ATOM 1559 O LEU A 504 21.846 5.288 13.245 1.00 21.51 ATOM 1560 N ALA A 505 22.120 6.547 15.083 1.00 20.16 ATOM 1561 CA ALA A 505 20.784 6.262 15.585 1.00 21.08 ATOM 1562 CB ALA A 505 20.605 6.868 16.980 1.00 23.57 ATOM 1563 C ALA A 505 19.738 6.832 14.628 1.00 20.20 ATOM 1564 O ALA A 505 18.754 6.164 14.293 1.00 17.31 ATOM 1565 N GLN A 506 19.954 8.066 14.184 1.00 22.11 ATOM 1566 CA GLN A 506 19.013 8.711 13.277 1.00 21.70 ATOM 1567 CB GLN A 506 19.502 10.111 12.903 1.00 22.26 ATOM 1568 CG GLN A 506 19.240 11.158 13.975 1.00 25.84 ATOM 1569 CD GLN A 506 20.187 12.333 13.857 1.00 32.88 ATOM 1570 OEI GLN A 506 20.704 12.614 12.777 1.00 31.23 ATOM 1571 NE2 GLN A 506 20.423 13.025 1=1.9681.00 32.97 ATOM 1572 C GLN A 506 18.813 7.881 12.016 1.00 ?3.57 ATOM 1573 O GLN A 506 17.684 7.715 11.550 1.00 21.83 ATOM 1574 N LEU A 507 19.905 7.354 11.474 1.00 19.98 ATOM 1575 CA LEU A 507 19.827 6.537 10.263 1.00 X2.03 ATOM 1576 CB LEU A 507 21.231 6.244 9.725 I.00 X3.02 ATOM 1577 CG LEU A 507 22.026 7.457 9.225 1.00 X5.80 ATOM IS78 CD1 LEU A 507 23.371 6.994 8.713 1.00 27.67 ATOM 1579 CD2 LEU A 507 21.264 8.176 8.130 1.00 ?5.62 ATOM 1580 C LEU A 507 19.090 5.219 10.496 1.00 22.35 ATOM 1581 O LEU A 507 18.242 4.825 9.695 1.00 19.33 ATOM 1582 N LEU A 508 19.402 4.539 11.592 1.00 21.29 ATOM 1583 CA LEU A 508 18.755 3.260 11.881 1.00 20.72 ATOM 1584 CB LEU A 508 19.501 2.535 13.001 1.00 22.29 ATOM 1585 CG LEU A 508 20.977 2.311 12.678 1.00 24 ATOM 1586 CD1 LEU A 508 21.642 1.551 13.814 1.00 .
21.37 ATOM 1587 CD2 LEU A 508 21.095 1.542 11.367 1.00 27.88 ATOM 1588 C LEU A 508 17.279 3.396 12.239 1.00 19.14 ATOM 1589 O LEU A 508 16.498 2.478 12.003 1.00 17.80 ATOM 1590 N LEU A 509 16.895 4.530 12.815 1.00 19 ATOM 1591 CA LEU A 509 15.495 4.747 13.173 1.00 .
20.14 ATOM 1592 CB LEU A 509 15.347 6.030 13.999 1.00 20.28 ATOM I CG LEU A 509 15.710 5.858 i 5.4791.00 21.35 ATOM 1594 CDi LEU A 509 15.354 7.106 16.263 1.00 19.29 ATOM 1595 CD2 LEU A 509 14.989 4.656 16.038 1.00 20 ATOM 1596 C LEU A 509 14.681 4.841 11.885 1.00 .
21.69 ATOM 1597 O LEU A 509 13.493 4.514 11.854 i.00 22.40 ATOM 1598 N ILE A 510 15.343 5.270 10.815 1.00 20.22 ATOM 1599 CA ILE A 510 14.710 5.397 9.508 1.00 20.40 ATOM 1600 CB ILE A 510 15.720 5.946 8.464 1.00 28.34 ATOM 1601 CG2 ILE A 510 15.208 5.710 7.056 1.00 32.54 ATOM 1602 CG ILE A S I 15.965 7.438 8.696 I 28.23 1 0 .00 ATOM 1603 CDI ILE A 510 14.789 8.189 9.288 1.00 33.16 ATOM 1604 C ILE A 510 14.210 4.025 9.049 1.00 ?3.21 ATOM 1605 O ILE A 510 13.120 3.906 8.474 1.00 21 ATOM 1606 N LEU A 511 14.998 2.989 9.323 1.00 .
18.38 ATOM 1607 CA LEU A 511 14.633 1.634 8.917 1.00 20.10 ATOM 1608 CB LEU A S I 15.754 0.656 9.267 1.00 21.69 ATOM 1609 CG LEU A 511 17.128 1.022 8.692 1.00 26.03 ATOM 1610 CD LEU A 511 18.024 -0.2068.724 1.00 22 ATOM 1611 CD2 LEU A 511 16.996 1.544 7.267 1.00 .
26.00 ATOM 1612 C LEU A 511 13.326 1.181 9.543 1.00 18.51 ATOM 1613 O LEU A S 11 12.663 0.283 9.025 1.00 I
7.40 ATOM 1614 N SER A 512 12.963 1.799 10.664 1.00 18.68 ATOM 161 CA SER A 5 I 11.718 1.471 11.331 I 18 S 2 .00 67 ATOM 1616 CB SER A 512 11.661 2.117 12.720 1.00 .
18.58 ATOM 1617 OG SER A 512 10.315 2.229 13.165 1.00 X7.92 ATOM 1618 C SER A 512 10.572 1.994 10.464 1.00 18.43 ATOM 1619 O SER A 512 9.584 1.296 10.236 1.00 13.91 ATOM 1620 N HIS A S i 10.713 3.228 9.982 1.00 18.95 ATOM 1621 CA HIS A S I 9.698 3.831 9.124 I 20.82 3 .00 ATOM 1622 CB HIS A S 13 10.013 5.31 8.894 1.00 24.36 S

ATOM 1623 CG HIS A S 13 9.923 6.146 10.136 1.00 32.13 S ATOM 1624 CD2 HIS A 513 8.863 6.744 10.734 1.00 35.29 ATOM 1625 ND1 HIS A 513 11.010 6.391 10.949 1.00 35.00 ATOM 1626 CE HIS A S 13 I 0.6247.101 11.995 1.00 34.67 ATOM 1627 NE2 HIS A S 13 9.326 7.328 1 I I 35.82 .889 .00 ATOM 1628 C HIS A S I 9.650 3.079 7.790 1.00 19.08 ATOM 1629 O HIS A 513 8.575 ?.863 7.220 1.00 21.20 ATOM 1630 N ILE A S 14 10.809 2.662 7.297 1.00 15.58 ATOM 1631 CA ILE A 514 10.849 1.921 6.038 1.00 16.48 ATOM 1632 CB ILE A S 14 12.312 1.678 S.S76 1.00 20.09 ATOM 1633 CG2 ILE A 514 12.349 0.602 4.499 1.00 19.55 1 ATOM 1634 CG ILE A S 14 12.891 2.986 S.OI I 22.62 S 1 9 .00 ATOM 1635 CD ILE A S 14 14.393 2.992 4.874 1.00 27.34 ATOM 1636 C ILE A 514 10.112 O.S90 6.210 1.00 16.40 ATOM 1637 O ILE A S 14 9.364 0.164 5.328 1.00 17.91 ATOM 1638 N ARG A S 1 10.301 -0.071 7.347 1.00 18.20 S

ATOM 1639 CA ARG A S 1 9.585 -1.327 7.564 1.00 1 S B.OS

ATOM 1640 CB ARG A 515 9.984 -1.980 8.889 1.00 18.36 ATOM 1641 CG ARG A 51 S 9.173 -3.237 9.213 1.00 17.84 ATOM 1642 CD ARG A 51 S 9.823 -4.470 8.606 1.00 17.94 ATOM 1643 NE ARG A 515 11.038 -4.813 9.334 1.00 26.96 2S ATOM 1644 CZ ARG A 51 S 11.406 -6.OS 9.641 1.00 25.13 I

ATOM 1645 NH ARG A S 1 10.654 -7.080 9.28 1.00 23.49 i S I

ATOM 1646 NH2 ARG A 515 I 2.S -6.254 10.340 I 32.16 i l .00 ATOM 1647 C ARG A S 1 8.089 -1.020 7.594 1.00 I
S 8.29 ATOM 1648 O ARG A S 1 7.275 -1.759 7.038 1.00 16.22 S

ATOM 1649 N HIS A S 16 7.726 0.085 8.237 1.00 19.33 ATOM 1650 CA HIS A S 16 6.317 0.441 8.330 1.00 17.78 ATOM 165 CB HIS A S 16 6.126 1.702 9.166 1.00 16.84 I

ATOM 1652 CG HIS A 516 4.692 2.101 9.312 1.00 18.16 ATOM 1653 CD2 HIS A 516 3.967 3.061 8.691 1.00 21.17 3 ATOM 1654 ND HIS A S 16 3.830 I .469 10. I 20.70 S I I 80 .00 ATOM 1655 CEI HIS A 516 2.633 2.022 10.089 1.00 21.52 ATOM 1656 NE2 HIS A 516 2.689 2.992 9.191 1.00 20.16 ATOM 1657 C HIS A S 16 5.708 0.659 6.954 1.00 16.63 ATOM 1658 O HIS A 516 4.598 0.216 6.689 1.00 18.58 ATOM 1659 N MET A 517 6.438 1.334 6.073 1.00 15.29 ATOM 1660 CA MET A 517 5.925 1.589 4.730 1.00 16.58 ATOM 1661 CB MET A S 17 6.837 2.576 4.002 1.00 18.66 ATOM 1662 CG MET A 517 6.805 3.978 4.631 1.00 16.88 ATOM 1663 SD MET A S 17 7.670 5.243 3.701 1.00 24.08 4S ATOM 1664 CE MET A S 17 9.390 4.777 3.962 1.00 14.30 ATOM 1665 C MET A S 17 5.773 0.289 3.940 1.00 I
7.86 ATOM 1666 O MET A S I 4.791 0.1 3.224 1.00 18.25 ATOM I 667 N SER A S 18 6.741 -0.610 4.086 1.00 17.43 ATOM 1668 CA SER A 518 6.697 -1.896 3.403 1.00 18.40 ATOM 1669 CB SER A 518 7.974 -2.695 3.680 1.00 16.77 ATOM 1670 OG SER A 518 7.834 -4.030 3.227 1.00 24.23 ATOM 1671 C SER A 518 5.476 -2.695 3.854 1.00 17.91 ATOM 1672 O SER A 518 4.788 -3.295 3.030 1.00 18.97 ATOM I N ASN A ~ 19 5.204 -2.697 5.159 1.00 21.82 ATOM 1674 CA ASN A 519 4.047 -3.418 5.696 1.00 21.99 ATOM 1675 CB ASN A 519 3.957 -3.257 7.216 1.00 23.24 ATOM 1676 CG ASN A 519 5.046 -4.011 7.957 1.00 31.14 ATOM 1677 OD ASN A 5 I 5.585 -4.999 7.461 1.00 32.50 ATOM 1678 ND2 ASN A 519 5.368 -3.545 9.163 1.00 29.10 ATOM 1679 C ASN A 5 i 2.761 -2.871 5.079 1.00 23.76 ATOM 1680 O ASN A 519 1.902 -3.632 4.631 1.00 24.48 ATOM 1681 N LYS A 520 2.627 -1.548 5.078 1.00 20.58 ATOM 1682 CA LYS A 520 1.449 -0.900 4.512 1.00 25.49 ATOM 1683 CB LYS A 520 1.484 0.607 4.786 1.00 24.73 ATOM I CG LYS A 520 1.512 0.996 6.264 1.00 32.3 684 i ATOM 1685 CD LYS A 520 0.656 0.080 7.133 1.00 37.11 ATOM 1686 CE LYS A 520 -0.787 0.547 7.181 1.00 41.56 ATOM 1687 NZ LYS A 520 -1.560 -0.134 8.261 1.00 42.66 ATOM 1688 C LYS A 520 1.380 -1.144 3.005 1.00 25.40 ATOM 1689 O LYS A 520 0.316 -1.436 2.467 1.00 26.44 ATOM 1690 N GLY A 521 2.520 -1.021 2.332 1.00 22.$8 ATOM 1691 CA GLY A 521 2.561 -1.236 0.897 1.00 21.53 ATOM 1692 C GLY A 521 2.177 -2.655 0.536 1.00 24.79 ATOM 1693 O GLY A 521 1.426 -2.878 -0.4131.00 25.71 ATOM 1694 N MET A 522 2.696 -3.619 1.290 1.00 22.75 ATOM 1695 CA MET A 522 2.393 -5.027 1.058 1.00 23.40 ATOM 1696 CB MET A 522 3.170 -5.898 2.042 1.00 25.74 ATOM 1697 CG MET A 522 3.396 -7.308 1.559 1.00 31.06 ATOM 1698 SD MET A 522 4.572 -7.352 0.202 1.00 34.06 ATOM 1699 CE MET A 522 6.125 -7.229 1.113 1.00 29.28 ATOM 1700 C MET A 522 0.893 -5.281 1.218 1.00 26.49 ATOM 1701 O MET A 522 0.268 -5.920 0.361 1.00 25.47 ATOM 1702 N GLU A 523 0.321 -4.790 2.318 1.00 24.95 ATOM 1703 CA GLU A 523 -1.110 -4.954 ?.566 1.00 27.15 ATOM 1704 CB GLU A 523 -1.555 -4.206 3.835 I.00 31.08 ATOM 1705 CG GLU A 523 -0.830 -4.564 5.124 I.00 38.93 ATOM 1706 CD GLU A 523 -1.153 -3.585 6.258 1.00 46.90 ATOM 1707 OE1 GLU A 523 -2.225 -2.938 6.200 1.00 47.40 ATOM 1708 OE2 GLU A 523 -0.337 -3.460 7.202 1.00 47.39 ATOM 1709 C GLU A 523 -1.872 -4.368 1.381 1.00 26.10 ATOM 1710 O GLU A 523 -2.817 -4.964 0.882 1.00 24.25 ATOM 1711 N HIS A 524 -1.449 -3.182 0.940 1.00 24.74 ATOM 1712 CA HIS A 524 -2.093 -2.505 -0.1731.00 26.17 ATOM 1713 CB HIS A 524 -1.481 -1.125 -0.3791.00 24.64 ATOM 1714 CG HIS A 524 -2.233 -0.278 -1.3551.00 30.59 ATOM 1715 CD2 HIS A 524 -3.227 0.624 -1.1721.00 32.15 ATOM I716 NDI HIS A 524 -2.008 -0.332 -2.7131.00 27.46 ATOM 1717 CEI HIS A 524 -2.829 0.502 -3.3261.00 34.58 ATOM 1718 NE2 HIS A 524 -3.580 1.094 -2.4131.00 30.50 ATOM 1719 C HIS A 524 -1.996 -3.294 -1.4741.00 28.06 ATOM 1720 O HIS A 524 -2.976 -3.419 -2.2171.00 ?9.81 ATOM 1721 N LEU A 525 -0.811 -3.824 -1.7461.00 27.07 ATOM 1722 CA LEU A 525 -0.594 -4.601 -2.9551.00 29.30 ATOM 1723 CB LEU A 525 0.865 -5.039 -3.0511.00 ?6.39 ATOM 1724 CG LEU A 525 1.307 -5.765 -4.3211.00 29.34 ATOM 1725 CDl LEU A 525 0.734 -5.076 -5.5621.00 29.61 ATOM 1726 CD2 LEU A 525 2.829 -5.769 -4.3701.00 X9.22 ATOM 1727 C LEU A 525 -1.497 -5.822 -2.9501.00 31.67 ATOM 1728 O LEU A 525 -2.128 -6.133 -3.9571.00 32.45 ATOM 1729 N TYR A 526 -1.559 -6.512 -1.814i.00 36.14 ATOM 1730 CA TYR A 526 -2.397 -7.698 -1.6961.00 40.36 ATOM 1731 CB TYR A 526 -2.221 -8.350 -0.3241.00 45.27 ATOM 1732 CG TYR A 526 -2.849 -9.722 -0.2291.00 50.62 ATOM 1733 CD1 TYR A 526 -2.114 -10.867-0.5371.00 54.55 ATOM 1734 CEI TYR A 526 -2.698 -12.136-0.4821.00 57.27 ATOM 1735 CD2 TYR A 526 -4.188 -9.876 0.142 1.00 53.48 ATOM 1736 CE2 TYR A 526 -4.781 -11.1410.201 1.00 55.93 ATOM 1737 CZ TYR A 526 -4.029 -12.264-0.1131.00 56.60 ATOM 1738 OH TYR A 526 -4.603 -13.515-0.0631.00 60.70 ATOM 1739 C TYR A 526 -3.852 -7.298 -1.8931.00 42.83 ATOM 1740 O TYR A 526 -4.673 -8.094 -2.3491.00 43.49 ATOM 1741 N SER A 527 -4.158 -6.055 -1.5431.00 41.55 ATOM 1742 CA SER A 527 -5.503 -5.523 -1.6861.00 44.04 ATOM 1743 CB SER A 527 -5.606 -4.169 -0.9791.00 43.47 ATOM 1744 OG SER A 527 -6.954 -3.789 -0.7861.00 47.51 ATOM 1745 C SER A 527 -5.817 -5.356 -3.1721.00 44.18 ATOM 1746 O SER A 527 -6.883 -5.757 -3.6421.00 44.88 ATOM 1747 N MET A 528 -4.883 -4.755 -3.9011.00 41.79 ATOM 1748 CA MET A 528 -5.047 -4.536 -5.3311.00 44.04 ATOM 1749 CB MET A 528 -3.898 -3.679 -5.8701.00 44.78 ATOM 1750 CG MET A 528 -3.965 -2.206 -5.4681.00 45.37 ATOM 1751 SD MET A 528 -5.652 -1.598 -5.2731.00 51.83 ATOM 1752 CE MET A 528 -5.553 -0.004 -6.0441.00 46.61 ATOM 1753 C MET A 528 -5.087 -5.871 -6.0711.00 44.29 ATOM 1754 O MET A 528 -5.689 -5.979 -7.1371.00 44.02 ATOM 1755 N LYS A 529 -4.443 -6.883 -5.4991.00 46.78 ATOM 1756 CA LYS A 529 -4.413 -8.213 -6.0991.00 51.28 ATOM 1757 CB LYS A 529 -3.550 -9.158 -5.2611.00 50.87 ATOM 1758 CG LYS A 529 -2.798 -10.204-6.0711.00 50.55 ATOM 1759 CD LYS A 529 -3.548 -11.520-6.104I ~
.00 1.25 ATOM 1760 CE LYS A 529 -2.616 -12.694-5.8561.00 ~3.2~

ATOM 1761 NZ LYS A 529 -2.420 -12.954-4.4021.00 X3.2?

ATOM 1762 C LYS A 529 -5.829 -8.768 -6.1821.00 5x.27 ATOM 1763 O LYS A 529 -6.325 -9.069 -7,2661.00 X5.50 WO 99/SOb58 PCT/US99/06937 ATOM 1764 N CYS A 530 -6.472 -8.901 -x.027 1.00 56.71 ATOM 1765 CA CYS A 530 -7.833 -9.416 -:1.9611.00 58.35 ATOM 1766 CB CYS A 530 -8.333 -9.380 -3.517 1.00 59.78 ATOM 1767 SG CYS A 530 -7.289 -10.304-?.358 1.00 63.19 ATOM 1768 C CYS A 530 -8.766 -8.609 -5.858 1.00 59.36 ATOM 1769 O CYS A 530 -9.644 -9.169 -6.514 1.00 59.52 ATOM 1770 N LYS A 531 -8.569 -7.293 -5.888 1.00 59.24 ATOM 1771 CA LYS A 531 -9.390 -6.411 -6.713 1.00 60.14 ATOM 1772.CB LYS A 531 -9.158 -4.952 -6.317 1.00 58.92 ATOM 1773 C LYS A 531 -9.073 -6.615 -8.195 1.00 61.48 ATOM 1774 O LYS A 531 -9.618 -5.928 -9.061 1.00 61.74 ATOM 1775 N ASN A 532 -8.179 -7.561 -8.474 1.00 61.65 ATOM 1776 CA ASN A 532 -7.783 -7.890 -9.840 1.00 61.60 ATOM 1777 CB ASN A 532 -8.966 -8.518 -10.5811.00 62.28 ATOM 1778 CG ASN A 532 -8.750 -9.985 -10.8781.00 64.66 ATOM 1779 ODI ASN A 532 -8.344 -10.352-11.9831.00 67.08 ATOM 1780 ND2 ASN A 532 -9.016 -10.836-9.891 1.00 62.68 ATOM 1781 C ASN A 532 -7.247 -6.710 -10.6481.00 59.75 ATOM 1782 O ASN A 532 -7.487 -6.615 -11.8501.00 57.50 ATOM 1783 N VAL A 533 -6.507 -5.822 -9.992 1.00 59.39 ATOM 1784 CA VAL A 533 -5.954 -4.656 -10.6691.00 58.22 ATOM 1785 CB VAL A 533 -6.223 -3.371 -9.865 1.00 59.20 ATOM 1786 CG1 VAL A 533 -6.181 -2.163 -10.7851.00 59.21 ATOM 1787 CG2 VAL A 533 -7.574 -3.467 -9.172 1.00 59.57 ATOM 1788 C VAL A 533 -4.452 -4.767 -10.9071.00 57.86 ATOM 1789 O VAL A 533 -3.846 -3.874 -11.4991.00 60.56 ATOM 1790 N VAL A 534 -3.852 -5.863 -10.4511.00 56.03 ATOM 1791 CA VAL A 534 -2.417 -6.063 -10.6211.00 54.11 ATOM 1792 CB VAL A 534 -I.767 -6.632 -9.341 1.00 54.02 ATOM 1793 CG1 VAL A 534 -0.300 -6.950 -9.601 1.00 52.37 ATOM 1794 CG2 VAL A 534 -1.900 -5.635 -8.200 1.00 55.70 ATOM 1795 C VAL A 534 -2.089 -7.008 -11.7701.00 54.31 ATOM 1796 O VAL A 534 -2.519 -8.164 -11.7801.00 51.66 ATOM 1797 N PRO A 535 -1.315 -6.527 -12.7551.00 53.54 ATOM 1798 CD PRO A 535 -0.749 -5.172 -12.8741.00 54.28 ATOM 1799 CA PRO A 535 -0.949 -7.373 -13.8931.00 53.24 ATOM 1800 CB PRO A 535 0.011 -6.500 -14.6971.00 52.71 ATOM 1801 CG PRO A 535 -0.353 -5.102 -14.319I.00 53.19 ATOM 1802 C PRO A 535 -0.296 -8.664 -13.4111.00 54.25 ATOM 1803 O PRO A 535 0.121 -8.768 -12.2541.00 54.56 ATOM 1804 N LEU A 536 -0.203 -9.645 -14.2991.00 53.63 ATOM 1805 CA LEU A 536 0.382 -10.926-13.9371.00 53.11 ATOM 1806 CB LEU A 536 -0.250 -12.046-14.7631.00 51.88 ATOM 1807 CG LEU A 536 -0.686 -13.256-13.9381.00 51.83 ATOM 1808 CDI LEU A 536 -1.953 -12.917-13.1731.00 49.51 ATOM 1809 CD2 LEU A 536 -0.905 -14.449-14.8511.00 53.43 ATOM 1810 C LEU A 536 1.895 -10.990-1=1.0811.00 52.58 ATOM 1811 O LEU A 536 2.414 -11.501-15.07 1.00 55.33 ATOM 1812 N TYR A 537 2.601 -10.462-13.0871.00 18.72 ATOM 1813 CA TYR A 537 4.057 -10.501-13.0931.00 44.22 ATOM 1814 CB TYR A 537 4.627 -9.134-12.7091.00 44.52 ATOM 1815 CG TYR A 537 -1.331 -8.053-13.7311.00 45.18 ATOM 1816 CD1 TYR A 537 3.623 -6.905-13.3761.00 43.77 ATOM 1817 CEI TYR A 537 3.334 -5.915-14.3171.00 45.23 ATOM 1818 CD2 TYR A 537 4.747 -8.187-15.0581.00 46.91 ATOM 1819 CE2 TYR A 537 4.462 -7.202-16.0081.00 43.93 ATOM 1820 CZ TYR A 537 3.757 -6.071-15.6311.00 46.70 ATOM 1821 OH TYR A 537 3.472 -5.097-16.5651.00 48.35 ATOM 1822 C TYR A 537 4.401 -11.562-12.0561.00 41.29 ATOM 1823 O TYR A 537 4.330 -11.319-10.8561.00 41.82 ATOM 1824 N ASP A 538 4.748 -12.748-12.5401.00 40.34 ATOM 1825 CA ASP A 538 5.055 -13.896-11.6911.00 38.84 ATOM 1826 CB ASP A 538 5.594 -15.037-12.5541.00 43.47 ATOM 1827 CG ASP A 538 4.571 -15.531-13.5661.00 47.67 ATOM 1828 OD1 ASP A 538 4.931 -16.373-14.4161.00 49.33 ATOM 1829 OD2 ASP A 538 3.405 -15.073-13.5111.00 48.07 ATOM 1830 C ASP A 538 5.991 -13.676-10.5081.00 37.28 ATOM 1831 O ASP A 538 5.620 -13.964-9.371 1.00 38.55 ATOM 1832 N LEU A 539 7.196 -13.200-10.7661.00 33.83 ATOM 1833 CA LEU A 539 8.155 -12.959-9.692 1.00 32.80 ATOM 1834 CB LEU A 539 9.419 -12.323-10.2631.00 32.78 ATOM 1835 CG LEU A 539 10.561 -12.031-9.292 1.00 30.93 ATOM 1836 CD1 LEU A 539 10.913 -13.280-8.492 1.00 33.81 ATOM 1837 CD2 LEU A 539 11.758 -11.538-10.0771.00 25.92 ATOM 1838 C LEU A 539 7.558 -12.050-8.614 1.00 31.85 ATOM 1839 O LEU A 539 7.590 -12.367-7.423 1.00 25.63 ATOM 1840 N LEU A 540 7.011 -10.917-9.042 1.00 32.07 ATOM 1841 CA LEU A 540 6.411 -9.976-8.111 1.00 31.03 ATOM 1842 CB LEU A 540 5.792 -8.800-8.861 1.00 30.56 ATOM 1843 CG LEU A 540 5.124 -7.774-7.945 1.00 31.12 ATOM 1844 CD1 LEU A 540 6.092 -7.357-6.838 1.00 29.76 ATOM 1845 CD2 LEU A 540 4.693 -6.572-8.762 1.00 30.85 ATOM 1846 C LEU A 540 5.337 -10.660-7.282 1.00 34.55 ATOM 1847 O LEU A 540 5.316 -10.522-6.063 1.00 31.60 ATOM 1848 N LEU A 541 4.446 -11.388-7.941 1.00 35.64 ATOM 1849 CA LEU A 541 3.378 -12.101-7.245 1.00 37.84 ATOM 1850 CB LEU A 541 2.452 -12.771-8.255 1.00 38.49 ATOM 1851 CG LEU A 541 I.244 -11.932-8.678 1.00 39.80 ATOM 1852 CD1 LEU A 541 0.476 -11.476-7.448 1.00 40.02 ATOM 1853 CD2 LEU A 541 1.713 -10.733-9.485 1.00 40.48 ATOM 1854 C LEU A 541 3.937 -13.147-6.275 1.00 40.10 ATOM 1855 O LEU A 541 3.472 -13.254-5.137 1.00 42.72 ATOM 1856 N GLU A 542 4.929 -13.915-6.723 1.00 38.45 ATOM 1857 CA GLU A 542 5.535 -14.932-5.868 1.00 39.59 ATOM 1858 CB GLU A 542 6.738 -15.566-6.564 1.00 41.73 ATOM 1859 CG GLU A 542 6.396 -16.327-7.831 1.00 48.34 ATOM 1860 CD GLU A 542 6.931 -17.747-7.819 1.00 52.57 ATOM 1861 OE1 GLU A 542 8.049 -17.961-7.298 I.00 52.70 ATOM 1862 OE2 GLU A 542 6.230 -18.647-8.331 1.00 53.69 ATOM 1863 C GLU A 542 5.989 -14.299-4.553 1.00 39.94 ATOM 1864 O GLU A 542 5.567 -14.710-3.472 1.00 40.99 ATOM 1865 N MET A 543 6.844 -13.287-4.663 1.00 38.29 ATOM i 866 CA MET A 543 7.380 -12.580-3.503 1.00 38.11 ATOM 1867 CB MET A 543 8.242 -11.408-3.963 1.00 37.34 ATOM 1868 CG MET A 543 9.311 -11.797-4.953 I.00 40.59 ATOM 1869 SD MET A 543 10.829 -12.223-4.114 1.00 45.64 ATOM 1870 CE MET A 543 12.014 -11.399-5.1 I 42.61 S 1 .00 ATOM 1871 C MET A 543 6.287 -12.064-2.581 1.00 37.94 ATOM 1872 O MET A 543 6.413 -12.127-1.358 1.00 39.20 ATOM 1873 N LEU A 544 5.218 -11.544-3.175 1.00 39.44 I ATOM 1874 CA LEU A 544 4.100 -11.013-2.408 1.00 40.91 ATOM 1875 CB LEU A 544 3.087 -10.344-3.341 1.00 39.88 ATOM 1876 CG LEU A 544 1.775 -9.905 -2.688 1.00 42.70 ATOM 1877 CD1 LEU A 544 2.060 -8.886 -1.586 1.00 37.35 ATOM 1878 CD2 LEU A 544 0.854 -9.317 -3.741 1.00 38.47 ATOM 1879 C LEU A 544 3.420 -12.120-1.614 1.00 42.83 ATOM 1880 O LEU A 544 2.957 -11.899-0.496 1.00 42.73 ATOM 1881 N ASP A 545 3.367 -13.313-2.197 1.00 46.32 ATOM 1882 CA ASP A 545 2.746 -14.456-1.539 1.00 50.65 ATOM 1883 CB ASP A 545 2.606 -15.617-2.524 1.00 53.67 ATOM 1884 CG ASP A 545 1.703 -15.278-3.691 1.00 57.35 ATOM 1885 OD1 ASP A 545 0.697 -14.568-3.475 1.00 59.99 ATOM 1886 OD2 ASP A 545 1.999 -15.718-4.824 1.00 59.68 ATOM 1887 C ASP A 545 3.559 -14.898-0.327 1.00 50.74 ATOM 1888 O ASP A 545 3.004 -15.3880.657 1.00 49.39 ATOM 1889 N ALA A 546 4.874 -14.723-0.401 1.00 51.82 ATOM 1890 CA ALA A 546 5.750 -15.0950.702 1.00 53.12 ATOM 1891 CB ALA A 546 7.180 -14.6780.395 1.00 53.19 ATOM 1892 C ALA A 546 5.269 -14.4241.987 1.00 54.67 ATOM 1893 O ALA A 546 5.476 -14.9403.085 1.00 52.32 ATOM 1894 N HIS A 547 4.622 -13.2701.838 1.00 56.66 ATOM 1895 CA HIS A 547 4.102 -12.5202.978 1.00 59.19 ATOM 1896 CB HIS A 547 4.144 -11.0172.684 1.00 56.70 ATOM 1897 CG HIS A 547 5.489 -10.3942.896 1.00 54.64 ATOM 1898 CD2 HIS A 547 6.644 -10.5062.199 1.00 53.92 ATOM 1899 ND1 HIS A 547 5.748 -9.514 3.925 1.00 52.17 ATOM 1900 CE1 HIS A 547 7.004 -9.111 3.853 I.00 52.16 ATOM 1901 NE2 HIS A 547 7.570 -9.698 2.814 1.00 51.90 ATOM 1902 C HIS A 547 2.668 -12.9403.306 1.00 62.77 ATOM 1903 O HIS A 547 1.842 -12.1203.707 1.00 63.24 ATOM 1904 N ARG A 548 2.381 -14.2243.133 1.00 68.37 ATOM 1905 CA ARG A 548 1.053 -14.7583.411 1.00 72.75 ATOM 1906 CB ARG A 548 0.243 -14.8642.113 1.00 73.73 ATOM 1907 CG ARG A 548 -1.149 -14.2432.186 1.00 74.04 ATOM 1908 CD ARG A 548 -1.081 -12.728?.297 1.00 74.50 ATOM 1909 NE ARG A 548 -2.305 -12.1672.863 1.00 75.04 ATOM 1910 CZ ARG A 548 -2.478 -10.8803.149 1.00 75.59 ATOM 1911 NHI ARG A 548 -1.506 -10.0062.919 1.00 75.79 ATOM 1912 NH2 ARG A 548 -3.627 -10.4643.662 1.00 76.00 ATOM 1913 C ARG A 548 1.179 -16.1334.061 1.00 74.94 ATOM I 914 O ARG A 548 0.197 -16.6974.549 1.00 75.15 ATOM 1915 N LEU A 549 2.398 -16.6654.063 1.00 76.49 ATOM 1916 CA LEU A 549 2.669 -17.9694.653 1.00 78.14 ATOM 1917 CB LEU A 549 2.971 -18.9863.557 1.00 77.55 ATOM 1918 C LEU A 549 3.846 -17.8705.619 1.00 79.13 ATOM 1919 O LEU A 549 4.892 -17.3175.215 1.00 80.40 ATOM 1920 OXT LEU A 549 3.708 -18.3416.769 1.00 79.46 HETATM 1921 CP9 DES A 600 5.390 -3.061-6.139 1.00 21.38 HETATM 1922 CP8 DES A 600 5.834 -1.989-5.134 1.00 22.41 HETATM 1923 CP7 DES A 600 5.038 -0.714-5.236 1.00 21.32 HETATM 1924 CP6 DES A 600 3.587 -0.864-5.062 1.00 25.87 HETATM 1925 CP DES A 600 2.987 -0.978-3.784 1.00 23.92 HETATM 1926 CP2 DES A 600 1.597 -1.150-3.684 1.00 29.77 HETATM 1927 CP3 DES A 600 0.842 -1.214-4.871 1.00 31.40 HETATM 1928 OP3 DES A 600 -0.506 -1.419-4.824 1.00 33.36 HETATM 1929 CP4 DES A 600 1.421 -1.099-6.143 1.00 27.01 HETATM 1930 CP5 DES A 600 2.793 -0.929-6.230 1.00 27.40 HETATM 1931 C7 DES A 600 5.671 0.461 -5.482 1.00 22.39 HETATM 1932 C6 DES A 600 7.113 0.561 -5.809 1.00 21.75 HETATM 1933 C5 DES A 600 7.541 0.306 -7.131 1.00 19.97 HETATM 1934 C4 DES A 600 8.889 0.429 -7.477 1.00 23.81 HETATM 1935 C3 DES A 600 9.814 0.804 -6.488 1.00 21.88 HETATM 1936 03 DES A 600 11.125 0.901 -6.839 1.00 22.32 HETATM 1937 C2 DES A 600 9.423 1.066 -5.161 1.00 19.74 HETATM 1938 C1 DES A 600 8.066 0.937 -4.838 1.00 21.25 HETATM 1939 C8 DES A 600 4.894 1.765 -5.443 1.00 21.47 HETATM 1940 C9 DES A 600 4.959 2.468 -4.070 1.00 21.38 HETATM 1941 CL CL A 601 14.781 -3.035-17.7391.00 24.10 ATOM 1942 CB SER B 305 12.321 21.08625.295 1.00 64.27 ATOM 1943 C SER B 305 12.672 22.10227.548 1.00 64.37 ATOM 1944 O SER B 305 13.701 22.76027.702 1.00 66.90 ATOM 1945 N SER B 305 12.045 23.52125.606 1.00 63.72 ATOM 1946 CA SER B 305 11.875 22.18726.251 1.00 64.21 ATOM 1947 N LEU B 306 12.193 21.29328.484 1.00 63.09 ATOM 1948 CA LEU B 306 12.884 21.13329.757 1.00 60.98 ATOM 1949 CB LEU B 306 11.884 21.20030.913 1.00 61.23 ATOM 1950 CG LEU B 306 12.221 20.41732.183 1.00 62.23 ATOM 1951 CD1 LEU B 306 13.304 21.14432.966 1.00 62.56 ATOM 1952 CD2 LEU B 306 10.965 20.25833.027 1.00 64.31 ATOM 1953 C LEU B 306 13.660 19.819?9.803 1.00 58.39 ATOM 1954 O LEU B 306 14.570 19.65430.614 1.00 58.56 ATOM 1955 N ALA B 307 13.293 18.88128.933 1.00 54.82 ATOM 1956 CA ALA B 307 13.971 17.58928.861 1.00 50.62 ATOM 1957 CB ALA B 307 13.092 16.58428.143 1.00 51.30 ATOM 1958 C ALA B 307 15.303 17.71928.122 1.00 .16.84 ATOM 1959 O ALA B 307 16.196 16.88528.274 1.00 45.62 ATOM 1960 N LEU B 308 15.431 18.76927.320 1.00 43.46 ATOM 1961 CA LEU B 308 16.643 18.98326.542 1.00 :13.01 ATOM 1962 CB LEU B 308 16.413 ?0.10025.526 1.00 11.32 ATOM 1963 CG LEU B 308 16.315 19.70824.051 1.00 43.10 ATOM 1964 CD LEU B 308 15.942 18.23923.903 1.00 40.51 I

ATOM 1965 CD2 LEU B 308 15.287 20.60223.375 1.00 39.80 ATOM 1966 C LEU B 308 17.874 19.29727.385 1.00 42.11 ATOM 1967 O LEU B 308 19.000 19.10226.932 1.00 44.34 ATOM 1968 N SER B 309 17.669 19.7752$.608 1.00 40.88 ATOM 1969 CA SER B 309 18.796 20.10029.475 1.00 42.79 ATOM 1970 CB SER B 309 18.562 21.44730.163 1.00 41.25 ATOM 1971 OG SER B 309 17.459 21.37931.046 1.00 46.67 ATOM 1972 C SER B 309 19.072 19.02830.529 I.00 42.60 ATOM 1973 O SER B 309 20.053 19.11931.269 1.00 44.18 ATOM 1974 N LEU B 310 18.217 18.01230.596 1.00 39.44 ATOM 1975 CA LEU B 310 18.394 16.93631.569 1.00 37.62 ATOM 1976 CB LEU B 310 17.205 15.969.31.4991.00 38.84 ATOM 1977 CG LEU B 310 16.216 15.87332.668 1.00 42.43 ATOM 1978 CD1 LEU B 310 16.040 17.21933.355 1.00 42.55 ATOM 1979 CD2 LEU B 310 14.881 15.38032.138 1.00 39.69 ATOM 1980 C LEU B 310 19.691 16.17431.285 1.00 34.11 ATOM 1981 O LEU B 310 20.111 16.07030.139 1.00 34.41 ATOM 1982 N THR B 311 20.339 15.66232.326 1.00 34.04 ATOM 1983 CA THR B 311 21.564 14.88832.127 1.00 32.34 ATOM 1984 CB THR B 311 22.434 14.82433.399 1.00 31.75 ATOM 1985 OGI THR B 311 21.724 14.11634.420 1.00 36.20 ATOM 1986 CG2 THR B 311 22.782 16.21233.893 1.00 31.05 ATOM 1987 C THR B 311 21.145 13.46031.790 1.00 32.37 ATOM 1988 O THR B 311 19.967 13.11731.899 1.00 28.16 ATOM 1989 N ALA B 312 22.106 12.62831.396 1.00 33.23 ATOM 1990 CA ALA B 312 21.811 11.23731.053 1.00 35.63 ATOM 1991 CB ALA B 312 23.077 10.52730.577 1.00 34.00 ATOM 1992 C ALA B 312 21.210 10.48932.240 I.00 34.29 ATOM 1993 O ALA B 312 20.226 9.766 32.089 1.00 33.10 ATOM 1994 N ASP B 313 21.800 10.66533.419 1.00 33.90 ATOM 1995 CA ASP B 313 21.304 9.994 34.615 1.00 34.19 ATOM 1996 CB ASP B 313 22.258 10.21935.788 I.00 42.09 ATOM 1997 CG ASP B 313 23.494 9.358 35.700 1.00 44.87 ATOM 1998 OD1 ASP B 313 24.586 9.858 36.040 1.00 51.57 ATOM 1999 OD2 ASP B 313 23.377 8.184 35.290 1.00 46.79 ATOM 2000 C ASP B 313 19.925 10.52034.971 1.00 31.99 ATOM 2001 O ASP B 313 19.056 9.768 35.426 1.00 32.03 ATOM 2002 N GLN B 314 19.733 11.81934.763 1.00 ?9.38 ATOM 2003 CA GLN B 314 18.458 12.45735.046 1.00 29.73 ATOM 2004 CB GLN B 314 18.562 13.966 3-1.8321.00 32.88 ATOM 2005 CG GLN B 314 18.970 14.732 36.0851.00 36.47 ATOM 2006 CD GLN B 314 I9.213 16.208 35.8151.00 36.76 ATOM 2007 OE1 GLN B 314 19.300 16.634 34.6641.00 38.79 ATOM 2008 NE2 GLN B 314 19.327 16.995 36.8801.00 39.72 ATOM 2009 C GLN B 314 17.409 11.873 34.1161.00 29.11 ATOM 2010 O GLN B 314 16.274 11.620 34.5221.00 28.82 ATOM 2011 N MET B 315 17.801 11.657 32.8641.00 27.27 ATOM 2012 CA MET B 315 16.900 11.079 31.8721.00 30.41 ATOM 2013 CB MET B 315 17.595 11.029 30.5091.00 30.10 ATOM 2014 CG MET B 315 16.787 I0.345 29.4211.00 38.02 ATOM 2015 SD MET B 315 15.252 11.220 29.0651.00 41.12 ATOM 2016 CE MET B 315 15.890 12.835 28.6111.00 39.32 ATOM 2017 C MET B 315 16.490 9.665 32.3111.00 27.99 ATOM 2018 O MET B 315 15.302 9.351 32.3961.00 26.60 ATOM 2019 N VAL B 316 17.481 8.823 32.5981.00 27.26 ATOM 2020 CA VAL B 316 17.229 7.447 33.0271.00 24.54 ATOM 2021 CB VAL B 316 18.554 6.708 33.3511.00 26.22 ATOM 2022 CG VAL B 316 18.272 5.404 34.0961.00 29.81 ATOM 2023 CG2 VAL B 316 19.302 6.410 32.0741.00 29.75 ATOM 2024 C VAL B 316 16.326 7.389 34.2581.00 27.22 ATOM 2025 O VAL B 316 15.397 6.579 34.3181.00 25.55 ATOM 2026 N SER B 317 16.601 8.243 35.2421.00 24.40 ATOM 2027 CA SER B 317 15.799 8.268 36.4601.00 27.63 ATOM 2028 CB SER B 317 16.358 9.294 37.45I1.00 31.68 ATOM 2029 OG SER B 317 17.492 8.771 38.1121.00 39.97 ATOM 2030 C SER B 317 14.346 8.600 36.1541.00 26.73 ATOM 2031 O SER B 317 13.434 7.932 36.6481.00 25.65 ATOM 2032 N ALA B 318 14.135 9.634 35.3421.00 24.19 ATOM 2033 CA ALA B 318 12.786 10.049 34.9691.00 24.17 ATOM 2034 CB ALA B 318 12.850 11.250 34.0221.00 21.44 ATOM 2035 C ALA B 318 12.038 8.890 34.3061.00 21.63 ATOM 2036 O ALA B 318 10.902 8.598 34.6481.00 20.25 ATOM 2037 N LEU B 319 12.695 8.225 33.3641.00 23.37 ATOM 2038 CA LEU B 319 12.098 7.102 32.6521.00 25.42 ATOM 2039 CB LEU B 319 13.050 6.635 31.5481.00 22.03 ATOM 2040 CG LEU B 319 13.264 7.622 30.3941.00 20.71 ATOM 2041 CDl LEU B 319 14.146 6.995 29.3311.00 23.60 ATOM 2042 CD2 LEU B 3I9 11.918 8.020 29.8031.00 23.82 ATOM 2043 C LEU B 319 11.729 5.926 33.5641.00 27.26 ATOM 2044 O LEU B 319 10.615 5.396 33.4881.00 28.91 ATOM 2045 N LEU B 320 12.656 5.516 34.4261.00 26.58 ATOM 2046 CA LEU B 320 12.399 4.405 35.3341.00 26.73 ATOM 2047 CB LEU B 320 13.657 4.075 36.1451.00 26.87 ATOM 2048 CG LEU B 320 14.846 3.460 35.3981.00 26.15 ATOM 2049 CD1 LEU B 320 16.053 3.375 36.3301.00 28.04 ATOM 2050 CD2 LEU B 320 14.484 2.076 3-1.8951.00 26.96 ATOM 2051 C LEU B 320 11.249 4.722 36.2901.00 29.19 ATOM 2052 O LEU B 320 10.449 3.849 36.631 1.00 X6.66 ATOM 2053 N ASP B 321 11.160 5.976 36.7I9 1.00 29.72 ~

ATOM 2054 CA ASP B 321 10.112 6.371 37.647 1.00 31.36 ATOM 2055 CB ASP B 321 10.494 7.683 38.336 1.00 36.60 ATOM 2056 CG ASP B 321 11.407 7.461 39.535 1.00 46.11 ATOM 2057 OD1 ASP B 321 10.897 7.058 40.605 1.00 46.64 ATOM 2058 OD2 ASP B 321 12.635 7.676 39.402 1.00 -15.98 ATOM 2059 C ASP B 321 8.742 6.494 36.989 1.00 ?8.29 ATOM 2060 O ASP B 321 7.715 6.432 37.661 1.00 27.19 ATOM 2061 N ALA B 322 8.726 6.650 35.672 1.00 28.34 ATOM 2062 CA ALA B 322 7.469 6.779 34.950 1.00 25.55 ATOM 2063 CB ALA B 322 7.668 7.668 33.728 1.00 24.11 ATOM 2064 C ALA B 322 6.911 5.420 34.523 1.00 22.80 ATOM 2065 O ALA B 322 5.810 5.338 33.979 1.00 24.54 ATOM 2066 N GLU B 323 7.662 4.355 34.781 1.00 20.16 ATOM 2067 CA GLU B 323 7.229 3.021 34.386 1.00 ?
1.44 ATOM 2068 CB GLU B 323 8.196 1.982 34.938 1.00 23.72 ATOM 2069 CG GLU B 323 9.393 1.746 34.024 1.00 23.58 ATOM 2070 CD GLU B 323 8.988 1.134 32.685 1.00 25.23 ATOM 2071 OE GLU B 323 8.852 1.881 31.692 1.00 21.74 ATOM 2072 OE2 GLU B 323 8.809 -0.09532.624 1.00 25.49 ATOM 2073 C GLU B 323 5.796 2.696 34.810 1.00 22.35 ATOM 2074 O GLU B 323 5.409 2.926 35.951 1.00 22.34 ATOM 2075 N PRO B 324 4.986 2.165 33.880 1.00 19.10 ATOM 2076 CD PRO B 324 5.286 1.806 32.483 1.00 19.11 ATOM 2077 CA PRO B 324 3.607 1.839 34.242 1.00 22.04 ATOM 2078 CB PRO B 324 2.919 1.658 32.893 1.00 21.96 ATOM 2079 CG PRO B 324 4.015 1.137 32.015 1.00 24.13 ATOM 2080 C PRO B 324 3.619 0.556 35.060 1.00 23.44 ATOM 2081 O PRO B 324 4.590 -0.20035.028 1.00 X2.20 ATOM 2082 N PRO B 325 2.540 0.287 35.801 1.00 X4.88 ATOM 2083 CD PRO B 325 1.299 1.068 35.945 1.00 26.67 ATOM 2084 CA PRO B 325 2.520 -0.94036.603 1.00 X5.10 ATOM 2085 CB PRO B 325 1.394 -0.69137.595 1.00 27.09 ATOM 2086 CG PRO B 325 0.448 0.205 36.854 1.00 26.87 ATOM 2087 C PRO B 325 2.270 -2.19235.776 1.00 25.77 ATOM 2088 O PRO B 325 1.853 -2.11834.617 1.00 21.69 ATOM 2089 N ILE B 326 2.538 -3.34436.379 1.00 24.05 ATOM 2090 CA ILE B 326 2.301 -4.62035.722 1.00 ?2.51 ATOM 2091 CB ILE B 326 3.303 -5.68836.185 1.00 25.81 ATOM 2092 CG2 ILE B 326 3.011 -7.01835.481 1.00 ''3.78 ATOM 2093 CG1 ILE B 326 4.729 -5.20935.900 1.00 25.75 ATOM 2094 CDI ILE B 326 5.241 -5.58534.533 1.00 X7.78 ATOM 2095 C ILE B 326 0.893 -5.02036.149 1.00 X3.63 ATOM 2096 O ILE B 326 0.632 -5.23137.332 1.00 X4.81 ATOM 2097 N LEU B 327 -0.018 -5.10435.188 1.00 19.44 ATOM 2098 CA LEU B 327 -1.399 -5.43735.493 1.00 17.03 ATOM 2099 CB LEU B 327 -2.336 -4.74734.493 1.00 t 8.39 ATOM 2100 CG LEU B 327 -2.201 -3.216 34.3731.00 20.69 ATOM 2101 CDI LEU B 327 -3.245 -2.679 33.4061.00 14.87 ATOM 2102 CD2 LEU B 327 -2.384 -2.570 35.7421.00 14.39 ATOM 2103 C LEU B 327 -1.662 -6.928 35.4991.00 19.87 ATOM 2104 O LEU B 327 -0.854 -7.722 35.0141.00 20.90 ATOM 2105 N TYR B 328 -2.803 -7.300 36.0661.00 20.92 ATOM 2106 CA TYR B 328 -3.202 -8.692 36.1351.00 21.79 ATOM 2107 CB TYR B 328 -3.658 -9.050 37.5501.00 22.91 ATOM 2108 CG TYR B 328 -2.515 -9.376 38.4681.00 24.60 ATOM 2109 CDI TYR B 328 -2.118 -10.69638.6771.00 25.93 ATOM 2110 CEI TYR B 328 -1.034 -11.00039.4981.00 28.10 ATOM 2111 CD2 TYR B 328 -1.802 -8.362 39.1031.00 29.46 ATOM 2112 CE2 TYR B 328 -0.716 -8.654 39.9261.00 35.30 ATOM 2113 CZ TYR B 328 -0.338 -9.973 40.1171.00 32.59 ATOM 2114 OH TYR B 328 0.739 -10.25740.9231.00 37.24 ATOM 2115 C TYR B 328 -4.336 -8.944 35.1681.00 22.25 ATOM 2116 O TYR B 328 -5.11 -8.039 34.8491.00 19.77 S

ATOM 2117 N SER B 329 -4.420 -10.18034.6981.00 25.81 ATOM 2118 CA SER B 329 -5.480 -10.57133.7871.00 29.39 ATOM 2119 CB SER B 329 -5.002 -11.71032.8871.00 27.65 ATOM 2120 OG SER B 329 -6.091 -12.32932.2331.00 28.98 ATOM 2121 C SER B 329 -6.625 -11.04234.6731.00 33.17 ATOM 2122 O SER B 329 -6.453 -11.15735.8881.00 32.52 ATOM 2123 N GLU B 330 -7.792 -11.28934.084i.00 38.75 ATOM 2124 CA GLU B 330 -8.930 -11.77634.8591.00 44.91 ATOM 2125 CB GLU B 330 -10.134 -11.99933.9511.00 45.63 ATOM 2126 C GLU B 330 -8.493 -13.09335.4911.00 48.62 ATOM 2127 O GLU B 330 -7.739 -13.85134.8821.00 52.37 ATOM 2128 N TYR B 331 -8.952 -13.36636.7071.00 51.75 ATOM 2129 CA TYR B 331 -8.575 -14.59637.3961.00 55.25 ATOM 2130 CB TYR B 331 -8.538 -14.36538.9111.00 53.04 ATOM 2131 CG TYR B 331 -9.769 -13.66839.4401.00 50.70 ATOM 2132 CD1 TYR B 331 -10.880 -14.40039.8561.00 47.09 ATOM 2133 CEl TYR B 331 -12.035 -13.76240.2921.00 46.43 ATOM 2134 CD2 TYR B 331 -9.842 -12.27339.4781.00 47.52 ATOM 2135 CE2 TYR B 331 -10.993 -11.62539.9131.00 43.98 ATOM 2136 CZ TYR B 331 -12.086 -12.37640.3141.00 44.33 ATOM 2137 OH TYR B 331 -13.239 -11.74740.7151.00 45.31 ATOM 2138 C TYR B 331 -9.528 -15.74337.0751.00 60.11 ATOM 2139 O TYR B 331 -10.748 -15.56937.0661.00 63.13 ATOM 2140 N ASP B 332 -8.952 -16.91336.8091.00 61.60 ATOM 2141 CA ASP B 332 -9.704 -18.12436.4901.00 63.58 ATOM 2142 CB ASP B 332 -10.637 -17.89535.2981.00 65.11 ATOM 2143 CG ASP B 332 -11.723 -18.95335.2001.00 65.32 ATOM 2144 OD1 ASP B 332 -11.420 -20.13635.4631.00 63.69 ATOM 2145 OD2 ASP B 332 -12.876 -18.60234.8661.00 63.61 ATOM 2146 C ASP B 332 -8.707 -19.22736.1531.00 62.86 ATOM 2147 O ASP B 332 -7.853 -19.05635.2871.00 62.26 ATOM ? N PRO B 333 -8.81 -20.37936.833 I 63.96 148 I .00 ATOM 2149 CD PRO B 333 -9.808 -20.69037.875 1.00 64.24 ATOM ? CA PRO B 333 -7.901 -21.50336.596 1.00 64.24 I

ATOM 2151 CB PRO B 333 -8.015 -22.32537.874 1.00 64.70 ATOM 2152 CG ~ B 333 -9.4I0 -22.07138.347 1.00 65.00 PRO

ATOM ? C PRO B 333 -8.180 -22.34035.351 1.00 63.90 ATOM 2154 O PRO B 333 -7.384 -23.21435.007 1.00 63.70 ATOM 2155 N THR B 334 -9.303 -22.08434.683 1.00 63.83 ATOM ? CA THR B 334 -9.649 -22.83233.475 I 63.77 156 .00 ATOM 2157 CB THR B 334 -11.065 -22.47732.975 1.00 64.63 ATOM 2158 OG1 THR B 334 -11.132 -21.07832.675 1.00 65.95 ATOM 2159 CG2 THR B 334 -12.102 -22.81734.036 1.00 65.09 ATOM ? C THR B 334 -8.634 -22.49932.388 1.00 62.62 ATOM 2161 O THR B 334 -8.931 -21.77431.437 1.00 60.15 ATOM 2162 N ARG B 335 -7.432 -23.04332.553 1.00 63.14 ATOM 2163 CA ARG B 335 -6.324 -22.82031.633 1.00 60.70 ATOM 2164 CB ARG B 335 -5.130 -23.66732.050 1.00 58.73 ATOM 2165 C ARG B 335 -6.667 -23.08630.174 1.00 59.71 ATOM 2166 O ARG B 335 -6.302 -22.29829.298 1.00 62.33 ATOM 2167 N PRO B 336 -7.377 -24.19429.884 1.00 55.25 ATOM 2168 CD PRO B 336 -7.938 -25.22730.769 1.00 53.53 ATOM 2169 CA PRO B 336 -7.698 -24.43728.471 1.00 50.10 ATOM 2170 CB PRO B 336 -8.399 -25.79928.476 1.00 49.70 ATOM 2171 CG PRO B 336 -8.164 -26.37229.844 1.00 50.71 ATOM 2172 C PRO B 336 -8.602 -23.32427.954 1.00 44.54 ATOM 2173 O PRO B 336 -9.809 -23.34228.179 1.00 44.14 ATOM 2174 N PHE B 337 -8.007 -22.35027.274 1.00 39.18 ATOM 2175 CA PHE B 337 -8.764 -21.22326.742 1.00 38.25 ATOM 2176 CB PHE B 337 -7.850 -20.00326.567 1.00 36.98 ATOM 2177 CG PHE B 337 -7.229 -19.51727.846 1.00 36.81 ATOM 2178 CD1 PHE B 337 -5.846 -19.51128.002 1.00 38.89 ATOM 2179 CD2 PHE B 337 -8.023 -19.06228.893 1.00 35.97 ATOM 2180 CEl PHE B 337 -5.262 -19.05929.185 1.00 36.85 ATOM 2181 CE2 PHE B 337 -7.449 -18.60830.079 1.00 37.15 ATOM 2182 CZ PHE B 337 -6.064 -18.60730.224 1.00 38.40 ATOM 2183 C PHE B 337 -9.420 -21.53525.402 1.00 36.81 ATOM 2184 O PHE B 337 -8.962 -22.39924.658 1.00 36.26 ATOM 2185 N SER B 338 -10.504 -20.82825.107 1.00 35.85 ATOM 2186 CA SER B 338 -11.198 -20.98123.836 1.00 34.76 ATOM 2187 CB SER B 338 -12.713 -20.94824.035 1.00 34.85 ~

ATOM 2188 OG SER B 338 -13.164 -19.62124.235 1.00 33.53 ATOM 2189 C SER B 338 -10.761 -19.76123.037 1.00 34.99 ATOM 2190 O SER B 338 -10.143 -18.85523.591 1.00 34.32 ATOM 2191 N GLU B 339 -11.075 -19.72221.750 1.00 33.01 ATOM 2192 CA GLU B 339 -10.682 -18.57920.950 1.00 33.94 ATOM 2193 CB GLU B 339 -II.146 -18.73719.501 1.00 33.79 ATOM 2194 CG GLU B 339 -10.758 -17.55318.623 1.00 39.11 ATOM 2195 CD GLU B 339 -10.865 -17.85217.137 1.00 43.17 ATOM ? OE GLU B 339 -11.990 -17.78516.600 1.00 -15.28 ATOM 2197 OE2 GLU B 339 -9.824 -18.15216.510 1.00 39.19 ATOM 2198 C GLU B 339 -11.265 -17.29521.531 1.00 34.28 ATOM 2199 O GLU B 339 -10.575 -16.28321.631 1.00 33.65 ATOM 2200 N ALA B 340 -12.535 -17.33921.920 1.00 31.12 ATOM ?201 CA ALA B 340 -13.194 -16.16422.469 1.00 ?9.10 ATOM 2202 CB ALA B 340 -14.696 -16.41222.573 1.00 33.84 ATOM 2203 C ALA B 340 -12.639 -15.73123.826 1.00 28.98 ATOM 2204 O ALA B 340 -12.431 -14.54124.060 1.00 30.48 ATOM 2205 N SER B 341 -12.407 -16.69124.719 1.00 26.66 ATOM 2206 CA SER B 341 -11.882 -16.38626.044 1.00 24.26 ATOM 2207 CB SER B 341 -11.867 -17.64326.923 1.00 ?7.04 ATOM 2208 OG SER B 341 -10.851 -18.54126.515 1.00 33.84 ATOM 2209 C SER B 341 -10.479 -15.79325.960 1.00 23.97 ATOM 2210 O SER B 341 -10.171 -14.82426.651 1.00 21.56 ATOM 2211 N MET B 342 -9.631 -16.36825.114 1.00 26.83 ATOM 2212 CA MET B 342 -8.271 -15.86524.954 1.00 ?
7.24 ATOM 2213 CB MET B 342 -7.477 -16.75824.001 1.00 30.45 ATOM 2214 CG MET B 342 -6.038 -16.30023.802 1.00 35.35 ATOM 2215 SD MET B 342 -4.866 -17.66723.777 1.00 44.57 ATOM 2216 CE MET B 342 -4.034 -17.34122.244 1.00 41.37 ATOM 2217 C MET B 342 -8.322 -14.44824.385 1.00 25.31 ATOM 2218 O MET B 342 -7.653 -I3.54124.874 1.00 26.67 ATOM 2219 N MET B 343 -9.114 -14.27823.345 1.00 25.75 ATOM 2220 CA MET B 343 -9.262 -12.97922.712 1.00 25.47 ATOM 2221 CB MET B 343 -10.210 -13.08821.528 1.00 23.51 ATOM 2222 CG MET B 343 -9.540 -13.61820.273 1.00 28.86 ATOM 2223 SD MET B 343 -8.325 -12.45619.609 1.00 29.25 ATOM 2224 CE MET B 343 -9.344 -11.01519.371 1.00 28.74 ATOM 2225 C MET B 343 -9.798 -11.96623.712 1.00 25.37 ATOM 2226 O MET B 343 -9.360 -10.81023.728 1.00 24.98 ATOM 2227 N GLY B 344 -10.739 -12.40324.536 1.00 23.91 ATOM 2228 CA GLY B 344 -11.320 -11.52625.536 1.00 22.43 ATOM 2229 C GLY B 344 -10.313 -11.10326.592 1.00 22.06 ATOM 2230 O GLY B 344 -10.262 -9.93426.982 1.00 20.87 ATOM 2231 N LEU B 345 -9.511 -12.04827.063 1.00 19.36 ATOM 2232 CA LEU B 345 -8.520 -11.74828.083 1.00 25.74 ATOM 2233 CB LEU B 345 -7.886 -13.04028.600 1.00 26.78 ATOM 2234 CG LEU B 345 -8.794 -I4.01029.362 1.00 30.04 ATOM 2235 CD1 LEU B 345 -8.099 -15.35729.488 1.00 28.39 ATOM 2236 CD2 LEU B 345 -9.122 -13.44330.736 1.00 29.93 ATOM 2237 C LEU B 345 -7.425 -10.82227.550 1.00 23.24 ATOM 2238 O LEU B 345 -7.037 -9.86528.212 1.00 23.43 ATOM 2239 N LEU B 346 -6.937 -11.10826.350 1.00 21.92 ATOM 2240 CA LEU B 346 -5.874 -10.30325.763 1.00 22.71 ATOM 2241 CB LEU B 346 -5.343 -10.96224.486 1.00 23.17 ATOM 2242 CG LEU B 346 -4.684 -12.33124.668 1.00 20.66 ATOM 2243 CD1 LEU B 346 -4.303 -12.91623.309 1.00 18.75 ATOM 2244 CD2 LEU B 346 -3.464 -12.18825.553 1.00 20.84 ATOM 2245 C LEU B 346 -6.304 -8.87325.458 1.00 22.99 ATOM 2246 O LEU B 346 -5.540 -7.93525.695 1.00 22.07 ATOM 2247 N THR B 347 -7.516 -8.69924.937 1.00 20.53 ATOM 2248 CA THR B 347 -7.987 -7.35724.608 1.00 21.89 ATOM 2249 CB THR B 347 -9.152 -7.38823.601 1.00 21.65 ATOM 2250 OGI THR B 347 -10.218 -8.19024.123 1.00 19.65 ATOM 2251 CG2 THR B 347 -8.676 -7.95522.262 1.00 22.01 ATOM 2252 C THR B 347 -8.426 -6.59025.853 1.00 23.60 ATOM 2253 O THR B 347 -8.358 -5.35725.883 1.00 20.31 ATOM 2254 N ASN B 348 -8.884 -7.31426.874 1.00 22.27 ATOM 2255 CA ASN B 348 -9.293 -6.66728.114 1.00 23.99 ATOM 2256 CB ASN B 348 -10.008 -7.642X9.056 1.00 22.32 ATOM 2257 CG ASN B 348 -10.342 -7.02230.398 1.00 28.26 ATOM 2258 OD1 ASN B 348 -9.478 -6:74631.216 1.00 27.14 ATOM 2259 ND2 ASN B 348 -11.647 -6.76430.625 1.00 27.02 ATOM 2260 C ASN B 348 -8.035 -6.12028.798 1.00 19.48 ATOM 2261 O ASN B 348 -8.014 -4.99129.271 1.00 18.26 ATOM 2262 N LEU B 349 -6.984 -6.93128.832 1.00 19.07 ATOM 2263 CA LEU B 349 -5.724 -6.51629.446 1.00 20.37 ATOM 2264 CB LEU B 349 -4.716 -7.67429.434 1.00 18.21 ATOM 2265 CG LEU B 349 -3.297 -7.31629.889 1.00 18.24 ATOM 2266 CD1 LEU B 349 -3.323 -6.90431.356 1.00 12.44 ATOM 2267 CD2 LEU B 349 -2.370 -8.50429.672 1.00 21.28 ATOM 2268 C LEU B 349 -5.131 -5.30728.718 1.00 19.92 ATOM 2269 O LEU B 349 -4.738 -4.32229.349 1.00 16.56 ATOM 2270 N ALA B 350 -5.067 -5.39127.391 1.00 16.67 ATOM 2271 CA ALA B 350 -4.529 -4.30826.578 1.00 17.11 ATOM 2272 CB ALA B 350 -4.587 -4.69025.095 1.00 14.15 ATOM 2273 C ALA B 350 -5.272 -2.98826.805 1.00 17.92 ATOM 2274 O ALA B 350 -4.650 -1.92626.904 i.00 18.71 ATOM 2275 N ASP B 351 -6.600 -3.05326.857 1.00 17.51 ATOM 2276 CA ASP B 351 -7.409 -1.85627.074 1.00 16.57 ATOM 2277 CB ASP B 351 -8.902 -2.20227.041 1.00 18.97 ATOM 2278 CG ASP B 351 -9.?85 -0.97426.858 1.00 21.80 ATOM 2279 ODI ASP B 351 -9.660 -0.29225.824 1.00 24.62 ATOM 2280 OD2 ASP B 351 -10.604 -0.68227.754 1.00 22.78 ATOM 2281 C ASP B 351 -7.064 -1.22828.415 1.00 16.81 ATOM 2282 O ASP B 351 -6.963 -0.00928.534 1.00 15.75 ATOM 2283 N ARG B 352 -6.894 -2.05629.438 1.00 13.97 ATOM 2284 CA ARG B 352 -6.552 -1.50930.742 1.00 16.09 ATOM 2285 CB ARG B 352 -6.728 -2.57131.833 1.00 15.78 ATOM 2286 CG ARG B 352 -8.189 -2.81932.189 1.00 17.93 ATOM 2287 CD ARG B 352 -8.323 -3.88233.279 1.00 19.84 ATOM 2288 NE ARG B 352 -8.010 -5.22232.785 1.00 21.36 ATOM 2289 CZ ARG B 352 -7.187 -6.07533.387 1.00 21.18 ATOM 2290 NH ARG B 352 -6.579 -5.74134.516 I 20.51 I .00 ATOM 2291 NH2 ARG B 352 -6.980 -7.27532.864 1.00 28.51 WO 99/50658 PCT/(iS99/06937 ATOM 2292 C ARG B 352 -5.123 -0.97530.7281.00 15.81 ATOM 2293 O ARG B 352 -4.835 0.057 31.3391.00 15.61 ATOM 2294 N GLU B 353 -4.231 -1.66530.0191.00 15.45 ATOM 2295 CA GLU B 353 -2.838 -1.22829.9351.00 16.59 ATOM 2296 CB GLU B 353 -1.990 -2.24329.1681.00 14.64 ATOM 2297 CG GLU B 353 -1.554 -3.45629.9731.00 18.23 ATOM 2298 CD GLU B 353 -0.620 -4.35529.1761.00 ?2.72 ATOM 2299 OE1 GLU B 353 -1.099 -5.07828.2751.00 ?1.94 ATOM 2300 OE2 GLU B 353 0.599 -4.32429.4421.00 24.41 ATOM 2301 C GLU B 353 -2.729 0.119 29.2191.00 15.85 ATOM 2302 O GLU B 353 -1.872 0.939 29.5401.00 13.76 ATOM 2303 N LEU B 354 -3.594 0.335 28.2351.00 12.93 ATOM 2304 CA LEU B 354 -3.556 1.575 27.4721.00 15.33 ATOM 2305 CB LEU B 354 -4.616 1.534 26.3601.00 16.44 ~

ATOM 2306 CG LEU B 354 -4.174 0.750 25.1121.00 17.03 ATOM 2307 CD LEU B 354 -5.373 0.509 24.1891.00 16.70 ATOM 2308 CD2 LEU B 354 -3.069 1.531 24.3841.00 14.52 ATOM 2309 C LEU B 354 -3.747 2.805 28.3611.00 12.78 ATOM 2310 O LEU B 354 -3.123 3.850 28.1411.00 14.28 ATOM 2311 N VAL B 355 -4.600 2.682 29.3691.00 12.60 ATOM 2312 CA VAL B 355 -4.844 3.791 30.2791.00 16.78 ATOM 2313 CB VAL B 355 -5.925 3.429 31.3271.00 16.84 ATOM 2314 CG1 VAL B 355 -6.070 4.561 32.3441.00 19.88 ATOM 231 CG2 VAL B 355 -7.254 3.187 30.6391.00 19.33 S

ATOM 2316 C VAL B 355 -3.533 4.161 30.9861.00 19.17 ATOM 2317 O VAL B 355 -3.158 5.328 31.0491.00 17.30 ATOM 2318 N HIS B 356 -2.826 3.160 31.4991.00 19.68 ATOM 2319 CA HIS B 356 -1.559 3.418 32.1771.00 20.64 ATOM 2320 CB HIS B 356 -1.110 2.174 32.9451.00 21.03 ATOM 2321 CG HIS B 356 -2.018 1.818 34.0851.00 22.88 ATOM 2322 CD2 HIS B 356 -3.128 1.045 34.1351.00 ?
1.70 ATOM 2323 ND1 HIS B 356 -1.838 2.312 35.3581.00 19.24 ATOM 2324 CE1 HIS B 356 -2.802 1.860 36.1451.00 18.84 ATOM 2325 NE2 HIS B 356 -3.598 1.088 35.4261.00 17.92 ATOM 2326 C HIS B 356 -0.479 3.861 31.1841.00 19.67 ATOM 2327 O HIS B 356 0.424 4.614 31.5471.00 19.61 ATOM 2328 N MET B 357 -0.566 3.413 29.9311.00 14.92 ATOM 2329 CA MET B 357 0.428 3.830 28.9391.00 15.13 ATOM 2330 CB MET B 357 0.239 3.099 27.6041.00 13.94 ATOM 2331 CG MET B 357 1.149 3.631 26.4761.00 14.71 ATOM 2332 SD MET B 357 0.747 3.014 24.8261.00 17.75 ATOM 2333 CE MET B 357 0.746 1.222 25.1221.00 15.21 ATOM 2334 C MET B 357 0.316 5.334 28.6991.00 14.94 ATOM 2335 O MET B 357 1.319 6.031 28.5601.00 17.0?

ATOM 2336 N ILE B 358 -0.909 5.839 28.6591.00 18.01 ATOM 2337 CA ILE B 358 -1.122 7.263 28.4231.00 19.77 ATOM 2338 CB ILE B 358 -2.634 7.577 28.2871.00 23.11 ATOM 2339 CG2 ILE B 358 -2.879 9.080 28.4501.00 ?5.00 ATOM 2340 CGI ILE B 358 -3.137 7.105 26.913 1.00 24.19 ATOM 2341 CD1 ILE B 358 -4.600 6.653 26.890 1.00 20.17 ATOM 2342 C ILE B 358 -0.501 8.100 29.550 1.00 22.93 ATOM 2343 O ILE B 358 0.080 9.153 29.299 1.00 23.33 ATOM 2344 N ASN B 359 -0.619 7.631 30.790 1.00 22.34 ATOM 2345 CA ASN B 359 -0.029 8.341 31.924 1.00 23.24 ATOM 2346 CB ASN B 359 -0.480 7.726 33.224 1.00 25.10 ATOM 2347 CG ASN B 359 -1.831 8.171 33.649 1.00 32.65 ATOM 2348 OD1 ASN B 359 -2.421 9.069 33.042 1.00 32.98 .

ATOM 2349 ND2 ASN B 359 -2.364 7.549 34.691 i.00 33.87 ATOM 2350 C ASN B 359 1.473 8.306 31.837 1.00 24.77 ATOM 2351 O ASN B 359 2.152 9.285 32.149 1.00 24.19 ATOM 2352 N TRP B 360 1.995 7.149 31.438 1.00 20.82 ATOM 2353 CA TRP B 360 3.439 6.965 31.310 1.00 19.29 ATOM 2354 CB TRP B 360 3.754 5.524 30.878 1.00 18.59 ATOM 2355 CG TRP B 360 5.085 5.363 30.176 1.00 18.21 ATOM 2356 CD2 TRP B 360 5.310 5.308 28.756 1.00 14.38 ATOM 2357 CE2 TRP B 360 6.698 5.129 28.561 1.00 13.42 ATOM 2358 CE3 TRP B 360 4.475 5.392 27.633 1.00 15.52 ATOM 2359 CD1 TRP B 360 6.306 5.221 30.762 1.00 13.34 ATOM 2360 NE1 TRP B 360 7.283 5.078 29.800 1.00 16.05 ATOM 2361 CZ2 TRP B 360 7.272 5.032 27.288 1.00 16.84 ATOM 2362 CZ3 TRP B 360 5.045 5.296 26.363 1.00 15.11 ATOM 2363 CH2 TRP B 360 6.431 5.115 26.202 1.00 16.12 ATOM 2364 C TRP B 360 3.979 7.939 30.273 1.00 20.13 ATOM 2365 O TRP B 360 4.991 8.606 30.497 1.00 17.26 ATOM 2366 N ALA B 361 3.295 8.012 29.135 1.00 19.34 ATOM 2367 CA ALA B 361 3.708 8.900 28.051 1.00 22.01 ATOM 2368 CB ALA B 361 2.682 8.855 26.921 1.00 19.53 ATOM 2369 C ALA B 361 3.883 10.33628.552 1.00 22.39 ATOM 2370 O ALA B 361 4.858 11.00528.210 1.00 19.57 ATOM 2371 N LYS B 362 2.932 10.79429.361 1.00 21.96 ATOM 2372 CA LYS B 362 2.966 12.13929.923 1.00 26.45 ATOM 2373 CB LYS B 362 1.741 12.36330.811 1.00 29.79 ATOM 2374 CG LYS B 362 0.426 12.41730.064 1.00 33.57 ATOM 2375 CD LYS B 362 -0.563 13.30430.805 1.00 36.83 ATOM 2376 CE LYS B 362 -1.620 12.49031.512 1.00 36.89 ATOM 2377 NZ LYS B 362 -2.873 13.27631.664 1.00 39.07 ATOM 2378 C LYS B 362 4.223 12.37930.757 1.00 27.77 ATOM 2379 O LYS B 362 4.661 13.51730.922 1.00 26.93 ATOM 2380 N ARG B 363 4.805 11.30231.278 1.00 26.61 ATOM 2381 CA ARG B 363 5.996 11.41432.109 1.00 27.74 ATOM 2382 CB ARG B 363 5.887 10.45733.298 1.00 28.93 ATOM 2383 CG ARG B 363 4.650 10.7043=1.1581.00 36.07 ATOM 2384 CD ARG B 363 4.569 9.745 ;5.344 1.00 42.83 ATOM 2385 NE ARG B 363 4.477 8.344 31.928 1.00 49.79 ATOM 2386 CZ ARG B 363 3.395 7.582 35.080 1.00 51.48 ATOM 2387 NHI ARG B 363 2.300 8.081 35.648 1.00 52.17 ATOM ?388 NH2 ARG B 363 3.405 6.316 34.668 1.00 40.24 ATOM 2389 C ARG B 363 7.308 11.190 31.367 1.00 25.80 ATOM '_'390O ARG B 363 8.374 11.183 31.975 1.00 29.36 ATOM 2391 N VAL B 364 7.231 11.009 30.053 1.00 24.28 S ATOM 2392 CA VAL B 364 8.431 10.823 29.248 1.00 21.87 ATOM ?393 CB VAL B 364 8.116 10.048 ?7.947 1.00 ~
1.84 ATOM ?394 CGI VAL B 364 9.267 10.184 26.968 1.00 15.85 ATOM 2395 CG2 VAL B 364 7.860 8.560 28.268 1.00 16.24 ATOM 2396 C VAL B 364 8.925 12.241 28.923 1.00 28.14 ATOM 2397 O VAL B 364 8.219 13.023 28.285 1.00 24.24 ATOM 2398 N PRO B 365 10.141 12.591 29.375 1.00 28.57 ATOM 2399 CD PRO B 365 11.061 11.726 30.137 1.00 30.58 ATOM 2400 CA PRO B 365 10.719 13.919 29.138 1.00 32.16 ATOM 2401 CB PRO B 365 12.189 13.739 29.507 1.00 32.70 I ATOM 2402 CG PRO B 365 12.170 12.671 30.545 1.00 33.35 S

ATOM 2403 C PRO B 365 10.546 14.464 27.726 1.00 32.22 ATOM 2404 O PRO B 365 11.056 13.897 26.766 1.00 37.04 ATOM 2405 N GLY B 366 9.821 1 S.S7027.609 1.00 34.09 ATOM 2406 CA GLY B 366 9.612 16.182 26.310 1.00 32.54 ATOM 2407 C GLY B 366 8.241 15.969 25.700 1.00 33.46 ATOM 2408 O GLY B 366 7.791 16.779 24.886 1.00 33.73 ATOM 2409 N PHE B 367 7.564 14.895 26.096 1.00 31.08 ATOM 2410 CA PHE B 367 6.250 14.593 25.542 1.00 28.60 ATOM 2411 CB PHE B 367 S.74S 13.244 26.058 1.00 25.96 2S ATOM 2412 CG PHE B 367 4.629 12.671 25.239 1.00 22.75 ATOM 2413 CDI PHE B 367 3.313 12.771 25.669 1.00 22.62 ATOM 2414 CD2 PHE B 367 4.897 i2.02S 24.033 1.00 22.29 ATOM 2415 CEI PHE B 367 2.272 12.233 24.914 1.00 25.63 ATOM 2416 CE2 PHE B 367 3.867 11.486 23.272 1.00 20.82 ATOM 2417 CZ PHE B 367 2.553 II.S88 23.711 1.00 25.50 ATOM 2418 C PHE B 367 5.178 15.646 25.781 1.00 26.79 ATOM 2419 O PHE B 367 4.458 16.001 24.854 1.00 23.37 ATOM 2420 N VAL B 368 5.049 16.143 27.009 1.00 31.26 ATOM 2421 CA VAL B 368 4.020 17.1 27.277 1.00 35.71 3S ATOM 2422 CB VAL B 368 3.817 17.412 28.795 1.00 35.98 ATOM 2423 CGI VAL B 368 2.944 16.320 29.392 1.00 37.64 ATOM 2424 CG2 VAL B 368 S.1S7 17.495 29.508 1.00 35.81 ATOM 2425 C VAL B 368 4.328 18.482 26.598 1.00 35.87 ATOM 2426 O VAL B 368 3.450 19.330 26.457 1.00 37.71 ATOM 2427 N ASP B 369 5.572 18.665 26.175 1.00 35.49 ATOM 2428 CA ASP B 369 S.9S0 19.904 25.503 1.00 36.54 ATOM 2429 CB ASP B 369 7.466 19.963 25.309 1.00 39.79 ATOM 2430 CG ASP B 369 8.213 20.169 26.61 1.00 44.33 S

ATOM 2431 ODl ASP B 369 9.409 19.807 26.684 1.00 48.45 4S ATOM 2432 OD2 ASP B 369 7.604 20.693 27.572 1.00 43.27 ATOM 2433 C ASP B 369 x.248 19.997 24.149 1.00 34.49 ATOM 2434 O ASP B 369 5.131 21.074 23.571 1.00 34.51 ATOM 2435 N LEU B 370 4.776 18.859 23.653 1.00 30.97 ATOM 2436 CA LEU B 370 4.086 18.809 22.370 1.00 X9.80 ATOM 2437 CB LEU B 370 4.145 17.389 21.799 1.00 27.27 ATOM 2438 CG LEU B 370 5.522 16.733 21.688 1.00 28.07 ATOM 2439 CD LEU B 370 5.353 15.242 21.400 I 30.38 1 .00 ATOM 2440 CD2 LEU B 370 6.316 17.396 20.574 1.00 22.82 ATOM 2441 C LEU B 370 2.628 19.218 22.521 1.00 28.04 ATOM 2442 O LEU B 370 2.066 19.151 23.611 1.00 29.71 ATOM 2443 N THR B 371 2.011 19.645 21.425 1.00 28.70 ATOM 2444 CA THR B 3?1 0.602 20.014 21.474 1.00 30.31 ATOM 2445 CB THR B 371 0.150 20.690 20.163 1.00 31.96 ATOM 2446 OG THR B 371 0.284 19.763 19.080 1.00 29.49 ATOM 2447 CG2 THR B 371 0.991 21.930 19.878 1.00 29.98 ATOM 2448 C THR B 371 -0.208 18.726 21.666 I.00 30.59 ATOM 2449 O THR B 371 0.300 17.624 21.431 1.00 27.10 I ATOM 2450 N LEU B 372 -1.461 18.863 22.087 1.00 27.65 S

ATOM 2451 CA LEU B 372 -2.323 17.702 22.303 1.00 30.86 ATOM 2452 CB LEU B 372 -3.722 18.147 22.737 1.00 30.11 ATOM 2453 CG LEU B 372 -4.715 17.006 22.960 1.00 32.80 ATOM 2454 CD1 LEU B 372 -4.231 16.147 24.126 1.00 34.10 ATOM 2455 CD2 LEU B 372 -6.105 17.562 23.246 1.00 31.16 ATOM 2456 C LEU B 372 -2.437 16.863 21.034 1.00 31.77 ATOM 2457 O LEU B 372 -2.417 15.629 21.078 1.00 27.06 ATOM 2458 N HIS B 373 -2.564 17.548 19.905 1.00 31.30 ATOM 2459 CA HIS B 373 -2.685 16.888 18.614 1.00 31.35 ~

ATOM 2460 CB HIS B 373 -2.844 17.935 17.503 1.00 34.30 ATOM 2461 CG HIS B 373 -2.503 17.430 16.132 1.00 41.27 ATOM 2462 CD2 HIS B 373 -3.293 17.105 15.079 1.00 42.50 ATOM 2463 ND1 HIS B 373 -1.205 17.220 15.715 1.00 43.69 ATOM 2464 CE1 HIS B 373 -1.210 16.787 14.465 1.00 48.87 ATOM 2465 NE2 HIS B 373 -2.465 16.708 14.056 1.00 43.72 ATOM 2466 C HIS B 373 -1.468 16.012 18.337 1.00 28.29 ATOM 2467 O HIS B 373 -1.610 14.878 17.897 1.00 30.21 ATOM 2468 N ASP B 374 -0.275 16.541 18.589 1.00 28.85 ATOM 2469 CA ASP B 374 0.950 15.783 18.350 1.00 28.28 ATOM 2470 CB ASP B 374 2.178 16.678 18.535 1.00 31.33 ATOM 2471 CG ASP B 374 2.433 17.577 17.333 1.00 39.07 ATOM 2472 OD1 ASP B 374 3.195 18.557 17.478 1.00 40.60 ATOM 2473 OD2 ASP B 374 1.874 17.305 16.246 1.00 38.64 ATOM 2474 C ASP B 374 1.029 14.592 19.303 1.00 29.05 ATOM 2475 O ASP B 374 1.432 13.494 18.908 1.00 24.26 ATOM 2476 N GLN B 375 0.642 14.814 20.556 1.00 24.52 ATOM 2477 CA GLN B 375 0.667 13.749 21.547 1.00 27.37 ATOM 2478 CB GLN B 375 0.213 14.270 22.901 1.00 26.66 ATOM 2479 CG GLN B 375 1.164 15.236 23.563 1.00 29.74 ATOM 2480 CD GLN B 375 0.623 15.691 24.890 1.00 33.13 ATOM 2481 OEI GLN B 375 -0.044 14.953 25.602 1.00 32.82 ATOM 2482 NE2 GLN B 375 0.895 16.953 25.236 1.00 33.98 ATOM 2483 C GLN B 375 -0.259 12.630 21.104 1.00 24.52 ATOM 2484 O GLN B 375 0.074 I 1.451? 1.2211.00 23.56 ATOM 2485 N VAL B 376 -1.426 13.01320.599 1.00 21.87 ATOM 2486 CA VAL B 376 -2.409 12.05520.140 1.00 23.44 ATOM 2487 CB VAL B 376 -3.718 12.76019.717 1.00 22.09 ATOM 2488 CG1 VAL B 376 -4.572 11.82318.877 1.00 24.14 ATOM 2489 CG2 VAL B 376 -4.486 13.19220.954 1.00 16.96 ATOM 2490 C VAL B 376 -1.852 11.25718.965 1.00 24.15 ATOM 2491 O VAL B 376 -1.949 10.03218.938 1.00 22.26 ATOM 2492 N HIS B 377 -1.251 11.95318.007 1.00 25.85 ATOM 2493 CA HIS B 377 -0.689 11.28416.843 1.00 25.68 ATOM 2494 CB HIS B 377 -0.078 12.30615.886 1.00 25.27 ATOM 2495 CG HIS B 377 0.535 11.69014.667 1.00 30.63 ATOM 2496 CD2 HIS B 377 I.828 11.55914.287 1.00 31.03 ATOM 2497 ND1 HIS B 377 -0.217 I1.08613.683 1.00 35.05 IS ATOM 2498 CEI HIS B 377 0.588 10.60712.750 1.00 33.12 ATOM 2499 NE2 HIS B 377 1.833 10.88213.093 1.00 31.06 ATOM 2500 C HIS B 377 0.365 10.23717.210 1.00 24.37 ATOM 2501 O HIS B 377 0.321 9.109 16.719 1.00 21.47 ATOM 2502 N LEU B 3?8 1.307 10.60918.072 1.00 19.24 ATOM 2503 CA LEU B 378 2.365 9.691 18.474 1.00 20.09 ATOM 2504 CB LEU B 378 3.363 10.40219.388 1.00 18.64 ATOM 2505 CG LEU B 378 4.230 11.48918.736 1.00 22.15 ATOM 2506 CDI LEU B 378 5.104 12.14819.796 1.00 22.51 ATOM 2507 CD2 LEU B 378 5.094 10.88517.638 1.00 20.68 ATOM 2508 C LEU B 378 1.832 8.433 19.161 i.00 18.91 ATOM 2509 O LEU B 378 2.262 7.320 18.859 1.00 17.52 ATOM 2510 N LEU B 379 0.888 8.610 20.077 1.00 18.25 ATOM 2511 CA LEU B 379 0.317 7.486 20.795 1.00 18.60 ATOM 2512 CB LEU B 379 -0.526 7.989 21.968 1.00 16.77 ATOM 2513 CG LEU B 379 0.292 8.353 23.214 1.00 17.90 ATOM 2514 CD LEU B 3 79 -0.578 9.092 24.211 1.00 15.84 ATOM 2515 CD2 LEU B 379 0.851 7.075 23.842 1.00 22.09 ATOM 2516 C LEU B 379 -0.518 6.605 19.872 1.00 20.17 ATOM 2517 O LEU B 379 -0.476 5.377 19.968 1.00 18.11 ATOM 2518 N GLU B 380 -1.273 7.222 18.971 1.00 19.40 ATOM 2519 CA GLU B 380 -2.086 6.435 18.049 1.00 20.19 ATOM 2520 CB GLU B 380 -2.994 7.350 17.222 1.00 22.43 ATOM 2521 CG GLU B 380 -4.182 7.874 18.007 1.00 25.30 ATOM 2522 CD GLU B 380 -5.070 8.789 17.188 1.00 29.44 ATOM 2523 OE1 GLU B 380 -6.206 9.066 17.625 1.00 31.70 ATOM 2524 OE2 GLU B 380 -4.631 9.230 16.110 1.00 31.75 ATOM 2525 C GLU B 380 -1.210 5.594 17.117 1.00 18.92 ATOM 2526 O GLU B 380 -1.586 4.491 16.722 1.00 19.83 ATOM 2527 N ACYS B 381 -0.039 6.113 16.77? 0.75 17.41 ATOM 2528 N BCYS B 381 -0.035 6.I 16.779 0.25 17.76 ATOM 2529 CA ACYS B 381 0.860 x.384 15.887 0.75 20.19 ATOM 2530 CA BCYS B 381 0.875 x.407 15.884 0.25 17.50 ATOM 2531 CB ACYS B 381 1.870 6.342 1 x.2480.75 24.20 ATOM 2532 CB BCYS 381 1.830 6.406 15.226 0.25 16.63 B

ATOM 2533 SG ACYS 381 1.167 7.518 14.060 0.75 33.54 B

ATOM 2534 SG BCYS 381 3.048 5.656 14.128 0.25 10.36 B

ATOM 2535 C ACYS 381 1.626 4.269 16.592 0.75 ?0.59 B

ATOM ?536 C BCYS 381 1.689 ~t.30516.561 0.25 19.19 B

ATOM 2537 O ACYS 381 1.737 3.161 16.069 0.75 19.16 B

ATOM 2538 O BCYS 381 1.904 3.241 15.982 0.25 19.25 B

ATOM 2539 N ALA B 382 2.134 4.560 17.785 1.00'19.04 ATOM 2540 CA ALA B 382 2.955 3.602 18.530 1.00 20.27 ATOM 2541 CB ALA B 382 4.135 4.364 19.143 1.00 18.68 ATOM 2542 C ALA B 382 2.356 2.702 19.607 1.00 16.82 ATOM 2543 O ALA B 382 3.070 1.852 20.142 1.00 13.37 ATOM 2544 N TRP B 383 1.074 2.855 19.916 1.00 15.30 ATOM 2545 CA TRP B 383 0.487 2.089 21.Oi3 1.00 15.80 I ATOM 2546 CB TRP B 383 -1.009 2.410 21.160 1.00 16.63 S

ATOM 2547 CG TRP B 383 -1.871 1.775 20.129 1.00 19.93 ATOM 2548 CD2 TRP B 383 -2.493 0.483 20.198 1.00 20.80 ATOM 2549 CE2 TRP B 383 -3.226 0.309 19.003 1.00 19.27 ATOM 2550 CE3 TRP B 383 -2.506 -0.54221.155 1.00 ?
1.32 ATOM 2551 CD1 TRP B 383 -2.236 2.312 18.933 1.00 18.59 ATOM 2552 NE1 TRP B 383 -3.051 1.439 18.250 1.00 23.67 ATOM 2553 CZ2 TRP B 383 -3.963 -0.85318.733 1.00 21.55 ATOM 2554 CZ3 TRP B 383 -3.243 -1.70220.888 1.00 20.29 ATOM 2555 CH2 TRP B 383 -3.960 -1.84419.686 1.00 19.03 ATOM 2556 C TRP B 383 0.701 0.579 21.020 1.00 17.35 ATOM 2557 O TRP B 383 0.982 0.010 22.077 1.00 13.92 ATOM 2558 N LEU B 384 0.568 -0.08719.879 1.00 14.07 ATOM 2559 CA LEU B 384 0.773 -1.53219.903 1.00 15.98 ATOM 2560 CB LEU B 384 0.181 -2.20018.656 1.00 12.19 ATOM 2561 CG LEU B 384 0.173 -3.73518.720 1.00 12.97 ATOM 2562 CD1 LEU B 384 -0.352 -4.24020.089 1.00 10.65 ATOM 2563 CD2 LEU B 384 -0.707 -4.25917.586 1.00 17.84 ATOM 2564 C LEU B 384 2.262 -1.86120.034 1.00 14.64 ATOM 2565 O LEU B 384 2.627 -2.83320.690 1.00 13.78 ATOM 2566 N GLU B 385 3.116 -1.04619.414 1.00 14.96 ATOM 2567 CA GLU B 385 4.565 -1.26019.509 1.00 13.79 ATOM 2568 CB GLU B 385 5.336 -0.17918.739 1.00 15.34 ATOM 2569 CG GLU B 385 5.297 -0.31217.207 1.00 15.38 ATOM 2570 CD GLU B 385 6.162 0.738 16.520 1.00 23.97 ATOM 2571 OE1 GLU B 385 7.381 0.500 16.358 1.00 21.03 ATOM 2572 OE2 GLU B 385 5.622 1.808 16.149 1.00 X2.19 ATOM 2573 C GLU B 385 4.963 -1.16120.987 1.00 15.79 ATOM 2574 O GLU B 385 5.788 -1.94221.463 1.00 IS.04 ATOM 2575 N ILE B 386 4.389 -0.21321.690 1.00 13.32 ATOM ?576 CA ILE B 386 4.723 -0.01923.108 1.00 14.06 ATOM 2577 CB ILE B 386 4.173 1.326 23.614 1.00 15.36 ATOM 2578 CG2 ILE B 386 4.37:1 1..451?5.130 1.00 15.97 ATOM 2579 CG ILE B 386 4.910 2.476 22.907 1.00 I
1 7.95 ATOM 2580 CD1 ILE B 386 4.118 3.768 '_x.8741.00 21.12 ATOM 2581 C ILE B 386 4.227 -1.164 X3.9931.00 14.97 ATOM 2582 O ILE B 386 4.905 -I.S60 ?4.9411.00 19.60 ATOM 2583 N LEU B 387 3.038 -1.675 23.7091.00 15.18 S ATOM 2584 CA LEU B 387 2.516 -2.791 '_'4.4781.00 15.98 ATOM 2585 CB LEU B 387 1.070 -3.097 ?4.0801.00 17.15 ATOM 2586 CG LEU B 387 -0.031 -2.113 ?4.4861.00 19.65 ATOM 2587 CD1 LEU B 387 -1.371 -2.628 ?3.9721.00 17.77 ATOM 2588 CD2 LEU B 387 -0.075 -1.966 ?6.0021.00 15.38 ATOM 2589 C LEU B 387 3.391 -4.013 ?4.1801.00 14.69 ATOM 2590 O LEU B 387 3.712 -4.792 ~~.0761.00 14.03 ATOM 2591 N MET B 388 3.785 -4.178 22.9211.00 ib.43 ATOM 2592 CA MET B 388 4.602 -5.329 22.5471.00 16.67 ATOM 2593 CB MET B 388 4.673 -5.460 21.0261.00 14.83 IS ATOM 2594 CG MET B 388 3.403 -6.066 20.4531.00 13.91 ATOM 2595 SD MET B 388 3.364 -6.193 18.6751.00 17.23 ATOM 2596 CE MET B 388 1.906 -7.225 18.5111.00 14.97 ATOM 2597 C MET B 388 6.004 -5.332 23.1331.00 20.19 ATOM 2598 O MET B 388 6.460 -6.366 23.6361.00 21.50 ATOM 2599 N ILE B 389 6.707 -4.203 23.0741.00 15.34 ATOM 2600 CA ILE B 389 8.044 -4.209 23.6341.00 15.59 ATOM 2601 CB ILE B 389 8.836 -2.911 23.3221.00 14.95 ATOM 2602 CG2 ILE B 389 8.330 -1.746 24.1581.00 12.81 ATOM 2603 CGI ILE B 389 10.325 -3.164 23.6021.00 17.24 2S ATOM 2604 CDI ILE B 389 11.228 -1.972 23.3571.00 15.65 ATOM 2605 C ILE B 389 7.950 -4.446 25.1471.00 14.30 ATOM 2606 O ILE B 389 8.844 -5.044 25.7391.00 18.72 ATOM 2607 N GLY B 390 6.855 -4.007 25.7611.00 13.99 ATOM 2608 CA GLY B 390 6.681 -4.219 27.1891.00 14.87 ATOM 2609 C GLY B 390 6.444 -5.702 27.4631.00 18.54 ATOM 2610 O GLY B 390 6.989 -6.282 X8.4031.00 16.54 ATOM 2611 N LEU B 391 5.623 -6.325 26.6281.00 16.1 S

ATOM 2612 CA LEU B 391 5.334 -7.743 26.7751.00 18.91 ATOM 2613 CB LEU B 39I 4.332 -8.179 25.6991.00 19.55 3S ATOM 2614 CG LEU B 391 4.157 -9.689 25.4571.00 20.91 ATOM 2615 CDI LEU B 391 3.580 -10.35126.6991.00 19.41 ATOM 2616 CD2 LEU B 391 3.232 -9.913 24.2681.00 20.70 ATOM 2617 C LEU B 391 6.649 -8.S 26.625I .00 20.31 ATOM 2618 O LEU B 391 7.002 -9.352 27.4651.00 18.66 ATOM 2619 N VAL B 392 7.378 -8.21 ~S.SS71.00 18.71 S

ATOM 2620 CA VAL B 392 8.649 -8.868 X5.2781.00 19.51 ATOM 2621 CB VAL B 392 9.288 -8.281 X4.0051.00 23.77 ATOM 2622 CG1 VAL B 392 10.751 -8.687 23.9201.00 24.63 ATOM 2623 CG2 VAL B 392 8.520 -8.773 22.7671.00 19.94 4S ATOM 2624 C VAL B 392 9.615 -8.707 '?6.4501.00 22.80 ATOM 2625 O VAL B 392 10.336 -9.637 ?6.8111.00 19.36 ATOM 2626 N TRP B 393 9.617 -7.522 ?7.0461.00 22.10 ATOM 2627 CA TRP B 393 i 0.492 -7.241 ~ 8.1711.00 23.20 ATOM 2628 CB TRP B 393 10.388 -5.773 28.578 1.00 19.22 ATOM 2629 CG TRP B 393 11.056 -5.479 29.895 1.00 '2.53 ATOM 2630 CD2 TRP B 393 12.453 -5.591 30.193 1.00 '0.36 ATOM 2631 CE2 TRP B 393 12.624 -5.208 31.545 1.00 ~5.6~

ATOM 2632 CE3 TRP B 393 13.578 -5.976 29.449 1.00 '2.12 ATOM 2633 CD1 TRP B 393 10.452 -5.046 31.044 1.00 ?3.02 ATOM 2634 NEI TRP B 393 11.387 -4.881 32.037 1.00 24.91 ATOM 2635 CZ2 TRP B 393 13.876 -5.200 32.171 1.00 X3.00 ATOM 2636 CZ3 TRP B 393 14.829 -5.968 30.072 1.00 X3.98 ATOM 2637 CH2 TRP B 393 14.964 -5.582 31.423 1.00 23.20 ATOM 2638 C TRP B 393 10.208 -8.114 29.388 1.00 24.36 ATOM 2639 O TRP B 393 11.128 -8.717 29.944 1.00 23.04 ATOM 2640 N ARG B 394 8.952 -8.189 29.819 1.00 21.29 ATOM 2641 CA ARG B 394 8.680 -9.003 30.990 1.00 ?2.43 I ATOM 2642 CB ARG B 394 7.365 -8.601 31.667 1.00 23.97 S

ATOM 2643 CG ARG B 394 6.259 -8.149 30.759 1.00 26.16 ATOM 2644 CD ARG B 394 5.026 -7.727 31.574 1.00 20.86 ATOM 2645 NE ARG B 394 3.817 -7.937 30.786 1.00 19.54 ATOM 2646 CZ ARG B 394 3.327 -7.059 29.915 1.00 20.58 ATOM 2647 NH ARG B 394 3.944 -5.902 29.722 1.00 17.41 ATOM 2648 NH2 ARG B 394 2.229 -7.347 29.220 1.00 16.82 ATOM 2649 C ARG B 394 8.695 -10.50230.713 1.00 21.78 ATOM 2650 O ARG B 394 8.657 -11.29431.648 1.00 23.44 ATOM 2651 N SER B 395 8.767 -10.88029.438 1.00 17.10 ATOM 2652 CA SER B 395 8.805 -12.28929.041 1.00 25.08 ATOM 2653 CB SER B 395 8.206 -12.47327.638 1.00 19.47 ATOM 2654 OG SER B 395 6.832 -12.13627.619 1.00 21.73 ATOM 2655 C SER B 395 10.239 -12.83129.031 1.00 26.29 ATOM 2656 O SER B 395 10.458 -14.03028.854 1.00 23.75 ATOM 2657 N MET B 396 11.206 -11.93829.210 1.00 30.79 ATOM 2658 CA MET B 396 12.620 -12.30729.205 1.00 35.07 ATOM 2659 CB MET B 396 13.479 -11.06329.423 1.00 33.84 ATOM 2660 CG MET B 396 14.155 -10.56928.171 1.00 36.88 ATOM 2661 SD MET B 396 15.149 -9.127 28.491 1.00 40.96 ATOM 2662 CE MET B 396 16.675 -9.849 28.998 1.00 39.67 ATOM 2663 C MET B 396 12.983 -13.35330.250 1.00 35.88 ATOM 2664 O MET B 396 13.828 -14.21530.011 1.00 34.52 ATOM 2665 N GLU B 397 12.348 -13.26631.410 1.00 36.19 ATOM 2666 CA GLU B 397 12.604 -14.20632.492 1.00 39.24 ATOM 2667 CB GLU B 397 12.153 -13.60533.821 1.00 44.38 ATOM 2668 CG GLU B 397 12.983 -12.42234.271 1.00 54.05 ATOM 2669 CD GLU B 397 13.483 -12.58735.686 1.00 56.78 ATOM 2670 OE1 GLU B 397 13.380 -11.62136.470 1.00 60.90 ATOM 2671 OE2 GLU B 397 13.975 -13.68836.013 1.00 60.82 ATOM 2672 C GLU B 397 11.878 -15.52832.273 1.00 36.65 ATOM 2673 O GLU B 397 12.021 -16.45933.061 1.00 35.84 ATOM 2674 N HIS B 398 11.100 -15.60931.202 1.00 32.14 ATOM 2675 CA HIS B 398 10.347 -16.82330.914 1.00 29.48 ATOM 2676 CB HIS B 398 8.863 -16.56731.178 1.00 29.87 ATOM 2677 CG HIS B 398 8.582 -16.11132.574 1.00 31.80 ATOM 2678 CD2 HIS B 398 8.215 -16.80133.678 1.00 29.12 ATOM 2679 NDI HIS B 398 8.727 -14.79932.972 1.00 33.27 ATOM 2680 CE1 HIS B 398 8.462 -14.70134.262 1.00 32.19 ATOM 2681 NE2 HIS B 398 8.148 -15.90234.714 1.00 33.48 ATOM 2682 C HIS B 398 10.556 -17.31729.492 1.00 25.95 ATOM 2683 O HIS B 398 9.637 -17.29128.672 1.00 27.47 ATOM 2684 N PRO B 399 11.771 -17.80129.186 1.00 29.09 ATOM 2685 CD PRO B 399 12.926 -17.92230.096 1.00 29.93 ATOM 2686 CA PRO B 399 12.079 -18.30027.845 1.00 27.40 ATOM 2687 CB PRO B 399 13.434 -18.98828.016 1.00 32.09 ATOM 2688 CG PRO B 399 14.062 -18.28429.170 1.00 30.81 ATOM 2689 C PRO B 399 11.009 -19.24627.319 1.00 29.76 ATOM 2690 O PRO B 399 10.552 -20.13728.035 1.00 29.18 ATOM 2691 N GLY B 400 10.601 -19.03526.071 1.00 27.45 ATOM 2692 CA GLY B 400 9.588 -19.88425.466 1.00 26.93 ATOM 2693 C GLY B 400 8.161 -19.53725.849 1.00 26.73 ATOM 2694 O GLY B 400 7.220 -20.15325.356 1.00 28.36 ATOM 2695 N LYS B 401 7.996 -18.55426.727 1.00 25.50 ATOM 2696 CA LYS B 401 6.668 -18.13927.165 1.00 23.45 ATOM 2697 CB LYS B 401 6.435 -18.56328.619 1.00 28.50 ATOM 2698 CG LYS B 401 6.476 -20.06928.879 1.00 28.58 ATOM 2699 CD LYS B 401 6.181 -20.35330.349 1.00 35.47 ATOM 2700 CE LYS B 401 6.073 -21.84730.635 1.00 38.59 ATOM 2701 NZ LYS B 401 7.177 -22.61129.989 1.00 42.39 ATOM 2702 C LYS B 401 6.493 -16.62227.060 1.00 21.78 ATOM 2703 O LYS B 401 7.465 -15.87227.035 1.00 21.45 ATOM 2704 N LEU B 402 5.241 -16.18126.995 1.00 23.45 ATOM 2705 CA LEU B 402 4.929 -14.75926.925 1.00 21.37 ATOM 2706 CB LEU B 402 4.088 -14.44925.689 1.00 18.47 ATOM 2707 CG LEU B 402 4.798 -14.67324.360 1.00 16.89 ATOM 2708 CD1 LEU B 402 3.821 -14.39523.211 1.00 21.23 ATOM 2709 CD2 LEU B 402 6.011 -13.76024.277 1.00 23.15 ATOM 2710 C LEU B 402 4.147 -14.39928.179 1.00 19.66 ATOM 2711 O LEU B 402 3.024 -14.88028.381 1.00 18.05 ATOM 2712 N LEU B 403 4.743 -13.55929.019 1.00 19.54 ATOM 2713 CA LEU B 403 4.099 -13.14830.259 1.00 20.21 ATOM 2714 CB LEU B 403 5.155 -12.85631.332 1.00 23.16 ATOM 2715 CG LEU B 403 4.639 -12.68232.766 1.00 29.54 ATOM 2716 CD1 LEU B 403 5.519 -13.45033.728 1.00 32.67 ATOM 2717 CD2 LEU B 403 4.626 -11.21333.138 1.00 32.38 ATOM 2718 C LEU B 403 3.219 -11.91830.043 1.00 20.42 ATOM 2719 O LEU B 403 3.638 -10.78730.291 1.00 19.18 ATOM 2720 N PHE B 404 2.003 -12.14529.565 1.00 21.44 ATOM 2721 CA PHE B 404 1.066 -11.05329.340 1.00 21.69 ATOM 2722 CB PHE B 404 -0.199 -11.59828.687 1.00 17.26 ATOM 2723 CG PHE B 404 -0.026 -11.89727.227 1.00 19.75 ATOM 2724 CD1 PHE B 404 0.364 -13.16726.801 t.00 17.90 ATOM 2725 CD2 PHE B 404 -0.210 -10.897?6.280 1.00 17.04 ATOM 2726 CE1 PHE B 404 0.572 -13.434?5.447 1.00 19.88 ATOM 2727 CE2 PHE B 404 -0.007 -11.14824.924 1.00 18.47 ATOM ?728 CZ PHE B 404 0.386 -12.41824.503 1.00 16.45 ATOM ?729 C PHE B 404 0.768 -10.40330.68 1.00 21.95 ~

ATOM 2730 O PHE B 404 0.656 -9.177 30.804 1.00 22.99 ATOM 2731 N ALA B 405 0.670 - I 31.702 1.00 21.12 1.247 ATOM 2732 CA ALA B 405 0.424 -10.81433.066 1.00 22.43 ATOM 2733 CB ALA B 405 -1.074 -10.60333.304 1.00 24.69 ATOM 2734 C ALA B 405 0.959 -11.92633.962 1.00 22.40 ATOM 2735 O ALA B 405 1.133 -13.06133.517 1.00 21.67 ATOM 2736 N PRO B 406 1.246 -11.61235.230 1.00 25.60 ATOM 2737 CD PRO B 406 1.129 -10.29435.878 1.00 23.65 ATOM 2738 CA PRO B 406 1.765 -12.63236.148 1.00 25.91 ATOM 2739 CB PRO B 406 1.899 -11.88237.475 1.00 27.04 ATOM 2740 CG PRO B 406 2.017 -10.43137.068 1.00 26.56 ATOM 2741 C PRO B 406 0.876 -13.87336.259 1.00 25.12 ATOM 2742 O PRO B 406 1.368 -14.96736.538 1.00 28.92 ATOM 2743 N ASN B 407 -0.426 -13.71336.039 1.00 23.53 ATOM 2744 CA ASN B 407 -1.345 -14.85236.109 1.00 24.09 ATOM 2745 CB ASN B 407 -2.553 -14.52636.986 t.00 24.08 ATOM 2746 CG ASN B 407 -3.327 -13.32836.486 1.00 26.72 ATOM 2747 ODI ASN B 407 -2.851 -12.57435.635 1.00 22.65 ATOM 2748 ND2 ASN B 407 -4.528 -13.14037.019 1.00 26.46 ATOM 2749 C ASN B 407 -1.820 -15.23134.714 1.00 26.91 ATOM 2750 O ASN B 407 -2.859 -15.87034.548 1.00 28.68 ATOM 2751 N LEU B 408 -1.059 -14.81633.708 1.00 27.28 ATOM 2752 CA LEU B 408 -1.387 -15.12432.327 1.00 27.23 ATOM 2753 CB LEU B 408 -2.247 -14.03031.699 1.00 26.61 ATOM 2754 CG LEU B 408 -2.8I5 -14.46430.341 1.00 27.51 ATOM 2755 CD1 LEU B 408 -3.702 -15.69230.546 1.00 28.75 ATOM 2756 CD2 LEU B 408 -3.598 -13.33029.694 1.00 25.48 ATOM 2757 C LEU B 408 -0.113 -15.31631.514 1.00 27.56 ATOM 2758 O LEU B 408 0.247 -14.46530.695 1.00 26.86 ATOM 2759 N LEU B 409 0.553 -16.42631.759 1.00 27.54 ATOM 2760 CA LEU B 409 1.786 -16.77431.065 1.00 31.96 ATOM 2761 CB LEU B 409 2.786 -17.35532.058 1.00 31.88 ATOM 2762 CG LEU B 409 4.186 -17.70331.562 1.00 37.72 ATOM 2763 CD1 LEU B 409 4.773 -16.55130.770 1.00 39.57 ATOM 2764 CD2 LEU B 409 5.066 -18.01832.758 1.00 41.72 ATOM 2765 C LEU B 409 1.401 -17.80530.009 1.00 31.53 ATOM 2766 O LEU B 409 0.921 -18.89230.340 1.00 32.67 ATOM 2767 N LEU B 410 1.604 -17.46 ?8.746 1.00 29.58 ATOM 2768 CA LEU B 410 1.228 -18.361?7.660 1.00 31.55 ATOM 2769 CB LEU B 410 0.192 -17.672?6.762 1.00 29.83 ATOM 2770 CG LEU B 410 -1.047 -17.08027.452 1.00 28.55 ATOM 2771 CDI LEU B 410 -1.770 -16.13 26.501 1.00 26.92 WO 99/50658 PC'T/US99/06937 ATOM 2772 CD2 LEU B 410 -1.979 -18.20027.891 1.00 30.49 ATOM 2773 C LEU B 410 2.397 -18.83926.814 1.00 33.88 ATOM 2774 O LEU B 410 3.427 -18.17026.726 1.00 36.49 ATOM 2775 N ASP B 411 2.238 -20.01326.206 1.00 38.80 S ATOM 2776 CA ASP B 411 3.275 -20.56225.336 1.00 38.39 ATOM 2777 CB ASP B 411 3.657 -21.99025.752 1.00 -14.53 ATOM 2778 CG ASP B 411 2.476 -22.94325.749 1.00 :4.90 ATOM 2779 OD1 ASP B 411 1.773 -23.03524.719 1.00 45.70 ATOM 2780 OD2 ASP B 411 2.254 -23.60326.786 1.00 X0.54 ATOM 2781 C ASP B 411 2.745 -20.55123.909 1.00 38.57 ATOM 2782 O ASP B 411 1.549 -20.34123.686 1.00 36.48 ATOM 2783 N ARG B 412 3.635 -20.77722.949 1.00 36.85 ATOM 2784 CA ARG B 412 3.259 -20.76321.541 1.00 38.32 ATOM 2785 CB ARG B 412 4.488 -21.08320.675 1.00 38.69 I ATOM 2786 CG ARG B 412 4.361 -22.31419.799 1.00 40.05 S

ATOM 2787 CD ARG B 412 5.644 -22.55219.012 1.00 12.98 ATOM 2788 NE ARG B 412 5.540 -22.09917.626 1.00 40.95 ATOM 2789 CZ ARG B 412 4.649 -22.59 16.753 1.00 41.11 ATOM 2790 NH ARG B 412 3.777 -23.49017.1 1.00 44.01 ATOM 2791 NH2 ARG B 412 4.632 -22.09115.515 1.00 41.28 ATOM 2792 C ARG B 412 2.107 -21.71221.217 1.00 37.64 ATOM 2793 O ARG B 412 1.287 -21.42720.343 1.00 36.51 ATOM 2794 N ASN B 413 2.041 -22.83421.923 1.00 35.32 ATOM 2795 CA ASN B 413 0.974 -23.79821.688 1.00 36.68 ATOM 2796 CB ASN B 413 1.170 -25.03522.570 1.00 37.54 ATOM 2797 CG ASN B 413 2.017 -26.10021.901 1.00 43.56 ATOM 2798 OD ASN B 413 2.309 -26.02220.704 1.00 46.11 ATOM 2799 ND2 ASN B 413 2.418 -27.10422.671 1.00 47.04 ATOM 2800 C ASN B 413 -0.383 -23.16821.982 1.00 34.01 ATOM 2801 O ASN B 413 -1.349 -23.37221.247 1.00 32.43 ATOM 2802 N GLN B 414 -0.447 -22.39723.063 1.00 32.85 ATOM 2803 CA GLN B 414 -1.685 -21.74123.449 1.00 31.91 ATOM 2804 CB GLN B 414 -1.558 -21.17224.863 1.00 33.17 ATOM 2805 CG GLN B 414 -1.528 -22.24225.948 1.00 32.31 ATOM 2806 CD GLN B 414 -1.293 -21.66727.327 1.00 34.63 ATOM 2807 OE1 GLN B 414 -0.176 -21.27727.666 1.00 33.23 ATOM 2808 NE2 GLN B 414 -2.349 -21.60628.131 1.00 34.56 ATOM 2809 C GLN B 414 -2.052 -20.63822.4b3 1.00 29.57 ATOM 2810 O GLN B 414 -3.195 -20.20422.409 1.00 31.32 ATOM 2811 N GLY B 41 -1.077 -20.19021.682 1.00 30.96 S

ATOM 2812 CA GLY B 415 -1.350 -19.16020.697 1.00 34.27 ATOM 2813 C GLY B 415 -2.184 -19.72519.562 1.00 35.27 ATOM 2814 O GLY B 415 -2.918 -19.00018.887 1.00 33.20 ATOM 2815 N LYS B 416 -2.070 -21.03119.354 1.00 35.28 ATOM 2816 CA LYS B 416 -2.819 -21.70718.299 1.00 38.26 ATOM 2817 CB LYS B 416 -2.398 -23.17718.201 1.00 38.00 ATOM 2818 CG LYS B 416 -0.973 -23.40717.736 1.00 40.0 ATOM 2819 CD LYS B 416 -0.40 -24.66818.369 1.00 44.10 ATOM 2820 CE LYS B -116 0.306 -25.54117.3461.00 41.85 ATOM 2821 NZ LYS B 416 1.286 -24.76016.5421.00 45.63 ATOM 2822 C LYS B 416 -4.321 -21.64518.5591.00 36.93 ATOM 2823 O LYS B 416 -5.121 -21.79017.6381.00 38.36 ATOM 2824 N CYS B 417 -4.698 -21.43019.8171.00 37.10 ATOM 2825 CA CYS B 417 -6.106 -21.371?0.1961.00 36.46 ATOM 2826 CB CYS B 417 -6.218 -21.22621.7171.00 39.01 ATOM 2827 SG CYS B 417 -5.674 -22.71022.6121.00 43.81 ATOM 2828 C CYS B 417 -6.899 -20.27719.4911.00 35.19 ATOM 2829 O CYS B 4 i -8.127 -20.29619.4851.00 33.92 ATOM 2830 N VAL B 418 -6.195 -19.31618.9061.00 36.04 ATOM 2831 CA VAL B 418 -6.838 -18.23618.1631.00 34.59 ATOM 2832 CB VAL B 418 -6.525 -16.85018.7751.00 34.87 ATOM 2833 CG1 VAL B 418 -6.831 -15.76317.7651.00 35.32 ATOM 2834 CG2 VAL B 418 -7.350 -16.63020.0361.00 33.65 ATOM 2835 C VAL B 418 -6.241 -18.3I716.7641.00 34.17 ATOM 2836 O VAL B 418 -5.020 -I8.32316.6111.00 32.73 ATOM 2837 N GLU B 419 -7.084 -18.3881 x.7401.00 33.44 ATOM 2838 CA GLU B 419 -6.554 -18.50014.3901.00 34.52 ATOM 2839 CB GLU B 419 -7.681 -18.72213.3801.00 36.21 ATOM 2840 CG GLU B 419 -8.597 -17.53813.1661.00 44.19 ATOM 2841 CD GLU B 419 -9.477 -17.72311.9461.00 48.47 ATOM 2842 OE1 GLU B 419 -9.157 -18.60511.1191.00 51.04 ATOM 2843 OE2 GLU B 419 -10.484 -16.99311.8131.00 48.91 ATOM 2844 C GLU B 419 -5.717 -17.28913.9971.00 32.89 ATOM 2845 O GLU B 419 -6.156 -16.14414.1231.00 31.09 ATOM 2846 N GLY B 420 -4.501 -17.56213.5351.00 32.84 ATOM 2847 CA GLY B 420 -3.594 -16.50613.1221.00 34.37 ATOM 2848 C GLY B 420 -2.722 -15.95514.2401.00 35.30 ATOM 2849 O GLY B 420 -1.745 -15.24613.9751.00 35.94 ATOM 2850 N MET B 421 -3.052 -16.28515.4861.00 30.08 ATOM 2851 CA MET B 421 -2.289 -15.78016.6251.00 29.22 ATOM 2852 CB MET B 421 -3.108 -15.92217.9141.00 22.54 ATOM 2853 CG MET B 421 -2.469 -15.27019.1241.00 23.82 ATOM 2854 SD MET B 421 -2.124 -13.49418.8721.00 28.40 ATOM 2855 CE MET B 421 -3.697 -12.80019.2331.00 24.67 ATOM 2856 C MET B 421 -0.912 -16.41616.8211.00 29.67 ATOM 2857 O MET B 421 0.022 -15.75117.2691.00 29.76 ATOM 2858 N VAL B 422 -0.766 -17.69416.4841.00 30.63 ATOM 2859 CA VAL B 422 0.524 -18.33816.6751.00 29.90 ATOM 2860 CB VAL B 422 0.482 -19.83516.2731.00 35.74 ATOM 2861 CGl VAL B 422 0.514 -19.99214.7531.00 37.64 ATOM 2862 CG2 VAL B 422 1.659 -20.55516.8971.00 31.68 ATOM 2863 C VAL B 422 1.669 -17.6401 ~.93~1.00 28.64 ATOM 2864 O VAL B 422 2.788 -17.57116.4411.00 26.15 ATOM 2865 N GLU B 423 1.402 -17.1131-1.7471.00 28.7p ATOM 2866 CA GLU B =i23 2.454 -16.43513.9971.00 31.34 ATOM 2867 CB GLU B 423 1.963 -16.05012.5961.00 36.21 ATOM 2868 CG GLU B 423 0.502 -16.37612.325 1.00 45.83 ATOM 2869 CD GLU B 423 0.250 -17.86512.144 1.00 46.71 ATOM 2870 OEI GLU B 423 -0.746 -18.36812.706 1.00 45.97 ATOM 2871 OE2 GLU B 423 1.045 -18.53011.442 1.00 50.05 ATOM 2872 C GLU B 423 2.928 -15.18614.744 1.00 30.57 ATOM 2873 O GLU B 423 4.119 -14.87014.759 1.00 26.59 ATOM 2874 N ILE B 424 2.001 -14.47815.378 1.00 26.19 ATOM 2875 CA ILE B 424 2.381 -13.27916.111 1.00 26.23 ATOM 2876 CB ILE B 424 1.134 -12.43516.452 1.00 29.33 ATOM 2877 CG2 ILE B 424 1.492 -11.31517.425 1.00 30.91 ATOM 2878 CG1 ILE B 424 0.584 -11.81715.160 1.00 29.09 ATOM 2879 CD1 ILE B 424 -0.895 -11.51415.187 1.00 30.51 ATOM 2880 C ILE B 424 3.153 -13.67317.370 1.00 24.22 ATOM 2881 O ILE B 424 4.152 -13.03717.725 1.00 21.05 ATOM 2882 N PHE B 425 2.708 -14.74618.023 1.00 21.71 ATOM 2883 CA PHE B 425 3.370 -15.23619.223 1.00 18.85 ATOM 2884 CB PHE B 425 2.650 -16.47919.768 1.00 22.98 ATOM 2885 CG PHE B 425 1.580 -16.18320.795 1.00 22.17 ATOM 2886 CD1 PHE B 425 1.287 -17.11221.792 1.00 25.47 ATOM 2887 CD2 PHE B 425 0.843 -15.00120.747 1.00 26.30 ATOM 2888 CE1 PHE B 425 0.273 -16.87122.724 1.00 24.33 ATOM 2889 CE2 PHE B 425 -0.174 -14.74921.676 1.00 25.03 ATOM 2890 CZ PHE B 425 -0.459 -15.68422.663 1.00 26.44 ATOM 2891 C PHE B 425 4.817 -15.61018.885 1.00 20.00 ATOM 2892 O PHE B 425 5.741 -15.29219.636 1.00 21.15 ATOM 2893 N ASP B 426 5.023 -16.28117.754 1.00 19.87 ATOM 2894 CA ASP B 426 6.378 -16.68517.377 1.00 23.20 ATOM 2895 CB ASP B 426 6.364 -17.51016.090 1.00 26.53 ATOM 2896 CG ASP B 426 5.992 -18.96516.335 1.00 34.28 ATOM 2897 ODI ASP B 426 6.242 -19.46717.455 1.00 35.24 ATOM 2898 OD2 ASP B 426 5.448 -19.60015.409 1.00 31.49 ATOM 2899 C ASP B 426 7.302 -15.48917.198 1.00 21.84 ATOM 2900 O ASP B 426 8.465 -15.52617.593 1.00 21.55 ATOM 2901 N MET B 427 6.788 -14.42916.591 1.00 20.12 ATOM 2902 CA MET B 427 7.597 -13.23416.382 1.00 21.02 ATOM 2903 CB MET B 427 6.836 -12.22815.520 1.00 18.53 ATOM 2904 CG MET B 427 6.864 -12.55914.038 1.00 27.92 ATOM 2905 SD MET B 427 6.011 -11.34113.024 1.00 32.84 ATOM 2906 CE MET B 427 4.363 -11.53213.581 1.00 33.63 ATOM 2907 C MET B 427 7.945 -12.61617.732 1.00 17.42 ATOM 2908 O MET B 427 9.073 -12.18017.950 1.00 22.09 ATOM 2909 N LEU B 428 6.968 -12.59718.634 1.00 20.47 ATOM 2910 CA LEU B 428 7.157 -12.03319.968 1.00 20.13 ATOM 2911 CB LEU B 428 5.812 -11.96420.706 1.00 17.58 ATOM 2912 CG LEU B 428 4.852 -10.88720.179 1.00 18.41 ATOM 2913 CDI LEU B 428 3.443 -11.15520.687 1.00 11.95 ATOM 2914 CD2 LEU B 428 5.324 -9.505 20.631 1.00 17.80 ATOM 2915 C LEU B 428 8.159 -12.85620.767 1.00 20.68 ATOM ?916 O LEU B -128 9.028 -12.30521.4451.00 20.45 ATOM 2917 N LEU B 429 8.037 -14.17820.6791.00 20.35 ATOM 2918 CA LEU B .129 8.938 -15.08221.3821.00 19.82 ATOM 2919 CB LEU B 429 8.470 -16.53221.2111.00 23.13 S ATOM 2920 CG LEU B 429 7.189 -16.83921.9971.00 21.85 ATOM 2921 CDI LEU B 429 6.SSi -18.12321.4941.00 25.39 ATOM ?922 CD2 LEU B 429 7.537 -16.94423.4751.00 24.91 ATOM 2923 C LEU B 429 10.361 -14.93620.8651.00 20.74 ATOM 2924 O LEU B 429 11.318 -14.96821.6381.00 21.02 ATOM 2925 N ALA B 430 10.495 -14.77019.8841.00 21.40 ATOM 2926 CA ALA B 430 11.808 -14.60918.9471.00 22.77 ATOM 2927 CB ALA B 430 11.677 -14.59617.4321.00 21.11 ATOM 2928 C ALA B 430 12.467 -13.31 19.440I 22.40 S .00 ATOM 2929 O ALA B 430 13.670 -13.27719.7131.00 20.62 IS ATOM 2930 N THR B 431 11.670 -12.25819.5671.00 21.09 ATOM 2931 CA THR B 431 12.183 -10.97420.0211.00 22.67 ATOM 2932 CB THR B 431 11.128 -9.866 19.8631.00 23.77 ATOM 2933 OGI THR B 431 10.572 -9.936 18.5471.00 23.84 ATOM 2934 CG2 THR B 431 11.762 -8.489 20.0731.00 21.78 ATOM 2935 C THR B 431 12.603 -11.03721.4801.00 21.98 ATOM 2936 O THR B 431 13.898 -10.42921.8791.00 19.85 ATOM 2937 N SER B 432 11.844 -11.77322.2801.00 24.24 ATOM 2938 CA SER B 432 12.169 -11.90623.6931.00 26.96 ATOM 2939 CB SER B 432 11.088 -12.66124.4231.00 28.00 2S ATOM 2940 OG SER B 432 11.404 -12.88825.7761.00 30.31 ATOM 2941 C SER B 432 13.491 -12.66023.8201.00 27.67 ATOM 2942 O SER B 432 14.305 -12.37724.7011.00 23.78 ATOM 2943 N SER B 433 13.691 -13.62822.9321.00 29.27 ATOM 2944 CA SER B 433 14.914 -14.42122.9281.00 31.96 ATOM 2945 CB SER B 433 14.790 -1 S.S7S21.9381.00 30.84 ATOM 2946 OG SER B 433 14.761 -16.80822.6251.00 38.26 ATOM 2947 C SER B 433 16.104 -13.88022.5481.00 31.47 ATOM 2948 O SER B 433 17.204 -13.70123.0871.00 28.43 ATOM 2949 N ARG B 434 15.878 -12.64121.6071.00 29.88 3S ATOM 2950 CA ARG B 434 16.926 -11.73921.1651.00 29.40 ATOM 2951 CB ARG B 434 16.437 -10.91219.9771.00 31.56 ATOM 2952 CG ARG B 434 17.428 -9.868 19.4931.00 36.76 ATOM 2953 CD ARG B 434 18.694 -10.50218.9191.00 37.76 ATOM 2954 NE ARG B 434 19.654 -9.479 18.8161.00 39.50 ATOM 2955 CZ ARG B 434 20.965 -9.673 18.4181.00 44.17 ATOM 2956 NH ARG B 434 2 I .492-10.861I 8.6961.00 43.17 ATOM 2957 NH2 ARG B 434 21.750 -8.671 18.0481.00 43.08 ATOM 2958 C ARG B 434 17.328 -10.82722.3261.00 29.18 ATOM 2959 O ARG B 434 18.8 -10.61222.5691.00 28.82 ATOM 2960 N PHE B 438 16.337 -10.29723.0391.00 24.88 ATOM 2961 CA PHE B 438 16.600 -9.422 24.1861.00 25.74 ATOM 2962 CB PHE B 438 15.278 -8.972 24.8251.00 26.53 ATOM 2963 CG PHE B 438 14.656 -7.758 24.1831.00 30.94 ATOM 2964 CD1 PHE B 435 15.118 -7.271 22.9661.00 32.65 ATOM ?965 CD2 PHE B 435 13.592 -7.108 24.7971.00 33.60 ATOM 2966 CE1 PHE B 435 14.529 -6.155 22.3721.00 36.84 ATOM 2967 CE2 PHE B 435 12.997 -5.989 24.2081.00 34.96 ATOM 2968 CZ PHE B 435 13.468 -5.516 22.995i 31.64 .00 ATOM ?969 C PHE B 435 17.426 -10.18425.233I.00 ?5.39 ATOM ?970 O PHE B 435 18.414 -9.675 25.7641.00 22.59 ATOM 2971 N ARG B 436 16.999 -11.40525.5281.00 24.58 ATOM 2972 CA ARG B 436 17.675 -12.25326.5031.00 30.25 ATOM 2973 CB ARG B 436 16.898 -13.56926.6621.00 33.32 ATOM 2974 CG ARG B 436 17.232 -14.35827.9151.00 38.17 ATOM 2975 CD ARG B 436 16.135 -15.36728.2601.00 37.27 ATOM 2976 NE ARG B 436 15.646 -16.08527.0861.00 43.92 ATOM 2977 CZ ARG B 436 14.433 -15.92326.5571.00 46.68 ATOM 2978 NH1 ARG B 436 13.578 -15.06127.0971.00 45.59 ATOM 2979 NH2 ARG B 436 14.074 -16.62025.4861.00 46.25 ATOM 2980 C ARG B 436 19.110 -12.53126.0481.00 29.82 ATOM 2981 O ARG B 436 20.057 -12.39726.823I.00 28.76 ATOM 2982 N AMET 437 19.269 -12.92124.7890.50 30.27 B

ATOM 2983 N BMET 437 19.252 -12.90624.7810.50 31.41 B

ATOM 2984 CA AMET 437 20.591 -13.21224.2530.50 31.98 B

ATOM 2985 CA BMET 437 20.547 -13.20624.1830.50 33.77 B

ATOM 2986 CB AMET 437 20.489 .-13.64622.7880.50 31.34 B

ATOM 2987 CB BMET 437 20.348 -13.59522.7140.50 35.88 B

ATOM 2988 CG AMET 437 20.179 -15.12722.5920.50 33.62 B

ATOM 2989 CG BMET 437 21.605 -13.59421.8610.50 40.47 B

ATOM 2990 SD AMET 437 20.354 -16.09924.1090.50 35.21 B

ATOM 2991 SD BMET 437 21.247 -13.93720.1150.50 46.79 B

ATOM 2992 CE AMET 437 22.155 -16.19424.2590.50 33.20 B

ATOM 2993 CE BMET 437 21.837 -15.63219.9760.50 43.22 B

ATOM 2994 C AMET 437 21.498 -11.99324.3660.50 33.33 B

ATOM 2995 C BMET 437 21.487 -12.00524.2890.50 34.45 B

ATOM 2996 O AMET 437 22.702 -12.12324.5940.50 33.54 B

ATOM 2997 O BMET 437 22.699 -12.16224.4380.50 34.43 B

ATOM 2998 N MET B 438 20.913 -10.80924.2151.00 32.07 ATOM 2999 CA MET B 438 21.674 -9.560 24.2981.00 32.48 ATOM 3000 CB MET B 438 20.930 -8.437 23.5781.00 29.74 ATOM 3001 CG MET B 438 21.161 -8.364 22.0931.00 36.73 ATOM 3002 SD MET B 438 20.425 -6.849 21.4621.00 38.21 ATOM 3003 CE MET B 438 21.693 -5.657 21.9431.00 35.91 ATOM 3004 C MET B 438 21.877 -9.122 25.738I.00 28.81 ATOM 3005 O MET B 438 22.686 -8.240 26.013I.00 30.13 ATOM 3006 N ASN B 439 21.120 -9.721 26.6461.00 27.14 ATOM 3007 CA ASN B 439 21.199 -9.359 28.0381.00 27.34 ATOM 3008 CB ASN B 439 22.592 -9.524 28.5981.00 34.85 ATOM 3009 CG ASN B 439 ?2.624 -9.480 30.0801.00 38.58 ATOM 3010 OD1 ASN B 439 31.584 -9.620 30.724I.00 42.99 ATOM 3011 ND2 ASN B 439 23.801 -9.260 30.6661.00 41.14 ATOM 3012 C ASN B 439 20.745 -7.903 28.2121.00. 26.24 ATOM 3013 O ASN B 439 21.396 -7.106 28.8911.00 19.76 ATOM 3014 N LEU B 440 19.625 -7.564 27.5731.00 24.90 ATOM 3015 CA LEU B 440 19.061 -6.214 27.6331.00 ?5.04 S ATOM 3016 CB LEU B 440 17.761 -6.157 26.8181.00 ?2.36 ATOM 3017 CG LEU B 440 17.087 -1.786 26.7401.00 ?6.33 ATOM 3018 CD1 LEU B 440 17.958 -3.843 25.9231.00 28.33 ATOM 3019 CD2 LEU B 440 15.704 -4.914 26.1111.00 24.81 ATOM 3020 C LEU B 440 18.782 -5.785 29.0741.00 24.71 ATOM 3021 O LEU B 440 18.131 -6.504 29.8301.00 26.96 ATOM 3022 N GLN B 441 19.268 -4.609 29.4521.00 25.54 ATOM 3023 CA GLN B 441 19.060 -4.099 30.8071.00 25.82 ATOM 3024 CB GLN B 441 20.250 -3.231 31.2341.00 30.41 ATOM 3025 CG GLN B 441 21.572 -3.956 31.2281.00 30.50 ATOM 3026 CD GLN B 441 21.610 -5.028 32.2791.00 32.75 ATOM 3027 OE1 GLN B 441 21.539 -4.772 33.4731.00 36.52 ATOM 3028 NE2 GLN B 441 21.703 -6.288 31.8231.00 31.09 ATOM 3029 C GLN B 441 17.789 -3.265 30.8831.00 26.93 ATOM 3030 O GLN B 441 17.303 -2.768 29.8661.00 25.40 ATOM 3031 N GLY B 442 17.266 -3.105 32.0961.00 24.56 ATOM 3032 CA GLY B 442 16.058 -2.327 32.2931.00 22.82 ATOM 3033 C GLY B 442 16.217 -0.873 31.8851.00 24.19 ATOM 3034 O GLY B 442 15.290 -0.279 31.3411.00 20.21 ATOM 3035 N GLU B 443 17.387 -0.293 32.1411.00 22.92 ATOM 3036 CA GLU B 443 17.635 1.102 31.7781.00 23.33 ATOM 3037 CB GLU B 443 18.960 1.590 32.3781.00 24.26 ATOM 3038 CG GLU B 443 19.005 1.525 33.8951.00 32.31 ATOM 3039 CD GLU B 443 19.701 0.270 34.4021.00 37.68 ATOM 3040 OEI GLU B 443 19.343 -0.841 33.9481.00 35.23 ATOM 3041 OE2 GLU B 443 20.607 0.394 35.2521.00 42.47 ATOM 3042 C GLU B 443 17.662 1.278 30.2621.00 23.08 ATOM 3043 O GLU B 443 17.265 2.328 29.7471.00 21.80 ATOM 3044 N GLU B 444 18.128 0.253 29.5521.00 21.16 ATOM 3045 CA GLU B 444 18.182 0.302 28.0931.00 22.60 ATOM 3046 CB GLU B 444 19.046 -0.834 27.5451.00 20.89 ATOM 3047 CG GLU B 444 20.545 -0.617 27.7051.00 23.24 ATOM 3048 CD GLU B 444 21.340 -1.869 27.3931.00 22.11 ATOM 3049 OE1 GLU B 444 20.817 -2.978 27.6291.00 20.89 ATOM 3050 OE2 GLU B 444 22.488 -1.746 26.9141.00 25.49 ATOM 3051 C GLU B 444 16.758 0.155 27.5521.00 21.06 ATOM 3052 O GLU B 444 16.377 0.822 26.5971.00 23.73 ATOM 3053 N PHE B 445 15.987 -0.730 28.1761.00 19.01 ATOM 3054 CA PHE B 445 14.600 -0.969 27.7921.00 19.44 ATOM 3055 CB PHE B 445 13.989 -2.067 28.6751.00 18.12 ATOM 3056 CG PHE B 445 12.483 -2.055 28.7091.00 18.13 ATOM 3057 CD PHE B 445 11.746 -2.386 27.5751.00 18.34 ATOM 3058 CD2 PHE B 445 11.802 -1.694 29.8721.00 16.59 ATOM 3059 CEI PHE B 445 10.346 -2.359 27.5921.00 17.15 ATOM 3060 CE2 PHE B 445 10.406 -1.662 ?9.9031.00 21.99 ATOM 3061 CZ PHE B 445 9.674 -1.997 28.7551.00 16.01 ATOM 3062 C PHE B :445 13.758 0.304 27.8881.00 15.87 ATOM 3063 O PHE B =t45 13.008 0.617 26.9661.00 20.27 ATOM 3064 N VAL B 446 13.872 1.044 28.9861.00 15.90 ATOM 3065 CA VAL B 146 13.074 2.269 ?9.1121.00 16.78 ATOM 3066 CB VAL B :146 13.165 2.895 30.5311.00 18.32 .ATOM 3067 CGI VAL B .146 12.574 1.923 31.5511.00 21.14 aTOM 3068 CG2 VAL B 446 14.598 3.251 30.8791.00 21.04 ATOM 3069 C VAL B 446 13.450 3.295 28.0511.00 17.91 ATOM 3070 O VAL B 446 12.596 4.028 27.5611.00 19.37 ATOM 3071 N CYS B 447 14.723 3.335 27.6741.00 18.81 ATOM 3072 CA CYS B 447 15.161 ~ 4.25526.6351.00 17.34 ATOM 3073 CB CYS B 447 16.682 4.224 26.5121.00 19.33 ATOM 3074 SG CYS B 447 17.538 5.134 27.7981.00 23.60 ATOM 3075 C CYS B 447 14.537 3.826 25.3011.00 18.09 ATOM 3076 O CYS B 447 13.988 4.643 24.5631.00 17.52 ATOM 3077 N LEU B 448 14.623 2.533 25.0061.00 15.60 ATOM 3078 CA LEU B 448 14.072 1.994 23.7671.00 16.67 ATOM 3079 CB LEU B 448 14.328 0.490 23.6841.00 14.82 ATOM 3080 CG LEU B 448 15.730 0.009 23.3011.00 23.57 ~

ATOM 3081 CD1 LEU B 448 15.722 -1.522 23.1691.00 21.61 ATOM 3082 CD2 LEU B 448 16.167 0.658 21.9861.00 18.92 ATOM 3083 C LEU B 448 12.573 2.249 23.6521.00 15.98 ATOM 3084 O LEU B 448 12.078 2.633 22.5901.00 18.91 ATOM 3085 N LYS B 449 11.849 2.037 24.7451.00 17.94 ATOM 3086 CA LYS B 449 10.405 2.232 24.7331.00 16.66 ATOM 3087 CB LYS B 449 9.796 1.745 26.0471.00 16.45 ATOM 3088 CG LYS B 449 8.285 1.861 26.1151.00 16.12 ATOM 3089 CD LYS B 449 7.?30 0.952 27.1931.00 19.09 ATOM 3090 CE LYS B 449 8.201 1.380 28.5801.00 17.04 ATOM 3091 NZ LYS B 449 7.159 1.088 29.5931.00 17.25 ATOM 3092 C LYS B 449 10.058 3.696 24.4861.00 18.78 ATOM 3093 O LYS B 449 9.103 3.996 23.7691.00 14.84 ATOM 3094 N SER B 450 10.837 4.610 25.0591.00 14.50 ATOM 3095 CA SER B 450 10.591 6.032 24.8491.00 17.11 ATOM 3096 CB SER B 450 11.440 6.866 25.8151.00 21.20 ATOM 3097 OG SER B 450 10.859 6.868 27.1081.00 30.66 ATOM 3098 C SER B 450 10.921 6.418 23.4051.00 17.84 ATOM 3099 O SER B 450 10.279 7.292 22.8211.00 18.82 ATOM 3100 N ILE B 451 11.926 5.768 22.8281.00 16.88 ATOM 3101 CA ILE B 451 12.305 6.063 21.4501.00 17.11 ATOM 3102 CB ILE B 451 13.564 5.268 21.0251.00 16.69 ATOM 3103 CG2 ILE B 451 13.724 5.298 19.5051.00 19.31 ATOM 3104 CG ILE B ~IS 14.804 5.897 ? 1.6761.00 18.96 ATOM 3105 CD ILE B -151 16.083 5.130 21.43 1.00 18.98 ATOM 3106 C ILE B -151 11.142 5.711 20.5? 1.00 18.09 ATOM 3107 O ILE B :151 10.820 6.464 19.6081.00 17.07 ATOM 3108 N ILE B 452 10.505 4.571 20.7861.00 18.13 ATOM 3109 CA ILE B 452 9.373 4.137 19.9761.00 16.77 ATOM 3110 CB ILE B 452 8.804 2.775 20.4771.00 17.40 ATOM 3111 CG2 ILE B 452 7.464 2.496 19.8311.00 14.33 S ATOM 3112 CG1 ILE B 452 9.763 1.635 20.1071.00 15.36 ATOM 3113 CD ILE B 452 9.449 0.323 20.8051.00 17.76 ATOM 3114 C ILE B 452 8.271 S.19S 20.024i.00 17.47 ATOM 311 O ILE B 452 7.733 S.S86 18.9921.00 16.50 S

ATOM 3116 N LEU B 453 7.943 S.66S 21.2221.00 16.06 ATOM 3117 CA LEU B 453 6.903 6.680 21.3741.00 17.17 ATOM 3118 CB LEU B 453 6.736 7.061 22.8501.00 16.23 ATOM 3119 CG LEU B 453 5. 792 8.228 23.1631.00 17.60 ATOM 3120 CDI LEU B 453 4.388 7.881 22.7041.00 16.94 ATOM 3121 CD2 LEU B 453 5.816 8.538 24.6671.00 17.17 1 ATOM 3122 C LEU B 453 7.198 7.941 20.5661.00 19.33 S

ATOM 3123 O LEU B 453 6.320 8.458 19.8791.00 21.37 ATOM 3124 N LEU B 454 8.434 8.428 20.6361.00 17.68 ATOM 3125 CA LEU B 454 8.789 9.653 19.9331.00 20.93 ATOM 3126 CB LEU B 454 9.959 10.347 20.6531.00 24.33 ATOM 3127 CG LEU B 454 9.735 10.699 22.1301.00 26.16 ATOM 3128 CDl LEU B 454 11.046 11.170 22.7491.00 24.82 ATOM 3129 CD2 LEU B 454 8.658 11.777 22.2591.00 23.79 ATOM 3130 C LEU B 454 9.120 9.494 18.4491.00 20.75 ATOM 3131 O LEU B 454 8.941 10.431 17.6731.00 21.33 ATOM 3132 N ASN B 4SS 9.566 8.311 18.0421.00 20.54 ATOM 3133 CA ASN B 4SS 9.951 8.093 16.6511.00 19.46 ATOM 3134 CB ASN B 4SS 11.147 7.149 16.5841.00 18.58 ATOM 3135 CG ASN B 455 11.576 6.871 15.1611.00 17.64 ATOM 3136 OD ASN B 4SS 12.106 7.749 14.4961.00 18.40 ATOM 3137 ND2 ASN B 4SS 11.343 5.648 14.6861.00 15.06 ATOM 3138 C ASN B 4SS 8.925 7.580 1 S.65S1.00 22.77 ATOM 3139 O ASN B 4SS 8.790 8.127 14.5641.00 21.94 ~

ATOM 3140 N SER B 456 8.224 6.514 16.0231.00 25.90 ATOM 3141 CA SER B 456 7.260 5.873 15.1351.00 24.76 3S ATOM 3142 CB SER B 456 6.402 4.894 15.9391.00 26.91 ~

ATOM 3143 OG SER B 456 7.212 3.818 16.3901.00 26.24 ATOM 3144 C SER B 456 6.385 6.774 14.2721.00 26.52 ATOM 3145 O SER B 456 6.323 6.588 13.0551.00 29.22 ATOM 3146 N GLY B 457 5.716 7.750 14.8721.00 22.07 ATOM 3147 CA GLY B 457 4.879 8.627 14.0761.00 25.19 ATOM 3148 C GLY B 457 S.S10 9.973 13.7651.00 28.59 ATOM 3149 O GLY B 457 4.851 10.850 13.2141.00 28.31 ATOM 31 N VAL B 458 6.789 I 0.13014.0921.00 31.65 SO

ATOM 3151 CA VAL B 458 7.486 11.396 13.8791.00 38.50 4S ATOM 3152 CB VAL B 458 8.950 11.310 14.3731.00 36.24 ATOM 3153 CG1 VAL B 458 9.827 10.650 13.3241.00 38.50 ATOM 31 CG2 VAL B 458 9.463 12.699 14.7011.00 39.84 ATOM 31 C VAL B 458 7.483 11.982 12.4641.00 46.30 SS

ATOM 3156 O VAL B 468 7.567 13.201 12.3021.00 47.67 ATOM 3157 N TYR B :159 7.393 11.138 11.4421.00 60.45 ATOM 3158 CA TYR B 469 7.385 11.640 10.0691.00 67.07 ATOM 3159 CB TYR B 459 8.233 10.740 9.170 1.00 57.05 6 ATOM 3160 CG TYR B 469 9.673 10.680 9.611 1.00 59.29 ATOM 3161 CD TYR B 459 10.284 11.786 10.2031.00 60.93 ATOM 3162 CE1 TYR B 459 11.591 11.726 10.6621.00 61.86 ATOM 3163 CD2 TYR B 469 10.414 9.510 9.486 1.00 59.46 ATOM 3164 CE2 TYR B 459 11.726 9.439 9.943 1.00 59.67 ATOM 3165 CZ TYR B 459 12.305 10.548 10.5321.00 60.84 ATOM 3166 OH TYR B 459 13.593 10.477 11.0091.00 61.39 ATOM 3167 C TYR B 459 5.976 11.753 9.514 1.00 61.22 ATOM 3168 O TYR B 459 5.629 12.750 8.874 1.00 62.89 ATOM 3 N THR B 460 5. i 10.730 9.768 1.00 65.15 ATOM 3170 CA THR B 460 3.783 10.702 9.309 1.00 67.76 ATOM 3171 CB THR B 460 3.178 9.283 9.464 1.00 68.02 ATOM 3172 OG1 THR B 460 1.890 9.235 8.836 1.00 67.03 ATOM 3173 CG2 THR B 460 3.040 8.916 10.9381.00 67.31 ATOM 3174 C THR B 460 2.945 11.700 10.1071.00 70.14 ATOM 3175 O THR B 460 1.715 11.641 10.0991.00 72.35 ATOM 3176 N PHE B 461 3.625 12.620 10.7881.00 72.64 ATOM 3177 CA PHE B 461 2.969 13.637 11.6071.00 75.05 ATOM 3178 CB PHE B 461 3.977 14.720 12.0121.00 75.47 ATOM 3179 CG PHE B 461 4.235 14.789 13.4921.00 74.32 ATOM 3180 CD1 PHE B 461 3.200 14.609 14.4041.00 73.98 ATOM 3181 CD2 PHE B 461 5.517 15.025 13.9751.00 75.22 ATOM 3182 CE1 PHE B 461 3.438 14.662 15.7751.00 74.02 ATOM 3183 CE2 PHE B 461 5.765 15.080 15.3441.00 74.50 ATOM 3184 CZ PHE B 461 4.722 14.897 16.2451.00 74.10 ATOM 3185 C PHE B 461 1.787 14.286 10.8961.00 76.78 ATOM 3186 O PHE B 461 1.775 14.279 9.645 1.00 77.08 ATOM 3187 CB GLU B 470 7.873 23.789 14.7181.00 80.19 ATOM 3188 C GLU B 470 8.958 21.731 15.6501.00 79.30 ATOM 3189 O GLU B 470 9.887 21.518 16.4321.00 78.21 ATOM 3190 N GLU B 470 9.096 22.235 13.2271.00 80.22 ATOM 3191 CA GLU B 470 9.060 22.830 14.5951.00 80.03 ATOM 3192 N GLU B 471 7.823 21.037 I6.6661.00 78.31 ATOM 3193 CA GLU B 471 7.596 19.956 16.6171.00 75.83 ATOM 3194 CB GLU B 471 6.118 19.543 16.6041.00 76.70 ATOM 3195 CG GLU B 471 5.742 18.544 15.5161.00 78.42 ATOM 3196 CD GLU B 471 5.062 19.198 14.3271.00 79.69 ATOM 3197 OE1 GLU B 471 3.829 19.398 14.3781.00 80.26 ATOM 3198 OE2 GLU B 471 5.763 19.511 13.3401.00 80.72 ATOM 3199 C GLU B 471 8.487 18.756 16.2921.00 73.13 ATOM 3200 O GLU B 471 8.897 18.021 17.1891.00 73.86 ATOM 3201 N LYS B 472 8.785 18.666 16.0091.00 69.65 ATOM 3202 CA LYS B 472 9.639 17.461 14.5811.00 64.40 ATOM 3203 CB LYS B 472 9.578 17.293 13.0601.00 63.78 ATOM 3204 CG LYS B 472 8.343 16.55212.566 I.00 64.49 ATOM 3205 CD LYS B 472 8.544 16.00211.161 1.00 63.81 ATOM 3206 CE LYS B 472 7.379 16.36810.249 1.00 64.90 ATOM 3207 NZ LYS B 472 6.475 15.2129.990 1.00 63.97 ATOM 3208 C LYS B 472 11.071 17.74915.014 1.00 61.03 ATOM 3209 O LYS B 472 11.848 16.83315.287 1.00 60.28 ATOM 3210 N ASP B 473 11.413 19.03315.076 1.00 56.84 ATOM 3211 CA ASP B 473 12.745 19.45115.488 1.00 51.69 ATOM 3212 CB ASP B 473 12.923 20.94015.242 1.00 50.36 ATOM 3213 C ASP B 473 12.923 19.13816.970 1.00 49.18 ATOM 3214 O ASP B 473 13.959 18.61917.385 1.00 46.85 ATOM 3215 N HIS B 474 11.898 19.44917.758 1.00 45.35 ATOM 3216 CA HIS B 474 11.923 19.20319.196 1.00 43.65 ATOM 3217 CB HIS B 474 10.652 19.76119.847 1.00 43.70 ATOM 3218 CG HIS B 474 10.458 19.32621.267 1.00 43.86 ATOM 3219 CD2 HIS B 474 11.095 19.68822.406 1.00 44.12 ATOM 3220 NDI HIS B 474 9.510 18.39521.638 1.00 46.60 ATOM 3221 CE1 HIS B 474 9.572 18.20222.943 1.00 45.29 ATOM 3222 NE2 HIS B 474 10.526 18.97523.434 1.00 47.96 ATOM 3223 C HIS B 474 12.030 17.70719.471 1.00 42.38 ATOM 3224 O HIS B 474 12.834 17.27320.298 1:00 42.83 ATOM 3225 N ILE B 475 11.214 16.92318.773 1.00 38.86 ATOM 3226 CA ILE B 475 11.222 15.47518.943 1.00 36.53 ATOM 3227 CB ILE B 475 10.105 14.82218.110 1.00 36.56 ATOM 3228 CG2 ILE B 475 10.390 I3.33517.911 1.00 36.17 ATOM 3229 CG ILE B 475 8.770 14.998I 8.832I 35.81 1 .00 ATOM 3230 CD1 ILE B 475 7.598 14.41018.094 1.00 41.77 ATOM 3231 C ILE B 475 12.575 14.89818.532 1.00 33.72 ATOM 3232 O ILE B 475 13.112 14.02319.207 1.00 31.50 ATOM 3233 N HIS B 476 13.121 15.37517.429 1.00 33.65 ATOM 3234 CA HIS B 476 14.421 14.88616.992 1.00 33.31 ATOM 3235 CB HIS B 476 14.782 15.48115.637 1.00 37.30 ATOM 3236 CG HIS B 476 14.132 14.78114.486 1.00 43.64 ATOM 3237 CD2 HIS B 476 13.723 13.49814.342 1.00 45.25 ATOM 3238 ND1 HIS B 476 13.816 15.41913.306 1.00 48.37 ATOM 3239 CE1 HIS B 476 13.238 14.56012.484 1.00 48.87 ATOM 3240 NE2 HIS B 476 13.170 13.38713.089 1.00 48.11 ATOM 3241 C HIS B 476 15.506 15.21318.022 1.00 31.20 ATOM 3242 O HIS B 476 16.442 14.43618.208 1.00 27.25 ATOM 3243 N ARG B 477 15.387 16.36518.684 1.00 30.64 ATOM 3244 CA ARG B 477 16.361 16.75419.703 1.00 30.09 ATOM 3245 CB ARG B 477 16.144 18.21420.121 1.00 33.46 ATOM 3246 CG ARG B 477 16.322 19.21218.982 1.00 40.74 ATOM 3247 CD ARG B 477 16.274 20.64919.479 1.00 45.91 ATOM 3248 NE ARG B 477 17.5 21.02020.155 I 51.37 i 4 .00 ATOM 3249 CZ ARG B 477 18.375 21.92719.702 1.00 53.68 ATOM 3250 NHI ARG B 477 18.140 X2.56718.560 1.00 53.04 ATOM 3251 NH2 ARG B 477 19.480 22.18520.389 1.00 51.79 ATOM 3252 C ARG B 477 16.232 1 x.83520.9251.00 26.97 ATOM 3253 O ARG B 477 I 7.233 1 x.3872I 1.00 27.34 .486 ATOM 3254 N VAL B 478 14.999 1 x.55821.3381.00 23.70 ATOM 3255 CA VAL B 478 14.780 14.685 22.4821.00 24.79 ATOM 3256 CB VAL B 478 13.286 14.613 22.8611.00 24.83 ATOM 3257 CG1 VAL B 478 13.088 13.646 24.0221.00 26.23 ATOM 3258 CG2 VAL B 478 12.781 15.996 23.2431.00 28.26 ATOM 3259 C VAL B 478 15.284 13.294 22.1121.00 26.10 ATOM 3260 O VAL B 478 15.919 12.613 22.9271.00 24.28 ATOM 3261 N LEU B 479 15.021 12.889 20.8701.00 22.92 ATOM 3262 CA LEU B 479 15.456 11.584 20.3791.00 21.96 ATOM 3263 CB LEU B 479 14.992 11.372 18.9301.00 22.63 ATOM 3264 CG LEU B 479 13.575 10.798 18.7561.00 20.82 ATOM 3265 CD1 LEU B 479 13.231 10.689 17.2741.00 22.53 1 ATOM 3266 CD2 LEU B 479 I 3.495 9.440 19.4201.00 23.08 S

ATOM 3267 C LEU B 479 16.975 11.471 20.4531.00 21.90 ATOM 3268 O LEU B 479 17.506 10.416 20.7781.00 23.11 ATOM 3269 N ASP B 480 17.675 12.560 20.1431.00 23.65 ATOM 3270 CA ASP B 480 19.141 12.566 20.1981.00 24.29 ATOM 3271 CB ASP B 480 19.692 13.889 19.6491.00 26.88 ATOM 3272 CG ASP B 480 19.773 13.914 18.1291.00 33.32 ATOM 3273 OD1 ASP B 480 19.857 12.836 17.4991.00 35.44 ATOM 3274 OD2 ASP B 480 19.757 15.022 17.5631.00 32.44 ATOM 3275 C ASP B 480 19.590 12.406 21.6561.00 24.13 ATOM 3276 O ASP B 480 20.551 11.697 21.9561.00 24.88 ATOM 3277 N LYS B 481 18.887 13.077 22.5601.00 25.18 ATOM 3278 CA LYS B 481 19.213 13.010 23.9801.00 26.78 ATOM 3279 CB LYS B 481 18.262 13.898 24.7851.00 31.37 ATOM 3280 CG LYS B 481 18.962 14.788 25.8041.00 43.84 ATOM 3281 CD LYS B 481 18.780 14.260 27.2191.00 46.08 ATOM 3282 CE LYS B 481 20.120 13.928 27.8651.00 50.99 ATOM 3283 NZ LYS B 481 21.177 14.922 27.5111.00 54.35 ATOM 3284 C LYS B 481 19.124 11.575 24.4951.00 26.87 ATOM 3285 O LYS B 481 19.951 11.145 25.3051.00 20.37 ATOM 3286 N ILE B 482 18.124 i 0.83024.0271.00 23.26 ATOM 3287 CA ILE B 482 17.981 9.452 24.4721.00 21.07 ATOM 3288 CB ILE B 482 16.655 8.828 24.0151.00 19.80 ATOM 3289 CG2 ILE B 482 16.580 7.370 24.4911.00 17.40 ATOM 3290 CG ILE B 482 15.479 9.606 24.6021.00 17.16 ATOM 3291 CD1 ILE B 482 14.136 9.209 23.9911.00 19.43 ATOM 3292 C ILE B 482 19.135 8.616 23.9471.00 20.21 ATOM 3293 O ILE B 482 19.621 7.722 24.6401.00 25.5 ATOM 3294 N THR B 483 19.569 8.896 22.7221.00 21.89 ATOM 3295 CA THR B 483 20.701 8.176 22.1411.00 22.67 ATOM 3296 CB THR B 483 21.030 8.662 20.6951.00 23.34 ATOM 3297 OG1 THR B 483 19.890 8.475 19.8511.00 27.33 ATOM 3298 CG2 THR B 483 22.203 7.882 20.1 I 24.46 i .00 ATOM 3299 C THR B 483 21.913 8.441 23.0351.00 23.51 ll7 ATOM 3300 O THR B -483 22.650 7.520 23.38 1.00 27.01 t ATOM 3301 N ASP B ~t84 22.119 9.703 ?3.4041.00 22.8$

ATOM 3302 CA ASP B -484 23.237 10.058 2:1.2761.00 24.93 ATOM 3303 CB ASP B :184 23.201 11.546 24.6521.00 28.69 ATOM 3304 CG ASP B =184 23.504 12.464 X3.4851.00 29.19 ATOM 3305 ODl ASP B 484 23.982 11.984 ?.437 1.00 29.63 ATOM 3306 OD2 ASP B 484 23.256 13.681 23.6271.00 32.02 ATOM 3307 C ASP B 484 23.125 9.249 '_'x.5671.00 24.40 ATOM 3308 O ASP B 484 24.125 8.780 X6.1031.00 25.60 ATOM 3309 N THR B 485 21.899 9.096 26.0661.00 20.16 ATOM 3310 CA THR B 485 21.670 8.365 27.3071.00 22.28 ATOM 3311 CB THR B 485 20.203 8.521 27.7631.00 24.64 ATOM 3312 OG1 THR B 485 19.878 9.914 27.8301.00 24.28 ATOM 3313 CG2 THR B 485 19.993 7.896 29.1331.00 23.32 ATOM 3314 C THR B 485 22.017 6.881 27.1881.00 22.13 ATOM 3315 O THR B 485 22.574 6.284 28.1151.00 23.30 ATOM 3316 N LEU B 486 21.686 6.290 26.0451.00 23.08 ATOM 3317 CA LEU B 486 21.969 4.881 X5.7921.00 22.26 ATOM 3318 CB LEU B 486 21.346 4.452 24.4641.00 20.93 ATOM 3319 CG LEU B 486 19.878 4.031 24.5331.00 24.92 ATOM 3320 CD1 LEU B 486 19.295 4.003 23.1231.00 21.96 ATOM 3321 CD2 LEU B 486 19.763 2.658 25. 1.00 23.90 i ATOM 3322 C LEU B 486 23.477 4.634 25.7421.00 24.12 ATOM 3323 O LEU B 486 23.984 3.681 26.3341.00 24.02 ATOM 3324 N ILE B 487 24.191 5.490 25.0221.00 24.53 ATOM 3325 CA ILE B 487 25.640 5.345 24.9131.00 25.16 ATOM 3326 CB ILE B 487 26.207 6.379 23.899i.00 25.57 ATOM 3327 CG2 ILE B 487 27.725 6.522 24.0511.00 24.54 ATOM 3328 CG1 ILE B 487 25.857 5.936 22.4701.00 25.63 ATOM 3329 CD1 ILE B 487 26.538 4.646 22.0211.00 25.68 ATOM 3330 C ILE B 487 26.275 5.518 26.3071.00 23.60 ATOM 3331 O ILE B 487 27.200 4.794 26.6711.00 23.65 ATOM 3332 N HIS B 488 25.755 6.456 27.0811.00 21.75 ATOM 3333 CA HIS B 488 26.251 6.720 28.4311.00 26.07 ATOM 3334 CB HIS B 488 25.450 7.871 29.0411.00 26.99 ATOM 3335 CG HIS B 488 25.818 8.196 30.45 1.00 33.06 ATOM 3336 CD2 HIS B 488 25.245 7.838 31.6291.00 32.79 ATOM 3337 ND1 HIS B 488 26.869 9.025 30.7791.00 36.45 ATOM 3338 CE1 HIS B 488 26.927 9.164 32.0911.00 35.93 ATOM 3339 NE2 HIS B 488 25.953 8.453 32.6301.00 33.88 ATOM 3340 C HIS B 488 26.123 5.463 29.2921.00 26.85 ATOM 3341 O HIS B 488 27.071 5.054 X9.9671.00 28.52 .

ATOM 3342 N LEU B 489 24.949 4.850 X9.2661.00 28.00 ATOM 3343 CA LEU B 489 24.715 3.642 30.0401.00 25 ATOM 3344 CB LEU B 489 23.298 3.127 X9.7881.00 .
27.07 ATOM 3345 CG LEU B 489 22.158 3.909 30.44 1.00 31 ATOM 3346 CDi LEU B 489 20.827 3.516 X9.7991.00 .
28.08 ATOM 3347 CD2 LEU B 489 22.143 3.616 31.9491.00 29.30 ATOM 3348 C LEU B 489 25.718 ?.561 29.642 1.00 ?6.84 ATOM 3349 O LEU B 489 26.241 1.832 30.486 1.00 X0.86 ATOM 3350 N MET B 490 25.978 2.453 28.345 1.00 ?3.82 ATOM 3351 CA MET B 490 26.900 1.438 27.857 1.00 ?6.38 ATOM 3352 CB MET B 490 26.775 1.306 26.336 1.00 '_'7.29 ATOM 3353 CG MET B 490 25.418 0.776 25.895 1.00 ?
1.68 ATOM 3354 SD MET B 490 25.208 0.739 24.106 1.00 '_'6.30 ATOM 3355 CE MET B 490 23.461 0.412 24.022 1.00 19.66 ATOM 3356 C MET B 490 28.341 1.743 28.247 1.00 '_'6.42 ATOM 3357 O MET B 490 29.109 0.833 28.574 1.00 ?4.76 ATOM 3358 N ALA B 491 28.713 3.018 28.207 1.00 26.67 ATOM 3359 CA ALA B 491 30.074 3.394 28.577 1.00 30.73 ATOM 3360 CB ALA B 491 30.299 4.882 28.335 1.00 26.66 ATOM 3361 C ALA B 491 30.250 3.053 30.056 1.00 32.08 ATOM 3362 O ALA B 491 31.194 2.361 30.438 1.00 34.66 ATOM 3363 N LYS B 492 29.316 3.523 30.878 1.00 33.17 ATOM 3364 CA LYS B 492 29.354 3.267 32.309 1.00 32.82 ATOM 3365 CB LYS B 492 28.110 3.849 32.976 1.00 36.38 ATOM 3366 CG LYS B 492 28.412 4.797 34.123 1.00 38.68 ATOM 3367 CD LYS B 492 27.242 4.887 35.084 1.00 41.41 ATOM 3368 CE LYS B 492 26.299 6.013 34.698 1.00 47.57 ATOM 3369 NZ LYS B 492 26.395 7.184 35.618 1.00 50.76 ATOM 3370 C LYS B 492 29.453 1.771 32.619 1.00 34.08 ATOM 3371 O LYS B 492 30.090 1.382 33.593 1.00 34.31 ATOM 3372 N ALA B 493 28.835 0.935 31.788 1.00 32.03 ATOM 3373 CA ALA B 493 28.867 -0.51031.998 1.00 30.70 ATOM 3374 CB ALA B 493 27.719 -1.18131.245 1.00 28.80 ATOM 3375 C ALA B 493 30.201 -1.15631.606 1.00 33.75 ATOM 3376 O ALA B 493 30.402 -2.35631.819 1.00 30.53 ATOM 3377 N GLY B 494 31.102 -0.37231.020 1.00 33.50 ATOM 3378 CA GLY B 494 32.405 -0.90330.656 1.00 33.71 ATOM 3379 C GLY B 494 32.639 -1.36029.230 1.00 34.40 ATOM 3380 O GLY B 494 33.663 -1.98928.950 1.00 33.13 ATOM 3381 N LEU B 495 31.712 -1.05628.326 1.00 31.76 ATOM 3382 CA LEU B 495 31.859 -1.45226.925 1.00 30.57 ATOM 3383 CB LEU B 495 30.494 -1.41526.216 1.00 30.67 ATOM 3384 CG LEU B 495 29.610 -2.67526.256 1.00 29.59 ATOM 3385 CD1 LEU B 495 29.315 -3.05827.700 1.00 26.60 ATOM 3386 CD2 LEU B 495 28.307 -2.41625.501 1.00 27.52 ATOM 3387 C LEU B 495 32.829 -0.51526.202 1.00 30.53 ATOM 3388 O LEU B 495 32.855 0.688 26.468 1.00 28.14 ATOM 3389 N THR B 496 33.628 -1.06425.291 1.00 28.03 ATOM 3390 CA THR B 496 34.567 -0.24324.529 1.00 ?9.06 ATOM 3391 CB THR B 496 35.511 -1.09523.665 1.00 29.40 ATOM 3392 OG1 THR B 496 34.753 -1.75822.641 1.00 30.29 ATOM 3393 CG2 THR B 496 36.228 -2.12224.515 1.00 28.12 ATOM 3394 C THR B 496 33.770 0.652 23.590 1.00 30.12 ATOM 3395 O THR B 496 32.580 0.433 23.380 1.00 ?9.74 ATOM 3396 N LEU B 197 34.430 1.654 ?3.0181.00 30.44 ATOM 3397 CA LEU B 497 33.762 2.567 22.1041.00 28.54 ATOM 3398 CB LEU B -197 34.768 3.564 ? 1.5291.00 31.14 ATOM 3399 CG LEU B -t97 35.209 4.719 ?2.4341.00 33.58 ATOM 3400 CD1 LEU B 497 36.120 5.659 21.6521.00 31.42 ATOM 3401 CD2 LEU B 497 33.992 x.469 ??.9421.00 35.08 ATOM 3402 C LEU B 497 33.095 1.800 ?0.9671.00 27.35 ATOM 3403 O LEU B 497 31.967 2.105 20.5741.00 24.03 ATOM 3404 N GLN B 498 33.798 0.797 20.4471.00 26.17 ATOM 3405 CA GLN B .198 33.289 -0.009 19.3481.00 26.32 ATOM 3406 CB GLN B 498 34.411 -0.876 18.7711.00 27.25 ATOM 3407 CG GLN B 498 33.967 -1.796 17.6451.00 32.67 ATOM 3408 CD GLN B 498 34.965 -2.912 17.3741.00 38.39 ATOM 3409 OE1 GLN B 498 35.737 -3.298 18.2541.00 36.78 ATOM 3410 NE2 GLN B 498 34.953 -3.437 16.1531.00 33.18 ATOM 3411 C GLN B 498 32.112 -0.888 19.7741.00 25.70 ATOM 3412 O GLN B 498 31.167 -1.076 19.0091.00 25.35 ATOM 3413 N GLN B 499 32.173 -1.434 20.9861.00 24.01 ATOM 3414 CA GLN B 499 31.093 -2.281 21.4871.00 25.34 ATOM 3415 CB GLN B 499 31.501 -2.935 22.8151.00 28.38 ATOM 3416 CG GLN B 499 32.537 -4.056 22.6691.00 29.13 ATOM 3417 CD GLN B 499 32.913 -4.687 23.9951.00 30.80 ATOM 3418 OE1 GLN B 499 33.306 -3.997 24.9371.00 33.62 ATOM 3419 NE2 GLN B 499 32.797 -6.004 24.0741.00 30.64 ATOM 3420 C GLN B 499 29.842 -1.430 21.6931.00 25.70 ATOM 3421 O GLN B 499 28.715 -1.910 21.5541.00 26.22 ATOM 3422 N GLN B 500 30.062 -0.160 22.0201.00 23.09 ATOM 3423 CA GLN B 500 28.989 0.793 22.2561.00 23.53 ATOM 3424 CB GLN B 500 29.564 2.107 22.7821.00 26.17 ATOM 3425 CG GLN B 500 29.958 2.073 24.2521.00 27.71 ATOM 3426 CD GLN B 500 30.812 3.262 24.6411.00 29.32 ATOM 3427 OE1 GLN B 500 30.559 4.386 24.2071.00 28.48 ATOM 3428 NE2 GLN B 500 31.831 3.021 25.4631.00 25.07 ATOM 3429 C GLN B 500 28.151 1.074 21.0151.00 24.24 ATOM 3430 O GLN B 500 26.923 0.949 21.0531.00 24.40 ATOM 3431 N HIS B 501 28.790 1.465 19.9151.00 23.08 ATOM 3432 CA HIS B 501 28.004 1.739 18.7241.00 26.92 ATOM 3433 CB HIS B 501 28.791 2.577 17.6971.00 32.00 ATOM 3434 CG HIS B 501 29.988 1.896 17.1051.00 36.97 ATOM 3435 CD2 HIS B 501 30.122 0.710 16.4651.00 40.32 ATOM 3436 ND1 HIS B 501 31.224 2.505 17.0421.00 37.88 ATOM 3437 CE1 HIS B ~O1 32.066 1.724 16.3891.00 38.81 ATOM 3438 NE2 HIS B ~O1 31.422 0.628 16.0281.00 41.21 ATOM 3439 C HIS B ~O1 27.451 0.457 18.1231.00 25.91 ATOM 3440 O HIS B ~O1 26.369 0.457 17.5311.00 20.13 ATOM 3441 N GLN B 502 28.165 -0.648 18.3171.00 24.94 ATOM 3442 CA GLN B 502 27.698 -1.926 17.8041.00 21.88 ATOM 3443 CB GLN B X02 28.785 -2.996 17.9531.00 24.62 ATOM 3444 CG GLN B 502 29.796 -3.001 16.7971.00 26.55 ATOM 3445 CD GLN B 502 30.843 -4.109 16.9021.00 27.06 ATOM 3446 OE1 GLN B 502 30.716 -5.033 17.7051.00 28.49 ATOM 3447 NE2 GLN B 502 31.882 -4.018 16.0781.00 21.90 ATOM 3448 C GLN B 502 26.428 -2.341 18.5541.00 22.39 ATOM 3449 O GLN B 502 25.464 -2.807 17.9441.00 22.24 ATOM 3450 N ARG B 503 26.421 -2.159 19.8741.00 20.54 ATOM 3451 CA ARG B 503 25.259 -2.523 20.6781.00 22.04 ATOM 3452 CB ARG B 503 25.602 -2.519 22.1801.00 22.51 ATOM 3453 CG ARG B 503 24.451 -3.022 23.0771.00 23.34 ~

ATOM 3454 CD ARG B 503 24.853 -3.110 24.5501.00 22.18 ATOM 3455 NE ARG B 503 23.743 -3.546 25.3951.00 19.62 ATOM 3456 CZ ARG B 503 23.329 -4.807 25.4971.00 19.88 ATOM 3457 NH1 ARG B 503 23.933 -5.765 24.8091.00 16.40 ATOM 3458 NH2 ARG B 503 22.303 -5.110 26.2801.00 19.71 ATOM 3459 C ARG B 503 24.102 -1.558 20.4091.00 19.05 ATOM 3460 O ARG B 503 22.945 -1.968 20.3511.00 18.87 ATOM 3461 N LEU B 504 24.414 -0.276 20.2391.00 20.19 ATOM 3462 CA LEU B 504 23.375 0.714 19.9691.00 19.33 ATOM 3463 CB LEU B 504 23.972 2.117 19.8551.00 16.25 ATOM 3464 CG LEU B 504 22.983 3.173 19.3441.00 20.35 ATOM 3465 CD LEU B 504 21.930 3.449 20.4271.00 17.97 ATOM 3466 CD2 LEU B 504 23.729 4.448 i 8.9551.00 20.86 ATOM 3467 C LEU B 504 22.659 0.357 18.6671.00 21.22 ATOM 3468 O LEU B 504 21.433 0.478 18.5661.00 19.28 ATOM 3469 N ALA B 505 23.428 -0.085 17.6761.00 18.55 ATOM 3470 CA ALA B 505 22.859 -0.473 16.3961.00 18.20 ATOM 3471 CB ALA B 505 23.973 -0.745 15.3821.00 18.45 ATOM 3472 C ALA B 505 21.986 -1.716 16.5621.00 19.54 ATOM 3473 O ALA B 505 20.871 -1.774 16.0411.00 17.63 ATOM 3474 N GLN B 506 22.497 -2.706 17.2931.00 20.30 ATOM 3475 CA GLN B 506 21.772 -3.955 17.5131.00 19.48 ATOM 3476 CB GLN B 506 22.590 -4.893 18.4091.00 21.75 ATOM 3477 CG GLN B 506 23.798 -5.551 17.7271.00 20.85 ATOM 3478 CD GLN B 506 24.819 -6.070 18.7361.00 26.18 ATOM 3479 OE1 GLN B 506 24.564 -6.084 19.9431.00 21.83 ATOM 3480 NE2 GLN B 506 25.977 -6.499 18.2451.00 25.39 ATOM 3481 C GLN B 506 20.421 -3.672 18.1661.00 21.39 ATOM 3482 O GLN B 506 19.396 -4.233 17.7661.00 20.87 ATOM 3483 N LEU B 507 20.433 -2.800 19.1711.00 19.52 ATOM 3484 CA LEU B 507 19.219 -2.4I8 19.8841.00 23.04 ATOM 3485 CB LEU B 507 19.548 -1.455 21.0301.00 22.82 ATOM 3486 CG LEU B 507 20.182 -2.011 22.3131.00 26.12 ATOM 3487 CDI LEU B 507 20.203 -0.916 23.3601.00 29.33 ATOM 3488 CD2 LEU B 507 19.415 -3.213 22.8161.00 ?7.80 ATOM 3489 C LEU B 507 18.212 -1.730 18.9711.00 22.19 ATOM 3490 O LEU B 507 17.036 -2.070 18.9641.00 23.00 ATOM 3491 N LEU B 508 18.678 -0.745 18.2141.00 21.53 ATOM 3492 CA LEU B 508 17.797 0.006 17.3321.00 20.60 ATOM 3493 CB LEU B 508 18.535 1.236 16.8051.00 17.57 ATOM 3494 CG LEU B 508 18.934 ?.218 17.9131.00 17.67 ATOM 3495 CD LEU B 508 19.566 3.446 17.3011.00 20.04 ATOM 3496 CD2 LEU B 508 17.724 2.611 18.7251.00 18.49 ATOM 3497 C LEU B 508 17.235 -0.831 16.1831.00 21.17 ATOM 3498 O LEU B 508 16.118 -0.597 15.7281.00 2I.88 ATOM 3499 N LEU B 509 18.000 -1.813 15.7131.00 21.89 ATOM 3500 CA LEU B 509 17.511 -2.657 14.6311.00 22.81 ATOM 3501 CB LEU B 509 18.603 -3.597 14.1451.00 22.65 ATOM 3502 CG LEU B 509 19.645 -2.891 13.2781.00 29.11 ATOM 3503 CD LEU B 509 20.697 -3.888 12.8291.00 25.69 ATOM 3504 CD2 LEU B 509 18.965 -2.248 12.0821.00 27.92 ATOM 3505 C LEU B 509 16.302 -3.462 15.0951.00 23.32 ATOM 3506 O LEU B 509 15.409 -3.759 14.3031.00 23.36 ATOM 3507 N ILE B 510 16.264 -3.796 16.3801.00 23.36 ATOM 3508 CA ILE B 510 15.148 -4.562 16.9121.00 20.99 ATOM 3509 CB ILE B 510 15.448 -5.041 18.3611.00 28.60 ATOM 3510 CG2 ILE B 510 14.162 -5.435 19.0751.00 28.10 ATOM 3511 CGI ILE B 510 16.383 -6.260 18.3081.00 26.57 ATOM 3512 CD1 ILE B 510 17.429 -6.301 19.4191.00 30.14 ATOM 3513 C ILE B 510 13.852 -3.746 16.8461.00 17.65 ATOM 3514 O ILE B 510 12.767 -4.308 16.7591.00 16.11 ATOM 3515 N LEU B 511 13.961 -2.421 16.8671.00 18.12 ATOM 3516 CA LEU B 511 12.772 -1.574 16.7741.00 16.95 ATOM 3517 CB LEU B 511 13.147 -0.100 16.9811.00 22.66 ATOM 3518 CG LEU B 511 13.607 0.262 18.4061.00 22.13 ATOM 3519 CD1 LEU B 511 13.404 1.751 18.6521.00 25.29 ATOM 3520 CD2 LEU B 511 12.830 -0.549 19.4251.00 25.08 ATOM 3521 C LEU B 511 12.112 -1.771 15.3971.00 16.65 ATOM 3522 O LEU B S1I 10.915 -1.578 15.2421.00 17.09 ATOM 3523 N SER B 512 12.901 -2.161 14.4011.00 15.83 ATOM 3524 CA SER B 512 12.355 -2.408 13.0721.00 18.66 ATOM 3525 CB SER B 512 13.484 -2.644 12.0741.00 17.62 ~

ATOM 3526 OG SER B 512 13.079 -3.550 11.0621.00 32.77 ATOM 3527 C SER B 512 11.454 -3.638 13.1541.00 18.54, ATOM 3528 O SER B 512 10.373 -3.683 12.5451.00 17.01 ATOM 3529 N HIS B S I3 11.899 -4.625 13.9291.00 15.54 ATOM 3530 CA HIS B 513 11.141 -5.860 14.1151.00 17.67 ATOM 3531 CB HIS B 513 12.013 -6.916 14.7901.00 19.03 ATOM 3532 CG HIS B 513 13.063 -7.475 13.8861.00 27.06 ATOM 3533 CD2 HIS B 513 12.980 -8.364 12.8681.00 28.40 ATOM 3534 ND1 HIS B 513 14.378 -7.066 13.9321.00 28.92 ATOM 3535 CEl HIS B 513 15.061 -7.678 12:9811.00 30.75 ATOM 3536 NE2 HIS B 513 14.235 -8.472 12.3211.00 30.08 ATOM 3537 C HIS B 513 9.895 -5.602 14.9581.00 15.35 ATOM 3538 O HIS B 513 8.846 -6.192 14.7041.00 14.83 ATOM 3539 N ILE B 514 10.012 -4.744 15.9421.00 13.35 ATOM 3540 CA ILE B ~ 14 8.865 -4.417 16.7761.00 15.48 ATOM 3541 CB ILE B 514 9.295 -3.534 17.9671.00 20.02 ATOM 3542 CG2 ILE B ~ 14 8.067 -2.918 18.6501.00 12.84 ATOM 3543 CGI ILE B ~ 14 10.093 -4.397 18.9621.00 22.87 ATOM 3544 CD1 ILE B 514 10.691 -3.641 20.1151.00 29.62 ATOM 3545 C ILE B ~ 14 7.797 -3.717 15.9231.00 15.16 ATOM 3546 O ILE B 514 6.606 -3.972 16.0781.00 16.61 ATOM 3547 N ARG B 515 8.224 -2.823 15.0301.00 16.33 ATOM 3548 CA ARG B 515 7.280 -2.138 14.1501.00 17.54 ATOM 3549 CB ARG B 515 8.010 -1.173 13.2141.00 20.15 ATOM 3550 CG ARG B 515 7.080 -0.454 12.2341.00 21.47 ATOM 3551 CD ARG B S 15 6.407 0.749 12.8911.00 26.05 ATOM 3552 NE ARG B 515 7.220 1.948 12.7161.00 24.91 ATOM 3553 CZ ARG B 515 6.734 3.175 12.5471.00 24.61 ATOM 3554 NH ARG B 515 5.424 3.393 12.5221.00 22.46 I

ATOM 3555 NH2 ARG B 515 7.569 4.182 12.3741.00 23.15 ATOM 3556 C ARG B 515 6.545 -3.182 13.3041.00 16.60 ATOM 3557 O ARG B 515 5.332 -3.093 13.0871.00 14.51 ATOM 3558 N HIS B 516 7.298 -4.171 12.8271.00 18.50 ATOM 3559 CA HIS B 516 6.743 -5.237 11.9971.00 17.26 ATOM 3560 CB HIS B 516 7.861 -6.176 11.5331.00 18.14 ATOM 3561 CG HIS B 516 7.405 -7.223 10.5681.00 24.87 ATOM 3562 CD2 HIS B 516 7.060 -8.521 10.7541.00 26.64 ATOM 3563 NDI HIS B 516 7.258 -6.978 9.220 1.00 21.82 ATOM 3564 CE1 HIS B 516 6.839 -8.078 8.619 1.00 28.42 ATOM 3565 NE2 HIS B 516 6.711 -9.028 9.526 1.00 24.47 ATOM 3566 C HIS B 516 5.685 -6.028 12.7591.00 16.87 ATOM 3567 O HIS B 516 4.596 -6.303 12.2401.00 14.81 ATOM 3568 N MET B 517 5.999 -6.396 13.9971.00 16.48 ATOM 3569 CA MET B 517 5.049 -7.162 14.8011.00 15.39 ATOM 3570 CB MET B 517 5.701 -7.587 16.1141.00 21.05 ATOM 3571 CG MET B 517 6.790 -8.638 15.9171.00 20.76 ATOM 3572 SD MET B 517 7.380 -9.320 17.4701.00 23.96 ATOM 3573 CE MET B 517 8.104 -7.879 18.2261.00 20.45 ATOM 3574 C MET B 517 3.789 -6.368 15.0801.00 16.23 ATOM 3575 O MET B 517 2.688 -6.924 15.1481.00 16.02 ATOM 3576 N SER B 518 3.954 -5.060 15.2471.00 13.32 ATOM 3577 CA SER B 518 2.827 -4.186 15.5051.00 16.34 ATOM 3578 CB SER B 518 3.316 -2.765 15.8351.00 17.48 ATOM 3579 OG SER B 518 2.234 -1.840 15.8431.00 17.46 ATOM 3580 C SER B 518 1.906 -4.147 14.2841.00 14.73 ATOM 3581 O SER B 518 0.688 -4.247 14.4171.00 19.16 ATOM 3582 N ASN B 519 2.474 -4.006 13.0911.00 14.52 ATOM 3583 CA ASN B 519 1.622 -3.953 11.9071.00 15.35 ATOM 3584 CB ASN B ~ 19 2.432 -3.509 10.6981.00 19.21 ATOM 3585 CG ASN B 519 2.700 -2.029 10.7291.00 20.58 ATOM 3586 ODI ASN B 519 1.839 -1.258 11.1501.00 26.36 ATOM 3587 ND2 ASN B 519 3.891 -1.618 10.3071.00 19.62 WO 99/50658 PC'TNS99/06937 ATOM 3588 C ASN B 519 0.911 -5.28011.658 1.00 16.74 ATOM 3589 O ASN B 519 -0.265 -5.29911.297 1.00 ?0.58 ATOM 3590 N LYS B 520 1.608 -6.38711.885 1.00 18.60 ATOM 3591 CA LYS B 520 0.992 -7.69911.717 1.00 ?0.04 ATOM 3592 CB LYS B 520 2.038 -8.80111.872 1.00 25.44 ATOM 3593 CG LYS B 520 3.037 -8.84910.728 1.00 31.68 ATOM 3594 CD LYS B 520 2.507 -9.6639.558 1.00 42.56 ATOM 3595 CE LYS B 520 2.186 -8.7788.364 1.00 45.61 ATOM 3596 NZ LYS B 520 1.435 -9.5267.312 1.00 46.00 ATOM 3597 C LYS B 520 -0.099 -7.86812.769 1.00 18.88 ATOM 3598 O LYS B 520 -1.183 -8.35812.478 1.00 21.75 ATOM 3599 N GLY B 521 0.191 -7.45513.998 1.00 17.83 ATOM 3600 CA GLY B 521 -0.792 -7.56915.058 1.00 16.19 ATOM 3601 C GLY B 521 -2.000 -6.67414.833 1.00 16.59 ATOM 3602 O GLY B 521 -3.128 -7.06015.125 1.00 16.57 ATOM 3603 N MET B 522 -1.766 -5.46714.326 1.00 17.48 ATOM 3604 CA MET B 522 -2.852 -4.52714.042 1.00 18.25 ATOM 3605 CB MET B 522 -2.276 -3.21213.516 1.00 21.27 ATOM 3606 CG MET B 522 -3.190 -2.01813.707 1.00 26.97 ATOM 3607 SD MET B 522 -3.199 -1.47715.417 1.00 30.35 ATOM 3608 CE MET B 522 -1.659 -0.60515.475 1.00 29.86 ATOM 3609 C MET B 522 -3.794 -5.11912.989 1.00 18.68 ATOM 3610 O MET B 522 -5.022 -5.00813.097 1.00 18.80 ATOM 3611 N GLU B 523 -3.205 -5.73111.966 1.00 18.22 ATOM 3612 CA GLU B 523 -3.968 -6.35710.889 1.00 23.41 ATOM 3613 CB GLU B 523 -3.031 -6.9469.830 1.00 28.74 ATOM 3614 CG GLU B 523 -2.224 -5.9359.030 1.00 34.42 ATOM 3615 CD GLU B 523 -1.095 -6.5978.239 1.00 45.58 ATOM 3616 OE1 GLU B 523 -0.131 -5.8947.857 1.00 49.48 ATOM 3617 OE2 GLU B 523 -1.169 -7.8257.999 1.00 45.97 ATOM 3618 C GLU B 523 -4.812 -7.48211.465 1.00 23.98 ATOM 3619 O GLU B 523 -5.993 -7.61611.147 1.00 ?2.08 ATOM 3620 N HIS B 524 -4.187 -8.28712.326 1.00 23.46 ATOM 3621 CA HIS B 524 -4.846 -9.42812.952 1.00 26.20 ATOM 3622 CB HIS B 524 -3.824 -10.24513.743 1.00 27.26 ATOM 3623 CG HIS B 524 -4.378 -11.50914.321 1.00 30.91 ATOM 3624 CD2 HIS B 524 -4.308 -12.79213.892 1.00 30.90 ATOM 3625 ND1 HIS B 524 -5.107 -11.53715.490 1.00 28.87 ATOM 3626 CEI HIS B 524 -5.461 -12.78015.757 1.00 30.45 ATOM 3627 NE2 HIS B 524 -4.989 -13.56114.803 1.00 ?9.19 ATOM 3628 C HIS B 524 -5.996 -9.02513.870 1.00 27.69 ATOM 3629 O HIS B 524 -7.061 -9.65613.860 1.00 25.00 ATOM 3630 N LEU B 525 -5.777 -7.97714.655 1.00 23.84 ATOM 3631 CA LEU B 525 -6.786 -7.49215.588 1.00 25.77 ATOM 3632 CB LEU B 525 -6.217 -6.35816.444 1.00 ?2.2?

ATOM 3633 CG LEU B 525 -7.164 -5.77817.498 1.00 26.8I

ATOM 3634 CDI LEU B 525 -7.763 -6.92218.321 1.00 23.32 ATOM 3635 CD2 LEU B 525 -6.414 -4.79318.399 1.00 18.95 ATOM 3636 C LEU B 525 -8.013 -6.995 14.8421.00 26.84 ATOM 3637 O LEU B 525 -9.154 -7.247 15.2491.00 26.73 ATOM 3638 N TYR B 526 -7.764 -6.271 13.7571.00 26.86 ATOM 3639 CA TYR B 526 -8.819 -5.726 12.9181.00 30.89 ATOM 3640 CB TYR B 526 -8.201 -4.818 11.8541.00 34.31 ATOM 3641 CG TYR B 526 -9.183 -4.223 10.8781.00 43.50 ATOM 3642 CD1 TYR B 526 -10.058 -3.211 11.2671.00 47.66 ATOM 3643 CE1 TYR B 526 -10.943 -2.636 10.3571.00 48.85 ATOM 3644 CD2 TYR B 526 -9.218 -4.651 9.552 1.00 48.52 ATOM 3645 CE2 TYR B 526 -10.098 -4.083 8.634 1.00 52.43 ATOM 3646 CZ TYR B 526 -10.955 -3.077 9.043 1.00 51.67 ATOM 3647 OH TYR B 526 -11.810 -2.504 8.129 1.00 57.01 ATOM 3648 C TYR B 526 -9.577 -6.880 12.2651.00 30.90 ATOM 3649 O TYR B 526 -10.793 -6.829 12.1131.00 31.48 ATOM 3650 N SER B 527 -8.849 -7.926 11.8891.00 31.39 ATOM 3651 CA SER B 527 -9.460 -9.095 11.2661.00 33.73 ATOM 3652 CB SER B 527 -8.377 -10.04810.7491.00 34.13 ATOM 3653 OG SER B 527 -8.945 -11.22210.1961.00 43.67 ATOM 3654 C SER B 527 -10.339 -9.813 12.2881.00 34.34 ATOM 3655 O SER B 527 -11.446 -10.26111.9731.00 33.42 ATOM 3656 N MET B 528 -9.840 -9.916 13.5/71.00 31.66 ATOM 3657 CA MET B 528 -10.574 -10.57214.5891.00 29.77 ATOM 3658 CB MET B 528 -9.682 -10.74315.8201.00 32.96 ATOM 3659 CG MET B 528 -8.651 -11.85915.6991.00 33.47 ATOM 3660 SD MET B 528 -9.359 -13.42715.1341.00 38.28 ATOM 3661 CE MET B 528 -10.265 -13.91516.5791.00 36.01 ATOM 3662 C MET B 528 -11.800 -9.747 14.9531.00 29.42 ATOM 3663 O MET B 528 -12.835 -10.29315.3311.00 28.65 ATOM 3664 N LYS B 529 -11.673 -8.429 14.8501.00 30.64 ATOM 3665 CA LYS B 529 -12.781 -7.533 15.1491.00 31.80 ATOM 3666 CB LYS B 529 -12.323 -6.079 15.0271.00 32.86 ATOM 3667 CG LYS B 529 -13.436 -5.043 15.1141.00 36.42 ATOM 3668 CD LYS B 529 -13.114 -3.852 14.2241.00 41.74 ATOM 3669 CE LYS B 529 -13.734 -2.564 14.7411.00 43.45 ATOM 3670 NZ LYS B 529 -15.221 -2.569 14.6341.00 46.51 ATOM 3671 C LYS B 529 -13.857 -7.840 14.1161.00 36.60 ATOM 3672 O LYS B 529 -15.049 -7.877 14.4241.00 34.04 ATOM 3673 N CYS B 530 -13.407 -8.083 12.8891.00 40.04 ATOM 3674 CA CYS B 530 -14.286 -8.409 11.7731.00 44.58 ATOM 3675 CB CYS B 530 -13.460 -8.535 10.4911.00 50.64 ATOM 3676 SG CYS B 530 -13.369 -7.034 9.504 1.00 67:65 ATOM 3677 C CYS B 530 -15.065 -9.692 12.0161.00 42.88 ATOM 3678 O CYS B 530 -16.274 -9.741 11.8071.00 40.15 ATOM 3679 N LYS B 531 -14.360 -10.73312.4471.00 41.92 ATOM 3680 CA LYS B 531 -14.980 -12.0231''.7281.00 42.60 ATOM 3681 CB LYS B 531 -13.907 -13.09112.9271.00 44.77 ATOM 3682 C LYS B 531 -15.844 -11.90713.9771.00 44.43 ATOM 3683 O LYS B 531 -16.623 -12.8041:1.2961.00 44.09 ATOM 3684 N ASN B 532 -15.678 -10.79314.6851.00 -14.98 ATOM 3685 CA ASN B 532 -16.437 -10.49615.8931.00 44.10 ATOM 3686 CB ASN B 532 -17.833 -10.00315.5061.00 45.14 ATOM 3687 CG ASN B 532 -18.526 -9.271 16.6331.00 46.54 ATOM 3688 OD1 ASN B 532 -19.729 -9.424 16.8371.00 50.62 ATOM 3689 ND2 ASN B 532 -17.771 -8.471 17.375I.00 46.07 ATOM 3690 C ASN B 532 -16.557 -11.65716.8821.00 43.34 ~

ATOM 3691 O ASN B 532 -17.655 -11.99417.3211.00 41.42 ATOM 3692 N VAL B 533 -15.434 -12.26417.2431.00 43.45 ATOM 3693 CA VAL B 533 -15.471 -13.37118.1901.00 =14.06 ATOM 3694 CB VAL B 533 -14.170 -14.21918.1201.00 45.56 ATOM 3695 CGI VAL B 533 -13.661 -14.26316.6831.00 45.67 ATOM 3696 CG2 VAL B 533 -13.107 -13.64419.0451.00 44.16 ATOM 3697 C VAL B 533 -15.670 -12.83519.6111.00 43.24 ATOM 3698 O VAL B 533 -15.894 -13.60220.5481.00 44.21 ATOM 3699 N VAL B 534 -15.596 -11.51119.7551.00 40.44 ATOM 3700 CA VAL B 534 -15.765 -10.84921.0491.00 37.80 ATOM 3701 CB VAL B 534 -14.630 -11.25922.0381.00 36.38 ATOM 3702 CGI VAL B 534 -13.324 -10.57521.6581.00 34.35 ATOM 3703 CG2 VAL B 534 -15.021 -10.91023.4631.00 39.34 ATOM 3704 C VAL B 534 -15.752 -9.329 20.8571.00 37.97 ATOM 3705 O VAL B 534 -15.026 -8.808 20.0081.00 39.45 ATOM 3706 N PRO B 535 -16.575 -8.597 21.6251.00 37.81 ATOM 3707 CD PRO B 535 -17.529 -9.078 22.6401.00 38.74 ATOM 3708 CA PRO B 535 -16.608 -7.135 21.4921.00 36.79 ATOM 3709 CB PRO B 535 -17.846 -6.729 22.2881.00 36.98 ATOM 3710 CG PRO B 535 -18.004 -7.809 23.2981.00 39.77 ATOM 3711 C PRO B 535 -15.338 -6.494 22.0491.00 33.95 ATOM 3712 O PRO B 535 -14.786 -6.963 23.0401.00 34.93 ATOM 3713 N LEU B 536 -14.881 -5.426 21.4091.00 33.42 ATOM 3714 CA LEU B 536 -13.675 -4.732 21.8511.00 33.40 ATOM 3715 CB LEU B 536 -12.829 -4.314 20.647I.00 29.31 ATOM 3716 CG LEU B 536 -12.219 -5.433 19.7981.00 30.06 ATOM 3717 CD1 LEU B 536 -11.344 -4.822 18.7141.00 30.85 ATOM 3718 CD2 LEU B 536 -11.398 -6.370 20.676I.00 28.96 ATOM 3719 C LEU B 536 -14.036 -3.498 22.666I.00 30.50 ATOM 3720 O LEU B 536 -15.024 -2.829 22.3831.00 29.91 ATOM 3721 N TYR B 537 -13.231 -3.194 23.6761.00 28.69 ATOM 3722 CA TYR B 537 -13.494 -2.032 24.5051.00 29.89 ATOM 3723 CB TYR B 537 -12.618 -2.071 25.7501.00 32.50 ATOM 3724 CG TYR B 537 -12.849 -3.327 26.5431.00 39.46 ATOM 3725 CD1 TYR B 537 -13.923 -3.431 27.4211.00 41.90 ATOM 3726 CE1 TYR B 537 -14.174 -4.609 28.1181.00 45.72 ATOM 3727 CD2 TYR B 537 -12.022 -4.435 26.3791.00 47.39 ATOM 3728 CE2 TYR B 537 -12.262 -5.620 27.0721.00 49.93 ATOM 3729 CZ TYR B 537 -13.340 -5.699 27.9401.00 48.80 ATOM 3730 OH TYR B 537 -13.582 -6.872 28.6241.00 53.90 ATOM 3731 C TYR B 537 -13.262 -0.761 23.7091.00 27.09 ATOM 3732 O TYR B X37 -I2.518 -0.757 22.729I.00 26.15 ATOM 3733 N ASP B 538 -13.909 0.315 24.141I.00 26.12 ATOM 3734 CA ASP B 538 -13.830 I.598 23.4611.00 25.27 ATOM 3735 CB ASP B 538 -14.748 2.598 24.1641.00 28.85 S ATOM 3736 CG ASP B 538 -16.227 2.285 23.9401.00 33.90 ATOM 3737 OD1 ASP B 538 -17.052 2.613 24.8191.00 32.68 ATOM 3738 OD2 ASP B 538 -16.562 1.707 22.8821.00 38.26 ATOM 3739 C ASP B 538 -12.447 2.217 23.2611.00 25.18 ATOM 3740 O ASP B 538 -12.120 2.626 22.1471.00 26.41 ~

ATOM 3741 N LEU B 539 -11.637 2.309 24.3131.00 20.76 ATOM 3742 CA LEU B 539 -10.312 2.911 24.1501.00 19.65 ATOM 3743 CB LEU B 539 -9.567 2.991 25.4961.00 17.48 ATOM 3744 CG LEU B 539 -8.116 3.511 25.4691.00 16.46 ATOM 3745 CD1 LEU B 539 -8.051 4.892 24.8381.00 16.43 ATOM 3746 CD2 LEU B 539 -7.564 3.569 26.8951.00 15.57 ATOM 3747 C LEU B 539 -9.484 2.127 23.1271.00 16.75 ATOM 3748 O LEU B 539 -8.862 2.716 22.2491.00 20.36 ATOM 3749 N LEU B 540 -9.487 0.803 23.239I.00 18.23 ATOM 3750 CA LEU B 540 -8.743 -0.048 22.3191.00 18.05 ATOM 3751 CB LEU B 540 -8.909 -1.528 22.7011.00 16.38 ATOM 3752 CG LEU B 540 -8.188 -2.554 21.8211.00 19.81 ATOM 3753 CDI LEU B 540 -6.679 -2.303 21.8281.00 19.27 ATOM 3754 CD2 LEU B 540 -8.473 -3.952 22.3271.00 18.00 ATOM 3755 C LEU B 540 -9.241 0.169 20.8911.00 21.50 ATOM 3756 O LEU B 540 -8.449 0.293 19.9641.00 20.41 ATOM 3757 N LEU B 541 -10.559 0.206 20.7261.00 22.40 ATOM 3758 CA LEU B 541 -11.164 0.419 19.4131.00 23.27 ATOM 3759 CB LEU B 541 -12.686 0.429 19.5271.00 25.12 ATOM 3760 CG LEU B 541 -13.410 -0.808 18.9991.00 36.53 ATOM 3761 CD1 LEU B 541 -14.910 -0.671 19.2731.00 30.98 ATOM 3762 CD2 LEU B 541 -13.136 -0.971 17.5081.00 31.93 ATOM 3763 C LEU B 541 -10.697 1.751 18.8421.00 22.46 ATOM 3764 O LEU B 541 -10.359 1.845 17.6661.00 26.29 ATOM 3765 N GLU B 542 -10.694 2.781 19.6801.00 23.96 ATOM 3766 CA GLU B 542 -10.248 4.106 19.2701.00 26.91 ATOM 3767 CB GLU B 542 -10.250 5.050 20.4681.00 30.84 ATOM 3768 CG GLU B 542 -11.166 6.245 20.3471.00 37.20 ATOM 3769 CD GLU B 542 -11.138 7.105 21.5971.00 39.98 ATOM 3770 OE1 GLU B 542 -12.223 7.385 22.1441.00 39.92 ATOM 3771 OE2 GLU B 542 -10.028 7.494 22.0341.00 38.96 ATOM 3772 C GLU B 542 -8.826 4.010 18.7241.00 27.90 ATOM 3773 O GLU B 542 -8.530 4.492 17.6341.00 29.32 ATOM 3774 N MET B 543 -7.945 3.388 19.4991.00 26.41 ATOM 3775 CA MET B 543 -6.552 3.237 19.1071.00 23.53 ATOM 3776 CB MET B 543 -5.749 2.591 20.2471.00 24.60 ATOM 3777 CG MET B 543 -5.812 3.338 21.5791.00 26.46 ATOM 3778 SD MET B 543 -5.3?3 x.084 21.4671.00 29.45 ATOM 3779 CE MET B 543 -3.585 4.971 21.3491.00 25.43 ATOM 3780 C MET B 543 -6.403 2.407 17.8321.00 25.80 ATOM 3781 O MET B 543 -S.S35 2.686 17.0041.00 23.59 ATOM 3782 N LEU B 544 -7.254 1.394 17.6731.00 27.74 ATOM 3783 CA LEU B 544 -7.202 O.S22 16.4991.00 26.32 S ATOM 3784 CB LEU B 544 -8.069 -0.721 16.7I91.00 26.75 ATOM 3785 CG LEU B 544 -8.274 -1.632 15.5021.00 28.12 ATOM 3786 CD1 LEU B 544 -6.956 -2.294 15.1361.00 26.36 ATOM 3787 CD2 LEU B 544 -9.330 -2.680 15.8031.00 27.00 ATOM 3788 C LEU B 544 -7.672 1.252 1 S.2S01.00 26.97 ATOM 3789 O LEU B 544 -7.036 1.181 14.1951.00 24.25 ATOM 3790 N ASP B 545 -8.787 1.961 15.3721.00 30.37 ATOM 3791 CA ASP B S4S -9.338 2.702 14.2441.00 32.34 ATOM 3792 CB ASP B 545 -10.668 3.346 14.6371.00 36.61 ATOM 3793 CG ASP B 545 -11.818 2.370 I4.S6S1.00 42.73 ATOM 3794 ODI ASP B S4S -12.858 2.624 15.2111.00 47.39 ATOM 3795 OD2 ASP B S4S -11.676 1.342 13.8631.00 46.96 ATOM 3796 C ASP B 545 -8.382 3.762 13.7111.00 31.27 ATOM 3?97 O ASP B S4S -8.443 4.120 12.5321.00 30.53 ATOM 3798 N ALA B 546 -7.506 4.272 14.5721.00 29.02 ATOM 3799 CA ALA B 546 -6.543 5.280 14.1411.00 31.21 ATOM 3800 CB ALA B 546 -5.646 5.693 15.3061.00 30.98 ATOM 3801 C ALA B 546 -5.697 4.731 12.9961.00 32.14 ATOM 3802 O ALA B 546 -5.189 5.490 12.1701.00 33.78 ATOM 3803 N HIS B 547 -S.SSS 3.410 12.9431.00 32.27 2S ATOM 3804 CA HIS B 547 -4.773 2.767 11.8921.00 37.73 ATOM 3805 CB HIS B 547 -3.991 1.576 12.4571.00 35.83 ATOM 3806 CG HIS B 547 -2.796 1.968 13.2691.00 34.54 ATOM 3807 CD2 HIS B 547 -2.698 2.553 14.4861.00 30.23 ATOM 3808 ND1 HIS B 547 -1.502 1.755 12.8401.00 34.23 ATOM 3809 CE1 HIS B 547 -0.659 2.193 13.7601.00 36.72 ATOM 3810 NE2 HIS B 547 -1.360 2.681 14.7681.00 31.48 ATOM 3811 C HIS B 547 -5.649 2.286 10.7351.00 43.69 ATOM 3812 O HIS B 547 -5.178 2.152 9.606 1.00 46.04 ATOM 3813 N ARG B 548 -6.919 2.020 11.0191.00 48.35 ATOM 3814 CA ARG B 548 -7.843 l .SS 9.993 1.00 54.74 ATOM 381 CB ARG B 548 -8.522 0.267 10.4521.00 54.66 S

ATOM 3816 C ARG B 548 -8.886 2.619 9.681 1.00 59.94 ATOM 3817 O ARG B 548 -8.580 3.812 9.672 1.00 62.81 ATOM 3818 N LEU B 549 -10.116 2.186 9.422 1.00 64.81 ATOM 3819 CA LEU B 549 -11.204 3.109 9.112 1.00 67.59 ATOM 3820 CB LEU B 549 -12.478 2.327 8.799 1.00 68.06 ATOM 3821 C LEU B 549 -11.449 4.069 10.2751.00 69.12 ATOM 3822 O LEU B 549 -11.451 5.297 10.0361.00 68.96 ATOM 3823 OXT LEU B 549 -11.634 3.579 11.4121.00 70.70 4S HETATM CP9 DES B 600 -4.547 -6.077 22.0001.00 18.55 HETATM CP8 DES B 600 -3.163 -6.365 21.4671.00 17.72 HETATM CP7 DES B 600 -2.89? -7.853 21.3811.00 21.17 HETATM CP6 DES B 600 -3.719 -8.SS 20.3741.00 22.05 WO 99/5065$ PCT/US99/06937 HETATM 3828 CP DES B 600 -3.405 -8.481 18.9981.00 ? 1.32 HETATM 3829 CP2 DES B 600 -4.239 -9.095 18.063I ~ 1 .00 61 HETATM 3830 CP3 DES B 600 -5.388 -9.771 18.5091.00 .

HETATM 3831 OP3 DES B 600 -6.244 -10.33917.6001.00 .

S HETATM 3832 CP4 DES B 600 -5.718 -9.858 19.8601.00 .
24.08 HETATM 3833 CPS DES B 600 -4.877 -9.240 20.7911.00 24 HETATM 3834 C7 DES B 600 -1.998 -8.460 22.1901.00 .
16.67 HETATM 3835 C6 DES B 600 -1.330 -7.834 23.3251.00 I5 HETATM 3836 CS DES B 600 -2.054 -7.642 24.5221.00 .

HETATM 3837 C4 DES B 600 -1.433 -7.072 25.6341.00 .

HETATM 3838 C3 DES B 600 -0.077 -6.685 25.5421.00 .

HETATM 3839 03 DES B 600 0.509 -6.113 26.6551.00 .
15.55 HETATM 3840 C2 DES B 600 0.669 -6.866 24.3531.00 18 HETATM 3841 C DES B 600 0.035 -7.440 23.2411.00 .

HETATM 3842 C8 DES B 600 -1.642 -9.903 21.9421.00 .

HETATM 3843 C9 DES B 600 -0.440 -10.00920.9981.00 .

HETATM 3844 C CBM B 417 -4.997 -22.99425.2731.00 .

HETATM 3845 04 CBM B 417 -4.789 -24.18725.0031.00 .

HETATM 3846 03 CBM B 417 -4.798 -22.55926.5521.00 .

HETATM 3847 C2 CBM B 417 -5.468 -21.96024.2641.00 .

HETATM 3848 C CBM B 530 -15.278 -5.124 10.243I .
1 .00 87 HETATM 3849 04 CBM B 530 -15.852 -5.086 9.064 1.00 .
87.68 HETATM 3850 03 CBM B 530 -15.832 -4.291 11.2011.00 86 HETATM 3851 C2 CBM B 530 -14.207 -5.886 10.6281.00 .

ATOM 3852 CB HIS C 687 9.818 -20.030-2.2111.00 .
63.34 ATOM 3853 C HIS C 687 10.133 -20.267-4.6891.00 63 ATOM 3854 O HIS C 687 11.204 -20.840-4.4721.00 .

ATOM 3855 N HIS C 687 7.944 -19.563-3.7581.00 .

ATOM 3856 CA HIS C 687 9.424 -19.484-3.5861.00 .

ATOM 3857 N LYS C 688 9.533 -20.281-5.8751.00 .

ATOM 3858 CA LYS C 688 10.101 -20.999-7.0091.00 .

ATOM 3859 CB LYS C 688 8.980 -21.540-7.9011.00 .

ATOM 3860 C LYS C 688 11.050 -20.127-7.8271.00 .

ATOM 3861 O LYS C 688 12.253 -20.379-7.8581.00 .

ATOM 3862 N ILE C 689 10.511 -19.103-8.4821.00 .

ATOM 3863 CA ILE C 689 11.326 -18.212-9.3061.00 .
53.09 ATOM 3864 CB ILE C 689 10.496 -17.057-9.8891.00 53 ATOM 3865 CG2 ILE C 689 II.334 -16.286 1.00 .

-10.902 54 ATOM 3866 CG1 ILE C 689 9.229 -17.603 1.00 .
-10.551 52 ATOM 3867 CD1 ILE C 689 8.406 -16.550 1.00 .

-11.258 50 ATOM 3868 C ILE C 689 12.513 -17.611-8.5601.00 .

ATOM 3869 O ILE C 689 13.616 -17.550-9.0971.00 .

ATOM 3870 N LEU C 690 12.288 -17.162-7.3291.00 .

ATOM 3871 CA LEU C 690 13.362 -16.570-6.5341.00 .

4S ATOM 3872 CB LEU C 690 12.812 -16.058-5.1991.00 .

ATOM 3873 CG LEU C 690 13.835 -15.501-4.2061.00 .

ATOM 3874 CD1 LEU C 690 14.575 -14.324-4.8311.00 .

ATOM 3875 CD2 LEU C 690 13.128 -15.078-2.9261.00 .
38.77 ATOM 3876 C LEU C 690 14.445 -17.615-6.282 1.00 -18.87 ATOM 3877 O LEU C 690 15.643 -17.340-6.393 1.00 x6.71 ATOM 3878 N HIS C 691 14.001 -18.818-5.939 1.00 51.36 ATOM 3879 CA HIS C 691 14.886 -19.946-5.675 1.00 53.35 ATOM 3880 CB HIS C 691 14.042 -21.203-5.460 1.00 58.64 ATOM 3881 CG HIS C 691 14.655 -22.195-4.526 1.00 62.94 ATOM 3882 CD2 HIS C 691 15.503 -23.227-4.751 1.00 64.95 ATOM 3883 ND1 HIS C 691 14.392 -22.202-3.173 1.00 65.49 ATOM 3884 CE1 HIS C 691 15.053 -23.195-2.605 1.00 68.18 ATOM 3885 NE2 HIS C 691 15.733 -23.833-3.540 1.00 68.77 ATOM 3886 C HIS C 691 15.824 -20.162-6.861 1.00 52.19 ATOM 3887 O HIS C 691 17.048 -20.153-6.717 1.00 47.53 ATOM 3888 N ARG C 692 15.222 -20.350-8.032 1.00 52.37 ATOM 3889 CA ARG C 692 15.949 -20.586-9.271 1.00 52.90 ATOM 3890 CB ARG C 692 14.955 -20.832-10.4101.00 54.04 ATOM 3891 CG ARG C 692 15.575 -20.826-11.7971.00 57.52 ATOM 3892 CD ARG C 692 14.528 -21.048-12.8741.00 58.25 ATOM 3893 NE ARG C 692 14.375 -19.878-13.7321.00 61.43 ATOM 3894 CZ ARG C 692 13.218 -19.260-13.9511.00 64.32 ATOM 3895 NH1 ARG C 692 12.108 -19.706-13.3781.00 63.22 ATOM 3896 NH2 ARG C 692 13.171 -18.197-14.7461.00 65.93 ATOM 3897 C ARG C 692 16.873 -19.434-9.639 1.00 53.09 ATOM 3898 O ARG C 692 18.047 -19.644-9.956 1.00 53.06 ATOM 3899 N LEU C 693 16.338 -18.217-9.607 1.00 50.73 ATOM 3900 CA LEU C 693 17.125 -17.039-9.945 1.00 49.53 ATOM 3901 CB LEU C 693 16.249 -15.784-9.881 1.00 49.56 ATOM 3902 CG LEU C 693 15.781 -15.245-11.2391.00 49.78 ATOM 3903 CD1 LEU C 693 15.219 -16.389-12.0791.00 50.30 ATOM 3904 CD2 LEU C 693 14.728 -14.170-11.0371.00 48.79 ATOM 3905 C LEU C 693 18.318 -16.904-9.006 1.00 48.38 ATOM 3906 O LEU C 693 19.382 -16.426-9.402 1.00 46.35 ATOM 3907 N LEU C 694 18.135 -17.329-7.761 1.00 46.74 ATOM 3908 CA LEU C 694 19.204 -17.272-6.775 1.00 49.41 ATOM 3909 CB LEU C 694 18.634 -17.415-5.362 1.00 45.20 ATOM 3910 CG LEU C 694 18.222 -16.128-4.643 1.00 40.19 ATOM 3911 CD1 LEU C 694 17.456 -16.474-3.371 1.00 41.65 ATOM 3912 CD2 LEU C 694 19.453 -15.307-4.317 1.00 35.91 ATOM 3913 C LEU C 694 20.172 -18.417-7.058 1.00 54.15 ATOM 3914 O LEU C 694 21.370 -18.320-6.776 1.00 53.55 ATOM 3915 N GLN C 695 19.634 -19.498-7.619 1.00 57.44 ATOM 3916 CA GLN C 695 20.416 -20.685-7.959 1.00 62.46 ATOM 3917 CB GLN C 695 19.477 -21.853-8.304 1.00 61.95 ATOM 3918 CG GLN C 695 19.548 -23.010-7.311 1.00 61.49 ATOM 3919 CD GLN C 695 18.454 -24.053-7.490 1.00 62.78 ATOM 3920 OE1 GLN C 695 18.262 -24.928-6.653 1.00 63.33 ATOM 3921 NE2 GLN C 695 17.720 -23.969-8.608 1.00 60.37 ATOM 3922 C GLN C 695 21.330 -20.414-9.149 1.00 65.13 ATOM 3923 O GLN C 695 22.517 -20.740-9.116 1.00 65.87 ATOM 3924 N ASP C 696 20.761 -19.824-10.1971.00 67.67 ATOM 3925 CA ASP C 696 21.492 -19.500-11.4201.00 70.66 ATOM 3926 CB ASP C 696 20.801 -18.348-12.1511.00 71.06 ATOM 3927 CG ASP C 696 20.127 -18.792-13.4301.00 71.70 ATOM 3928 OD1 ASP C 696 20.637 -18.455-14.5211.00 72.47 ATOM 3929 OD2 ASP C 696 19.086 -19.478-13.3421.00 71.41 ATOM 3930 C ASP C 696 22.951 -19.132-11.1691.00 72.41 ATOM 3931 O ASP C 696 23.245 -18.115-10.5411.00 72.56 ATOM 3932 N SER C 697 23.859 -19.967-11.6681.00 74.67 ATOM 3933 CA SER C 697 25.291 -19.741-11.5071.00 76.45 ATOM 3934 CB SER C 697 26.019 -21.076-11.3771.00 76.00 ATOM 3935 C SER C 697 25.841 -18.960-12.6961.00 78.44 ATOM 3936 O SER C 697 26.286 -17.809-12.4891.00 79.20 ATOM 3937 OXT SER C 697 25.818 -19.510-13.8201.00 80.07 ATOM 3938 CB LYS D 686 -14.070 13.66116.843 1.00 50.28 ATOM 3939 C LYS D 686 -13.682 14.41819.199 1.00 51.59 ATOM 3940 O LYS D 686 -12.629 14.73819.759 1.00 50.42 ATOM 3941 N LYS D 686 -12.910 15.79617.283 1.00 50.43 ATOM 3942 CA LYS D 686 -13.976 14.87217.769 1.00 50.62 ATOM 3943 N HIS D 687 -14.617 13.67619.787 1.00 49.91 ATOM 3944 CA HIS D 687 -14.447 13.17621.144 1.00 51.28 ATOM 3945 CB HIS D 687 -15.806 12.98421.828 1.00 54.12 ATOM 3946 CG HIS D 687 -15.713 12.33623.177 1.00 60.06 ATOM 3947 CD2 HIS D 687 -15.418 11.06423.539 1.00 61.05 ATOM 3948 ND1 HIS D 687 -15.911 13.03024.352 1.00 62.39 ATOM 3949 CE1 HIS D 687 -15.741 12.21525.378 1.00 62.76 ATOM 3950 NE2 HIS D 687 -15.441 11.01624.912 1.00 63.46 ATOM 3951 C HIS D 687 -13.691 11.84921.163 1.00 49.55 ATOM 3952 O HIS D 687 -14.099 10.87820.524 1.00 50.84 ATOM 3953 N LYS D 688 -12.593 11.81621.909 1.00 44.00 ATOM 3954 CA LYS D 688 -11.784 10.61122.038 1.00 40.31 ATOM 3955 CB LYS D 688 -10.446 10.77321.299 1.00 41.42 ATOM 3956 CG LYS D 688 -10.513 10.59519.780 1.00 42.76 ATOM 3957 CD LYS D 688 -9.123 10.71619.152 1.00 38.66 3S ATOM 3958 CE LYS D 688 -9.162 10.52917.640 1.00 38.28 ATOM 3959 NZ LYS D 688 -7.894 10.97016.986 1.00 31.58 ATOM 3960 C LYS D 688 -11.506 10.37823.517 1.00 36.70 ATOM 3961 O LYS D 688 -11.271 11.32624.266 1.00 33.38 ATOM 3962 N ILE D 689 -11.549 9.122 23.942 1.00 33.06 ATOM 3963 CA ILE D 689 -11.255 8.806 25.328 1.00 28.70 ATOM 3964 CB ILE D 689 -11.438 7.301 25.607 1.00 30.88 ATOM 3965 CG2 ILE D 689 -10.725 6.912 26.899 1.00 31.45 ATOM 3966 CG1 ILE D 689 -12.927 6.971 25.721 1.00 32.57 ATOM 3967 CD1 ILE D 689 -13.308 5.679 25.031 1.00 ?9.79 ATOM 3968 C ILE D 689 -9.790 9.193 25.541 1.00 27.64 ATOM 3969 O ILE D 689 -9.405 9.649 26.611 1.00 ?5.54 ATOM 3970 N LEU D 690 -8.985 9.021 24.496 1.00 ?4.25 ATOM 3971 CA LEU D 690 -7.563 9.348 24.549 1.00 ?6.63 ATOM 3972 CB LEU D 690 -6.903 9.021 23.2001.00 22.83 ATOM 3973 CG LEU D 690 -5.433 9.387 22.9921.00 25.47 ATOM 3974 CDl LEU D 690 -4.595 8.772 24.1081.00 24.03 ATOM 3975 CD2 LEU D 690 -4.956 8.898 21.6161.00 20.87 ATOM 3976 C LEU D 690 -7.344 10.823 24.9021.00 26.64 ATOM 3977 O LEU D 690 -6.408 11.165 25.6251.00 28.34 ATOM 3978 N HIS D 691 -8.206 11.694 24.3831.00 27.77 ATOM ;979 CA HIS D 691 -8.107 13.125 24.665i.00 29.16 ATOM 3980 CB HIS D 691 -9.156 13.907 23.8611.00 30.89 ATOM 3981 CG HIS D 691 -8.903 13.935 22.3861.00 37.09 ATOM 3982 CD2 HIS D 691 -7.750 14.000 21.6791.00 41.39 ATOM 3983 ND1 HIS D 691 -9.920 13.906 21.4581.00 41.65 ATOM 3984 CE1 HIS D 691 -9.407 13.953 20.2421.00 44.64 ATOM 3985 NE2 HIS D 691 -8.091 14.010 20.3471.00 41.94 ATOM 3986 C HIS D 691 -8.338 13.373 26.1591.00 26.65 ATOM 3987 O HIS D 691 -7.602 14.120 26.8021.00 24.50 ATOM 3988 N ARG D 692 -9.371 12.742 26.7031.00 25.70 ATOM 3989 CA ARG D 692 -9.691 12.912 28.1141.00 29.11 ATOM 3990 CB ARG D 692 -10.959 12.134 28.4721.00 30.84 ATOM 3991 CG ARG D 692 -11.255 12.129 29.9631.00 41.63 ATOM 3992 CD ARG D 692 -12.502 11.327 30.2901.00 48.83 ATOM 3993 NE ARG D 692 -13.618 12.198 30.6471.00 54.50 ATOM 3994 CZ ARG D 692 -14.498 12.677 29.7741.00 59.37 ATOM 3995 NH1 ARG D 692 -14.392 12.371 28.4861.00 60.97 ATOM 3996 NH2 ARG D 692 -15.483 13.464 30.1881.00 59.07 ATOM 3997 C ARG D 692 -8.548 12.451 29.0111.00 28.30 ATOM 3998 O ARG D 692 -8.139 13.167 29.9291.00 26.50 ATOM 3999 N LEU D 693 -8.030 11.259 28.7371.00 24.87 ATOM 4000 CA LEU D 693 -6.943 10.705 29.5361.00 27.17 ATOM 4001 CB LEU D 693 -6.674 9.254 29.1161.00 28.45 ATOM 4002 CG LEU D 693 -7.844 8.300 29.3911.00 30.40 ATOM 4003 CD1 LEU D 693 -7.575 6.932 28.7781.00 34.79 ATOM 4004 CD2 LEU D 693 -8.043 8.171 30.8941.00 32.02 ATOM 4005 C LEU D 693 -5.670 11.539 29.4401.00 25.96 ATOM 4006 O LEU D 693 -4.948 11.700 30.4281.00 27.01 ATOM 4007 N LEU D 694 -5.395 12.080 28.2571.00 25.33 ATOM 4008 CA LEU D 694 -4.207 12.906 28.0621.00 27.22 ATOM 4009 CB LEU D 694 -3.948 13.126 26.5721.00 24.61 ATOM 4010 CG LEU D 694 -3.118 12.080 25.8251.00 22.20 ATOM 4011 CD1 LEU D 694 -3.230 12.332 24.3241.00 21.13 ATOM 4012 CD2 LEU D 694 -1.666 12.148 26.2751.00 21.34 ATOM 4013 C LEU D 694 -4.336 14.270 28.7421.00 32.40 ATOM 4014 O LEU D 694 -3.339 14.889 29.1021.00 31.55 ATOM 401 N GLN D 695 -5.570 14.733 28.9151.00 36.93 S

ATOM 4016 CA GLN D 695 -5.820 16.032 29.5281.00 43.18 ATOM :1017CB GLN D 695 -7.022 16.694 28.86?1.00 40.48 ATOM :1018CG GLN D 695 -6.772 17.071 27.4221.00 37.99 ATOM :1019CD GLN D 695 -7.943 I7.764 26.7951.00 35.86 ATOM 4020 OEI GLN D 695 -7.863 18.895?6.342 1.00 38.84 ATOM 4021 NE2 GLN D 695 -9.082 17.06026.757 1.00 31.62 ATOM 4022 C GLN D 695 -6.049 16.00931.034 1.00 48.74 ATOM 4023 O GLN D 695 -6.119 17.06531.660 1.00 ~
I
.25 ATOM 4024 N ASP D 696 -6.175 14.81831.611 1.00 54.01 ATOM 4025 CA ASP D 696 -6.398 14.70233.047 1.00 62.23 ATOM 4026 CB ASP D 696 -6.217 13.23833.485 1.00 63.97 ATOM 4027 CG ASP D 696 -7.527 12.46733.475 1.00 67.72 ATOM 4028 ODI ASP D 696 -8.528 12.99632.941 1.00 68.11 ATOM 4029 OD2 ASP D 696 -7.552 11.33334.003 1.00 68.95 ATOM 4030 C ASP D 696 -5.456 15.62233.840 1.00 65.60 ATOM 4031 O ASP D 696 -4.312 15.18934.134 1.00 68.33 ATOM 4032 OXT ASP D 696 -5.874 16.75534.140 1.00 69.20 HETATM 4033 O HOH 1 16.153 -0.605-4.425 1.00 17.11 HETATM 4034 O HOH 2 16.570 -5.304-16.5601.00 21.44 HETATM 4035 O HOH 3 18.526 0.742 -4.495 1.00 23.43 HETATM 4036 O HOH 4 13.647 -?.1878.588 1.00 25.82 HETATM 4037 O HOH 5 9.778 -5.8252.509 1.00 20.58 HETATM 4038 O HOH 6 17.072 -3.605-8.015 1.00 18.38 HETATM 4039 O HOH 7 24.920 -1.689-2.780 1.00 25.74 HETATM 4040 O HOH 8 7.321 -5.6495.061 1.00 24.11 HETATM 4041 O HOH 9 25.976 -3.53515.158 1.00 26.78 HETATM 4042 O HOH Z O 15.088 -7.006-15.1921.00 19.64 HETATM 4043 O HOH 11 14.070 0.925 -5.953 1.00 20.55 HETATM 4044 O HOH 12 18.008 3.407 -6.654 1.00 32.30 HETATM 4045 O HOH 13 31.949 -8.39313.487 1.00 30.64 HETATM 4046 O HOH 14 19.625 -2.804-4.279 1.00 24.45 HETATM 4047 O HOH 15 11.741 1.079 -21.1401.00 25.87 HETATM 4048 O HOH 16 25.067 13.95114.153 1.00 31.07 HETATM 4049 O HOH 17 15.501 1.323 -10.3931.00 21.01 HETATM 4050 O HOH 18 13.880 3.349 -11.4821.00 24.28 HETATM 4051 O HOH 19 17.591 0.979 -8.828 1.00 35.26 HETATM 4052 O HOH 20 23.682 -2.041-0.314 1.00 37.90 HETATM 4053 O HOH 21 15.754 9.496 11.841 1.00 39.44 HETATM 4054 O HOH 22 -4.943 7.574 -3.066 1.00 37.67 HETATM 4055 O HOH 23 6.877 0.354 -15.9821.00 36.92 HETATM 4056 O HOH 24 15.806 -4.0028.671 1.00 30.38 HETATM 4057 O HOH 25 17.185 -3.158-5.321 1.00 28.89 HETATM 4058 O HOH 26 17.572 9.249 17.009 1.00 30.15 HETATM 4059 O HOH 27 24.096 -2.929I 1.6041.00 31.37 HETATM 4060 O HOH 28 22.324 -5.871-11.9801.00 32.74 HETATM 4061 O HOH 29 27.547 -12.361-0.801 1.00 36.61 HETATM 4062 O HOH 30 11.173 13.442-2.719 1.00 35.41 HETATM 4063 O HOH 31 15.438 -9.5275.483 1.00 29.88 HETATM 4064 O HOH 32 9.946 -6.5645.983 1.00 35.05 HETATM 4065 O HOH 33 7.599 11.680-15.2611.00 38.68 HETATM 4066 O HOH 34 20.112 10.503-5.109 1.00 42.66 HETATM 4067 O HOH 35 15.972 10.34314.897 1.00 41.73 HETATM 4068 O HOH 36 22.401 -x.914 -9.527 1.00 28.08 HETATM 4069 O HOH 37 16.128 -0.899 -8.109 1.00 33.13 HETATM 4070 O HOH 38 3.581 15.655 -3.706 1.00 41.37 HETATM 4071 O HOH 39 31.900 13.545 ? 1.3391.00 37.79 HETATM 4072 O HOH 40 20.058 -7.530 14.119 1.00 47.51 HETATM 4073 O HOH 41 34.634 6.668 1 x.6321.00 29.24 HETATM 4074 O HOH 42 17.968 10.511 -9.085 1.00 44.60 HETATM 4075 O HOH 43 23.258 -17.325--1.0881.00 44.10 HETATM 4076 O HOH 44 4.034 -1.472 27.521 1.00 15.22 HETATM 4077 O HOH 45 . -5.943 -0.018 36.088 1.00 21.11 HETATM 4078 O HOH 46 6.084 -1.509 29.478 1.00 19.51 HETATM 4079 O HOH 47 9.762 1.061 15.621 1.00 27.74 HETATM 4080 O HOH 48 1.804 0.7I7 I7.260 1.00 20.97 HETATM 4081 O HOH 49 0.929 0.421 30.281 1.00 19.64 HETATM 4082 O HOH 50 9.627 4.271 31.231 1.00 19.02 HETATM 4083 O HOH S I 2.121 -0.261 13.654 1.00 26.09 HETATM 4084 O HOH 52 20.060 10.275 17.71 1.00 25.49 I

HETATM 4085 O HOH 53 -6.786 0.736 33.483 1.00 22.34 HETATM 4086 O HOH 54 2.751 -4.136 27.760 1.00 19.93 :

HETATM 4087 O HOH 55 5.994 -4.079 31.292 1.00 32.27 HETATM 4088 O HOH 56 19.416 16.921 21.645 1.00 25.54 HETATM 4089 O HOH 57 4.833 2.325 29.006 1.00 19.00 HETATM 4090 O HOH 58 -7.638 -8.931 37.809 1.00 24.79 HETATM 4091 O HOH 59 28.442 -4.673 21.875 1.00 24.32 HETATM 4092 O HOH 60 1.094 -4.893 32.100 1.00 24.27 HETATM 4093 O HOH 61 0.905 -7.306 32.783 1.00 21.33 HETATM 4094 O HOH 62 3.396 -2.971 32.306 1.00 26.13 HETATM 4095 O HOH 63 10.363 4.576 28.391 1.00 33.43 HETATM 4096 O HOH 64 19.551 -6.473 16.597 1.00 35.38 HETATM 4097 O HOH 65 -2.888 -19.62715.665 1.00 27.99 HETATM 4098 O HOH 66 -7.275 -9.745 31.077 1.00 27.00 HETATM 4099 O HOH 67 10.189 3.580 16.510 1.00 24.19 HETATM 4100 O HOH 68 2.741 0.716 28.382 1.00 16.48 HETATM 4101 O HOH 69 23.522 -4.323 13.943 1.00 27.48 HETATM 4102 O HOH 70 17.133 8.133 19.686 1.00 32.24 HETATM 4103 O HOH 71 -0.295 4.535 35.884 1.00 33.42 HETATM 4104 O HOH 72 9.519 10.828 34.842 1.00 29.38 HETATM 4105 O HOH 73 6.291 14.878 29.070 1.00 28.21 HETATM 4106 O HOH 74 -1.721 6.480 13.381 1.00 49.91 HETATM 4107 O HOH 75 10.091 -15.42726.194 1.00 24.17 HETATM 4108 O HOH 76 5.029 7.461 17.718 1.00 18.91 HETATM 4109 O HOH 77 3.758 2.086 14.306 1.00 28.28 HETATM 4110 O HOH 78 -1.390 -18.73933.183 1.00 41.11 HETATM 4111 O HOH 79 12.703 -8.687 32.119 1.00 36.21 HETATM 4112 O HOH 80 22.270 -6.451 14.844 1.00 33.21 HETATM 4113 O HOH 81 1.458 4.605 34.026 1.00 23.59 HETATM 4114 O HOH 82 1.759 -2.158 30.374 1.00 28.78 HETATM 4115 O HOH 83 6.153 -21.37223.188 1.00 31.14 HETATM 4116 O HOH 84 36.525 0.463 20.7921.00 -1.26 HETATM 4117 O HOH 85 13.832 9.696 13.7921.00 33.12 HETATM 4118 O HOH 86 31.166 6.635 24.9241.00 35.19 HETATM 4119 O HOH 87 8.844 -10.38934.1801.00 48.80 HETATM 4120 O HOH 88 9.581 -6.956 34.1361.00 -12.95 HETATM 4121 O HOH 89 -1.563 15.887 ?7.5961.00 39.35 HETATM 4122 O HOH 90 -5.286 10.345 32.7571.00 35.20 HETATM 4123 O HOH 91 15.035 0.607 13.3391.00 29.53 HETATM 4124 O HOH 92 -10.984 -1.500 30.2721.00 ?9.84 HETATM 4125 O HOH 93 -7.239 -0.271 -1.2071.00 48.98 HETATM 4126 O HOH 94 18.022 -4.902 34.2861.00 35.28 HETATM 4127 O HOH 95 29.347 -6.319 19.9201.00 37.20 HETATM 4128 O HOH 96 -14.309 -19.36920.9451.00 30.23 HETATM 4129 O HOH 97 31.496 4.614 18.716I .00 3 8.79 1 HETATM 4130 O HOH 98 26.567 9.759 25.6291.00 29.72 S

HETATM 4131 O HOH 99 2.848 14.531 1.134 1.00 38.08 HETATM 4132 O HOH 100 -9.373 5.699 -7.9531.00 53.23 HETATM 4133 O HOH 101 -10.137 -0.553 -6.7421.00 47.72 HETATM 4134 O HOH 102 10.558 -10.36315.4031.00 40.97 HETATM 4135 O HOH 103 21.079 17.166 18.9291.00 32.40 HETATM 4136 O HOH 104 25.810 -5.921 22.5061.00 37.69 HETATM 4137 O HOH 105 22.493 -1.311 34.4651.00 49.94 HETATM 4138 O HOH 106 19.317 10.977 38.7031.00 40.60 HETATM 4139 O HOH 107 4.479 13.951 3.045 1.00 45.33 HETATM 4140 O HOH 108 20.418 19.353 34.0441.00 42.18 HETATM 4141 O HOH 109 -3.065 8.936 14.0621.00 38.41 HETATM 4142 O HOH 110 26.856 -4.674 -10.9401.00 55.67 HETATM 4143 O HOH 111 2.032 -6.387 5.614 1.00 42.23 HETATM 4144 O HOH 112 0.601 0.228 -17.2681.00 40.57 HETATM 4145 O HOH 113 4.903 13.488 -14.0501.00 47.72 HETATM 4146 O HOH 114 3.986 16.140 -0.9601.00 40.66 HETATM 4147 O HOH 115 12.968 -19.5612.741 1.00 40.76 HETATM 4148 O HOH 116 7.170 15.583 2.599 1.00 43.69 HETATM 4149 O HOH 117 -1.966 10.606 3.572 1.00 52.63 HETATM 4150 O HOH 118 29.030 10.644 6.707 1.00 42.54 HETATM 41 O HOH 119 0.468 4.354 8.374 1.00 38.69 HETATM 4152 O HOH 120 29.086 17.119 19.2721.00 45.51 HETATM 4153 O HOH 121 24.614 17.609 20.1741.00 53.55 HETATM 4154 O HOH 122 -15.318 0.362 26.6861.00 36.77 HETATM 4155 O HOH 123 -3.857 -24.78628.3251.00 39.64 HETATM 4156 O HOH 124 21.728 22.178 31.9831.00 43.73 HETATM 4157 O HOH 125 31.650 -7.370 21.6421.00 40.53 HETATM 4158 O HOH 126 25.421 10.436 21.1611.00 32.31 HETATM 4159 O HOH 127 10.317 -9.457 12.9981.00 37.77 HETATM 4160 O HOH 128 22.723 14.887 15.4271.00 17.90 HETATM 4161 O HOH 129 6.702 9.556 37.5961.00 47.81 HETATM 4162 O HOH 130 27.987 13.557 7.167 1.00 41.15 HETATM 4163 O HOH 131 30.798 16.499 7.588 1.00 58.47 HETATM 4164 O HOH 132 10.071 -0.571 -20.3931.00 38.79 HETATM 4165 O HOH 133 9.562 8.334 -21.3921.00 36.80 HETATM 4166 O HOH 134 6.712 6.058 8.822 1.00 37.43 HETATM 4167 O HOH 135 5.927 8.454 10.594 1.00 42.34 HETATM 4168 O HOH 136 4.472 6.306 10.973 1.00 37.35 HETATM 4169 O HOH 137 6.792 7.721 7.051 1.00 47.23 HETATM 4170 O HOH 138 24.513 11.582 33.724 1:00 45.55 HETATM 4171 O HOH 139 -2.528 -20.36112.354 1.00 52.13 HETATM 4172 O HOH 140 -7.864 7.706 19.248 1.00 47.82 HETATM 4173 O HOH 141 11.577 -16.96224.398 1.00 39.43 HETATM 4174 O HOH 142 18.087 12.263 -x.507 1.00 33.36 HETATM 4175 O HOH 143 -6.816 -14.19010.674 1.00 51.32 HETATM 4176 O HOH 144 -7.377 -16.70133.528 1.00 57.11 HETATM 4177 O HOH 145 -5.379 -20.10732.689 1.00 43.01 HETATM 4178 O HOH 146 8.766 -7.947 -16.2741.00 49.96 HETATM 4179 O HOH 147 10.946 -7.937 -18.1421.00 55.67 END

Appendix 2 Atomic Coordinates for Human ERa Complexed With OHT
CRYST1 X8.242 X8.242 277.467 90.00 90.00 120.00 P 6~ 2 2 12 ORIGX 1.0000000.000000 0.0000000.00000 ORIGX2 0.000000 1.000000 0.0000000.00000 ORIGX3 0.000000 0.000000 1.0000000.00000 SCALE 0.017170 0.009913 0.0000000.00000 SCALE2 0.000000 0.019826 0.0000000.00000 SCALE3 0.000000 0.000000 0.0036040.00000 ATOM 1 CB LEU 306 6.638 11.502 3.9891.00 61.20 ATOM ? C LEU 306 7.381 10.684 6.2311.00 61.47 1 ATOM 3 O LEU 306 6.407 11.020 6.9051.00 62.09 S

ATOM :1N LEU 306 6.369 9.128 4.5881.00 62.32 ATOM ~ CA LEU 306 7.232 10.330 4.7541.00 61.30 ATOM 6 N ALA 307 8.609 10.605 6.7301.00 60.52 ATOM 7 CA ALA 307 8.891 10.912 8.1251.00 58.77 ATOM 8 CB ALA 307 10.318 i 0.501 8.4651.00 59.70 ATOM 9 C ALA 307 8.692 12.393 8.4291.00 57.51 ATOM I0O ALA 307 8.451 12.770 9.5741.00 57.64 ATOM 11N LEU 308 8.789 13.228 7.400I.00 55.82 ATOM 12CA LEU 308 8.638 14.668 7.5731.00 56.62 ATOM 13CB LEU 308 9.298 15.402 6.4061.00 57.48 ATOM 14CG LEU 308 10.637 14.822 5.9481.00 59.17 ATOM I CD1 LEU 308 10.474 14.189 4.5691.00 60.38 S

ATOM I6CD2 LEU 308 11.694 15.920 5.9331.00 58.46 ATOM 17C LEU 308 7.190 15.130 7.7101.00 X6.51 ATOM 18O LEU 308 6.935 16.307 7.9611.00 X5.58 ATOM 19N SER 309 6.246 14.208 7.5461.00 X7.04 ATOM ?0CA SER 309 4.828 14.544 7.6571.00 56.46 ATOM 21CB SER 309 4.034 13.896 6.5141.00 56.79 ATOM '_'2OG SER 309 4.071 12.479 6.5881.00 57.23 ATOM 23C SER 309 4.261 14.095 9.0031.00 X6.13 ATOM 24O SER 309 3.166 14.507 9.3981.00 55.17 ATOM ?5N LEU 310 5.016 13.257 9.7061.00 54.31 ATOM ?6CA LEU 310 4.591 12.749 11.0041.00 53.55 ATOM ''7CB LEU 310 5.651 11.811 11.5821.00 54.40 ATOM '_'8CG LEU 310 5.586 10.333 11.1891.00 X6.49 ATOM ?9CD1 LEU 310 5.530 10.200 9.6761.00 X7.06 ATOM 30CD2 LEU 310 6.809 9.610 11.7391.00 X7.28 ATOM 3IC LEU 310 4.330 13.865 12.0031.00 X3.18 ATOM 3?O LEU 310 4.993 14.905 11.9841.00 X3.17 ATOM 33N THR 311 3.352 13.641 12.8741.00 ~
1.71 ATOM 3-1CA THR 311 3.017 14.604 13.9I21.00 -19.93 ATOM 3 CB THR 3 1.527 14.554 14.2751.00 48.96 ~ I

ATOM 36 OG1 THR 311 1.242 13.311 14.930 1.00 47.20 ATOM 37 CG2 THR 311 0.666 14.688 13.027 1.00 X0.99 ATOM 38 C THR 311 3.815 14.201 1 x.1451.00 48.84 ATOM 39 O THR 3 4.371 13.103 1 x.1971.00 46.66 I

ATOM 40 N :ALA 312 3.857 15.078 16.141 1.00 48.76 ATOM 41 CA .-ALA312 4.590 14.798 17.369 1.00 47.75 ATOM 42 CB ALA 312 4.359 15.910 18.378 1.00 47.06 ATOM 43 C ALA 312 4.171 13.460 17.964 1.00 47.41 ATOM 44 O ALA 312 5.009 12.609 18.262 1.00 45.52 ATOM 45 N ASP 313 2.868 13.275 18.143 1.00 47.58 ATOM 46 CA ASP 313 2.367 12.032 18.714 1.00 47.63 ATOM 47 CB ASP 313 0.848 12.100 18.879 1.00 51.96 ATOM 48 CG ASP 313 0.430 12.872 20.118 1.00 56.21 ATOM 49 ODI ASP 313 1.314 13.234 20.929 1.00 56.38 I ATOM 50 OD2 ASP 313 -0.785 13.117 20.282 1.00 59.15 S

ATOM S C ASP 3 2.745 10.846 17.835 1.00 43.93 ATOM 52 O ASP 313 2.959 9.741 18.330 1.00 44.77 ATOM 53 N GLN 314 2.826 11.081 16.531 1.00 44.52 ATOM 54 CA GLN 314 3.182 10.028 15.588 1.00 44.73 ATOM 55 CB GLN 314 2.849 10.464 14.156 1.00 45.05 ATOM 56 CG GLN 314 1.534 9.886 13.626 1.00 48.47 ATOM 57 CD GLN 314 0.982 10.646 12.428 1.00 50.37 ATOM 58 OEI GLN 314 1.649 11.515 11.856 1.00 49.38 ATOM 59 NE2 GLN 314 -0.248 10.318 12.043 1.00 51.74 ATOM 60 C GLN 314 4.673 9.722 15.707 1.00 43.26 ATOM 61 O GLN 314 5.100 8.580 15.555 1.00 43.93 ATOM 62 N MET 315 5.459 10.757 15.980 1.00 42.29 ATOM 63 CA MET 315 6.901 10.606 16.130 1.00 41.26 ATOM 64 CB MET 315 7.565 11.985 16.224 1.00 42.43 ATOM 65 CG MET 315 9.082 11.939 16.356 1.00 42.34 ATOM 66 SD MET 31 9.906 11.190 14.925 1.00 46.22 S

ATOM 67 CE MET 315 9.547 12.408 13.680 1.00 37.32 ATOM 68 C MET 31 7.218 9.791 17.379 1.00 38.89 S

ATOM 69 O MET 315 8.002 8.841 17.335 1.00 40.02 ATOM 70 N VAL 316 6.599 10.165 18.491 1.00 37.65 ATOM 71 CA VAL 316 6.819 9.476 19.756 1.00 39.56 ATOM 72 CB VAL 316 6.023 10.136 20.897 1.00 39.22 ATOM 73 CGI VAL 316 6.245 9.373 22.192 1.00 44.43 ATOM 74 CG2 VAL 316 6.446 11.583 21.059 1.00 41.04 ATOM 75 C VAL 316 6.404 8.012 19.664 1.00 40.04 ATOM 76 O VAL 316 7.141 7.117 20.077 1.00 37.86 ATOM 77 N SER 317 5.215 7.767 19.127 1.00 41.90 ATOM 78 CA SER 317 4.733 6.400 18.997 1.00 41.68 ATOM 79 CB SER 317 3.311 6.402 18.415 1.00 43.85 4~ ATOM 80 OG SER 317 3.225 5.631 17.230 1.00 49.38 ATOM 81 C SER 317 5.696 5.601 18.114 1.00 39.72 ATOM 82 O SER 317 6.011 4.446 18.407 1.00 40.21 ATOM 83 N ALA 318 6.182 6.220 17.043 1.00 38.35 WO 99/50658 PC'T/US99/06937 ATOM 84 CA ALA 318 7.114 x.540 16.153 1.00 36.96 ATOM 8~ CB ALA 318 7.485 6.448 14.986 1.00 37.92 ATOM 86 C ALA 318 8.375 5.137 16.920 1.00 38.31 ATOM 87 O ALA 318 8.820 3.992 16.844 1.00 33.94 ATOM 88 N LEU 319 8.938 6.089 17.664 1.00 36.92 ATOM 89 CA LEU 319 10.161 5.854 18.438 1.00 38.56 ATOM 90 CB LEU 319 10.660 7.174 19.040 1.00 40.86 ATOM 91 CG LEU 319 i 1.1368.264 18.071 1.00 41.25 ATOM 92 CD1 LEU 319 11.714 9.440 18.857 1.00 44.30 ATOM 93 CD2 LEU 319 12.182 7.b93 17.140 1.00 42.61 ATOM 94 C LEU 319 9.965 4.826 19.549 1.00 38.33 ATOM 95 O LEU 319 10.779 3.916 19.729 1.00 33.91 ATOM 96 N LEU 320 8.879 4.982 20.297 1.00 37.39 ATOM 97 CA LEU 320 8.567 4.067 21.387 1.00 41.55 ATOM 98 CB LEU 320 7.239 4.467 22.049 1.00 38.47 ATOM 99 CG LEU 320 7.236 5.582 23.099 1.00 44.81 ATOM 100 CDi LEU 320 5.876 5.634 23.802 1.00 44.96 ATOM 101 CD2 LEU 320 8.334 5.332 24.112 1.00 43.36 ATOM 102 C LEU 320 8.46b 2.642 20.843 1.00 41.11 ATOM 103 O LEU 320 8.971 1.697 21.443 1.00 41.87 ATOM 104 N ASP 321 7.812 2.504 19.696 1.00 43.94 ATOM 105 CA ASP 321 7.613 1.210 19.053 1.00 44.77 ATOM 106 CB ASP 321 6.669 1.372 17.860 1.00 48.39 ATOM 107 CG ASP 321 5.206 1.318 18.255 1.00 52.39 ATOM 108 OD ASP 321 4.901 1.422 19.464 I 53.56 1 .00 ATOM 109 OD2 ASP 321 4.357 1.172 17.346 1.00 55.81 ATOM 110 C ASP 321 8.911 0.565 18.568 1.00 44.37 ATOM 111 O ASP 321 9.030 -0.661 18.533 1.00 44.67 ATOM 112 N ALA 322 9.878 1.395 18.193 1.00 40.75 ATOM 113 CA ALA 322 1 I 0.905 i 7.6861.00 37.81 .153 ATOM II4 CB ALA 322 11.772 1.954 16.776 1.00 38.07 ATOM 115 C ALA 322 12.148 0.513 18.769 1.00 35.52 ATOM 116 O ALA 322 13.219 -0.020 18.473 1.00 36.11 ATOM 117 N GLU 323 11.799 0.768 20.022 1.00 35.61 ATOM 118 CA GLU 323 12.704 0.460 21.117 1.00 36.39 ATOM 119 CB GLU 323 12.042 0.768 22.459 1.00 35.09 ATOM 120 CG GLU 323 12.209 2.210 22.899 1.00 37.93 ATOM 121 CD GLU 323 13.657 2.569 23.200 1.00 37.29 ATOM 122 OEI GLU 323 14.313 3.173 22.326 1.00 34.21 ATOM 123 OE2 GLU 323 14.134 2.245 24.309 1.00 38.02 ATOM 124 C GLU 323 13.205 -0.978 21.110 1.00 38.01 ATOM 125 O GLU 323 12.425 -1.931 20.999 1.00 38.37 ATOM 126 N PRO 324 14.527 -1.151 21.225 1.00 36.03 ATOM I CD PRO 324 I 5.522-0.069 2 i 1.00 36.69 27 .345 ATOM 128 CA PRO 324 15.158 -2.474 21.240 1.00 36.42 ATOM 129 CB PRO 324 16.633 -2.166 21.003 1.00 3.75 ATOM 130 CG PRO 324 16.811 -0.807 21.610 1.00 35.46 ATOM 131 C PRO 324 14.940 -3.162 22.583 1.00 35.7 ATOM 132 O PRO 324 14.616 -2.517 23.580 1.00 34.97 ATOM 133 N PRO 325 15.134 -4.485 22.631 1.00 35.24 ATOM 134 CD PRO 325 15.530 -5.386 21.534 1.00 37.02 ATOM 135 CA PRO 325 14.942 -5.208 23.889 1.00 34.65 ATOM 136 CB PRO 325 14.753 -6.652 23.439 1.00 35.83 ATOM 137 CG PRO 325 15.589 -6.743 22.200 1.00 34.88 ATOM 138 C PRO 325 16.132 -5.070 24.824 1.00 34.51 ATOM 139 O PRO 325 17.237 -4.723 24.399 1.00 29.92 ATOM 140 N ILE 326 15.899 -5.322 26.106 1.00 33.62 ATOM 141 CA ILE 326 16.975 -5.265 27.075 1.00 35.02 ATOM 142 CB ILE 326 16.458 -4.891 28.473 1.00 38.11 ATOM 143 CG2 ILE 326 17.557 -5.110 29.504 1.00 38.70 ATOM 144 CG1 ILE 326 15.987 -3.431 28.466 1.00 40.48 ATOM 145 CDI ILE 326 16.035 -2.747 29.815 1.00 42.96 I ATOM 146 C ILE 326 17.567 -6.668 27.103 1.00 34.14 S

ATOM 147 O ILE 326 16.875 -7.634 27.427 1.00 34.88 ATOM 148 N LEU 327 18.840 -6.784 26.745 1.00 29.64 ATOM 149 CA LEU 327 19.493 -8.083 26.716 1.00 29.54 ATOM 150 CB LEU 327 20.528 -8.135 25.587 1.00 27.76 ATOM 151 CG LEU 327 19.978 -7.800 24.196 1.00 29.02 ATOM IS2 CDI LEU 327 21.068 -7.993 23.139 1.00 28.76 ATOM 153 CD2 LEU 327 18.775 -8.688 23.891 1.00 31.26 ATOM 154 C LEU 327 20.156 -8.438 28.030 1.00 31.21 ATOM 155 O LEU 327 20.393 -7.578 28.891 1.00 30.12 ATOM 156 N TYR 328 20.445 -9.725 28.I81 1.00 30.99 ATOM 157 CA TYR 328 21.087 -10.22929.381 1.00 30.95 ATOM 158 CB TYR 328 20.409 -11.52029.842 1.00 33.38 ATOM 159 CG TYR 328 19.194 -11.27230.686 1.00 33.05 ATOM 160 CD1 TYR 328 19.253 -11.39832.071 1.00 31.92 ATOM 161 CE1 TYR 328 18.152 -11.11432.864 1.00 36.01 ATOM 162 CD2 TYR 328 17.996 -10.86230.110 1.00 36.05 ATOM 163 CE2 TYR 328 16.880 -10.57430.899 1.00 37.2?

ATOM 164 CZ TYR 328 16.973 -10.70232.274 1.00 37.66 ATOM 165 OH TYR 328 I5.896 -10.39733.071 1.00 44.66 ATOM 166 C TYR 328 22.529 -10.52029.067 1.00 33.66 ATOM 167 O TYR 328 22.884 -10.74427.910 1.00 34.78 ATOM 168 N SER 329 23.359 -10.49630.103 1.00 33.97 ATOM 169 CA SER 329 24.767 -10.80029.962 1.00 37.29 ATOM 170 CB SER 329 25.526 -10.34231.204 1.00 36.51 ATOM 171 OG SER 329 26.787 -10.96531.282 1.00 37.13 ATOM 172 C SER 329 24.835 -12.31729.832 1.00 40.43 ATOM 173 O SER 329 23.980 -13.02830.363 1.00 40.11 ATOM 174 N GLU 330 25.845 -12.81129.128 1.00 41.40 ATOM 175 CA GLU 330 25.992 -14.24228.928 1.00 47.43 ATOM 176 CB GLU 330 26.423 -14.52427.484 1.00 48.64 ATOM 177 CG GLU 330 25.278 -14.87026.542 1.00 50.20 ATOM 178 CD GLU 330 25.765 -15.40525.198 1.00 53.25 ATOM 179 OE1 GLU 330 25.909 -16.64025.062 1.00 53.27 ATOM 180 OE2 GLU 330 26.004 - i 4.59024.280 1.00 ~
1.80 ATOM 181 C GLU 330 26.999 -14.852 29.893 1.00 49.67 ATOM 182 O GLU 330 28.207 -14.741 29.696 1.00 50.11 ATOM 183 N TYR 331 26.498 -15.493 30.942 1.00 X3.62 ATOM 184 CA TYR 331 27.373 -16.130 31.921 1.00 58.16 ATOM 185 CB TYR 331 28.092 -15.078 32.774 1.00 59.55 ATOM 186 CG TYR 331 27.239 -14.460 33.860 1.00 63.08 ATOM 187 CD1 TYR 331 26.656 -13.205 33.682 1.00 64.50 ATOM 188 CE1 TYR 331 25.864 -12.630 34.676 1.00 65.99 ATOM 189 CD2 TYR 331 27.010 -I x.12835.065 1.00 63.52 ATOM 190 CE2 TYR 331 26.219 -14.563 36.066 1.00 65.60 ATOM 191 CZ TYR 331 25.648 -13.314 35.864 1.00 67.20 ATOM 192 OH TYR 331 24.855 -12.753 36.839 1.00 67.40 ATOM 193 C TYR 331 26.603 -17.080 32.823 1.00 59.05 ATOM 194 O TYR 331 25.393 -16.942 33.002 1.00 59.22 ATOM 195 N ASP 332 27.320 -18.045 33.387 1.00 61.62 ATOM 196 CA ASP 332 26.719 -19.026 34.281 1.00 64.20 ATOM 197 CB ASP 332 27.681 -20.194 34.500 1.00 65.99 ATOM 198 CG ASP 332 26.961 -21.516 34.648 1.00 68.11 ATOM 199 OD1 ASP 332 27.575 -22.564 34.351 1.00 69.54 .

ATOM 200 OD2 ASP 332 25.781 -21.505 35.060 1.00 67.40 ATOM 201 C ASP 332 26.393 -18.371 35.619 1.00 63.33 ATOM 202 O ASP 332 27.292 -18.073 36.406 1.00 63.90 ATOM 203 N PRO 333 25.096 -18.148 35.896 1.00 63.64 ATOM 204 CD PRO 333 23.945 -18.509 35.053 1.00 64.35 ATOM 205 CA PRO 333 24.677 -17.521 37.154 1.00 63.52 ATOM 206 CB PRO 333 23.165 -17.333 36.993 1.00 63.53 ATOM 207 CG PRO 333 22.866 -17.611 35.556 1.00 64.15 ATOM 208 C PRO 333 25.010 -18.419 38.332 1.00 63.29 ATOM 209 O PRO 333 25.129 -17.964 39.468 1.00 63.28 ATOM 210 N THR 334 25.160 -19.704 38.037 1.00 64.26 ATOM 211 CA THR 334 25.475 -20.697 39.050 1.00 66.09 ATOM 212 CB THR 334 24.929 -22.080 38.645 1.00 66.90 ATOM 213 OG1 THR 334 25.571 -22.513 37.439 1.00 68.06 ATOM 214 CG2 THR 334 23.423 -22.012 38.411 1.00 67.57 ATOM 215 C THR 334 26.982 -20.804 39.269 1.00 65.67 ATOM 216 O THR 334 27.432 -21.323 40.289 1.00 64.77 ATOM 217 N ARG 335 27.759 -20.308 38.313 1.00 65.65 ATOM 218 CA ARG 335 29.214 -20.360 38.421 1.00 66.60 ATOM 219 CB ARG 335 29.835 -20.500 37.030 1.00 66.74 ATOM 220 C ARG 335 29.757 -19.113 39.123 1.00 67.09 ATOM 221 O ARG 335 29.100 -18.071 39.148 1.00 67.31 ATOM 222 N PRO 336 30.968 -19.207 39.702 1.00 67.62 ATOM 223 CD PRO 336 31.820 -20.408 39.713 1.00 67.30 ATOM 224 CA PRO 336 31.601 -18.086 40.410 1.00 67.42 ATOM 225 CB PRO 336 32.982 -18.621 10.783 1.00 66.43 ATOM 226 CG PRO 336 32.829 -20.097 40.779 1.00 67.52 ATOM 227 C PRO 336 31.701 -16.828 39.561 1.00 68.26 ATOM 228 O PRO 336 31.996 -16.89538.371 1.00 69.04 ATOM ?29 N PHE 337 31.460 -15.68140.183 1.00 69.49 ATOM 230 CA PHE 337 31.529 -14.40839.480 1.00 71.39 ATOM 231 CB PHE 337 30.818 -13.32340.294 1.00 72.31 ATOM 232 CG PHE 337 31.219 -II.92439.921 1.00 73.21 ATOM 233 CDI PHE 337 30.632 -11.28738.833 1.00 72.82 ATOM 234 CD2 PHE 337 32.191 -11.24540.653 1.00 73.43 ATOM 235 CEI PHE 337 31.006 -9.993 38.479 1.00 73.28 ATOM 236 CE2 PHE 337 32.573 -9.950 40.306 1.00 73.00 ATOM 237 CZ PHE 337 3I.980 -9.323 39.217 1.00 72.90 ATOM 238 C PHE 337 32.985 -14.01339.245 1.00 71.38 ATOM 239 O PHE 337 33.336 -13.48738.189 1.00 71.56 ATOM 240 N SER 338 33.825 -14.27340.241 1.00 71.53 ATOM 241 CA SER 338 35.248 -13.94740.172 1.00 70.98 ATOM 242 CB SER 338 35.957 -14.48741.414 1.00 70.43 ATOM 243 OG SER 338 35.547 -15.81841.679 1.00 69.59 ATOM 244 C SER 338 35.931 -14.50438.924 1.00 71.20 ATOM 245 O SER 338 36.951 -13.97238.475 1.00 71.35 ATOM 246 N GLU 339 35.368 -15.57338.369 1.00 70.20 ATOM 247 CA GLU 339 35.930 -16.21537.183 1.00 69.48 ATOM 248 CB GLU 339 35.279 -17.58536.971 1.00 71.07 ATOM 249 CG GLU 339 35.996 -18.74037.656 1.00 72.60 ATOM 250 CD GLU 339 35.382 -20.08937.318 1.00 74.26 ATOM 251 OE1 GLU 339 34.786 -20.22036.227 1.00 73.51 ATOM 252 OE2 GLU 339 35.496 -21.02038.144 1.00 76.44 ATOM 253 C GLU 339 35.770 -15.38535.910 1.00 68.15 ATOM 254 O GLU 339 36.722 -15.21635.144 1.00 68.99 ATOM 255 N ALA 340 34.562 -14.87435.694 1.00 64.41 ATOM 256 CA ALA 340 34.246 -14.08334.507 1.00 60.69 ATOM 257 CB ALA 340 32.767 -13.70934.523 1.00 61.17 ATOM 258 C ALA 340 35.096 -12.82434.326 1.00 X7.00 ATOM 259 O ALA 340 35.634 -12.27035.287 1.00 X7.46 ATOM 260 N SER 341 35.215 -12.38833.076 1.00 X2.15 ATOM 261 CA SER 341 35.972 -11.18832.736 1.00 46.53 ATOM 262 CB SER 341 36.839 -11.43931.497 1.00 48.64 ATOM 263 OG SER 341 37.I84 -10.22630.846 1.00 46.48 ATOM 264 C SER 341 34.957 -10.08732.444 1.00 43.52 ATOM 265 O SER 341 34.090 -10.24831.589 1.00 39.92 ATOM 266 N MET 342 35.052 -8.978 33.166 1.00 41.24 ATOM 267 CA MET 342 34.121 -7.875 32.960 1.00 .2.46 ATOM 268 CB MET 342 34.449 -6.723 33.912 1.00 45.61 ATOM 269 CG MET 342 33.228 -6.089 34.560 1.00 X2.39 ATOM 270 SD MET 342 31.791 -7.201 34.631 1.00 X7.92 ATOM 271 CE MET 342 31.999 -7.881 36.239 1.00 X6.18 ATOM 272 C MET 342 34.124 -7.365 31.516 1.00 -X0.22 ATOM 273 O MET 342 33.063 -7.121 30.938 1.00 39.23 ATOM 274 N MET 343 35.307 -7.204 30.930 1.00 38.72 ATOM 275 CA MET 343 35.395 -6.708 X9.558 1.00 38.50 ATOM 276 CB MET 343 36.838 -6.318 ?9.216 1.00 41.15 ATOM 277 CG MET 343 37.022 -5.749 ?7.844 1.00 40.31 ATOM 278 SD MET 343 36.032 -4.260 ?7.427 1.00 45.23 ATOM 279 CE MET 343 36.113 -3.358 28.987 1.00 40.45 ATOM 280 C MET 343 34.880 -7.741 ?8.561 1.00 35.36 ATOM 281 O MET 343 34.368 -7.384 ?7.501 1.00 35.51 ATOM 282 N GLY 344 35.017 -9.020 28.902 1.00 35.53 ATOM 283 CA GLY 344 34.533 -10.07228.024 1.00 33.41 ATOM 284 C GLY 344 33.015 -10.06328.047 1.00 31.74 ATOM 285 O GLY 344 32.359 -10.23327.019 1.00 29.58 ATOM 286 N LEU 345 32.459 -9.860 ?9.238 1.00 32.89 ATOM 287 CA LEU 345 31.011 -9.804 29.415 1.00 34.95 ATOM 288 CB LEU 345 30.665 -9.631 30.902 1.00 37.56 ATOM 289 CG LEU 345 30.942 -10.77431.883 1.00 43.03 ATOM 290 CD1 LEU 345 30.537 -10.35733.297 1.00 41.57 ATOM 291 CD2 LEU 345 30.164 -11.99831.449 1.00 42.80 ATOM 292 C LEU 345 30.430 -8.614 28.633 1.00 33.71 ATOM 293 O LEU 345 29.479 -8.757 27.868 1.00 30.29 ATOM 294 N LEU 346 31.021 -7.443 28.843 1.00 30.20 ATOM 295 CA LEU 346 30.569 -6.217 28.193 1.00 32.00 ATOM 296 CB LEU 346 31.317 -5.016 28.771 1.00 28.16 ATOM 297 CG LEU 346 31.091 -4.767 30.269 1.00 29.84 ATOM 298 CD1 LEU 346 31.815 -3.498 30.668 1.00 29.98 ATOM 299 CD2 LEU 346 29.614 -4.644 30.581 1.00 33.97 ATOM 300 C LEU 346 30.732 -6.250 26.682 1.00 30.70 ATOM 301 O LEU 346 29.869 -5.765 25.955 1.00 29.13 ATOM 302 N THR 347 31.839 -6.816 26.212 1.00 30.47 ATOM 303 CA THR 347 32.086 -6.911 24.781 1.00 30.93 ATOM 304 CB THR 347 33.472 -7.501 24.497 1.00 29.97 ATOM 305 OG1 THR 347 34.481 -6.604 24.982 1.00 35.40 ATOM 306 CG2 THR 347 33.666 -7.707 23.004 1.00 33.58 ATOM 307 C THR 347 31.036 -7.804 24.122 1.00 31.97 ATOM 308 O THR 347 30.516 -7.486 23.049 1.00 30.75 ATOM 309 N ASN 348 30.737 -8.926 24.768 1.00 29.31 ATOM 310 CA ASN 348 29.757 -9.868 24.242 1.00 32.63 ATOM 311 CB ASN 348 29.767 -11.161?5.065 1.00 31.64 ATOM 312 CG ASN 348 28.646 -12.11724.662 1.00 39.14 ATOM 313 OD1 ASN 348 27.549 -12.078?5.220 1.00 41.91 ATOM 314 ND2 ASN 348 28.920 -12.97023.683 1.00 42.05 ATOM 315 C ASN 348 28.361 -9.251 24.262 1.00 29.02 ATOM 316 O ASN 348 27.558 -9.477 X3.353 1.00 32.76 ATOM 317 N LEU 349 28.078 -8.467 ?5.298 1.00 28.74 ATOM 318 CA LEU 349 26.782 -7.811 X5.421 1.00 28.58 ATOM 319 CB LEU 349 26.650 -7.148 X6.795 1.00 26.56 ATOM 320 CG LEU 349 25.376 -6.328 ?7.050 1.00 33.67 ATOM 321 CD1 LEU 349 24.140 -7.199 ?6.840 1.00 28.82 ATOM 322 CD2 LEU 349 25.392 -5.779 28.471 1.00 33.11 ATOM 323 C LEU 349 26.638 -6.762 ~=1.3191.00 28.07 ATOM 324 O LEU '_'S.6I6-6.703 23.629 1.00 X5 ATOM 325 N ALA ~7.67~ -5.941 24.157 1.00 .

ATOM 326 CA ALA '_'7.668-4.886 23.148 1.00 .

ATOM 327 CB ALA ''8.972 -4.094 23.209 1 .
350 00 ?8 ATOM 328 C ALA ?7.468 -5.461 21.750 . .
350 1.00 28 ATOM 329 O ALA '6.649 -4.958 20.983 1.00 .

ATOM 330 N ASP 351 '8.213 -6.509 21.420 1.00 .

ATOM 331 CA ASP 351 ?8.093 -7.143 20.112 1.00 .

ATOM 332 CB ASP 351 X9.036 -8.345 20.010 1 .

ATOM 333 CG ASP 351 30.498 -7.940 19.978 . .
1.00 37 ATOM 334 ODl ASP 351 3I.354 -8.831 20.148 1.00 .

ATOM 335 OD2 ASP 351 30.789 -6.738 19.784 1.00 .

ATOM 336 C ASP 351 26.661 -7.600 19.813 1.00 .

ATOM 337 O ASP 351 ?6.193 -7.458 18.687 1 .

ATOM 338 N ARG 352 X5.968 -8.150 20.811 . .
1.00 27 ATOM 339 CA ARG 352 24.593 -8.602 20.605 1.00 .

ATOM 340 CB ARG 352 24.148 -9.534 21.752 1.00 .

ATOM 341 CG ARG 352 X4.567 -10.99121.532 1.00 .

ATOM 342 CD ARG 352 24.128 -11.91122.666 1 .

ATOM 343 NE ARG 352 24.898 -I1.67523.879 . .
1.00 30 ATOM 344 CZ ARG 352 24.364 -11.36325.054 1.00 .

ATOM 345 NH1 ARG 352 X3.050 -11.25125.177 1.00 .

ATOM 346 NH2 ARG 352 25.144 -11.14826.104 1.00 .

ATOM 347 C ARG 352 23.642 -7.411 20.502 1 .

ATOM 348 O ARG 352 X2.702 -7.426 19.708 . .
1.00 26 ATOM 349 N GLU 353 23.896 -6.370 21.291 1.00 .

ATOM 350 CA GLU 353 23.045 -5.178 21.261 1.00 .

ATOM 351 CB GLU 353 23.461 -4.204 22.365 1.00 .

ATOM 352 CG GLU 353 X3.147 -4.669 23.771 1 .

ATOM 353 CD GLU 353 X3.425 -3.587 24.795 . .
1.00 30 ATOM 354 OE1 GLU 353 24.564 -3.534 25.304 1.00 .

ATOM 355 OE2 GLU 353 X2.506 -2.789 25.085 1.00 .

ATOM 356 C GLU 353 23.131 -4.456 19.920 1.00 .

ATOM 357 O GLU 353 X2.169 -3.826 19.467 1 .

ATOM 358 N LEU 354 24.296 -4.540 19.293 . .
1.00 26 ATOM 359 CA LEU 354 24.522 -3.872 18.017 1.00 .

ATOM 360 CB LEU 354 25.952 -4.121 17.543 1.00 .

ATOM 361 CG LEU 354 26.372 -3.257 16.351 1.00 .

ATOM 362 CD1 LEU 354 26.243 -1.774 16.722 1 .

ATOM 363 CD2 LEU 354 27.794 -3.607 15.962 . .
1.00 28 ATOM 364 C LEU 354 23.559 -4.300 16.926 1.00 .

ATOM 365 O LEU 354 23.074 -3.475 16.152 1.00 .

ATOM 366 N VAL 355 ?3.291 -5.598 16.854 1.00 .

ATOM 367 CA VAL 355 ?2.386 -6.125 15.844 1 .

ATOM 368 CB VAL 355 ?2.259 -7.655 15.975 . .
1.00 31 ATOM 369 CG VAL 355 ? 1.423 -8.205 14.834 1.00 .

ATOM 370 CG2 VAL 355 ?3.649 -8.282 15.998 1.00 .

ATOM 371 C VAL 355 ? 1.020 -5.499 16.035 1.00 .
27.71 ATOM 372 O VAL 355 20.382 -5.039 15.080 1.00 29.61 ATOM 373 N HIS 356 20.580 -5.473 17.288 1.00 27.76 ATOM 374 CA HIS 356 19.291 -4.906 17.627 1.00 28.35 ATOM 375 CB HIS 356 18.936 -5.231 19.079 1.00 31.12 ATOM 376 CG HIS 356 18.602 -6.675 19.307 1.00 35.93 ATOM 377 CD2 HIS 356 I9.352 -7.700 19.779 1.00 33.95 ATOM 378 ND1 HIS 356 17.363 -7.208 19.018 1.00 36.62 ATOM 379 CE HIS 356 17.364 -8.499 19.304 1.00 33.33 ATOM 380 NE2 HIS 356 18.559 -8.823 19.767 1.00 32.16 ATOM 381 C HIS 356 19.300 -3.398 17.412 1.00 28.25 ATOM 382 O HIS 356 18.272 -2.812 17.100 1.00 28.99 ATOM 383 N MET 357 20.457 -2.765 i 7.5741.00 25.31 ATOM 384 CA MET 357 20.526 -1.322 17.369 1.00 24.63 ATOM 385 CB MET 357 21.902 -0.789 17.766 1.00 23.61 ATOM 386 CG MET 357 22.011 0.736 17.699 1.00 24.66 ATOM 387 SD MET 357 23.732 1.290 17.859 1.00 27.30 ATOM 388 CE MET 357 24.140 0.672 19.514 1.00 23.62 ATOM 389 C MET 357 20.256 -1.011 15.898 1.00 24.83 ATOM 390 O MET 357 19.619 -0.003 15.569 1.00 26.78 ATOM 391 N ILE 358 20.757 -1.874 15.020 1.00 26.25 ATOM 392 CA ILE 358 20.553 -1.721 13.576 1.00 30.33 ATOM 393 CB ILE 358 21.204 -2.888 12.789 1.00 33.86 ATOM 394 CG2 ILE 358 20.759 -2.860 11.334 1.00 33.68 ATOM 395 CG1 ILE 358 22.728 -2.799 12.874 1.00 36.89 ATOM 396 CDI ILE 358 23.299 -1.469 12.451 1.00 39.10 ATOM 397 C ILE 358 19.055 -1.721 13.310 1.00 32.20 ATOM 398 O ILE 358 18.519 -0.817 12.662 1.00 32.02 ATOM 399 N ASN 359 18.379 -2.748 13.814 1.00 33.12 ATOM 400 CA ASN 359 16.945 -2.861 13.638 1.00 33.35 ATOM 401 CB ASN 359 16.434 -4.101 14.363 1.00 37.59 ATOM 402 CG ASN 359 16.739 -5.374 13.627 1.00 44.38 ATOM 403 OD1 ASN 359 17.045 -5.329 12.437 1.00 47.35 ATOM 404 ND2 ASN 359 16.673 -6.508 14.320 1.00 42.48 ATOM 405 C ASN 359 16.224 -1.634 14.149 1.00 32.74 ATOM 406 O ASN 359 15.261 -1.163 13.530 1.00 31.39 ATOM 407 N TRP 360 16.706 -1.104 15.264 1.00 27.92 ATOM 408 CA TRP 360 16.102 0.087 15.842 1.00 29.47 ATOM 409 CB TRP 360 16.703 0.347 17.228 1.00 27.66 ATOM 410 CG TRP 360 16.522 1.747 17.707 1.00 30.40 ATOM 411 CD2 TRP 360 17.493 2.801 17.657 1.00 27.54 ATOM 412 CE2 TRP 360 16.888 3.954 18.204 1.00 29.42 ATOM 413 CE3 TRP 360 18.819 2.883 17.205 1.00 28.37 ATOM 414 CD TRP 360 15.399 2.284 18.264 1.00 27.75 ATOM 415 NE TRP 360 15.609 3.611 18.566 I .00 30.84 ATOM 416 CZ2 TRP 360 17.558 5.180 18.310 1.00 27.74 ATOM 417 CZ3 TRP 360 19.488 4.106 17.309 1.00 24.49 ATOM 418 CH2 TRP 360 18.853 5.232 17.858 1.00 25.09 ATOM 419 C TRP 360 16.312 1.296 14.926 1.00 27.90 ATOM 420 O TRP 15.360 2.002 14.581 1.00 ''8 ATOM 421 N ALA 17.559 1.520 14.523 1.00 .

ATOM 422 CA ALA 17.894 2.637 13.645 1.00 .

ATOM 423 CB ALA 19.346 2.539 13.220 1.00 .
361 ~8 g9 S ATOM 424 C ALA 17.006 2.685 12.403 1.00 .

ATOM 425 O ALA 16.531 3.746 12.011 1.00 .

ATOM 426 N LYS 362 16.795 1.526 11.783 1.00 .

ATOM 427 CA LYS 362 15.981 1.443 I O.S811.00 .

ATOM 428 CB LYS 362 16.012 0.016 10.023 1 .

ATOM 429 CG LYS 362 17.252 -0.281 9.198 . .
1.00 39 ATOM 430 CD LYS 362 17.547 -1.774 9.136 1.00 .

ATOM 431 CE LYS 362 18.852 -2.046 8.389 1.00 .
:17 ATOM 432 NZ LYS 362 19.178 -3.507 8.288 1.00 .

ATOM 433 C LYS 362 14.545 1.872 10.815 1.00 .

1S ATOM 434 O LYS 362 13.821 2.168 9.859 1.00 .

ATOM 435 N ARG 363 14.134 1.921 12.079 1.00 .

ATOM 436 CA ARG 363 12.770 2.313 12.409 1.00 .

ATOM 437 CB ARG 363 12.178 1.307 13.391 1.00 .

ATOM 438 CG ARG 363 12.169 -0.110 12.827 1.00 .

ATOM 439 CD ARG 363 11.468 -1.086 13.746 1.00 .

ATOM 440 NE ARG 363 10.161 -0.586 14.158 1.00 .

ATOM 441 CZ ARG 363 9.314 -1.262 14.929 1.00 .

ATOM 442 NH1 ARG 363 9.642 -2.467 15.374 1.00 .

ATOM 443 NH2 ARG 363 8.143 -0.729 15.261 1.00 .

2S ATOM 444 C ARG 363 12.654 3.743 12.943 1.00 .

ATOM 445 O ARG 363 11.567 4.199 13.303 1.00 .

ATOM 446 N VAL 364 13.785 4.442 13.002 1.00 .

ATOM 447 CA VAL 364 13.804 5.836 13.431 1.00 .

ATOM 448 CB VAL 364 15.231 6.271 13.827 1 .

ATOM 449 CG1 VAL 364 15.293 7.779 13.995 . .
1.00 31 ATOM 450 CG2 VAL 364 15.641 S.S71 15.113 1.00 .

ATOM 4S C VAL 364 13.360 6.591 I2.171 I .
1 .00 33 ATOM 452 O VAL 364 14.028 6.531 11.146 1.00 .

ATOM 453 N PRO 365 12.225 7.310 12.234 1 .

3S ATOM 454 CD PRO 365 11.359 7.492 13.4I3 . .
1.00 34 ATOM 4SS CA PRO 365 11.724 8.050 11.069 1.00 .

ATOM 456 CB PRO 365 I0.608 8.918 I1.64S 1.00 .

ATOM 457 CG PRO 365 10.135 8.157 12.842 1.00 .

ATOM 458 C PRO 365 12.756 8.878 10.321 1 .

ATOM 459 O PRO 365 13.430 9.726 10.907 . .
1.00 40 ATOM 460 N GLY 366 12.878 8.624 9.023 1.00 .

ATOM 461 CA GLY 366 13.816 9.371 8.212 1.00 .

ATOM 462 C GLY 366 15.168 8.722 8.007 1.00 .

ATOM 463 O GLY 366 1 S.8S8 9.035 7.034 1.00 .

4S ATOM 464 N PHE 367 1 S.SS4 7.814 8.901 1.00 .

ATOM 465 CA PHE 367 16.860 7.164 8.787 1.00 , ATOM 466 CB PHE 367 17.138 6.291 10.016 1.00 .

ATOM 467 CG PHE 367 18.544 5.773 10.080 1.00 .
30.60 ATOM 468 CD1 PHE 367 18.827 4.446 9.751 1.00 3I.94 ATOM 469 CD2 PHE 367 19.589 6.60I 10.485 1.00 X9.20 ATOM 470 CE1 PHE 367 20.133 3.950 9.828 1.00 ?8.30 ATOM 471 CE2 PHE 367 20.896 6.122 10.568 1.00 28.12 ATOM 472 CZ PHE 367 21.171 4.791 10.240 1.00 ?5.41 ATOM 473 C PHE 367 17.033 6.333 7.524 1.00 31.46 ATOM 474 O PHE 367 18.073 6.405 6.883 1.00 32.30 ATOM 475 N VAL 368 16.027 5.541 7.165 1.00 35.20 ATOM 476 CA VAL 368 16.123 4.718 S.9S9 1.00 38.98 ATOM 477 CB VAL 368 15.076 3.584 S.94S 1.00 40.61 ATOM 478 CG1 VAL 368 15.543 2.447 6.843 1.00 41.48 ATOM 479 CG2 VAL 368 13.717 4.113 6.390 1.00 41.60 ATOM 480 C VAL 368 1 S.96S S.S23 4.673 1.00 40.06 ATOM 481 O VAL 368 i 6.1 4.992 3.579 1.00 41.66 1S ATOM 482 N ASP 369 15.608 6.798 4.798 1.00 38.65 ATOM 483 CA ASP 369 1 S.46S 7.646 3.621 1.00 37.1 S

ATOM 484 CB ASP 369 14.700 8.929 3.954 1.00 39.89 ATOM 485 CG ASP 369 13.254 8.671 4.302 1.00 45.59 ATOM 486 OD1 ASP 369 12.686 7.672 3.806 1.00 46.34 ATOM 487 OD2 ASP 369 12.681 9.472 5.074 1.00 49.13 ATOM 488 C ASP 369 16.855 8.010 3.136 1.00 34.91 ATOM 489 O ASP 369 17.038 8.431 1.995 1.00 34.25 ATOM 490 N LEU 370 17.838 7.841 4.016 1.00 31.76 ATOM 491 CA LEU 370 19.229 8.1 3.705 1.00 28.08 2S ATOM 492 CB LEU 370 20.020 8.339 5.003 1.00 28.81 ATOM 493 CG LEU 370 19.523 9.395 6.000 1.00 28.74 ATOM 494 CD1 LEU 370 20.315 9.275 7.299 1.00 30.81 ATOM 495 CD2 LEU 370 19.693 10.792 5.404 1.00 29.77 ATOM 496 C LEU 370 19.884 7.043 2.893 1.00 31.25 ATOM 497 O LEU 370 19.341 5.943 2.784 1.00 31.78 ATOM 498 N THR 371 21.052 7.333 2.331 1.00 ?8.86 ATOM 499 CA THR 371 21.793 6.336 1.569 1.00 32.90 ATOM 500 CB THR 371 22.979 6.944 0.818 1.00 33.44 ATOM SO1 OG1 THR 371 23.880 7.523 1.766 1.00 34.59 3S ATOM 502 CG2 THR 371 22.514 8.002 -0.178 1.00 32.63 ATOM 503 C THR 371 22.373 S.31S 2.539 1.00 35.31 ATOM 504 O THR 371 22.536 S.S9i 3.733 1.00 31.27 ATOM SOS N LEU 372 22.702 4.141 2.01 1.00 34.34 S

ATOM 506 CA LEU 372 23.273 3.073 2.822 1.00 35.46 ATOM 507 CB LEU 372 23.518 1.841 1.944 1.00 37.73 ATOM 508 CG LEU 372 24.362 0.704 2.S 1.00 42.43 ATOM 509 CD1 LEU 372 23.690 0.145 3.757 1.00 45.60 ATOM 510 CD2 LEU 372 24.534 -0.383 1.455 1.00 44.29 ATOM S C LEU 372 24.587 3.548 3.444 I 36.95 11 .00 4S ATOM 512 O LEU 372 24.813 3.374 4.643 1.00 35.57 ATOM 513 N HIS 373 25.442 4.159 2.627 1.00 35.68 ATOM S CA HIS 373 26.729 4.656 3.099 1.00 36.60 ATOM S CB HIS 373 27.506 5.282 1.935 1.00 44.01 S

ATOM ~ CG HIS 373 28.538 6.280 ?.360 1.00 50.69 ATOM ~ CD2 HIS 373 29.857 6.138 2.636 1.00 54.69 ATOM 518 ND1 HIS 373 28.246 7.613 2.561 1.00 53.77 ATOM 519 CE1 HIS 373 29.339 8.248 2.945 1.00 57.09 ~ ATOM 520 NE2 HIS 373 30.331 7.376 2.999 1.00 57.23 ATOM 521 C HIS 373 26.575 5.669 4.244 1.00 36.22 ATOM 522 O HIS 373 27.350 5.650 5.201 1.00 33.05 ATOM 523 N ASP 374 25.580 6.549 4.148 1.00 32.03 ATOM 524 CA ASP 374 25.342 7.541 5.196 1.00 30.76 ATOM 525 CB ASP 374 24.354 8.603 4.713 1.00 30.12 ATOM 526 CG ASP 374 25.018 9.672 3.860 1.00 35.83 ATOM 527 ODI ASP 374 26.264 9.744 3.842 1.00 34.39 ATOM 528 OD2 ASP 374 24.291 10.440 3.199 1.00 35.39 ATOM 529 C ASP 374 24.805 6.876 6.472 1.00 30.33 ATOM 530 O ASP 374 25.152 7.275 7.587 1.00 27.04 ATOM 531 N GLN 375 23.944 5.877 6.309 1.00 25.71 ATOM 532 CA GLN 375 23.403 5.157 7.454 1.00 26.68 ATOM 533 CB GLN 375 22.424 4.077 6.993 1.00 29.70 ATOM 534 CG GLN 375 21.101 4.616 6.484 i.00 29.16 ATOM 535 CD GLN 375 20.219 3.514 5.940 1.00 35.87 ATOM 536 OE1 GLN 375 20.155 2.426 6.510 1.00 30.97 ATOM 537 NE2 GLN 375 19.541 3.785 4.827 1.00 34.51 ATOM 538 C GLN 375 24.556 4.502 8.214 1.00 25.51 ATOM 539 O GLN 375 24.585 4.513 9.442 1.00 28.14 ATOM 540 N VAL 376 25.504 3.938 7.475 1.00 26.62 ATOM 541 CA VAL 376 26.659 3.281 8.071 1.00 29.24 .

ATOM 542 CB VAL 376 27.531 2.597 7.003 1.00 29.66 ATOM 543 CG1 VAL 376 28.812 2.071 7.635 1.00 28.29 ATOM 544 CG2 VAL 376 26.745 1.469 6.341 1.00 29.90 ATOM 545 C VAL 376 27.526 4.285 8.821 1.00 30.87 ATOM 546 O VAL 376 27.953 4.029 9.948 1.00 30.09 ATOM 547 N HIS 377 27.785 5.428 8.191 1.00 28.05 ATOM 548 CA HIS 377 28.602 6.457 8.814 1.00 28.68 ATOM 549 CB HIS 377 28.792 7.639 7.864 1.00 30.26 ATOM 550 CG HIS 377 29.508 8.791 8.488 1.00 33.89 ATOM 551 CD2 HIS 377 29.073 10.017 8.863 1.00 34.99 ATOM 552 ND1 HIS 377 30.846 8.740 8.823 1.00 37.01 ATOM 553 CE1 HIS 377 31.201 9.884 9.377 1.00 34.79 ATOM 554 NE2 HIS 377 30.144 10.677 9.413 1.00 34.95 ATOM 555 C HIS 377 27.983 6.954 10.114 1.00 25.13 ATOM 556 O HIS 377 28.677 7.102 11.11 1.00 25.93 S

ATOM 557 N LEU 378 26.678 7.206 10.107 1.00 24.58 ATOM 558 CA LEU 378 26.015 7.695 11.315 1.00 26.40 ATOM 559 CB LEU 378 24.542 8.001 11.027 1.00 26.29 ATOM 560 CG LEU 378 24.291 9.180 10.073 1.00 28.06 ATOM 561 CD1 LEU 378 22.778 9.353 9.869 1.00 27.66 ATOM 562 CD2 LEU 378 24.911 10.458 10.642 1.00 30.08 ATOM 563 C LEU 378 26.120 6.695 12.459 1.00 28.55 ATOM 564 O LEU 378 ?6.379 7.075 13.605 1.00 ?4.76 ATOM 565 N LEU 379 ?5.919 5.414 12.153 1.00 ?4.29 ATOM 566 CA LEU 379 ?6.000 4.388 13.182 1.00 ?7.03 ATOM 567 CB LEU 379 ?5.401 3.073 12.667 1.00 ?8.53 S ATOM 568 CG LEU 379 ?3.875 3.023 12.845 1.00 30.29 ATOM 569 CDI LEU 379 23.248 1.943 11.963 1.00 33.04 ATOM 570 CD2 LEU 379 ?3.563 2.759 14.312 1.00 29.45 ATOM 571 C LEU 379 27.430 4.176 13.670 1.00 ?7.18 ATOM 572 O LEU 379 ?7.653 3.979 14.866 1.00 ?5.95 ATOM 573 N GLU 380 28.402 4.236 12.762 1.00 ?5.86 ATOM 574 CA GLU 380 29.786 4.054 13.173 1.00 ?7.58 ATOM 575 CB GLU 380 30.730 4.036 11.968 1.00 30.36 ATOM 576 CG GLU 380 32.172 3.785 12.380 1.00 37.98 ATOM 577 CD GLU 380 33.080 3.471 11.210 1.00 45.23 ATOM 578 OE1 GLU 380 32.869 4.048 10.120 1.00 42.99 ATOM 579 OE2 GLU 380 34.004 2.646 11.386 1.00 45.79 ATOM 580 C GLU 380 30.218 5.159 14.133 1.00 ?7.50 ATOM 581 O GLU 380 31.056 4.937 15.010 1.00 ?6.67 ATOM 582 N ACYS 29.637 6.339 13.965 0.75 24.89 ATOM 583 N BCYS 29.645 6.352 13.980 0.25 25.79 ATOM 584 CA ACYS 29.969 7.466 14.826 0.75 24.12 ATOM 585 CA BCYS 29.993 7.481 14.847 0.25 24.86 ATOM 586 CB ACYS 29.621 8.781 14.122 0.75 25.96 ATOM 587 CB BCYS 29.766 8.814 14.115 0.25 25.62 ATOM 588 SG ACYS 30.698 9.192 12.732 0.75 31.63 ATOM 589 SG BCYS 30.227 10.312 15.059 0.25 25.40 ATOM 590 C ACYS 29.237 7.422 16.162 0.75 22.07 ATOM 591 C BCYS 29.211 7.498 16.159 0.25 23.97 ATOM 592 O ACYS 29.812 7.730 17.206 0.75 21.97 ATOM 593 O BCYS 29.724 7.940 17.187 0.25 23.99 ATOM 594 N ALA 382 27.974 7.012 16.128 1.00 23.41 ATOM 595 CA ALA 382 27.140 7.015 17.318 1.00 22.83 ATOM 596 CB ALA 382 25.785 7.587 16.948 1.00 ?5.50 ATOM 597 C ALA 382 26.913 5.755 18.131 1.00 25.39 ATOM 598 O ALA 382 26.374 5.837 19.234 1.00 23.09 ATOM 599 N TRP 383 27.311 4.602 17.615 1.00 25.98 ATOM 600 CA TRP 383 27.026 3.354 18.318 1.00 23.80 ATOM 601 CB TRP 383 27.669 2.172 17.580 1.00 22.52 ATOM 602 CG TRP 383 29.130 2.054 17.762 1.00 24.42 ATOM 603 CD2 TRP 383 29.797 1.347 18.803 1.00 27.31 ATOM 604 CE2 TRP 383 31.182 1.484 18.579 1.00 28.24 ATOM 605 CE3 TRP 383 29.360 0.609 19.912 1.00 27.37 ATOM 606 CD1 TRP 383 30.102 2.578 16.965 1.00 ?4.58 ATOM 607 NE1 TRP 383 31.342 2.239 17.446 1.00 ?7.35 ATOM 608 CZ2 TRP 383 32.133 0.909 19.420 1.00 28.76 ATOM 609 CZ3 TRP 383 30.305 0.039 20.745 1.00 28.09 ATOM 610 CH2 TRP 383 31.674 0.191 20.496 1.00 ?9.77 ATOM 611 C TRP 383 ?7.356 3.309 19.802 1.00 23.54 ATOM 612 O TRP 383 26.526 2.866 ?0.584 1.00 22.90 ATOM 613 N LEU 384 28.542 3.765 ?0.211 1.00 20.37 ATOM 614 CA LEU 384 28.864 3.713 ? 1.640I 22.41 .00 ATOM 615 CB LEU 384 30.369 3.890 ? 1.8831.00 24.98 ATOM 616 CG LEU 384 30.824 3.645 '_'3.3361.00 27.33 ATOM 617 CD1 LEU 384 30.273 2.305 ?3.853 1.00 29.71 ATOM 618 CD2 LEU 384 32.336 3.648 '_'3.3981.00 26.07 ATOM 619 C LEU 384 28.075 4.732 ?2.453 1.00 19.44 ATOM 620 O LEU 384 27.706 4.458 23.595 1.00 23.24 ATOM 621 N GLU 385 27.807 5.909 21.885 1.00 20.80 ATOM 622 CA GLU 385 27.011 6.895 22.612 1.00 21.32 ATOM 623 CB GLU 385 26.861 8.177 21.797 1.00 21.91 ATOM 624 CG GLU 385 28.115 9.020 21.705 1.00 21.61 ATOM 625 CD GLU 385 27.882 10.256 20.860 1.00 29.53 ATOM 626 OEI GLU 385 27.374 11.256 21.401 1.00 30.54 ATOM 627 OE2 GLU 385 28.188 10.219 19.658 1.00 29.97 ATOM 628 C GLU 385 25.616 6.292 ?2.836 1.00 22.26 ATOM 629 O GLU 385 25.022 6.438 23.902 1.00 22.26 ATOM 630 N ILE 386 25.101 x.617 21.812 1.00 22.03 ATOM 631 CA ILE 386 23.779 4.995 21.896 1.00 22.74 ATOM 632 CB ILE 386 23.328 4.455 20.498 1.00 22.88 ATOM 633 CG2 ILE 386 22.009 3.647 20.618 1.00 23.85 ATOM 634 CG1 ILE 386 23.085 5.651 I9.561 1.00 25.05 ATOM 635 CD1 ILE 386 22.994 5.297 18.078 1.00 26.42 ATOM 636 C ILE 386 23.766 3.897 22.961 1.00 22.50 ATOM 637 O ILE 386 22.823 3.818 23.746 1.00 24.75 ATOM 638 N LEU 387 24.810 3.071 23.020 1.00 22.25 ATOM 639 CA LEU 387 24.868 2.030 24.051 1.00 22.95 ATOM 640 CB LEU 387 26.096 1.132 23.864 1.00 24.61 ATOM 641 CG LEU 387 26.070 0.194 22.654 1.00 23.21 ATOM 642 CDI LEU 387 27.297 -0.709 ?2.705 1.00 25.36 ATOM 643 CD2 LEU 387 24.791 -0.631 22.652 1.00 26.29 ATOM 644 C LEU 387 24.944 2.660 25.438 1.00 26.22 ATOM 645 O LEU 387 24.287 2.204 26.386 1.00 23.55 ATOM 646 N MET 388 25.751 3.713 25.554 1.00 23.92 ATOM 647 CA MET 388 25.924 4.385 26.835 1.00 24.26 ATOM 648 CB MET 388 27.088 5.378 26.761 1.00 23.87 ATOM 649 CG MET 388 28.440 4.722 26.?43 1.00 24.08 ATOM 650 SD MET 388 29.726 5.992 26.736 1.00 27.70 ATOM 651 CE MET 388 31.139 5.041 27.078 1.00 21.74 ATOM 652 C MET 388 24.660 5.094 27.321 1.00 23.33 ATOM 653 O MET 388 24.341 5.026 28.SOa 1.00 25.58 ATOM 654 N ILE 389 23.935 5.775 26.436 1.00 24.62 ATOM 655 CA ILE 389 22.729 6.440 26.905 1.00 24.03 ATOM 656 CB ILE 389 22.132 7.439 25.852 1.00 27.01 ATOM 657 CG2 ILE 389 21.413 6.705 24.706 1.00 23.98 ATOM 658 CGI ILE 389 21.185 8.402 ?6.584 1.00 25.49 ATOM 659 CDI ILE 389 20.431 9.383 2.683 1.00 25.45 ATOM 660 C ILE 389 '_ 1.6945.401 27.349 1.00 26.54 ATOM 661 O ILE 389 20.938 5.631 28.294 1.00 22.58 ATOM 662 N GLY 390 21.679 4.247 26.687 1.00 27.14 ATOM 663 CA GLY 390 20.753 3.201 27.090 1.00 28.42 ATOM 664 C GLY 390 21.133 2.719 28.482 1.00 29.67 ATOM 665 O GLY 390 20.275 2.521 29.348 1.00 29.21 ATOM 666 N LEU 391 22.433 2.547 28.699 1.00 26.06 ATOM 667 CA LEU 391 22.955 2.091 29.983 1.00 29.23 ATOM 668 CB LEU 391 24.476 1.937 29.899 1.00 28.37 ATOM 669 CG LEU 391 25.206 1.656 31.210 1.00 30.81 ATOM 670 CD1 LEU 391 24.717 0.332 31.793 1.00 25.73 ATOM 671 CD2 LEU 391 26.709 1.619 30.958 1.00 25.25 ATOM 672 C LEU 391 22.603 3.070 31.104 1.00 30.84 ATOM 673 O LEU 391 22.156 2.669 32.186 1.00 29.19 ATOM 674 N VAL 392 22.817 4.355 30.850 1.00 28.91 ATOM 675 CA VAL 392 22.506 5.369 31.851 1.00 28.86 ATOM 676 CB VAL 392 22.923 6.770 31.353 1.00 30.08 ATOM 677 CG1 VAL 392 22.329 7.854 32.237 1.00 32.32 ATOM 678 CG2 VAL 392 24.442 6.870 31.372 1.00 28.52 ATOM 679 C VAL 392 21.013 5.327 32.165 1.00 28.42 ATOM 680 O VAL 392 20.621 5.345 33.327 1.00 30.38 ATOM 681 N TRP 393 20.191 5.241 31.125 1.00 28.23 ATOM 682 CA TRP 393 18.732 5.186 31.280 1.00 29.70 ATOM 683 CB TRP 393 18.066 5.046 29.906 1.00 30.09 ATOM 684 CG TRP 393 16.605 4.670 29.953 1.00 33.50 ATOM 685 CD2 TRP 393 15.516 5.499 30.369 1.00 31.76 ATOM 686 CE2 TRP 393 14.336 4.725 30.264 1.00 38.11 ATOM 687 CE3 TRP 393 15.419 6.821 30.824 1.00 32.56 ATOM 688 CD1 TRP 393 16.057 3.459 29.618 1.00 34.31 ATOM 689 NE1 TRP 393 14.696 3.486 29.801 1.00 34.36 ATOM 690 CZ2 TRP 393 13.073 5.233 30.597 1.00 37.93 ATOM 691 CZ3 TRP 393 14.162 7.326 31.155 1.00 35.24 ATOM 692 CH2 TRP 393 13.007 6.531 31.039 1.00 37.77 ATOM 693 C TRP 393 18.256 4.051 32.191 1.00 32.07 ATOM 694 O TRP 393 17.460 4.275 33.109 1.00 32.12 ATOM 695 N ARG 394 18.738 2.837 31.957 1.00 31.90 ATOM 696 CA ARG 394 18.288 1.729 32.787 1.00 36.63 ATOM 697 CB ARG 394 18.492 0.389 32.065 I.00 36.41 ATOM 698 CG ARG 394 19.914 0.009 31.764 1.00 36.50 ATOM 699 CD ARG 394 19.929 -1.132 30.748 1.00 36.34 ATOM 700 NE ARG 394 21.282 -1.561 30.417 1.00 33.97 ATOM 701 CZ ARG 394 21.864 -1.350 29.239 1.00 31.61 ATOM 702 NH ARG 394 2 i .208-0.715 28.281 1.00 32.42 I

ATOM 703 NH2 ARG 394 23.098 -1.784 29.022 1.00 29.81 ATOM 704 C ARG 394 18.911 1.697 34.180 1.00 36.69 ATOM 705 O ARG 394 18.445 0.966 35.048 1.00 37.07 ATOM 706 N SER 395 19.954 2.492 34.395 1.00 33.63 ATOM 707 CA SER 395 20.603 2.564 35.701 1.00 35.69 WO 99/50658, PCT/US99/06937 ATOM 708 CB SER 395 22.112 2.784 35.540 1.00 32 ATOM 709 OG SER 395 22.696 1.811 34.688 1.00 .

ATOM 710 C SER 395 20.010 3.713 36.531 1.00 .

ATOM 7II O SER 395 20.389 3.916 37.687 1.00 .

ATOM 712 N MET 19.076 4.449 35.937 1.00 .

ATOM 713 CA MET 396 18.431 5.588 36.589 1.00 .

ATOM 714 CB MET 396 17.275 6.104 35.725 1.00 .

ATOM 715 CG MET 396 17.481 7.507 35.176 1.00 .

ATOM 716 SD MET 396 15.962 8.278 34.581 1 .

ATOM 717 CE MET 396 14.988 8.298 36.065 . .
1.00 53 ATOM 718 C MET 396 17.906 5.303 37.992 1.00 .

ATOM 719 O MET 396 18.125 6.089 38.913 1.00 .

ATOM 720 N GLU 397 17.215 4.180 38.152 1.00 .

ATOM 721 CA GLU 397 16.645 3.821 39.444 1 .

ATOM 722 CB GLU 397 15.296 3.130 39.246 . .
1.00 55 ATOM 723 CG GLU 397 14.166 4.073 38.873 1.00 .

ATOM 724 CD GLU 397 13.195 3.448 37.891 1.00 .

ATOM 725 OEI GLU 397 13.660 2.925 36.854 1.00 .

ATOM 726 OE2 GLU 397 11.972 3.475 38.155 1 .

ATOM 727 C GLU 397 17.548 2.933 40.283 . .
1.00 52 ATOM 728 O GLU 397 17.071 2.18? 41.139 1.00 .

ATOM 729 N HIS 398 18.851 3.014 40.040 1.00 .

ATOM 730 CA HIS 398 19.813 2.220 40.792 1.00 .

ATOM 731 CB HIS 398 20.271 I.OI8 39.963 1 .

ATOM 732 CG HIS 398 19.187 0.017 39.721 . .
1.00 53 ATOM 733 CD2 HIS 398 18.750 -1.022 40.472 1.00 .

ATOM 734 NDl HIS 398 18.374 0.054 38.608 1.00 .

ATOM 735 CE1 HIS 398 17.482 -0.917 38.685 1.00 .

ATOM 736 NE2 HIS 398 17.688 -1.585 39.806 1 .

ATOM 737 C HIS 398 20.999 3.084 41.196 . .
I.00 47 ATOM 738 O HIS 398 22.121 2.887 40.?30 1.00 .

ATOM 739 N PRO 399 20.755 4.049 42.096 1.00 .

ATOM 740 CD PRO 399 19.443 4.300 42.721 1.00 .

ATOM 741 CA PRO 399 21.785 4.968 42.586 1 .

ATOM 742 CB PRO 399 21.I27 5.631 43.793 . .
1.00 47 ATOM 743 CG PRO 399 19.660 5.561 43.504 1.00 .

ATOM 744 C PRO 399 23.086 4.270 42.958 1.00 .

ATOM 745 O PRO 399 23.078 3.233 43.627 1.00 .

ATOM 746 N GLY 400 24.202 4.840 42.509 1 .

ATOM 747 CA GLY 400 25.506 4.281 42.813 . .
1.00 39 ATOM 748 C GLY 400 25.907 3.047 42.022 1.00 .

ATOM 749 O GLY 400 27.027 2.560 42.I76 1.00 .

ATOM 750 N LYS 401 25.012 2.537 41.180 1.00 .

ATOM 751 CA LYS 25.315 1.344 40.390 1 .

ATOM 752 CB LYS 24.562 0.130 40.947 . .
401 1.00 36 ATOM 753 CG LYS 24.633 -0.007 42.466 1.00 .

ATOM 754 CD LYS 24.288 -1.429 42.903 1.00 .

ATOM 755 CE LYS 24.459 -1.605 44.408 1.00 .
401 46.68 ATOM 756 NZ LYS :101 24.968 -2.969 -14.7471.00 53.37 ATOM 757 C LYS 401 24.969 1.485 38.911 1.00 32.34 ATOM 758 O LYS 401 24.141 2.308 38.531 1.00 31.16 ATOM 759 N LEU 402 25.612 0.663 38.086 1.00 28.52 ATOM 760 CA LEU 402 25.358 0.658 36.648 1.00 29.06 ATOM 761 CB LEU 402 26.661 0.847 35.867 1.00 ?9.26 ATOM 762 CG LEU 402 27.278 2.242 36.029 1.00 24.67 ATOM 763 CDl LEU 402 28.623 2.310 35.310 1.00 27.47 ATOM 764 CD2 LEU 402 26.312 3.277 35.482 1.00 24.93 ATOM 765 C LEU 402 24.755 -0.686 36.292 1.00 30.43 ATOM 766 O LEU 402 25.367 -1.727 36.535 1.00 31.36 ATOM 767 N LEU 403 23.552 -0.658 35.735 ,1.00 31.07 ATOM 768 CA LEU 403 22.873 -1.880 35.335 1.00 32.96 ATOM 769 CB LEU 403 21.361 -1.693 35.434 1.00 33.86 1 ATOM 770 CG LEU 403 20.551 -2.991 35.415 1.00 39.29 S

ATOM 771 CD1 LEU 403 20.584 -3.637 36.806 1.00 43.62 ATOM 772 CD2 LEU 403 19.128 -2.689 34.998 1.00 41.32 ATOM 773 C LEU 403 23.255 -2.218 33.899 1.00 30.06 ATOM 774 O LEU 403 22.543 -1.870 32.956 1.00 31.63 ATOM 775 N PHE 404 24.383 -2.893 33.733 1.00 29.19 ATOM 776 CA PHE 404 24.834 -3.256 32.403 1.00 28.93 ATOM 777 CB PHE 404 26.201 -3.929 32.493 1.00 30.05 ATOM 778 CG PHE 404 27.305 -2.998 32.926 1.00 30.78 ATOM 779 CDI PHE 404 27.794 -3.033 34.228 1.00 32.91 ATOM 780 CD2 PHE 404 27.848 -2.078 32.030 1.00 32.75 ATOM 781 CE1 PHE 404 28.816 -2.160 34.638 1.00 34.73 ATOM 782 CE2 PHE 404 28.864 -1.205 32.423 1.00 30.68 ATOM 783 CZ PHE 404 29.350 -1.242 33.727 1.00 31.43 ATOM 784 C PHE 404 23.809 -4.181 31.756 1.00 30.80 ATOM 785 O PHE 404 23.625 -4.175 30.538 1.00 28.09 ATOM 786 N ALA 405 23.138 -4.967 32.594 1.00 30.25 ATOM 787 CA ALA 405 22.104 -5.910 32.163 1.00 29.78 ATOM 788 CB ALA 405 22.745 -7.172 31.598 1.00 29.97 ATOM 789 C ALA 405 21.309 -6.237 33.429 1.00 31.95 ATOM 790 O ALA 405 21.785 -5.995 34.535 1.00 32.36 ATOM 791 N PRO 406 20.088 -6.779 33.288 1.00 34.40 ATOM 792 CD PRO 406 19.356 -7.102 32.053 1.00 35.81 ATOM 793 CA PRO 406 19.303 -7.101 34.490 1.00 36.41 ATOM 794 CB PRO 406 17.985 -7.654 33.935 1.00 35.38 ATOM 795 CG PRO 406 17.922 -7.153 32.519 1.00 36.49 ATOM 796 C PRO 406 19.997 -8.084 35.433 1.00 37.32 ATOM 797 O PRO 406 19.698 -8.112 36.626 1.00 38.34 ATOM 798 N ASN 407 20.924 -8.877 34.902 1.00 36.69 ATOM 799 CA ASN 407 21.652 -9.847 35.712 1.00 38.85 ATOM 800 CB ASN 407 21.582 -11.24335.083 1.00 39.69 ATOM 801 CG ASN 407 22.232 -11.30633.711 1.00 44.10 ATOM 802 ODl ASN 407 22.345 -10.29633.009 1.00 37.78 ATOM 803 ND2 ASN 407 22.660 -12.50333.319 1.00 45.74 ATOM 804 C ASN ?3.100 -9.435 35.874 1.00 38.12 ATOM 805 O ASN 23.965 -10.25636.178 1.00 39 ATOM 806 N LEU 408 ?3.364 -8.149 35.671 1.00 .

ATOM 807 CA LEU 408 24.713 -7.631 35.799 1.00 .

ATOM 808 CB LEU 408 25.449 -7.720 34.459 1.00 .

ATOM 809 CG LEU 408 26.972 -7.609 34.550 1.00 .

ATOM 810 CDI LEU 408 27.525 -8.775 35.354 1.00 .

ATOM 811 CD2 LEU 408 27.578 -7.587 33.158 1.00 .
36.85 ATOM 812 C LEU 408 24.670 -6.187 36.286 1.00 40 ATOM 813 O LEU 408 24.646 -5.248 35.491 1.00 .

ATOM 814 N LEU 409 24.644 -6.034 37.607 1.00 .

ATOM 815 CA LEU 409 24.606 -4.733 38.257 1.00 .
11.00 ATOM 816 CB LEU 409 23.392 -4.658 39.184 1.00 =13.69 ATOM 817 CG LEU 409 23.164 -3.382 39.993 1.00 47 I ATOM 818 CD LEU 409 22.848 -2.233 39.058 1.00 .
S 1 =17 ATOM 819 CD2 LEU 409 22.014 -3.603 40.976 1.00 .

ATOM 820 C LEU 409 25.894 -4.566 39.060 1.00 .
:11 ATOM 821 O LEU 409 26.178 -5.358 39.960 1.00 .

ATOM 822 N LEU 410 26.676 -3.544 38.727 1.00 .

ATOM 823 CA LEU 410 27.931 -3.296 39.423 1.00 .

ATOM 824 CB LEU 410 29.106 -3.354 38.442 1.00 .

ATOM 825 CG LEU 410 29.457 -4.660 37.716 1.00 .

ATOM 826 CDI LEU 410 30.972 -4.728 37.554 1.00 .

ATOM 827 CD2 LEU 410 28.949 -5.872 38.484 1.00 .

ATOM 828 C LEU 410 27.946 -1.944 40.132 1.00 .

ATOM 829 O LEU 410 27.361 -0.970 39.652 1.00 .

ATOM 830 N ASP 411 28.610 -1.890 41.281 1.00 .

ATOM 831 CA ASP 411 28.717 -0.640 42.025 1.00 .

ATOM 832 CB ASP 411 28.490 -0.874 43.528 1.00 .

ATOM 833 CG ASP 411 29.655 -1.578 44.210 1.00 .

ATOM 834 OD1 ASP 411 29.537 -1.849 45.426 1.00 .

ATOM 835 OD2 ASP 411 30.680 -1.861 43.553 1.00 .

ATOM 836 C ASP 411 30.088 -0.016 41.779 1.00 .

ATOM 837 O ASP 411 30.933 -0.610 41.107 1.00 .

ATOM 838 N ARG 412 30.295 1.181 42.321 1.00 .

ATOM 839 CA ARG 412 31.554 1.905 42.171 1.00 .

ATOM 840 CB ARG 412 31.601 3.090 43.138 1.00 .

ATOM 841 CG ARG 412 30.971 4.364 42.614 1.00 .

ATOM 842 CD ARG 412 31.644 5.580 43.219 1.00 .

ATOM 843 NE ARG 412 33.071 5.615 42.912 1.00 .

ATOM 844 CZ ARG 412 33.827 6.708 42.985 1.00 .

ATOM 845 NH1 ARG 412 33.291 7.866 43.356 1.00 .

ATOM 846 NH2 ARG 412 35.120 6.645 42.682 1.00 .

ATOM 847 C ARG 412 32.771 1.026 42.429 1.00 .

ATOM 848 O ARG 412 33.628 0.866 41.561 1.00 .
~ 1 ATOM 849 N ASN 413 32.844 0.469 43.633 I .
.00 ~ 1 ATOM 850 CA ASN 413 33.969 -0.375 44.021 1.00 .

ATOM 851 CB ASN 413 33.719 -0.980 45.403 1.00 .
55.88 ATOM 852 CG ASN -1 33.654 0.073 :16.4961.00 57.99 t ATOM 853 ODI ASN 413 33.697 1.276 .16.2231.00 58.27 ATOM 854 ND2 ASN 413 33.551 -0.375 -17.7421.00 57.90 ATOM 8SS C ASN 413 34.235 -1.480 13.013 1.00 S3.9S

S ATOM 856 O ASN 413 35.386 -1.743 12.659 1.00 53.67 ATOM 857 N GLN 414 33.173 -2.129 42.547 1.00 SS.33 ATOM 858 CA GLN 414 33.326 -3.198 41.573 1.00 SS.42 ATOM 859 CB GLN 414 31.991 -3.904 41.343 1.00 SS.44 ATOM 860 CG GLN 414 31.645 -4.933 42.391 1.00 56.07 ATOM 861 CD GLN 4i4 30.203 -5.376 42.336 1.00 57.40 ATOM 862 OEI GLN 414 29.296 -4.536 42.402 1.00 60.22 ATOM 863 NE2 GLN 414 29.973 -6.664 42.199 1.00 57.27 ATOM 864 C GLN 414 33.850 -2.630 40.259 1.00 SS.S

ATOM 865 O GLN 414 34.654 -3.265 39.578 1.00 56.16 1 ATOM 866 N GLY 41 33.398 -1.430 39.910 1.00 57.07 S S

ATOM 867 CA GLY 41 33.849 -0.806 38.680 1.00 SB.S

ATOM 868 C GLY 41 35.350 -O.S82 38.689 1.00 61.10 S

ATOM 869 O GLY 415 36.023 -0.748 37.671 1.00 59.47 ATOM 870 N LYS 416 35.877 -0.211 39.851 1.00 62.77 ATOM 871 CA LYS 416 37.305 0.041 40.011 1.00 65.49 ATOM 872 CB LYS 416 37.634 0.262 41.491 1.00 66.04 ATOM 873 CG LYS 416 38.121 1.663 41.823 1.00 68.71 ATOM 874 CD LYS 416 37.078 2.439 42.613 1.00 70.98 ATOM 875 CE LYS 416 37.404 2.448 44.100 1.00 71.84 2S ATOM 876 NZ LYS 416 36.225 2.079 44.933 1.00 71.95 ATOM 877 C LYS 416 38.159 -I.IOS 39.472 1.00 66.41 ATOM 878 O LYS 416 39.361 .-0.94639.269 1.00 67.15 ATOM 879 N CYS 417 37.538 -2.257 39.238 1.00 67.33 ATOM 880 CA CYS 417 38.270 -3.414 38.741 1.00 68.16 ATOM 881 CB CYS 417 37.951 -4.642 39.602 1.00 70.88 ATOM 882 SG CYS 417 38.592 -4.549 41.301 1.00 76.09 ATOM 883 C CYS 417 38.015 -3.736 37.270 1.00 67.54 ATOM 884 O CYS 417 38.632 -4.653 36.720 1.00 68.48 ATOM 885 N VAL 418 37.111 -2.994 36.631 1.00 64.67 3S ATOM 886 CA VAL 418 36.817 -3.226 35.218 1.00 59.97 ATOM 887 CB VAL 418 35.326 -2.917 34.879 1.00 S9.60 ATOM 888 CG1 VAL 418 34.971 -1.503 35.284 1.00 59.13 ATOM 889 CG2 VAL 418 35.072 -3.121 33.391 1.00 S4.8S

ATOM 890 C VAL 418 37.739 -2.362 34.355 1.00 58.37 ATOM 891 O VAL 418 37.799 -1.140 34.512 1.00 SS.44 ATOM 892 N GLU 419 38.463 -3.012 33.450 1.00 56.02 ATOM 893 CA GLU 419 39.403 -2.328 32.570 1.00 54.28 ATOM 894 CB GLU 419 40.149 -3.351 31.710 1.00 57.57 ATOM 895 CG GLU 419 39.385 -3.779 30.468 1.00 60.87 4S ATOM 896 CD GLU 419 40.179 -4.72? 29.584 1.00 63.34 ATOM 897 OE1 GLU 419 40.432 -5.870 30.011 1.00 64.90 ATOM 898 OE2 GLU 419 40.546 -4.313 28.462 1.00 63.18 ATOM 899 C GLU 419 38.761 -1.281 31.662 1.00 S2.OS

ATOM 900 O GLU 419 37.665 -1.481 31.131 1.00 49.82 ATOM 901 N GLY 420 39.465 -0.165 31.491 1.00 49.45 ATOM 902 CA GLY 420 38.983 0.908 30.642 1.00 46.22 ATOM 903 C GLY 420 37.895 1.767 31.254 1.00 44.55 ATOM 904 O GLY 420 37.417 2.705 30.619 1.00 42.08 ATOM 905 N MET 421 37.503 1.471 32.488 1.00 43.41 ATOM 906 CA MET 421 36.449 2.248 33.123 1.00 42.48 ATOM 907 CB MET 421 35.306 1.327 33.554 1.00 42.34 ATOM 908 CG MET 421 34.590 0.635 32.396 1.00 38.22 ATOM 909 SD MET 421 32.927 0.102 32.843 1.00 38.56 ATOM 910 CE MET 421 32.003 1.699 32.766 1.00 35.54 ATOM 911 C MET 421 36.923 3.059 34.312 1.00 41.64 ATOM 912 O MET 421 36.113 3.512 35.111 1.00 39.77 ATOM 913 N VAL 422 38.232 3.256 34.430 1.00 43.42 ATOM 914 CA VAL 422 38.757 4.019 35.557 1.00 44.79 ATOM 915 CB VAL 422 40.285 4.248 35.433 1.00 46.54 ATOM 916 CGI VAL 422 40.595 5.086 34.206 1.00 48.25 ATOM 917 CG2 VAL 422 40.813 4.920 36.696 1.00 46.24 ATOM 918 C VAL 422 38.056 5.372 35.689 1.00 44.09 ATOM 919 O VAL 422 37.691 5.783 36.783 1.00 44.12 ATOM 920 N GLU 423 37.846 6.055 34.570 1.00 42.07 ATOM 921 CA GLU 423 37.192 7.356 34.616 1.00 40.24 ATOM 922 CB GLU 423 37.909 8.338 33.684 1.00 44.02 ATOM 923 CG GLU 423 39.411 8.467 33.893 1.00 50.04 ATOM 924 CD GLU 423 40.096 9.158 32.719 1.00 55.64 ATOM 925 OEI GLU 423 39.539 10.156 32.205 1.00 56.66 ATOM 926 OE2 GLU 423 41.188 8.703 32.306 1.00 58.02 ATOM 927 C GLU 423 35.704 7.337 34.250 1.00 35.77 ATOM 928 O GLU 423 34.881 7.955 34.919 1.00 33.20 ATOM 929 N ILE 424 35.345 6.617 33.197 1.00 36.16 ATOM 930 CA ILE 424 33.949 6.643 32.771 1.00 31.63 ATOM 931 CB ILE 424 33.803 6.087 31.347 1.00 33.58 ATOM 932 CG2 ILE 424 34.639 6.936 30.395 1.00 33.48 ATOM 933 CGI ILE 424 34.204 4.617 31.296 1.00 34.46 ATOM 934 CD1 ILE 424 33.857 3.955 29.978 1.00 34.67 ATOM 935 C ILE 424 32.890 6.035 33.685 1.00 28.89 ATOM 936 O ILE 424 31.729 6.443 33.632 1.00 26.49 ATOM 937 N PHE 425 33.261 5.091 34.542 1.00 29.26 , ATOM 938 CA PHE 425 32.257 4.520 35.447 1.00 29.87 ATOM 939 CB PHE 425 32.903 3.529 36.423 1.00 31.26 ATOM 940 CG PHE 425 31.948 2.496 36:959 1.00 32.17 ATOM 941 CDI PHE 425 31.124 2.783 38.048 1.00 33.70 ATOM 942 CD2 PHE 425 31.881 1.230 36.381 1.00 30.64 ATOM 943 CEI PHE 425 30.244 1.814 38.563 1.00 32.60 ATOM 944 CE2 PHE 425 31.010 0.256 36.881 1.00 31.55 ATOM 945 CZ PHE 425 30.189 0.549 37.973 1.00 33.34 ATOM 946 C PHE 425 31.594 5.649 36.240 1.00 30.17 ATOM 947 O PHE 425 30.368 x.774 36.276 1.00 26.71 WO 99/50658 PC'T/US99/06937 ATOM 948 N ASP 426 32.41 6.483 36.870 1.00 29.45 S

ATOM 949 CA ASP 426 31.893 7.587 37.661 1.00 32.29 ATOM 950 CB ASP 426 33.031 8.291 38.401 1.00 33.49 ATOM 951 CG ASP 426 33.455 7.546 39.655 1.00 39.42 S ATOM 952 OD1 ASP 426 32.767 6.574 40.038 1.00 38.35 ATOM 953 OD2 ASP 426 34.480 7.934 40.256 1.00 39.58 ATOM 954 C ASP 426 31.133 8.592 36.806 1.00 29.02 ATOM 9SS O ASP 426 30.154 9.175 37.257 1.00 31.34 ATOM 956 N MET 427 31.585 8.797 35.572 1.00 30.69 ATOM 957 CA MET 427 30.919 9.736 34.675 1.00 28.63 ATOM 958 CB MET 427 31.744 9.912 33.407 1.00 26.83 ATOM 959 CG MET 427 33.032 10.680 33.608 1.00 31.41 ATOM 960 SD MET 427 33.962 10.783 32.077 1.00 34.87 ATOM 961 CE MET 427 35.409 11.753 32.643 1.00 44.60 1 ATOM 962 C MET 427 29.526 9.202 34.324 1.00 28.70 S

ATOM 963 O MET 427 28.536 9.947 34.302 1.00 25.01 ATOM 964 N LEU 428 29.451 7.902 34.057 1.00 25.13 ATOM 965 CA LEU 428 28.173 7.292 33.730 1.00 27.60 ATOM 966 CB LEU 428 28.379 5.824 33.332 1.00 28.00 ATOM 967 CG LEU 428 29.039 5.682 31.957 1.00 26.99 ATOM 968 CD1 LEU 428 29.678 4.303 31.782 1.00 27.80 ATOM 969 CD2 LEU 428 27.995 5.927 30.894 1.00 25.33 ATOM 970 C LEU 428 27.210 7.412 34.916 1.00 29.59 ATOM 971 O LEU 428 26.04I 7.743 34.743 1.00 27.07 2S ATOM 972 N LEU 429 27.701 7.147 36.126 1.00 30.40 ATOM 973 CA LEU 429 26.859 7.251 37.323 1.00 30.59 ATOM 974 CB LEU 429 27.675 6.884 38.571 1.00 31.76 ATOM 975 CG LEU 429 28.078 5.41 38.757 1.00 32.43 S

ATOM 976 CDI LEU 429 28.961 5.264 39.995 1.00 31.60 ATOM 977 CD2 LEU 429 26.825 4.573 38.903 1.00 34.66 ATOM 978 C LEU 429 26.319 8.681 37.466 1.00 30.46 ATOM 979 O LEU 429 25.143 8.901 37.769 1.00 28.40 ATOM 980 N ALA 430 27.193 9.656 37.237 1.00 31.34 ATOM 981 CA ALA 430 26.806 11.059 37.332 1.00 29.83 3S ATOM 982 CB ALA 430 28.017 11.951 37.078 1.00 31.29 ATOM 983 C ALA 430 25.696 11.387 36.344 I.00 31.04 ATOM 984 O ALA 430 24.753 12.107 36.674 1.00 30.79 ATOM 985 N THR 431 25.802 10.854 35.128 1.00 30.30 ATOM 986 CA THR 431 24.786 11.105 34.112 1.00 28.81 ATOM 987 CB THR 431 25.207 10.533 32.737 1.00 30.55 ATOM 988 OG THR 431 26.569 10.893 32.465 1.00 31.88 ATOM 989 CG2 THR 431 24.321 11.087 31.634 1.00 25.63 ATOM 990 C THR 431 23.462 10.481 34.530 1.00 29.49 ATOM 991 O THR 431 22.402 11.099 34.397 1.00 26.18 4S ATOM 992 N SER 432 23.520 9.253 35.037 1.00 28.11 ATOM 993 CA SER 432 22.308 8.573 35.480 1.00 29.78 ATOM 994 CB SER 432 22.639 7.177 36.008 1.00 33.1 i ATOM 995 OG SER 432 21.454 6.412 36.136 1.00 36.92 ATOM 996 C SER 432 21.651 9.399 36.589 1.00 31 ATOM 997 O SER 432 20.433 9.576 36.613 1.00 .
30.09 ATOM 998 N ASER 433 22.476 9.901 37.496 0.75 32 ATOM 999 N BSER 433 22.474 9.906 37.500 0.25 .
31.10 ATOM 1000 CA ASER 433 22.002 10.715 38.605 0.75 35 ATOM 1001 CA BSER 433 21.985 10.717 38.608 0.25 .

ATOM 1002 CB ASER 433 23.185 11.097 39.502 0.75 .

ATOM i CB BSER 433 23.145 11.104 39.529 0.25 .
003 31.45 ATOM 1004 OG ASER 433 22.823 12.090 40.443 0.75 44 ATOM 1005 OG BSER 433 23.785 9.953 40.053 0.25 .

ATOM 1006 C ASER 433 21.299 11.971 38.091 0.75 .

ATOM 1007 C BSER 433 21.295 11.976 38.092 0.25 .

ATOM 1008 O ASER 433 20.257 12.373 38.612 0.75 .

ATOM 1009 O BSER 433 20.264 12.391 38.622 0.25 .

ATOM 1010 N ARG 434 21.867 12.579 37.054 1.00 .
33.38 ATOM 1011 CA ARG 434 21.300 13.788 36.470 1.00 34 ATOM IOI2 CB ARG 434 22.239 14.354 35.400 1.00 .

ATOM 1013 CG ARG 434 21.670 15.528 34.625 1.00 .

ATOM 1014 CD ARG 434 21.559 16.787 35.479 1 .

ATOM 1015 NE ARG 434 21.158 17.944 34.680 . .
1.00 37 ATOM 1016 CZ ARG 434 20.488 18.995 35.149 1.00 .

ATOM 1017 NH ARG 434 20.132 19.049 36.428 1.00 .

ATOM 1018 NH2 ARG 434 20.175 19.998 34.337 1.00 .
38.78 ATOM 1019 C ARG 434 19.937 13.491 35.873 1.00 33 ATOM 1020 O ARG 434 18.996 14.266 36.053 1.00 .

ATOM 1021 N PHE 435 19.831 12.371 35.158 1.00 .

ATOM 1022 CA PHE 435 18.563 11.963 34.549 1.00 .

ATOM 1023 CB PHE 435 18.727 10.634 33.796 1.00 .

ATOM 1024 CG PHE 435 19.240 10.779 32.386 1.00 .

ATOM 1025 CDI PHE 435 19.459 12.035 31.824 1.00 .

ATOM 1026 CD2 PHE 435 19.521 9.649 31.623 1.00 .

ATOM 1027 CE PHE 435 19.953 12.164 30.521 1.00 .

ATOM 1028 CE2 PHE 435 20.016 9.768 30.322 1.00 .

ATOM 1029 CZ PHE 435 20.233 11.029 29.775 1.00 .

ATOM 1030 C PHE 435 17.527 11.780 35.657 1.00 .

ATOM 1031 O PHE 435 16.361 12.135 35.496 1.00 .

ATOM 1032 N ARG 436 17.968 11.216 36.777 1.00 .

ATOM 1033 CA ARG 436 17.094 10.982 37.924 1.00 .

ATOM 1034 CB ARG 436 t 7.844I 0.215 39.012 1.00 .

ATOM 1035 CG ARG 436 16.942 9.590 40.068 1.00 .

ATOM I036 CD ARG 436 17.648 8.459 40.810 1.00 .

ATOM 1037 NE ARG 436 18.982 8.841 41.275 1.00 .

ATOM 1038 CZ ARG 436 20.119 8.361 40.777 1.00 .

ATOM 1039 NH ARG 436 20.099 7.472 39.790 1.00 .

ATOM 1040 NH2 ARG 436 21.283 8.770 41.266 1.00 .

ATOM 1041 C ARG 436 16.576 12.302 38.493 1.00 .

ATOM 1042 O ARG 436 15.382 I2.458 38.730 1.00 .

ATOM 1043 N MET 437 17.477 13.252 38.706 1.00 .
40.02 ATOM 1044 CA MET 437 17.090 14.546 39.245 I -t .00 i .02 ATOM 1045 CB MET 437 18.329 15.427 39.440 1.00 -10.29 ATOM 1046 C MET 437 16.099 15.221 38.299 1.00 -40.81 ATOM 1047 O MET 437 15.I11 15.805 38.734 1.00 -12.46 ATOM 1048 N MET 438 16.367 15.127 37.001 1.00 39.02 ATOM 1049 CA MET 438 15.510 15.732 35.988 1.00 :10.11 ATOM 1050 CB MET 438 16.237 15.793 34.651 1.00 38.16 ATOM 1051 CG MET 438 17.352 16.794 34.601 1.00 41.52 ATOM 1052 SD MET 438 17.999 16.862 32.943 1.00 -13.94 ATOM 1053 CE MET 438 16.698 17.748 32.096 1.00 39.96 ATOM 1054 C MET 438 14.221 14.964 35.783 1.00 37.72 ATOM 1055 O MET 438 13.305 15.451 35.125 1.00 36.82 ATOM 1056 N ASN 439 14.155 13.759 36.337 1.00 38.$1 ATOM 1057 CA ASN 439 12.981 12.919 36.174 1.00 40.77 ATOM 1058 CB ASN 439 11.762 13.556 36.847 1.00 44.52 ATOM 1059 CG ASN 439 10.566 12.620 36.887 1.00 x8.29 ATOM 1060 OD ASN 439 10.721 11.400 36.964 l -18.48 1 .00 ATOM 1061 ND2 ASN 439 9.365 13.189 36.829 1.00 50.23 ATOM 1062 C ASN 439 12.725 12.744 34.677 1.00 39.36 ATOM 1063 O ASN 439 11.637 13.037 34.172 1.00 37.76 ATOM 1064 N LEU 440 13.749 12.274 33.972 1.00 37.65 ATOM 1065 CA LEU 440 13.655 12.052 32.532 1.00 35.22 ATOM 1066 CB LEU 440 14.999 11.576 31.987 1.00 34.70 ATOM 1067 CG LEU 440 15.022 11.467 30.462 1.00 35.45 ~

ATOM 1068 CD1 LEU 440 14.890 12.862 29.869 1.00 35.24 ATOM 1069 CD2 LEU 440 16.297 10.795 29.999 1.00 35.30 ATOM 1070 C LEU 440 12.587 11.024 32.196 1.00 36.48 ATOM 1071 O LEU 440 12.518 9.967 32.826 1.00 37.36 ATOM 1072 N GLN 441 11.763 11.328 31.197 1.00 36.82 ATOM 1073 CA GLN 441 10.696 10.420 30.785 1.00 38.51 ATOM 1074 CB GLN 441 9.43I 11.211 30.443 1.00 38.23 ATOM 1075 CG GLN 441 8.912 12.063 31.592 1.00 42.46 ATOM 1076 CD GLN 441 8.362 11.227 32.729 1.00 44.91 ATOM 1077 OE GLN 441 7.268 10.668 32.629 1.00 17.31 ATOM 1078 NE2 GLN 441 9.119 11.132 33.818 1.00 44.06 ATOM 1079 C GLN 441 11.099 9.565 29.585 1.00 38.48 ATOM 1080 O GLN 441 11.923 9.976 28.763 1.00 35.80 ATOM 1081 N GLY 442 10.500 8.378 29.494 1.00 36.03 ATOM 1082 CA GLY 442 10.792 7.468 28.401 1.00 37.72 ATOM 1083 C GLY 442 10.599 8.112 27.043 1.00 36.88 ATOM 1084 O GLY 442 11.381 7.877 26.123 1.00 33.72 ATOM 1085 N GLU 443 9.556 8.925 26.918 1.00 36.59 ATOM 1086 CA GLU 443 9.269 9.603 25.661 1.00 37.13 ATOM 1087 CB GLU 443 7.956 10.379 25.764 1.00 -11.57 ATOM 1088 CG GLU 443 6..723 9.488 25.879 1.00 -17.76 ATOM 1089 CD GLU 443 6.483 9.008 27.302 1.00 53.96 ATOM 1090 OE1 GLU 443 5.619 8.123 27.498 1.00 57.66 ATOM 1091 OE2 GLU 443 7.159 9.515 28.225 1.00 56.13 ATOM 1092 C GLU .143 10.408 10.55 '5.311 1.00 35.27 ATOM 1093 O GLU 443 10.759 10.704 24.145 1.00 33.85 ATOM 1094 N GLU 444 10.984 11.179 ?6.331 1.00 32.09 ATOM 1095 CA GLU 444 12.097 12.095 ?6.126 1.00 33.92 S ATOM 1096 CB GLU 444 12.332 12.924 '_'7.3881.00 34.97 ATOM 1097 CG GLU 444 11.169 13.845 ?7.732 1.00 38.28 ATOM 1098 CD GLU 444 11.383 I4.610 29.023 1.00 38.11 ATOM 1099 OE1 GLU 444 11.800 13.993 30.026 1.00 39.53 ATOM 1100 OE2 GLU 444 11.132 15.834 X9.036 1.00 40.77 ATOM 1101 C GLU 444 13.356 11.305 X5.770 1.00 33.59 ATOM 1102 O GLU 444 14.085 11.670 ?4.842 1.00 33.35 ATOM 1103 N PHE 445 13.590 10.21 26.501 1.00 30.68 S

ATOM 1104 CA PHE 445 14.753 9.357 26.276 1.00 32.49 ATOM 1105 CB PHE 445 14.703 8.139 X7.203 1.00 29.35 ATOM 1106 CG PHE 445 I 5.667 7.047 26.828 1.00 30.78 ATOM 1107 CD1 PHE 445 17.036 7.201 X7.030 1.00 28.25 ATOM 1108 CD2 PHE 445 15.205 5.863 X6.266 1.00 30.62 ATOM 1109 CEi PHE 445 17.933 6.195 26.675 1.00 28.67 ATOM 1110 CE2 PHE 445 16.095 4.848 ''5.9081.00 31.37 ATOM 1 I CZ PHE 445 17.460 S.OI 26.113 1.00 30.37 ATOM 1112 C PHE 445 14.850 8.885 24.829 1.00 31.11 ATOM 1113 O PHE 445 15.924 8.947 24.221 1.00 32.20 ATOM 1114 N VAL 446 13.739 8.41 24.266 1.00 28.63 S

ATOM 1 I CA VAL 446 13.787 7.943 22.889 1.00 27.94 I
S

2S ATOM 1116 CB VAL 446 12.478 7.193 22.478 1.00 28.48 ATOM 1117 CGl VAL 446 12.318 5.939 23.343 1.00 29.61 ATOM 1118 CG2 VAL 446 11.265 8.092 22.607 1.00 27.23 ATOM 1119 C VAL 446 14.099 9.064 21.900 1.00 27.28 ATOM 1120 O VAL 446 14.781 8.837 20.904 1.00 28.07 ATOM 1121 N CYS 447 13.619 10.275 22.166 1.00 28.97 ATOM 1122 CA CYS 447 13.919 I 1.394? 1.2721.00 29.14 ATOM 1123 CB CYS 447 13.156 12.653 21.693 1.00 28.90 ATOM I 124 SG CYS 447 I 1.389 12.591 ? 1.3091.00 35.68 ATOM 1125 C CYS 447 15.420 11.677 21.328 1.00 28.03 3S ATOM 1126 O CYS 447 16.063 11.885 20.302 1.00 29.34 ATOM 1127 N LEU 448 I 5.969 11.686 X2.538 1.00 27.28 ATOM 1128 CA LEU 448 17.392 11.938 22.729 1.00 25.30 ATOM 1129 CB LEU 448 17.733 11.932 24.220 1.00 27.72 ATOM 1130 CG LEU 448 17.248 13.135 25.040 1.00 29.54 ATOM 1131 CDI LEU 448 17.807 13.042 X6.454 1.00 30.85 ATOM 1132 CD2 LEU 448 17.688 14.434 ?4.376 1.00 30.24 ATOM 1133 C LEU 448 18.245 10.902 '2.008 1.00 27.62 ATOM 1134 O LEU 448 19.207 1 I ~ 1.3271.00 25.10 .252 ATOM 1135 N LYS 449 17.905 9.621 '2.162 i.00 25.16 ATOM 1136 CA LYS 449 18.673 8.570 ? 1.5061.00 27.55 ATOM i 137 CB LYS 449 18.135 7.185 ~ 1.9001.00 28.99 ATOM I 138 CG LYS 449 19.134 6.052 ~ 1.694I 34.70 .00 ATOM 1139 CD LYS 449 18.737 4.789 ?2.459 1.00 32.67 ATOM 1 140 LYS 449 I 7.267 4.419 X2.220 i 31 ATOM 1141 NZ LYS 449 17.022 ?.967 22.472 . .
1.00 X9 ATOM 1142 C LYS 449 18.626 8.749 19.990 1.00 .

ATOM 1143 O LYS 449 19.610 8.489 19.296 1 .

ATOM 1144 N SER 450 17.482 9.197 19.480 . .

ATOM 1145 CA SER 450 17.323 9.421 18.052 . .
1.00 27 ATOM 1146 CB SER 450 15.857 9.705 I7.72I 1.00 .

ATOM 1147 OG SER 450 15.098 8.519 17.779 1 .

ATOM 1148 C SER 450 18.176 10.607 17.618 . .

ATOM 1149 O SER 450 18.763 10.598 16.535 . .

ATOM I150 N ILE 451 18.231 11.632 18.463 . .
1.00 26 ATOM 11 CA ILE 451 19.032 12.810 18.155 1 .

ATOM 1152 CB ILE 451 18.950 13.850 19.291 . .
1.00 27 ATOM 1153 CG2 ILE 451 2Q.019 14.929 i 9.1011 , ATOM 1154 CGI ILE 451 17.553 14.475 19.322 . .
1.00 29 ATOM 1155 CD1 ILE 451 17.377 15.473 20.447 1.00 .

ATOM 1156 C ILE 451 20.489 12.381 I7.989 1.00 .

ATOM 1157 O ILE 451 21.161 12.771 17.034 1.00 .

ATOM 1158 N ILE 452 20.977 11.582 t 8.9311 .

ATOM 1159 CA ILE 452 22.359 11.120 18.880 . .

ATOM 1160 CB ILE 452 22.660 10.155 20.050 . .

ATOM 1161 CG2 ILE 452 23.982 9.435 19.804 . .

ATOM 1162 CG ILE 452 22.718 10.949 21.371 . .

ATOM 1163 CDI ILE 452 22.768 10.060 22.624 . .

ATOM 1164 C ILE 452 22.656 10.419 17.557 . .

ATOM 1165 O ILE 452 23.650 10.708 i 6.885. .

ATOM 1166 N LEU 453 21.779 9.497 17.173 . .

ATOM 1167 CA LEU 453 21.984 8.768 15.935 . .
1.00 22 ATOM 1168 CB LEU 453 20.843 7.764 15.733 1 .

ATOM 1169 CG LEU 453 20.712 7.189 14.324 . .

ATOM I 170 CD LEU 453 21.815 6.165 14. . .

ATOM 1171 CD2 LEU 453 19.328 6.535 14.156 . .

ATOM 1172 C LEU 453 22.092 9.687 14.717 . .

ATOM 1173 O LEU 453 22.962 9.501 13.860 . .

ATOM 1174 N LEU 454 21.220 10.687 14.638 . .

ATOM 1175 CA LEU 454 21.234 11.599 13.494 . .

ATOM 1176 CB LEU 454 19.852 12.242 13.330 . .
1.00 25 ATOM 1177 CG LEU 454 18.737 11.222 13.052 1 .

ATOM 1178 CD LEU 454 17.405 11.926 12.955 . .

ATOM 1179 CD2 LEU 454 19.037 10.478 11.759 . .

ATOM 1180 C LEU 454 22.292 12.703 13.552 . .

ATOM 1181 LEU 454 22.778 13.148 12.513 . .

ATOM 1182 ASN 455 22.638 13.146 14.757 . .

ATOM 1183 ASN 455 ?3.604 14.236 14.934 . .
CA 1 ?6 ATOM 1184 ASN ?3.284 14.998 16.224 . .
CB 455 1 '6 ATOM 1185 ASN 24.174 16.217 16.419 . .
CG 455 1 ?7 ATOM 1186 ASN 24.171 17.134 15.602 . .

ATOM 1187 ASN 24.931 16.230 17.506 . .
ND2 455 1.00 27.16 ATOM 1188 C ASN 455 ?5.062 13.782 14.954 1.00 30.63 ATOM 1189 O ASN 455 25.965 14.517 14.525 1.00 27.69 ATOM 1190 N SER 456 25.268 12.569 15.461 1.00 30.48 ATOM 1191 CA SER 456 26.572 11.928 15.579 1.00 35.26 S ATOM 1192 CB SER 456 26.393 10.393 1 S.SOSI 39.69 .00 ATOM 1193 OG SER 456 25.871 9.953 14.243 1.00 30.73 ATOM 1194 C SER 456 27.627 12.344 14.562 1.00 35.56 ATOM 1195 O SER 456 28.599 13.041 14.884 1.00 33.00 ATOM 1196 N GLY 457 27.437 11.886 13.334 1.00 33.88 ATOM 1197 CA GLY 457 28.393 12.189 12.292 1.00 36.77 ATOM 1198 C GLY 457 27.876 13.017 11.136 1.00 37.02 ATOM 1199 O GLY 457 28.310 12.805 10.013 1.00 38.66 ATOM 1200 N VAL 458 26.967 13.956 11.392 1.00 39.12 ATOM 1201 CA VAL 458 26.438 14.802 10.317 1.00 43.81 1 ATOM 1202 CB VAL 458 25.231 15.648 10.755 1.00 44.25 S

ATOM 1203 CG VAL 458 24.209 15.713 9.631 1.00 44.51 ATOM 1204 CG2 VAL 458 24.638 15.098 12.013 1.00 SO.S3 ATOM 1205 C VAL 458 27.472 I5.801 9.817 1.00 46.72 ATOM 1206 O VAL 458 27.391 16.265 8.681 1.00 47.08 ATOM 1207 N TYR 459 28.432 16.144 10.670 1.00 50.74 ATOM 1208 CA TYR 459 29.456 17.114 10.301 1.00 SS.43 ATOM 1209 CB TYR 459 29.647 18.129 11.433 1.00 56.62 ATOM 1210 CG TYR 459 28.375 18.870 11.781 1.00 59.34 ATOM 1211 CD TYR 459 28.094 19.229 13.095 1.00 60.73 2S ATOM 1212 CE1 TYR 459 26.900 19.867 13.429 1.00 62.14 ATOM 1213 CD2 TYR 459 27.430 19.175 10.795 1.00 62.16 ATOM 1214 CE2 TYR 459 26.234 19.812 11.118 1.00 63.83 ATOM 121 CZ TYR 459 25.976 20.1 12.437 I 62.88 S S4 .00 ATOM 1216 OH TYR 459 24.790 20.764 12.767 1.00 62.56 ATOM 1217 C TYR 459 30.791 16.489 9.928 1.00 S7.2I

ATOM 1218 O TYR 459 31.793 17.189 9.798 1.00 56.86 ATOM 1219 N THR 460 30.800 15.173 9.750 1.00 59.22 ATOM 1220 CA THR 460 32.018 14.474 9.366 1.00 62.25 ATOM 1221 CB THR 460 32.502 13.531 10.499 1.00 63.07 3S ATOM 1222 OG THR 460 33.474 12.613 9.983 1.00 67.80 I

ATOM 1223 CG2 THR 460 31.344 12.759 11.084 1.00 60.23 ATOM 1224 C THR 460 31.759 13.678 8.086 1.00 63.54 ATOM 1225 O THR 460 32.457 12.708 7.782 1.00 63.91 ATOM 1226 N PHE 461 30.758 14.113 7.326 1.00 65.06 ATOM 1227 CA PHE 461 30.395 13.446 6.080 1.00 67.00 ATOM 1228 CB PHE 461 29.052 13.975 S.S63 1.00 66.48 ATOM 1229 CG PHE 461 27.867 13.147 5.991 1.00 66.30 ATOM 1230 CD PHE 461 26.657 13.754 6.312 1.00 65.58 ATOM 1231 CD2 PHE 461 27.963 11.760 6.085 1.00 66.41 4S ATOM 1232 CEI PHE 461 25.562 12.996 6.723 1.00 65.45 ATOM 1233 CE2 PHE 461 26.872 10.994 6.494 1.00 66.83 ATOM 1234 CZ PHE 461 25.670 11.616 6.814 1.00 65.12 ATOM 1235 C PHE 461 31.463 13.604 5.004 1.00 68.38 ATOM 1236 O PHE =t61 32.181 14.606 -1.962 1.00 68.98 ATOM 1237 N LEU 462 31.542 12.601 4.132 1.00 69.57 ATOM 1238 CA LEU 462 32.511 12.545 3.039 1.00 71.68 ATOM 1239 CB LEU 462 32.080 I1.475 2.030 1.00 71.00 ATOM 1240 C LEU 462 32.810 13.856 2.304 1.00 72.40 ATOM 1241 O LEU 462 33.725 14.590 2.680 1.00 73.45 ATOM 1242 N SER 463 32.043 14.141 1.253 1.00 73.22 ATOM 1243 CA SER 463 32.262 15.343 0.449 1.00 72.61 ATOM 1244 CB SER 463 32.544 14.942 -1.005 1.00 73.38 ATOM 1245 C SER 463 31.126 16.362 0.491 1.00 71.17 ATOM 1246 O SER 463 30.455 16.528 1.511 1.00 72.05 ATOM 1247 N SER 464 30.932 17.049 -0.633 1.00 68.86 ATOM 1248 CA SER 464 29.892 18.063 -0.759 1.00 66.06 ATOM 1249 CB SER 464 30.514 19.457 -0.704 1.00 66.26 1 ATOM I C SER 464 29.108 17.887 -2.060 1.00 63.72 ATOM 1251 O SER 464 28.657 18.862 -2.662 1.00 62.88 ATOM 1252 N THR 465 28.954 16.638 -2.493 1.00 60.93 ATOM 1253 CA THR 465 28.205 16.343 -3.709 1.00 57.47 ATOM 1254 CB THR 465 28.185 14.824 -4.004 1.00 57.80 ATOM 1255 OG1 THR 465 27.525 14.135 -2.934 1.00 54.75 ATOM 1256 CG2 THR 465 29.606 14.287 -4.149 1.00 57.49 ATOM 1257 C THR 465 26.767 16.824 -3.523 1.00 54.93 ATOM 1258 O THR 465 26.349 17.129 -2.407 1.00 54.26 ATOM 1259 N LEU 466 26.013 16.892 -4.614 1.00 51.85 ATOM 1260 CA LEU 466 24.625 17.330 -4.550 1.00 49.25 ATOM 1261 CB LEU 466 24.013 17.349 -5.956 1.00 48.74 ATOM 1262 CG LEU 466 22.953 18.415 -6.253 1.00 48.72 ATOM 1263 CD LEU 466 22.156 18.002 -7.482 1.00 48.32 I

ATOM 1264 CD2 LEU 466 22.033 18.594 -5.057 1.00 48.14 ATOM 1265 C LEU 466 23.817 16.397 -3.650 1.00 48.16 ATOM 1266 O LEU 466 22.961 16.845 -2.883 1.00 45.90 ATOM 1267 N LYS 467 24.093 15.099 -3.750 1.00 46.47 ATOM 1268 CA LYS 467 23.399 14.100 -2.947 1.00 47.45 ATOM 1269 CB LYS 467 23.802 12.693 -3.395 1.00 49.38 ATOM 1270 CG LYS 467 22.829 11.602 -2.974 1.00 52.70 ATOM 1271 CD LYS 467 23.561 10.301 -2.682 1.00 56.48 ATOM 1272 CE LYS 467 23.105 9.180 -3.604 1.00 59.54 ATOM 1273 NZ LYS 467 24.150 8.117 -3.732 1.00 61.22 ATOM 1274 C LYS 467 23.738 14.284 -1.472 1.00 46.89 ATOM 1275 O LYS 467 22.884 14.108 -0.604 1.00 46.06 ATOM 1276 N SER 468 24.989 14.644 -1.202 1.00 45.82 ATOM 1277 CA SER 468 25.457 14.854 0.160 1.00 46.82 ATOM 1278 CB SER 468 ?6.976 15.050 0.173 1.00 47.85 ATOM 1279 OG SER 468 27.407 15.537 1.435 1.00 X5.73 ATOM 1280 C SER 468 24.778 16.063 0.790 1.00 44.24 ATOM 1281 O SER 468 24.473 16.062 1.983 1.00 42.98 ATOM 1282 N LEU 469 24.547 17.100 -0.011 1.00 42.33 ATOM 1283 CA LEU 469 23.890 18.301 0.486 1.00 40.42 ATOM 1284 CB LEU 469 24.002 / 9.427-0.545 1.00 14.47 ATOM 1285 CG LEU 469 25.438 19.874 -0.849 1.00 16.70 ATOM 1286 CD LEU 469 25.514 ?0.477 -2.246 1.00 16.70 ATOM 1287 CD2 LEU 469 25.890 ?0.883 0.199 1.00 47.32 ATOM 1288 C LEU 469 22.423 17.996 0.786 1.00 39.06 ATOM 1289 O LEU 469 21.856 18.505 1.760 1.00 34.97 ATOM 1290 N GLU 470 21.814 17.151 -0.046 1.00 35.46 ATOM 1291 CA GLU 470 20.418 16.768 0.145 1.00 34.38 ATOM 1292 CB GLU 470 19.914 15.963 -1.052 1.00 38.02 ATOM 1293 CG GLU 470 19.77? 16.773 -2.329 1.00 42.67 ATOM 1294 CD GLU 470 19.339 15.923 -3.509 1.00 48.30 ATOM 1295 OE1 GLU 470 19.671 14.716 -3.538 1.00 50.53 ATOM 1296 OE2 GLU 470 18.666 16.463 -4.412 1.00 51.06 ATOM 1297 C GLU 470 20.290 15.916 1.403 1.00 34.37 ATOM 1298 O GLU 470 19.321 16.035 2.157 1.00 32.60 ATOM 1299 N GLU 471 21.274 15.046 1.606 1.00 34.66 ATOM 1300 CA GLU 471 21.309 14.162 2.766 1.00 35.68 ATOM 1301 CB GLU 471 22.51 / 3.2222.671 I 34.57 ~ .00 ATOM 1302 CG GLU 471 22.376 12.122 1.614 1.00 37.98 ATOM 1303 CD GLU 471 21.476 10.989 2.063 1.00 39.79 ATOM 1304 OE GLU 471 20.268 11.027 1.743 1.00 41.
1 l ATOM 1305 OE2 GLU 471 21.974 10.061 2.737 1.00 32.11 ATOM 1306 C GLU 471 21.393 14.983 4.052 1.00 34.79 ATOM 1307 O GLU 471 20.596 14.793 4.969 1.00 32.80 ATOM 1308 N LYS 472 22.358 15.898 4.1I2 1.00 33.93 ATOM 1309 CA LYS 472 22.518 16.739 5.291 1.00 35.58 ATOM 1310 CB LYS 472 23.683 17.710 5.097 1.00 39.11 ATOM 1311 CG LYS 472 25.050 17.050 5.138 1.00 41.47 ATOM 1312 CD LYS 472 26.080 17.957 5.794 1.00 46.97 ATOM 1313 CE LYS 472 27.445 17.286 5.862 1.00 48.40 ATOM 1314 NZ LYS 472 27.850 16.702 4.547 1.00 51.55 ATOM 1315 C LYS 472 21.237 17.523 5.582 1.00 34.78 ATOM 1316 O LYS 472 20.795 17.607 6.724 1.00 33.95 ATOM 1317 N ASP 473 20.643 18.097 4.545 1.00 33.47 ATOM 1318 CA ASP 473 19.420 18.865 4.720 1.00 34.63 ATOM 1319 CB ASP 473 18.923 19.404 3.380 1.00 37.21 ATOM 1320 CG ASP 473 17.654 20.221 3.522 1.00 43.24 ATOM 1321 OD1 ASP 473 16.559 19.687 3.230 1.00 45.20 ATOM 1322 OD2 ASP 473 17.750 21.396 3.932 1.00 45.59 ATOM 1323 C ASP 473 18.339 17.998 5.338 1.00 32.93 ATOM 1324 O ASP 473 17.642 18.416 6.264 1.00 32.87 ATOM 1325 N HIS 474 18.199 16.784 4.827 1.00 32.74 ATOM 1326 CA HIS 474 17.185 15.882 5.343 1.00 32.21 ATOM 1327 CB HIS 474 17.185 14.575 4.568 1.00 32.79 ATOM 1328 CG HIS 474 16.047 13.675 4.924 1.00 36.22 ATOM 1329 CD2 HIS 474 14.711 13.813 4.750 1.00 38.33 ATOM 1330 NDI HIS 474 16.227 12.456 5.542 1.00 38.97 ATOM 1331 CE1 HIS 474 15.053 11.883 5.732 1.00 37.99 ATOM 1332 NE2 HIS .17414.116 12.686 x.261 1.00 37.43 ATOM 1333 C HIS 474 17.403 15.573 6.815 I.00 X9.74 ATOM 1334 O HIS 474 16.460 I5.543 7.596 1.00 29.90 ATOM 1335 N ILE .17518.653 15.326 7.185 1.00 27.80 ATOM 1336 CA ILE 475 18.971 15.014 8.571 1.00 25.61 ATOM 1337 CB ILE 475 20.478 14.708 8.720 1.00 25.59 ATOM 1338 CG2 ILE 475 20.877 14.713 10.193 1.00 27.17 ATOM 1339 CG1 ILE 475 20.787 13.341 8.092 1.00 26.17 ATOM 1340 CD1 ILE 475 22.258 13.071 7.849 1.00 27.07 ATOM 1341 C ILE 475 18.576 16.201 9.460 1.00 27.91 ATOM 1342 O ILE 475 17.928 16.038 10.485 1.00 29.16 ATOM 1343 N HIS 476 18.956 17.404 9.054 1.00 29.41 ATOM 1344 CA HIS 476 18.621 18.575 9.846 1.00 29.73 ATOM 1345 CB HIS 476 19.342 19.796 9.281 1.00 32.27 ATOM 1346 CG HIS 476 20.777 19.867 9.699 1.00 39.44 ATOM 1347 CD2 HIS 476 21.355 19.707 10.915 1.00 39.81 ATOM 1348 NDl HIS 476 21.809 20.067 8.808 1.00 39.79 ATOM 1349 CEI HIS 476 22.959 20.027 9.456 1.00 39.98 ATOM 1350 NE2 HIS 476 22.712 19.809 10.735 1.00 40.26 ATOM 1351 C HIS 476 17.120 18.810 9.948 1.00 31.40 ATOM 1352 O HIS 476 16.636 19.336 10.951 1.00 29.79 ATOM 1353 N ARG 477 16.374 18.396 8.929 1.00 31.82 ATOM 1354 CA ARG 477 14.929 18.570 8.956 1.00 31.53 ATOM 1355 CB ARG 477 14.343 18.376 7.557 1.00 34.95 ATOM 1356 CG ARG 477 14.425 19.627 6.700 1.00 40.46 ATOM 1357 CD ARG 477 13.698 19.445 5.370 1.00 45.22 ATOM 1358 NE ARG 477 14.107 20.456 4.399 1.00 53.05 ATOM 1359 CZ ARG 477 13.647 21.705 4.376 1.00 55.89 ATOM 1360 NH1 ARG 477 12.756 22.106 5.274 1.00 56.17 ATOM 1361 NH2 ARG 477 14.084 22.558 3.457 1.00 59.49 ATOM 1362 C ARG 477 14.310 17.582 9.931 1.00 30.70 ATOM 1363 O ARG 47? 13.360 17.903 10.649 1.00 30.24 ATOM 1364 N VAL 478 14.863 16.375 9.972 1.00 29.67 ATOM 1365 CA VAL 478 14.351 15.369 10.887 1.00 29.68 ATOM 1366 CB VAL 478 14.937 13.975 10.575 1.00 32.01 ATOM 1367 CGI VAL 478 14.461 12.973 11.609 1.00 32.93 ATOM 1368 CG2 VAL 478 14.506 13.528 9.169 1.00 31.00 ATOM 1369 C VAL 478 14.696 15.774 12.316 1.00 29.81 ATOM 1370 O VAL 478 13.860 15.677 13.220 1.00 30.25 ATOM 1371 N LEU 479 15.929 16.232 12.516 1.00 28.81 ATOM 1372 CA LEU 479 16.360 16.674 13.836 1.00 28.74 ATOM 1373 CB LEU 479 17.799 17.210 13.779 1.00 26.65 ATOM 1374 CG LEU 479 18.910 16.152 13.853 1.00 26.05 ATOM 1375 CDl LEU 479 20.231 16.772 13.395 1.00 25.81 ATOM 1376 CD2 LEU 479 19.028 15.603 15.277 1.00 25.34 ATOM 1377 C LEU 479 15.411 17.777 11.313 1.00 29.54 ATOM 1378 O LEU 479 14.997 17.786 15.472 1.00 29.00 ATOM 1379 N ASP 480 15.076 18.703 13.41 I .00 31.52 ~

ATOM 1380 CA ASP 480 14.162 19.800 13.741 1.00 33.84 ATOM 1381 CB ASP 480 13.943 20.712 12.528 1.00 34.37 ATOM 1382 CG ASP 480 15.055 21.743 12.345 1.00 36.26 ATOM 1383 ODl ASP 480 15.119 22.354 I1.257 1.00 36.56 ATOM 1384 OD2 ASP 480 15.860 21.951 13.274 1.00 34.19 ATOM 1385 C ASP 480 12.818 19.222 14.174 1.00 33.48 ATOM 1386 O ASP 480 12.186 19.724 15.105 1.00 33.89 ATOM 1387 N LYS 481 12.379 18.161 13.498 1.00 33.90 ATOM 1388 CA LYS 481 11.106 17.536 13.839 1.00 32.97 ATOM 1389 CB LYS 481 10.719 16.489 12.784 1.00 34.66 ATOM 1390 C LYS 481 11.164 16.895 15.225 1.00 33.57 ATOM 1391 O LYS 481 10.167 16.869 I5.943 1.00 35.37 ATOM 1392 N ILE 482 I2.328 16.377 15.607 1.00 32.71 ATOM 1393 CA ILE 482 12.457 15.764 16.922 1.00 31.60 ATOM 1394 CB ILE 482 i 3.74314.913 17.028 1.00 32.65 ATOM 1395 CG2 ILE 482 13.877 14.338 18.430 1.00 32.50 ATOM 1396 CG ILE 482 13.697 13.785 15.995 1.00 32.72 ATOM 1397 CD1 ILE 482 14.978 12.969 15.908 1.00 33.37 ATOM 1398 C ILE 482 12.456 16.853 17.994 1.00 31.69 ATOM 1399 O ILE 482 11.946 16.649 19.097 1.00 29.98 ATOM 1400 N THR 483 13.027 18.012 17.679 1.00 31.33 ATOM 1401 CA THR 483 13.022 19.109 18.644 1.00 31.71 ATOM 1402 CB THR 483 13.756 20.351 18.109 1.00 32.92 ATOM 1403 OG1 THR 483 15.111 20.012 17.788 1.00 29.99 ATOM 1404 CG2 THR 483 13.756 21.452 19.160 1.00 30.47 ATOM 1405 C THR 483 11.559 19.483 18.920 1.00 32.85 ATOM 1406 O THR 483 11.146 19.598 20.070 1.00 31.83 ATOM 1407 N ASP 484 10.785 19.656 17.851 1.00 31.91 ATOM 1408 CA ASP 484 9.369 20.003 17.965 1.00 34.15 ATOM 1409 CB ASP 484 8.708 20.013 16.591 1.00 37.41 ATOM 1410 CG ASP ~ 484 9.270 21.080 15.680 1.00 :12.02 ATOM 1411 OD1 ASP 484 9.871 22.045 16.198 1.00 43.26 ATOM 1412 OD2 ASP 484 9.106 20.952 14.445 1.00 42.49 ATOM 1413 C ASP 484 8.657 18.985 18.840 1.00 33.I6 ATOM 1414 O ASP 484 7.830 19.339 19.676 1.00 34.86 ATOM 1415 N THR 485 8.996 17.715 18.646 1.00 33.91 ATOM 1416 CA THR 485 8.396 16.635 19.414 1.00 34.41 ATOM I417 CB THR 485 8.875 I5.268 18.885 1.00 33.58 ATOM 1418 OG1 THR 485 8.400 15.094 17.542 1.00 37.04 ATOM 1419 CG2 THR 485 8.347 14.138 19.751 1.00 30.89 ATOM 1420 C THR 485 8.708 16.757 20.903 1.00 35.15 ATOM 1421 O THR 485 7.818 16.600 21.744 1.00 31.99 ATOM 1422 N LEU 486 9.966 17.046 21.229 1.00 33.77 ATOM 1423 CA LEU 486 10.368 17.192 22.621 1.00 34.31 ATOM 1424 CB LEU 486 11.879 17.448 22.721 1.00 32.00 ATOM 1425 CG LEU 486 12.776 16.201 22.754 1.00 34.99 ATOM 1426 CD1 LEU 486 14.233 16.613 22.521 1.00 32.65 ATOM 1427 CD2 LEU 486 12.635 15.481 24.105 1.00 X9.90 WO 99/SOb58 PCTNS99/06937 ATOM 1428 C LEU 486 9.597 18.348 23.256 1.00 34.87 ATOM 1429 O LEU 486 9.078 18.225 24.362 1.00 35.85 ATOM 1430 N ILE 487 9.513 19.469 '_'2.5481.00 35.59 ATOM 1431 CA ILE 487 8.787 20.62 23.064 1.00 36.79 ATOM 1432 CB ILE 487 8.890 21.826 22.095 1.00 37.32 ATOM 1433 CG2 ILE 487 7.833 22.884 22.443 1.00 40.19 ATOM 1434 CGl ILE 487 10.292 22.443 22.181 1.00 36.00 ATOM 1435 CD1 ILE 487 10.635 23.041 23.544 1.00 33.58 ATOM 1436 C ILE 487 7.315 20.257 23.276 1.00 38.56 ATOM 1437 O ILE 487 6.708 20.628 24.282 1.00 38.52 ATOM 1438 N HIS 488 6.749 19.521 22.326 1.00 40.33 ATOM 1439 CA HIS 488 5.357 19.096 22.427 1.00 42.29 ATOM 1440 CB HIS 488 4.962 18.282 21.197 1.00 44.26 ATOM 1441 CG HIS 488 3.612 17.647 21.305 1.00 47.75 I ATOM 1442 CD2 HIS 488 2.369 18.175 21.214 1.00 47.46 S

ATOM 1443 ND HIS 488 3.440 16.298 21.534 I .00 S
1 1.09 ATOM 1444 CE HIS 488 2.148 16.023 21.577 1.00 ~
1 1.15 ATOM 1445 NE2 HIS 488 1.477 17.144 21.385 1.00 50.22 ATOM 1446 C HIS 488 5.154 i 8.25423.685 1.00 42.55 ATOM 1447 O HIS 488 4.233 18.498 24.467 1.00 43.02 ATOM 1448 N LEU 489 6.022 17.266 23.879 1.00 39.91 ATOM 1449 CA LEU 489 5.936 16.399 25.048 1.00 39.93 ATOM 1450 CB LEU 489 7.087 15.396 25.048 1.00 38.83 ATOM 1451 CG LEU 489 6.961 14.242 24.056 1.00 39.31 ATOM 1452 CD LEU 489 8.259 13.456 24.027 1.00 39.01 ATOM 1453 CD2 LEU 489 5.799 13.345 24.459 1.00 41.98 ATOM 1454 C LEU 489 5.973 17.203 26.339 1.00 40.24 ATOM 1455 O LEU 489 5.267 16.888 27.298 1.00 38.72 ATOM 1456 N MET 490 6.798 18.246 26.353 1.00 39.94 ATOM 1457 CA MET 490 6.939 19.102 27.522 1.00 41.50 ATOM 1458 CB MET 490 8.208 19.953 27.394 1.00 39.1 S

ATOM 1459 CG MET 490 9.495 19.169 27.608 1.00 41.69 ATOM 1460 SD MET 490 10.978 20.106 27.161 1.00 35.76 ATOM 1461 CE MET 490 12.178 18.775 27.056 1.00 39.22 ATOM 1462 C MET 490 5.718 20.004 27.717 1.00 42.33 ATOM 1463 O MET 490 5.296 20.258 28.848 1.00 41.09 ATOM 1464 N ALA 491 5.162 20.498 26.616 1.00 43.15 ATOM 1465 CA ALA 491 3.983 21.351 26.693 1.00 43.79 ATOM 1466 CB ALA 491 3.622 21.879 25.311 1.00 43.93 ATOM 1467 C ALA 491 2.841 20.510 27.251 1.00 46.16 ATOM 1468 O ALA 491 2.073 20:967 28.095 1.00 44.69 ATOM 1469 N LYS 492 2.752 19.268 26.783 1.00 46.29 ATOM 1470 CA LYS 492 1.711 18.351 27.222 1.00 49.90 ATOM 1471 CB LYS 492 1.772 17.053 26.411 1.00 50.03 ATOM 1472 CG LYS 492 1.087 17.13 3.062 1.00 X3.81 ATOM 1473 CD LYS 492 -0.002 16.084 24.930 1.00 59.00 ATOM 1474 CE LYS 492 -0.988 16.453 23.827 1.00 61.85 ATOM 1475 NZ LYS 492 -1.351 15.281 22.976 1.00 62.89 ATOM 1476 C LYS 492 1.841 I 8.02528.701 1.00 ~ 1.1 S

ATOM 1477 O LYS 492 0.845 17.784 29.379 1.00 53.37 ATOM I N ALA 493 3.072 18.012 29.199 I 50.
478 .00 I
S

ATOM 1479 CA ALA 493 3.321 17.706 30.600 1.00 49.17 ATOM 1480 CB ALA 493 4.777 17.314 30.794 1.00 50.39 ATOM 1481 C ALA 493 2.971 18.885 31.501 1.00 49.36 ATOM 1482 O ALA 493 3.089 18.799 32.723 I ~ 1.57 .00 ATOM 1483 N GLY 494 2.554 19.989 30.893 1.00 48.61 ATOM 1484 CA GLY 494 2.185 21.159 31.671 1.00 46.92 ATOM 1485 C GLY 494 3.322 22.107 32.006 1.00 45.46 ATOM 1486 O GLY 494 3.206 22.921 32.919 1.00 43.58 ATOM 1487 N LEU 495 4.431 22.009 31.284 1.00 44.81 ATOM 1488 CA LEU 495 5.555 22.899 31.540 1.00 42.34 ATOM 1489 CB LEU 495 6.847 22.293 30.988 1.00 43.79 ATOM 1490 CG LEU 495 7.712 21.459 31.936 1.00 40.99 ATOM 1491 CD1 LEU 495 7.022 20.156 32.260 1.00 44.70 ATOM 1492 CD2 LEU 495 9.072 21.189 31.270 1.00 42.12 ATOM 1493 C LEU 495 5.278 24.227 30.847 1.00 42.13 ATOM 1494 O LEU 495 4.664 24.258 29.778 1.00 42.49 ATOM 1495 N THR 496 5.718 25.324 31.452 1.00 42.73 ATOM 1496 CA THR 496 5.521 26.636 30.845 1.00 43.56 ATOM 1497 CB THR 496 5.841 27.767 31.829 1.00 46.09 ATOM 1498 OG THR 496 7.222 27.688 32.208 1.00 43.92 ATOM 1499 CG2 THR 496 4.965 27.662 33.064 1.00 45.63 ATOM 1500 C THR 496 6.471 26.764 29.660 1.00 45.54 ATOM 1501 O THR 496 7.370 25.939 29.488 1.00 43.39 ATOM 1502 N LEU 497 6.280 27.800 28.849 1.00 45.02 ATOM 1503 CA LEU 497 7.135 28.020 27.688 1.00 45.12 ATOM 1504 CB LEU 497 6.710 29.286 26.944 1.00 46.62 ATOM I505 CG LEU 497 5.933 29.080 25.640 1.00 50.20 ATOM 1506 CD LEU 497 5.886 30.397 24.875 1.00 50.95 ATOM 1507 CD2 LEU 497 6.589 27.990 24.798 1.00 50.91 ATOM 1508 C LEU 497 8.599 28.135 28.101 1.00 44.94 ATOM 1509 O LEU 497 9.474 27.516 27.493 1.00 45.03 ATOM 1510 N GLN 498 8.862 28.927 29.137 1.00 41.14 ATOM 1511 CA GLN 498 10.221 29.101 29.627 1.00 40.54 ATOM 1 CB GLN 498 10.246 30.140 30.743 1.00 43.82 S
I

ATOM 1513 CG GLN 498 11.585 30.270 31.437 1.00 43.37 ATOM 1514 CD GLN 498 11.539 31.260 32.584 1.00 47.03 ATOM 1515 OEI GLN 498 I0.565 31.308 33.332 1.00 49.18 ATOM 1 NE2 GLN 498 12.591 32.054 32.727 1.00 45.30 S

ATOM 1517 C GLN 498 10.777 27.773 30.145 1.00 39.39 ATOM 1518 O GLN 498 11.923 27.422 29.866 1.00 35.05 ATOM 1519 N GLN 499 9.965 27.040 30.902 1.00 36.49 ATOM 1520 CA GLN 499 10.391 25.748 31.434 1.00 36.91 ATOM 1521 CB GLN 499 9.311 25.155 32.344 1.00 38.84 ATOM 1522 CG GLN 499 9.155 25.825 33.703 1.00 41.33 ATOM 1523 CD GLN 499 8.039 25.187 34.512 1.00 42.74 ATOM 1524 OE1 GLN 499 7.027 24.760 33.955 1.00 :15.44 ATOM 1525 NE2 GLN 499 8.222 ?5.107 35.829 1.00 :13.48 ATOM 1526 C GLN 499 10.655 24.773 30.285 1.00 35.03 ATOM 1527 O GLN 499 11.446 ?3.832 30.422 1.00 36.59 ATOM 1528 N GLN 500 9.980 ?4.994 ?9.162 1.00 34.14 ATOM 1529 CA GLN 500 10.136 ?4.138 ?7.990 1.00 34.65 ATOM 1530 CB GLN 500 9.042 ?4.436 ?6.958 1.00 33.90 ATOM 1531 CG GLN 500 7.672 23.872 27.315 1.00 36.62 ATOM 1532 CD GLN 500 6.558 24.419 26.435 1.00 40.17 ATOM 1533 OE GLN 500 6.660 ?4.417 25.207 i 40.22 1 .00 ATOM 1534 NE2 GLN 500 5.482 24.886 27.064 1.00 41.82 ATOM 1535 C GLN 500 11.511 24.350 27.358 1.00 34.96 ATOM 1536 O GLN 500 12.256 23.387 27.124 1.00 30.79 ATOM 1537 N HIS 501 11.835 25.612 27.078 1.00 34.21 ATOM 1538 CA HIS 501 13.117 25.966 ?6.480 1.00 37.42 ATOM 1539 CB HIS 501 13.195 27.476 ?6.246 1.00 43.08 ATOM 1540 CG HIS SO1 12.043 28.027 25.468 1.00 ~
1.13 ATOM 1541 CD2 HIS 501 11.534 27.678 24.263 1.00 53.05 ATOM 1542 ND1 HIS 501 11.264 ?9.068 25.926 1.00 54.54 ATOM 1543 CEI HIS 501 10.325 29.337 25.037 1.00 54.36 ATOM 1544 NE2 HIS 501 10.466 28.508 24.018 1.00 55.19 ATOM 1545 C HIS 501 14.255 25.543 27.395 1.00 35.79 ATOM 1546 O HIS 501 15.271 24.996 26.945 1.00 36.20 ATOM 1547 N GLN 502 14.086 25.799 28.685 1.00 33.90 ATOM 1548 CA GLN 502 15.110 25.438 29.650 1.00 32.18 ATOM 1549 CB GLN 502 14.740 25.977 31.033 1.00 35.84 ATOM 1550 CG GLN 502 14.787 27.498 31.113 1.00 32.66 ATOM 1551 CD GLN 502 14.420 28.028 32.486 1.00 36.62 ATOM 1552 OEI GLN 502 14.102 27.262 33.397 1.00 33.99 ATOM 1553 NE2 GLN 502 14.462 29.348 32.640 1.00 36.22 ATOM 1554 C GLN 502 15.340 23.932 29.716 1.00 31.79 ATOM 1555 O GLN 502 16.483 23.479 29.769 1.00 28.00 ATOM 1556 N ARG 503 14.266 23.146 29.705 1.00 30.99 ATOM 1557 CA ARG 503 14.436 21.704 29.779 1.00 29.91 ATOM 1558 CB ARG 503 13.107 21.011 30.052 1.00 32.79 ATOM 1559 CG ARG 503 13.258 19.541 30.400 1.00 30.84 ATOM 1560 CD ARG 503 11.930 18.935 30.798 1.00 30.61 ATOM 1561 NE ARG 503 12.021 17.490 30.992 1.00 28.50 ATOM 1562 CZ ARG 503 12.489 16.908 32.093 1.00 29.00 ATOM 1563 NH1 ARG 503 12.917 17.640 33.114 1.00 29.85 ATOM 1564 NH2 ARG 503 12.512 15.583 32.180 1.00 33.73 ATOM 1565 C ARG 503 15.051 21.152 28.496 1.00 29.89 ATOM 1566 O ARG 503 15.895 20.259 28.548 1.00 X9.69 ATOM 1567 N LEU 504 14.624 21.675 27.351 1.00 X8.99 ATOM 1568 CA LEU 504 15.164 21.223 26.075 1.00 28.90 ATOM 1569 CB LEU 504 14.566 22.023 24.916 1.00 27.72 ATOM 1570 CG LEU 504 15.327 21.901 23.593 1.00 30.47 ATOM 1571 CD1 LEU 504 15.252 20.453 23.117 1.00 31.74 ATOM 1572 CD2 LEU 504 14.742 22.843 ?2.542 1.00 29.85 ATOM 1573 C LEU X04 16.681 21.419 ?6.089 1.00 29.69 ATOM 1574 O LEU 504 17.439 20.536 ?5.672 1.00 26.38 ATOM 1575 N ALA 505 17.114 22.585 ?6.564 1.00 28.51 S ATOM 1576 CA ALA SOS 18.535 22.899 ?6.632 1.00 25.98 ATOM 1577 CB ALA SOS 18.735 24.361 ?7.039 1.00 29.86 ATOM 1578 C ALA SOS 19.261 21.977 ?7.604 1.00 26.67 ATOM 1579 O ALA SOS 20.340 21.462 ?7.290 1.00 25.54 ATOM 1580 N GLN 506 18.677 21.771 28.784 1.00 23.59 ATOM 1S8I CA GLN 506 19.299 20.907 29.785 1.00 27.67 ATOM 1582 CB GLN 506 18.434 20.796 31.043 1.00 27.75 ATOM 1583 CG GLN 506 18.414 22.027 ~ 31.9451.00 32.48 ATOM 1584 CD GLN 506 17.111 22.116 32.736 1.00 38.40 ATOM 1 S8S OE1 GLN 506 16.319 21.167 32.754 1.00 35.97 1 ATOM 1586 NE2 GLN 506 16.879 23.257 33.386 I.00 38.07 S

ATOM 1587 C GLN 506 19.500 19.509 29.217 1.00 24.53 ATOM 1588 O GLN 506 20.536 18.889 29.441 1.00 26.42 ATOM 1589 N LEU 507 18.505 19.017 28.484 1.00 26.78 ATOM 1590 CA LEU 507 18.578 17.678 27.902 1.00 26.18 ATOM 1591 CB LEU 507 17.225 17.286 27.295 1.00 31.48 ATOM 1592 CG LEU 507 16.052 16.961 28.231 1.00 32.59 ATOM 1593 CD1 LEU 507 14.836 16.561 27.389 1.00 33.78 ATOM 1594 CD2 LEU 507 16.431 15.838 29.174 1.00 30.18 ATOM 1 S9S C LEU 507 19.652 17.583 26.819 1.00 26.03 2S ATOM 1596 O LEU 507 20.421 16.621 26.?71 1.00 27.28 ATOM 1597 N LEU 508 19.713 18.583 25.950 1.00 24.31 ATOM 1598 CA LEU 508 20.690 18.557 24.863 1.00 23.68 ATOM 1599 CB LEU 508 20.339 19.629 23.828 1.00 23.91 ATOM 1600 CG LEU 508 19.004 19.436 23.102 1.00 24.68 ATOM 1601 CD LEU 508 18.905 20.416 21.945 1.00 25.11 ATOM 1602 CD2 LEU 508 18.903 17.994 22.580 1.00 27.53 ATOM 1603 C LEU 508 22.127 18.727 35.341 1.00 22.93 ATOM 1604 O LEU 508 23.062 18.200 24.736 1.00 21.36 ATOM 1605 N LEU 509 22.302 19.451 26.441 1.00 23.86 3S ATOM 1606 CA LEU 509 23.637 19.661 26.991 1.00 26.28 ATOM 1607 CB LEU 509 23.598 20.735 28.095 1.00 28.08 ATOM 1608 CG LEU 509 23.578 22.214 27.672 1.00 33.98 ATOM 1609 CDI LEU 509 23.529 23.114 28.921 1.00 35.23 ATOM 1610 CD2 LEU 509 24.818 22.525 26.856 1.00 30.48 ATOM 1611 C LEU 509 24.1 18.327 27.540 1.00 26.08 ATOM 1612 O LEU 509 25.354 18.068 27.547 1.00 23.92 ATOM 1613 N ILE 510 23.254 17.462 27.993 1.00 24.60 ATOM 1614 CA ILE 510 23.712 16.172 28.496 1.00 25.12 ATOM 161 CB ILE S 22.568 15.368 29.161 1.00 28.51 4S ATOM I616 CG2 ILE S 23.05 13.965 ?9.506 1.00 3 .67 ATOM 1617 CGI ILE 510 22.141 16.060 30.459 1.00 31.18 ATOM 1618 CD ILE S 20.712 I 5.74930.882 1.00 37.16 ATOM 1619 C ILE S 24.337 1 S.3S ?7.364 1.00 23.86 ATOM 1620 O ILE 510 25.225 14.534 27.600 1.00 '_4.14 ATOM 1621 N LEU 511 23.889 IS.S86 26.133 1.00 X5.10 ATOM 1622 CA LEU 511 24.420 14.862 24.977 1.00 ''5.63 ATOM 1623 CB LEU S 23.628 1 S.22S23.714 1.00 '_'3.89 I

S ATOM 1624 CG LEU S 22.1 14.801 23.659 I X5.78 11 S2 .00 ATOM 1625 CD1 LEU 511 21.648 14.920 22.224 1.00 '_'6.SS

ATOM 1626 CD2 LEU S 21.990 13.363 24.146 1.00 '_6.29 ATOM 1627 C LEU S 25.912 1 S.1 24.771 1.00 '_7.10 ATOM 1628 O LEU S 26.641 14.332 24.214 1.00 ?.L98 ATOM 1629 N SER S 26.372 16.319 25.213 1.00 ?4.75 ATOM 1630 CA SER 512 27.787 16.637 25.076 1.00 '_'3.68 ATOM 1631 CB SER S 28.023 18.129 25.358 1.00 ?6.12 ATOM 1632 OG SER S 29.271 18.327 25.986 1.00 37.17 ATOM 1633 C SER S 28.594 1 S.76S26.050 1.00 23.1 1 ATOM i 634 O SER S 29.742 15.383 25.769 1.00 ?2.

S

ATOM 1635 N AHIS 513 27.993 IS.4S6 27.192 O.SO 2I.S3 ATOM 1636 N BHIS S 28.008 1 S.4S327.202 O.SO ?0.99 ATOM 1637 CA AHIS S 28.645 14.624 28.196 O.SO ?
13 1.79 ATOM 1638 CA BHIS 513 28.696 14.6U7 28.174 O.SO X0.94 ATOM 1639 CB AHIS 513 27.920 14.776 29.536 0.50 23.59 ATOM 1640 CB BHIS 513 27.991 14.636 29.536 O.SO 31.59 ATOM 1641 CG AHIS S 28.145 16.109 30.179 0.50 27.34 I

ATOM 1642 CG BHIS S 28.800 14.032 30.642 0.50 23.94 ATOM 1643 CD2AHIS 513 29.223 16.616 30.824 0.50 27.56 2S ATOM 1644 CD2BHIS S 30.095 14.211 31.001 0.50 24.22 ATOM 1645 ND S 27.204 17.117 30.160 0.50 30.62 AHIS

ATOM 1646 ND1BHIS 513 28.285 13.105 31.523 O.SO 27.00 ATOM 1647 CEIAHIS 513 27.693 18.185 30.763 O.SO 26.32 ATOM 1648 CE1BHIS 513 29.225 12.740 32.376 O.SO 24.40 ATOM I 649 NE2AHIS S 28.916 17.908 31.176 O.SO 28.30 ATOM 1650 NE2BHIS 513 30.334 13.396 32.081 O.SO ?S.S4 ATOM I 6S C AHIS S 28.666 13.164 27.738 O.SO 19.81 ATOM 1652 C BHIS 513 28.720 13.171 27.652 O.SO 19.42 ATOM 1653 O AHIS 513 29.601 12.426 28.026 O.SO 22.45 3S ATOM 1654 O BHIS 513 29.707 12.457 27.809 0.50 X2.62 ATOM 1655 N ILE S 27.633 12.753 27.01 1.00 ''0.76 ATOM 1656 CA ILE S 27.572 11.396 26.492 1.00 X0.94 ATOM 1657 CB ILE S 26.1 1 I 25.953 1.00 ?
14 S4 .086 7.76 ATOM 1658 CG2 ILE 514 26.169 9.800 25.123 1.00 28.26 ATOM 1659 CGI ILE 514 25.185 10.965 27.139 1.00 X7.91 ATOM 1660 CDl ILE 514 23.752 10.649 26.753 1.00 34.31 ATOM 1661 C ILE 514 28.641 11.256 25.398 1.00 ?0.66 ATOM 1662 O ILE 514 29.298 10.226 25.285 1.00 '?x.21 ATOM 1663 N ARG S 28.825 12.294 24.589 1.00 ?0.48 4S ATOM 1664 CA ARG 51 29.861 12.243 23.554 1.00 ?
S 1.98 ATOM 1665 CB ARG S ?9.861 13.535 22.726 I ?3.11 1 .00 S

ATOM 1666 CG ARG S 31.003 13.611 21.737 1.00 _'5.76 S

ATOM 1667 CD ARG S 30.664 12.818 20.491 1.00 ?8.SS

S

ATOM 1668 NE ARG 515 29.580 13.482 19.788 1.00 36.24 ATOM 1669 CZ ARG 515 29.615 13.827 i 8.5081.00 38.91 ATOM 1670 NHI ARG ~ 30.689 13.566 17.776 1.00 35.37 I
~

ATOM 1671 NH2 ARG ~ 28.579 14.459 I 7.9711.00 40.27 ATOM 1672 C ARG 515 31.221 12.087 24.225 1.00 21.29 ATOM 1673 O ARG ~ 32.068 11.305 23.795 1.00 20.06 I
S

ATOM 1674 N HIS ~ 31.420 12.844 25.293 1.00 23.23 ATOM 1675 CA HIS ~ 32.675 12.812 26.034 1.00 24.75 I

ATOM 1676 CB HIS ~ 32.566 13.794 27.206 1.00 24.03 ATOM 1677 CG HIS ~ 33.826 13.948 27.990 1.00 31.42 ATOM I678 CD2 HIS ~ 34.138 13.587 29.257 1.00 35.87 ATOM 1679 ND1 HIS 516 34.938 14.586 27.489 1.00 33.59 ATOM 1680 CE1 HIS 516 35.882 14.613 28.411 1.00 35.70 ATOM 1681 NE2 HIS 516 35.422 14.013 29.495 1.00 33.35 ATOM 1682 C HIS ~ 32.965 11.390 26.537 1.00 24.02 ATOM 1683 O HIS ~ 34.059 10.852 26.362 1.00 23.66 ATOM 1684 N MET ~ 31.969 10.786 27.168 1.00 20.91 ATOM 1685 CA MET 517 32.109 9.436 27.684 1.00 24.21 ATOM 1686 CB MET ~ 30.837 9.038 28.424 1.00 23.88 ATOM 1687 CG MET ~ 30.607 9.903 29.652 1.00 26.32 ATOM 1688 SD MET 517 29.435 9.222 30.790 1.00 26.67 ATOM 1689 CE MET 517 27.914 9.390 29.807 1.00 23.26 ATOM 1690 C MET 517 32.399 8.448 26.564 1.00 23.26 ATOM 1691 O MET 517 33.213 7.547 26.728 1.00 26.08 ATOM 1692 N SER 518 31.736 8.612 25.423 1.00 21.93 ATOM 1693 CA SER 518 31.977 7.717 24.301 1.00 23.08 ATOM 1694 CB SER 518 30.976 8.027 23.173 1.00 22.02 ATOM 1695 OG SER 518 31.283 7.336 21.978 1.00 24.01 ATOM 1696 C SER 518 33.432 7.862 23.810 1.00 25.1 S

ATOM 1697 O SER ~ 34.111 6.866 23.532 1.00 22.94 l ATOM 1698 N ASN 519 33.923 9.097 23.713 1.00 22.42 ATOM 1699 CA ASN 519 35.295 9.309 23.260 1.00 21.87 ATOM 1?00 CB ASN 519 35.605 10.807 23.157 1.00 24.46 ATOM 1701 CG ASN 519 34.864 11.469 22.021 1.00 29.02 ATOM 1702 OD1 ASN 519 34.661 10.864 20.965 1.00 31.93 ATOM 1703 ND2 ASN 519 34.459 12.715 22.224 I.00 28.81 ATOM 1704 C ASN 519 36.292 8.643 24.201 1.00 21.46 ATOM 1705 O ASN 519 37.251 8.015 23.752 1.00 23.56 ATOM 1706 N LYS 520 36.070 8.782 25.504 1.00 23.23 ATOM 1707 CA LYS 520 36.964 8.171 26.488 1.00 26.35 ATOM 1708 CB LYS 520 36.581 8.592 27.912 1.00 27.53 ATOM 1709 CG LYS 520 36.618 10.101 28.174 1.00 33.74 ATOM 1710 CD LYS 520 37.962 10.710 27.811 1.00 42.09 ATOM 1711 CE LYS 520 39.047 10.307 28.802 1.00 43.97 ATOM 1712 NZ LYS 520 39.858 11.480 29.254 1.00 48.07 ATOM 1713 C LYS 520 36.899 6.644 26.376 1.00 27.71 ATOM 1714 O LYS 530 37.913 5.957 26.501 1.00 27.15 ATOM 1715 N GLY 521 35.704 6.117 26.141 1.00 25.02 ATOM 1716 CA GLY 521 35.562 4.676 26.003 1.00 26.67 ATOM 1717 C GLY 521 36.254 4.168 24.753 1.00 ?7.06 ATOM 1718 O GLY 521 36.924 3.128 24.775 1.00 X6.84 ATOM 1719 N AMET522 36.101 4.893 23.650 0.50 X5.87 ATOM 1720 N BMET 522 36.095 4.908 23.658 0.50 X7.62 ATOM 1721 CA AMET522 36.727 4.491 22.401 0.50 X7.27 ATOM 1722 CA BMET 522 36.703 4.551 22.384 0.50 30.14 ATOM 1723 CB AMET 522 36.267 5.396 21.260 0.50 X6.50 ATOM 1724 CB BMET 522 36.252 5.525 21.288 0.50 32.46 ATOM 1725 CG AMET 522 34.827 5.162 20.866 0.50 X5.05 ATOM 1726 CG BMET 522 35.681 4.854 20.045 0.50 35.70 ATOM 1727 SD AMET 522 34.585 3.587 20.020 0.50 27.07 ATOM 1728 SD BMET 522 34.197 5.672 19.408 0.50 40.01 ATOM I CE AMET 522 33.142 4.017 19.031 0.50 31.29 ATOM 1730 CE BMET 522 34.733 6.085 17.745 0.50 42.12 ATOM 1731 C AMET 522 38.242 4.532 22.512 0.50 28.99 ATOM 1732 C BMET 522 38.224 4.567 22.483 0.50 30.76 ATOM 1733 O AMET 522 38.939 3.743 21.870 0.50 31.65 ATOM 1734 O BMET 522 38.905 3.793 21.807 0.50 32.87 ATOM 1735 N GLU 523 38.749 5.452 23.324 1.00 30.85 ATOM 1736 CA GLU 523 40.190 5.576 23.513 1.00 34.09 ATOM 1737 CB GLU 523 40.515 6.725 24.480 1.00 35.59 ATOM 1738 CG GLU 523 40.658 8.079 23.784 1.00 43.35 ATOM 1739 CD GLU 523 40.560 9.265 24.739 1.00 46.63 ATOM 1740 OE1 GLU 523 39.832 10.240 24.416 1.00 47.64 ATOM 1741 OE2 GLU 523 41.212 9.225 25.805 1.00 43.09 ATOM 1742 C GLU 523 40.718 4.260 24.061 1.00 34.62 ATOM 1743 O GLU 523 41.733 3.747 23.596 1.00 33.87 ATOM 1744 N HIS 524 40.021 3.700 25.042 1.00 36.33 ATOM 1745 CA HIS 524 40.455 2.427 25.607 1.00 39.20 ATOM 1746 CB HIS 524 39.678 2.093 26.878 1.00 40.75 ATOM 1747 CG HIS 524 40.061 0.774 27.473 1.00 48.10 ATOM 1748 CD2 HIS 524 41.192 0.376 28.104 1.00 48.56 ATOM 1749 NDI HIS 524 39.247 -0.338 27.412 1.00 48.84 ATOM 1750 CEI HIS 524 39.859 -1.362 27.978 1.00 50.19 ATOM 1751 NE2 HIS 524 41.041 -0.956 28.407 1.00 51.61 ATOM 1752 C HIS 524 40.290 1.282 24.613 1.00 38.06 ATOM 1753 O HIS 524 41.226 0.521 24.371 1.00 38.18 ATOM 1754 N LEU 525 39.101 1.162 24.034 1.00 36.96 ATOM 1755 CA LEU 525 38.831 0.093 23.084 1.00 37.40 ATOM 1756 CB LEU 525 37.416 0.241 22.514 1.00 35.89 ATOM 1757 CG LEU 525 36.268 0.107 23.527 1.00 33.17 ATOM 1758 CD1 LEU 525 34.936 0.246 22.811 1.00 31.77 ATOM 1759 CD2 LEU 525 36.343 -1.240 24.238 1.00 35.92 ATOM 1760 C LEU 525 39.859 0.057 21.954 1.00 :~
1.32 ATOM 1761 O LEU 525 40.244 -1.015 21.487 1.00 40.76 ATOM 1762 N TYR 526 40.314 1.227 21.522 1.00 -13.68 ATOM 1763 CA TYR 526 11.300 1.297 20.449 1.00 -19.00 WO 99/50658 PCT/US99/0693~
ATOM 1764 CB TYR 526 -11.3762.722 19.890 1.00 51.86 ATOM 1765 CG TYR 526 :12.3052.878 18.704 1.00 57.70 ATOM 1766 CDI TYR 526 -11.8352.718 17.400 1.00 58.93 ATOM 1767 CE TYR 526 42.681 2.875 16.305 1.00 61.2 ATOM 1768 CD2 TYR 526 43.653 3.200 18.883 1.00 58.58 ATOM 1769 CE2 TYR 526 44.510 3.359 17.790 1.00 61.15 ATOM 1770 CZ TYR 526 :14.0163.194 16.505 1.00 61.09 ATOM 1771 OH TYR 526 44.851 3.343 15.417 1.00 63.79 ATOM 1772 C TYR 526 42.671 0.871 20.964 1.00 50.14 ATOM 1773 O TYR 526 43.471 0.303 20.223 1.00 50.73 ATOM 1774 N SER 527 42.930 1.139 22.240 1.00 52.72 ATOM 1775 CA SER 527 44.205 0.790 22.857 1.00 55.88 ATOM 1776 CB SER 527 44.351 1.516 24.199 1.00 55.00 ATOM 1777 OG SER 527 43.752 0.788 25.257 1.00 52.46 ATOM 1778 C SER 527 44.365 -0.718 23.054 1.00 60.39 ATOM 1779 O SER 527 45.398 -1.185 ?3.534 1.00 60.43 ATOM 1780 N MET 528 43.335 -1.472 22.678 1.00 63.86 ATOM 1781 CA MET 528 43.347 -2.929 22.788 1.00 67.95 ATOM 1782 CB MET 528 42.534 -3.381 24.008 1.00 67.85 ATOM 1783 CG MET 528 41.237 -2.606 24.222 1.00 70.10 ATOM 1784 SD MET 528 39.895 -3.569 24.983 1.00 71.70 ATOM 1785 CE MET 528 39.231 -4.412 23.554 1.00 72.57 ATOM 1786 C MET 528 42.726 -3.502 21.5I3 1.00 70.33 ATOM 1787 O MET 528 42.170 -4.602 21.513 1.00 72.43 ATOM 1788 N LYS 529 42.834 -2.739 20.428 1.00 71.53 ATOM 1789 CA LYS 529 42.274 -3.122 19.136 1.00 72.00 ATOM 1790 CB LYS 529 42.508 -2.004 I8.119 1.00 71.30 ATOM 1791 C LYS 529 42.813 -4.439 18.587 1.00 72.47 ATOM 1792 O LYS 529 43.990 -4.762 18.751 1.00 70.37 ATOM 1793 N CYS 530 41.932 -5.191 17.930 1.00 74.48 ATOM 1794 CA CYS 530 42.279 -6.474 17.325 1.00 76.67 ATOM 1795 CB CYS 530 41.004 -7.245 16.952 1.00 77.23 ATOM 1796 SG CYS 530 40.447 -8.491 18.146 1.00 79.38 ATOM 1797 C CYS 530 43.098 -6.220 16.065 1.00 78.08 ATOM 1798 O CYS 530 43.241 -5.076 15.623 1.00 78.81 ATOM 1799 N LYS 531 43.637 -7.289 15.487 1.00 78.22 ATOM 1800 CA LYS 531 44.424 -7.187 14.267 1.00 78.15 ATOM 1801 CB LYS 531 45.600 -8.182 14.305 1.00 78.33 ATOM 1802 C LYS 531 43.508 -7.467 13.067 1.00 77.93 ATOM 1803 O LYS 531 42.549 -6.734 12.839 1.00 78.07 ATOM 1804 N ASN 532 43.784 -8.539 12.328 1.00 77.80 ATOM 1805 CA ASN 532 42.984 -8.902 11.152 1.00 77.30 ATOM 1806 CB ASN 532 43.550 -10.166 10.521 1.00 77.55 ATOM 1807 C ASN 532 41.485 -9.082 11.423 1.00 77.34 ATOM 1808 O ASN 532 40.904 -10.123 11.118 1.00 78.13 ATOM 1809 N VAL 533 40.859 -8.055 11.988 1.00 76.13 ATOM 1810 CA VAL 533 39.436 -8.098 12.280 1.00 73.77 ATOM 1811 CB VAL 533 39.155 -7.715 13.752 1.00 73.62 ATOM 1812 CG1 VAL X33 39.690 -6.327 14.047 1.00 73.13 ATOM 1813 CG2 VAL X33 37.662 -7.782 14.021 1.00 73.14 ATOM 1814 C VAL X33 38.685 -7.143 11.352 1.00 72.97 ATOM 1815 O VAL X33 39.024 -5.960 11.252 1.00 73.91 ATOM 1816 N VAL X34 37.671 -7.666 IO.b66 1.00 70.02 ATOM 1817 CA VAL X34 36.866 -6.867 9.747 1.00 66.70 ATOM 1818 CB VAL X34 35.619 -7.646 9.328 1.00 67.32 ATOM 1819 C VAL X34 36.463 -5.541 10.393 1.00 63.87 ATOM 1820 O VAL X34 35.895 -5.519 11.486 1.00 63.55 ATOM 1821 N PRO X35 36.756 -4.415 9.719 1.00 60.92 ATOM 1822 CD PRO 535 37.424 -4.354 8.408 1.00 61.01 ATOM 1823 CA PRO 535 36.424 -3.077 10.229 1.00 X6.83 ATOM 1824 CB PRO 535 36.867 -2.135 9.107 1.00 58.70 ATOM 1825 CG PRO 535 37.023 -3.009 7.893 1.00 61.55 ATOM 1826 C PRO X35 34.944 -2.902 10.571 1.00 52.90 ATOM 1827 O PRO X35 34.067 -3.461 9.908 1.00 52.01 ATOM 1828 N LEU 536 34.672 -2.120 11.610 1.00 48.60 ATOM I829 CA LEU X36 33.301 -1.874 12.042 1.00 45.08 ATOM 1830 CB LEU 536 33.280 -0.796 13.128 1.00 44.35 ATOM 1831 CG LEU 536 32.267 -0.911 14.273 1.00 43.48 ATOM 1832 CD LEU 536 3 I .9190.490 14.745 I 43.41 1 .00 ATOM 1833 CD2 LEU 536 31.022 -1.654 13.835 1.00 39.55 ATOM 1834 C LEU 536 32.434 -1.433 10.871 1.00 43.58 ATOM 1835 O LEU 536 31.287 -1.862 10.734 1.00 42.14 ATOM 1836 N TYR 537 32.992 -0.575 10.024 1.00 43.02 ATOM 1837 CA TYR 537 32.269 -0.066 8.866 1.00 43.34 ATOM 1838 CB TYR 537 33.200 0.786 7.997 1.00 44.76 ATOM 1839 CG TYR 537 32.483 1.558 6.913 1.00 48.28 ATOM 1840 CD1 TYR 537 32.190 0.964 5.687 1.00 48.46 ATOM 1841 CE1 TYR 537 31.504 1.660 4.693 1.00 52.48 ATOM 1842 CD2 TYR 537 32.073 2.875 7.123 1.00 49.99 ATOM 1843 CE2 TYR 537 31.383 3.584 6.135 1.00 53.73 ATOM 1844 CZ TYR 537 31.100 2.967 4.924 1.00 54.01 ATOM 1845 OH TYR 537 30.401 3.648 3.952 1.00 55.90 ATOM 1846 C TYR 537 31.683 -1.199 8.032 1.00 43.15 ATOM 1847 O TYR 537 30.500 -1.191 7.696 1.00 41.54 ATOM 1848 N ASP 538 32.521 -2.175 7.702 1.00 44.67 ATOM 1849 CA ASP 538 32.097 -3.309 6.893 1.00 45.49 ATOM 1850 CB ASP 538 33.322 -4.126 6.479 1.00 51.32 ATOM 1851 CG ASP X38 34.361 -3.284 x.748 1.00 56.17 ATOM 1852 ODI ASP X38 35.436 -3.820 5.396 I.00 57.29 ATOM 1853 OD2 ASP X38 34.097 -2.079 x.526 1.00 59.24 ATOM 1854 C ASP X38 31.071 -4.195 7.587 1.00 43.48 ATOM 1855 O ASP X38 30.177 -4.738 6.940 1.00 43.95 ATOM 1856 N LEU X39 31.193 -4.345 8.901 1.00 41.57 ATOM 1857 CA LEU X39 30.244 -5.157 9.654 1.00 39.11 ATOM 1858 CB LEU X39 30.734 -x.351 11.092 1.00 41.88 ATOM 1859 CG LEU X39 29.770 -6.06 12.044 1.00 46.11 ATOM 1860 CD LEU 539 29.298 -7.379 11.423 1.00 46.99 ATOM 1861 CD2 LEU 539 30.474 -6.319 13.377 1.00 45.76 ATOM 1862 C LEU 539 28.891 -4.451 9.651 1.00 36.38 ATOM 1863 O LEU 539 27.849 -5.070 9.436 1.00 3.74 ATOM 1864 N LEU 540 28.919 -3.146 9.894 1.00 35.50 ATOM 1865 CA LEU 540 27.703 -2.336 9.903 1.00 35.59 ATOM 1866 CB LEU 540 28.061 -0.877 10.219 1.00 37.63 ATOM 1867 CG LEU 540 27.856 -0.252 11.605 1.00 10.28 ATOM 1868 CD1 LEU 540 27.526 -1.299 12.645 1.00 38.55 ATOM 1869 CD2 LEU 540 29.114 0.506 11.985 1.00 41.04 ATOM 1870 C LEU 540 27.060 -2.415 8.510 1.00 35.50 ATOM 1871 O LEU 540 25.846 -2.585 8.371 1.00 33.21 ATOM 1872 N LEU 541 27.892 -2.289 7.483 1.00 37.01 ATOM 1873 CA LEU 541 27.418 -2.340 6.101 1.00 38.51 ATOM 1874 CB LEU 541 28.591 -2.152 5.145 1.00 39.67 ATOM 1875 CG LEU 541 28.301 -2.112 3.643 1.00 40.92 ATOM 1876 CDI LEU 541 27.184 -1.130 3.348 1.00 42.44 ATOM 1877 CD2 LEU 541 29.572 -1.716 2.908 1.00 44.18 ATOM 1878 C LEU 541 26.723 -3.676 5.833 1.00 39.75 ATOM 1879 O LEU 541 25.616 -3.713 5.297 1.00 36.48 ATOM 1880 N GLU 542 27.366 -4.770 6.230 1.00 40.88 ATOM 1881 CA GLU 542 26.790 -6.097 6.037 1.00 41.89 ATOM 1882 CB GLU 542 27.719 -7.170 6.620 1.00 44.11 ATOM 1883 CG GLU 542 27.010 -8.457 7.052 1.00 50.60 ATOM 1884 CD GLU 542 26.434 -9.245 5.887 1.00 55.80 ATOM 1885 OE1 GLU 542 25.570 -10.1176.130 1.00 58.81 ATOM 1886 OE2 GLU 542 26.842 -8.996 4.728 1.00 57.19 ATOM 1887 C GLU 542 25.414 -6.195 6.691 1.00 41.58 ATOM 1888 O GLU 542 24.472 -6.720 6.102 1.00 42.82 ATOM 1889 N MET 543 25.298 -5.686 7.915 1.00 40.09 ATOM 1890 CA MET 543 24.036 -5.731 8.634 1.00 36.43 ATOM 1891 CB MET 543 24.270 -5.424 10.111 1.00 39.95 ATOM 1892 CG MET 543 25.137 -6.459 10.808 1.00 41.95 ATOM 1893 SD MET 543 24.918 -6.445 12.604 1.00 47.17 ATOM 1894 CE MET 543 25.324 -4.749 12.964 1.00 40.88 ATOM 1895 C MET 543 23.001 -4.769 8.072 1.00 35.02 ATOM 1896 O MET 543 21.808 -5.073 8.048 1.00 35.31 ATOM 1897 N LEU 544 23.457 -3.605 7.629 1.00 32.90 ATOM 1898 CA LEU 544 22.559 -2.603 7.074 1.00 36.88 ATOM 1899 CB LEU 544 23.225 -1.226 7.111 1.00 34.51 ATOM 1900 CG LEU 544 23.268 -0.562 8.490 1.00 31.94 ATOM 1901 CD1 LEU 544 24.284 0.564 8.478 1.00 32.27 ATOM 1902 CD2 LEU 544 2I.897 -0.029 8.846 1.00 29.02 ATOM 1903 C LEU 544 22.148 -2.941 5.640 1.00 38.94 ATOM 1904 O LEU 544 20.971 -2.842 5.294 1.00 39.52 ATOM 1905 N ASP 545 23.118 -3.338 4.817 1.00 :11.05 ATOM 1906 CA ASP 545 22.850 -3.685 3.418 1.00 -10.78 ATOM 1907 CB ASP 545 24.159 -3.780 2.620 1.00 37.75 ATOM 1908 CG ASP S4S 23.922 -3.937 1.120 1.00 35.19 ATOM 1909 ODI ASP S4S 24.881 -4.265 0.380 1.00 33.48 ATOM 1910 OD2 ASP 545 22.768 -3.734 0.691 1.00 31.33 ATOM 1911 C ASP 545 22.116 -5.01 3.349 1.00 42.87 S

ATOM 1912 O ASP S4S 22.681 -6.030 ?.929 1.00 44.32 ATOM 1913 N ALA 546 20.853 -5.009 3.755 1.00 43.49 ATOM 1914 CA ALA 546 20.069 -6.229 3.746 1.00 46.96 ATOM 191 CB ALA 546 19.213 -6.305 5.006 1.00 47.82 S

ATOM 1916 C ALA 546 19.193 -6.362 2.508 1.00 49.55 ATOM 1917 O ALA 546 18.804 -5.368 1.883 1.00 48.75 ATOM 1918 N HIS 547 I 8.895-7.606 2.1 1.00 50.98 ATOM 1919 CA HIS 547 18.042 -7.884 1.006 1.00 53.77 ATOM 1920 CB HIS 547 18.431 -9.223 0.369 i.00 52.69 ATOM 1921 CG HIS 547 18.395 -10.382 1.317 1.00 SS.OS

1 ATOM 1922 CD2 HIS 547 17.477 -10.752 2.242 1.00 53.94 S

ATOM 1923 NDI HIS 547 19.395 -11.329 1.371 1.00 56.23 ATOM 1924 CEI HIS 547 19.095 -12.232 2.286 1.00 SS.36 ATOM 1925 NE2 HIS 547 17.936 -11.906 2.830 1.00 57.01 ATOM 1926 C HIS 547 16.603 -7.936 1.518 1.00 SS.69 ATOM 1927 O HIS 547 16.362 -7.796 2.720 1.00 54.30 ATOM 1928 N ARG 548 1 S.6S3-8.139 0.612 1.00 57.00 ATOM 1929 CA ARG 548 14.245 -8.212 0.987 1.00 60.65 ATOM 1930 CB ARG 548 13.432 -7.171 0.208 1.00 62.69 ATOM 1931 CG ARG 548 14.272 -6.222 -0.637 1.00 67.54 2S ATOM 1932 CD ARG 548 13.448 -5.061 -1.171 1.00 71.92 ATOM 1933 NE ARG 548 13.702 -3.826 -0.432 1.00 76.95 ATOM 1934 CZ ARG 548 14.864 -3.178 -0.429 1.00 79.04 ATOM 1935 NHI ARG 548 15.891 -3.644 -1.128 1.00 80.66 ATOM 1936 NH2 ARG 548 15.001 -2.063 0.278 1.00 80.39 ATOM 1937 C ARG 548 13.695 -9.608 0.711 1.00 61.65 ATOM 1938 O ARG 548 12.500 -9.781 0.466 1.00 62.05 ATOM 1939 N LEU 549 14.576 -10.603 0.756 1.00 62.39 ATOM 1940 CA LEU 549 14.188 -11.985 O.S07 1.00 64.02 ATOM 1941 CB LEU 549 15.433 -12.828 0.195 1.00 62.14 3S ATOM 1942 CG LEU 549 16.461 -12.191 -0.753 1.00 60.76 ATOM 1943 CDI LEU 549 17.699 -13.074 -0.878 1.00 57.77 ATOM 1944 CD2 LEU 549 15.823 -11.972 -2.108 1.00 58.38 ATOM 1945 C LEU 549 13.431 -12.574 1.702 1.00 66.65 ATOM 1946 O LEU 549 12.759 -13.600 1.577 1.00 67.15 ATOM 1947 N HIS SSO 13.541 -11.920 2.856 1.00 67.72 ATOM 1948 CA HIS SSO 12.858 -12.378 4.065 1.00 69.93 ATOM 1949 CB HIS SSO 13.753 -12.190 5.298 1.00 70.76 ATOM 1950 CG HIS SSO 14.977 -13.054 5.306 1.00 71.50 ATOM 1951 CD2 HIS SSO 15.539 -13.821 4.341 1.00 71.63 =ISATOM 1952 ND1 HIS SSO 15.793 -13.172 6.411 1.00 71.98 ATOM 1953 CEI HIS 550 16.805 -13.972 6.126 1.00 72.04 ATOM I9S4 NE2 HIS 550 16.674 -14.379 -1.876 1.00 71.39 ATOM 1955 C HIS 550 11.556 -11.603 4.275 1.00 71.15 ATOM 1956 O HIS 550 10.940 -11.684 5.340 1.00 70.66 ATOM 1957 N ALA 55i II.I43 -10.851 3.258 1.00 72.22 ATOM 1958 CA ALA 551 9.919 -10.057 3.338 1.00 73.58 ATOM 1959 CB ALA 551 9.904 -9.014 2.221 1.00 73.21 ATOM 1960 C ALA 551 8.658 -10.920 3.266 1.00 74.69 ATOM 1961 O ALA 551 7.684 -10.474 2.621 1.00 76.12 ATOM 1962 OXT ALA 551 8.651 -12.025 3.852 1.00 73.79 HETATM 1963 C10 OHT 600 30.581 1.481 29.471 1.00 ?6.84 HETATM 1964 C9 OHT 600 30.713 -0.043 29.358 1.00 ?2.85 HETATM 1965 C8 OHT 600 31.366 -0.385 28.037 1.00 ?5.56 HETATM 1966 C11 OHT 600 32.761 0.051 27.916 1.00 X7.51 HETATM 1967 C OHT 600 33.218 0.797 26.797 1.00 ?8.35 HETATM 1968 C15 OHT 600 34.551 1.237 26.747 1.00 30.39 HETATM 1969 C14 OHT 600 35.443 0.923 27.792 1.00 30.23 HETATM 1970 C OHT 600 35.004 0.185 28.890 1.00 31.45 HETATM I 971 C OHT 600 33.666 -0.241 28.955 1.00 27.93 HETATM 1972 C7 OHT 600 30.682 -1.089 27.077 1.00 24.41 HETATM 1973 C1 OHT 600 29.211 -1.258 27.052 1.00 24.26 HETATM 1974 C2 OHT 600 28.644 -2.526 26.706 1.00 25.92 HETATM 1975 C3 OHT 600 27.254 -2.668 26.580 1.00 26.32 HETATM 1976 C4 OHT 600 26.438 -1.553 26.813 1.00 29.02 HETATM 1977 04 OHT 600 25.072 -1.605 26.716 1.00 28.42 HETATM 1978 C5 OHT 600 26.980 -0.286 27.130 1.00 26.98 HETATM 1979 C6 OHT 600 28.362 -0.147 27.231 1.00 25.23 HETATM 1980 C17 OHT 600 31.370 -1.692 25.942 1.00 26.61 HETATM 1981 C OHT 600 32.508 -2.498 26.151 1.00 26.77 HETATM 1982 C OHT 600 33.166 -3.052 25.072 1.00 27.50 I

HETATM 1983 C20 OHT 600 32.676 -2.794 23.786 1.00 27.50 HETATM 1984 020 OHT 600 33.206 -3.566 22.795 1.00 31.35 HETATM 1985 C23 OHT 600 33.009 -3.135 21.448 1.00 40.09 HETATM 1986 C24 OHT 600 34.226 -3.490 20.575 1.00 44.80 HETATM 1987 N24 OHT 600 34.141 -4.901 20.203 1.00 49.00 HETATM 1988 C25 OHT 600 33.375 -5.040 18.933 1.00 51.64 HETATM 1989 C26 OHT 600 35.495 -5.459 20.004 1.00 52.06 HETATM 1990 C21 OHT 600 31.540 -2.005 23.558 1.00 27.19 HETATM 1991 C22 OHT 600 30.892 -1.450 24.645 1.00 27.92 HETATM 1992 OI HOH 1 20.714 -12.010 23.057 1.00 27.20 HETATM 1993 O1 HOH 2 22.563 -0.070 25.819 1.00 25.77 HETATM 1994 O1 HOH 3 25.183 19.202 23.149 1.00 42.52 HETATM 1995 OI HOH 4 35.158 5.823 37.390 1.00 33.92 HETATM 1996 OI HOH 5 22.116 -9.922 18.914 1.00 30.18 HETATM 1997 O1 HOH 6 29.812 6.536 19.652 1.00 26.11 HETATM 1998 O1 HOH 7 13.362 4.463 20.376 1.00 X9.40 HETATM 1999 O1 HOH 8 19.799 -11.295 20.187 1.00 28.70 HETATM 2000 O1 HOH 9 21.205 1.466 23.794 1.00 X2.47 HETATM 2001 O1 HOH 10 21.177 -4.961 29.066 1.00 33.00 HETATM 2002 O1 HOH 11 18.591 1.863 20.518 1.00 32.59 HETATM 2003 O1 HOH I2 16.298 21.566 15.992 1.00 33.42 HETATM 2004 O1 HOH 13 18.611 1.976 24.494 1.00 29.70 HETATM 2005 O HOH ~ 38.009 8.910 21.156 1.00 39.92 HETATM 2006 O1 HOH 15 26.549 11.664 18.080 1.00 30.25 HETATM 2007 O1 HOH 16 20.282 -1.239 26.512 1.00 32.70 HETATM 2008 O1 HOH 17 32.858 8.754 20.237 1.00 29.88 HETATM 2009 OI HOH 18 8.497 16.136 29.934 1.00 46.80 HETATM 2010 O1 HOH 19 21.940 19.301 31.632 1.00 35.72 HETATM 2011 O1 HOH 20 35.153 2.682 14.122 1.00 41.02 HETATM 2012 O1 HOH 21 20.358 -2.268 21.013 1.00 29.43 HETATM 2013 OI HOH 22 35.562 10.036 36.334 1.00 41.37 HETATM 2014 O1 HOH 23 17.248 18.187 17.571 1.00 33.96 HETATM 2015 O1 HOH 24 18.445 20.973 12.346 1.00 43.44 HETATM 2016 O1 HOH 25 12.152 23.054 33.132 1.00 36.04 HETATM 2017 O1 HOH 26 13.181 22.222 9.699 1.00 37.03 HETATM 2018 O1 HOH 27 19.399 -6.090 12.808 1.00 44.86 HETATM 2019 O1 HOH 28 37.895 13.599 31.395 1.00 47.26 HETATM 2020 O1 HOH 29 11.570 6.212 7.962 1.00 51.10 HETATM 2021 O1 HOH 30 20.172 -2.568 23.445 1.00 51.70 HETATM 2022 OI HOH 31 36.402 -5.369 23.729 1.00 58.20 HETATM 2023 O1 HOH 32 25.127 13.802 19.187 1.00 35.29 HETATM 2024 O1 HOH 33 23.181 4.937 38.538 1.00 33.77 HETATM 2025 O1 HOH 34 20.550 0.421 21.276 1.00 29.12 HETATM 2026 O1 HOH 35 39.599 13.954 27.312 1.00 44.08 HETATM 2027 O1 HOH 36 26.445 13.863 21.285 1.00 34.97 HETATM 2028 O1 HOH 37 13.759 5.079 9.108 1.00 38.54 HETATM 2029 O1 HOH 38 14.150 24.731 34.529 1.00 49.72 HETATM 2030 O1 HOH 39 21.060 13.886 -6.319 1.00 59.79 HETATM 2031 O1 HOH 40 32.215 6.217 8.726 1.00 60.22 HETATM 2032 O1 HOH 41 35.105 15.704 9.069 1.00 45.15 HETATM 2033 O1 HOH 42 11.427 19.451 9.903 1.00 38.56 HETATM 2034 OI HOH 43 19.662 23.472 10.333 1.00 47.71 HETATM 2035 O1 HOH 44 9.231 3.690 12.337 1.00 45.98 HETATM 2036 O1 HOH 45 15.313 -6.036 17.192 1.00 39.07 HETATM 2037 O1 HOH 46 15.517 -3.266 17.907 1.00 37.67 HETATM 2038 OI HOH 47 28.784 -16.713 25.163 1.00 55.44 HETATM 2039 O1 HOH 48 27.868 -10.898 28.271 1.00 31.27 HETATM 2040 O1 HOH 49 6.955 13.568 28.233 1.00 48.83 HETATM 2041 O1 HOH 50 22.051 -15.030 28.603 1.00 36.91 HETATM 2042 O1 HOH 51 7.026 31.002 30.284 1.00 46.73 HETATM 2043 O1 HOH 52 -1.489 12.385 15.164 1.00 51.17 HETATM 2044 O1 HOH 53 3.499 6.444 14.452 1.00 50.38 HETATM 2045 O1 HOH 54 18.655 -2.048 25.518 1.00 52.29 HETATM 2046 O1 HOH 55 28.188 -15.195 38.996 1.00 55.22 HETATM 2047 Oi HOH 56 35.275 -10.556 38.061 1.00 57.39 HETATM 2048 O1 HOH 57 37.771 -9.103 34.605 1.00 54.17 HETATM 2049 OI HOH 58 31.403 -3.039 17.983 1.00 46.80 HETATM 2050 O1 HOH 59 30.455 -6.352 17.005 1.00 47.05 HETATM 2051 O1 HOH 60 25.985 8.25 0.416 1.00 43.32 HETATM 2052 O1 HOH 61 35.679 0.749 10.462 1.00 42.99 HETATM 2053 O1 HOH 62 14.741 4.029 33.936 1.00 49.59 HETATM 2054 O1 HOH 63 16.333 2.592 35.952 1.00 45.13 HETATM 2055 O1 HOH 64 23.809 7.186 39.798 1.00 45.36 HETATM 2056 O1 HOH 65 27.012.-1.948 46.995 1.00 63.39 HETATM 2057 O1 HOH 66 25.956 -6.422 42.144 1.00 44.94 HETATM 2058 O1 HOH 67 23.510 -8.414 39.036 1.00 39.06 HETATM 2059 OI HOH 68 41.475 0.971 33.110 1.00 55.50 HETATM 2060 O1 HOH 69 36.519 8.863 38.836 1.00 41.56 HETATM 2061 O1 HOH 70 30.111 14.823 12.793 1.00 44.58 HETATM 2062 OI HOH 71 26.850 -6.092 1.594 1.00 40.15 HETATM 2063 O1 HOH 72 20.448 -3.169 1.055 1.00 42.50 HETATM 2064 O1 HOH 73 33.896 3.047 16.172 1.00 46.39 HETATM 2065 OI HOH 74 16.884 0.446 26.043 1.00 61.50 I S HETATM 2066O HOH 75 18.595 0.296 27.866 1.00 47.33 HETATM 2067 OI HOH 76 6.166 21.439 19.124 1.00 47.94 HETATM 2068 O1 HOH 77 18.484 20.060 16.232 1.00 35.52 HETATM 2069 O1 HOH 78 1.985 23.265 29.187 1.00 46.42 HETATM 2070 O1 HOH 79 12.729 30.461 27.530 1.00 62.79 END

WO 99/5065$ PCT/US99/06937 SEQUENCE LISTING
<110> Shiau, Andrew Kushner, Peter J
Agard, David A
Greene, Geoffrey L
<120> Methods and Compounds for Modulating Nuclear Receptor Activity <130> UCAL 256/OlWO
<140>
<141>
<150> 60/079,956 <151> 1998-03-30 <150> 60/113,146 <151> 1998-12-16 <I50> 60/113,014 <151> 1998-12-16 <160> 26 <170> PatentIn Ver. 2.0 <210> 1 <211> 5 <212> PRT
<213> Homo sapiens <220>
<221> BINDING
<222> (1)..(5) <223> residues 2 and 3 can be any amino acid <400> 1 Leu Xaa Xaa Leu Leu <210> 2 <211> 5 <212> PRT
<213> Homo sapiens <220>
<221> BINDING
<222> (1)..(5) <223> residues 2 and 3 can be any amino acid <400> 2 Leu Xaa Xaa Met Leu SUBSTITUTE SHEET (RULE 26) <210> 3 <211> 5 <212> PRT
<213> Homo sapiens <400> 3 Leu Leu Gln Met Leu <210> 4 <211> 13 <212> PRT
<213> Homo sapiens <400> 4 Lys His Lys Ile Leu His Arg Leu Leu Gln Asp Ser Ser <210> 5 <211> 33 <212> PRT
<213> Homo sapiens <400> 5 Thr Pro Ala Ile Thr Arg Val Val Asp Phe Ala Lys Lys Leu Pro Met Phe Cys Glu Leu Pro Cys Glu Asp Gln Ile Ile Leu Leu Lys Gly Cys Cys <210> 6 <211> 12 <212> PRT
<213> Homo sapiens <400> 6 Leu Phe Pro Pro Leu Phe Leu Glu Val Phe Glu Asp <210> 7 <211> 33 <212> PRT
<213> Homo sapiens <400> 7 Thr Pro Ala Ile Thr Arg Val Val Asp Phe Ala Lys Lys Leu Pro Met Phe Ser Glu Leu Pro Cys Glu Asp Gln Ile Ile Leu Leu Lys Cys Cys SUBSTITUTE SHEET (RULE 26) WO 99/50658 _ 3 _ PC'TNS99/06937 Cys <210> 8 <211> 12 <212> PRT
<213> Homo sapiens <400> 8 Leu Phe Pro Pro Leu Phe Leu Glu Val Phe Glu Asp <210>

<211>

<212>
PRT

<213> sapiens Homo <400>

Thr Lys Ile Ile Lys Ile Val Glu Phe Ala Lys Arg Cys Leu Pro Gly Phe Thr Leu Ser Ile Ala Asp Gln Ile Thr Leu Leu Gly Lys Ala Ala ~

Cys <210>

<211>

<212>
PRT

<213> sapiens Homo <400> 10 Pro Met Pro Pro Leu Ile Arg Glu Met Leu Glu Asn <210> 11 <211> 33 <212> PRT
<213> Homo sapiens <400> 11 Asp Lys Gln Leu Phe Thr Leu Val Glu Trp Ala Lys Arg Ile Pro His Phe Ser Glu Leu Pro Leu Asp Asp Gln Val Ile Leu Leu Arg Ala Gly Trp <210> 12 <211> 12 SUBSTITUTE SHEET (RULE 26) <212> PRT
<213> Homo sapiens <400> 12 Pro Ile Asp Thr Phe Leu Met Glu Met Leu Glu Ala <210> 13 <211> 33 <212> PRT
<213> Homo sapiens <400> 13 Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Asn Ile Pro Gly Phe Ile Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr Gly Val <210> 14 <211> 12 <212> PRT
<213> Homo sapiens <400> 14 Ser Leu His Pro Leu Leu Gln Glu.Ile Tyr Lys Asp <210> 15 <211> 33 <212> PRT
<213> Homo sapiens <400> 15 Ser Tyr Ser Ile Gln Lys Val Ile Gly Phe Ala Lys Met Ile Pro Gly Phe Arg Asp Leu Thr Ser Glu Asp Gln Ile Val Leu Leu Lys Ser Ser Ala <210> 16 <211> 12 <212> PRT
<213> Homo sapiens <400> 16 Lys Leu Thr Pro Leu Val Leu Glu Val Phe Gly Asn SUBSTITUTE SHEET (RULE 26~

<210> 17 <211> 33 <2I2> PRT
<213> Homo sapiens <400> 17 Asp Arg Glu Leu Val His Met Ile Asn Trp Ala Lys Arg Val Pro Gly Phe Val Asp Leu Thr Leu His Asp Gln Val His Leu Leu Glu Cys Ala Trp <210> 18 <211> 12 <212> PRT
<213> Homo sapiens <400> 18 Pro Leu Tyr Asp Leu Leu Leu Glu Met Leu Asp Ala <210> 19 <211> 33 <212> PRT
<213> Homo sapiens <400> 19 Gly Arg Gln Val Ile Ala Ala Val Lys Trp Ala Lys Ala Ile Pro Gly Phe Arg Asn Leu His Leu Asp Asp Gln Met Thr Leu Leu Gln Tyr Ser Trp <210> 20 <211> 12 <212> PRT
<213> Homo sapiens <400> 20 Glu Phe Pro Glu Met Leu Ala Glu Ile Ile Thr Asn <210> 21 <211> 33 <212> PRT
<213> Homo sapiens <400> 21 SUBSTITUTE SHEET (RULE 26) Glu Arg Gln Leu Leu Ser Val Val Lys Trp Ser Lys Ser Leu Pro Gly Phe Arg Asn Leu His Ile Asp Asp Gln Ile Thr Leu Ile Gln Tyr Ser Trp <210> 22 <211> 12 <212> PRT
<213> Homo sapiens <400> 22 Glu Phe Pro Glu Met Met Ser Glu Val Ile Ala Ala <210> 23 <211> 33 <212> PRT
<213> Homo Sapiens <400> 23 Gly Lys Gln Met Ile Gln Val Val Lys Trp Ala Lys Val Leu Pro Gly Phe Lys Asn Leu Pro Leu Glu Asp Gln Ile Thr Leu Ile Gln Tyr Ser Trp <210> 24 <211> 12 <212> PRT
<213> Homo Sapiens <400> 24 Glu Phe Pro Ala Met Leu Val Glu Ile Ile Ser Asp <210> 25 <211> 33 <212> PRT
<2I3> Homo sapiens <400> 25 Glu Arg Gln Leu Val His Val Val Lys Trp Ala Lys Ala Leu Pro Gly Phe Arg Asn Leu His Val Asp Asp Gln Met Ala Val Ile Gln Tyr Ser SUBSTITUTE SHEET (RULE 26) WO 99/50658 _ 7 _ PCTNS99/06937 Trp <210> 26 <211> 12 <212> PRT
<213> Homo sapiens <400> 26 Asp Phe Pro Glu Met Met Ala Glu Ile Ile Ser Val SUBSTITUTE SHEET (RULE 26~

Claims (71)

WHAT IS CLAIMED IS:

1. A method of identifying a compound that modulates nuclear receptor activity, said method comprising:
modeling test compounds that fit spatially into a nuclear receptor ligand binding domain of interest using an atomic structural model of the estrogen receptor a ligand binding domain or portion thereof, screening said test compounds in an assay characterized by binding of a test compound to the ligand binding domain, and identifying a test compound that modulates nuclear receptor activity, wherein said atomic structural model comprises atomic coordinates of amino acid residues corresponding to residues of human estrogen receptor .alpha. Met343, Leu346, Ala350, G1u353.
Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521. His524, Leu525 and Met528.

2. The method of Claim 1 wherein the amino acid residues correspond to residues Met343, Met421, His524, Leu525 and Met528.

3. The method of Claim 1 wherein the test compound is an agonist and nuclear receptor activity is measured by binding of a coactivator to the coactivator binding site.

4. The method of Claim 1 wherein the test compound is an antagonist and nuclear receptor activity is measured by the unwinding of helix 12.

5. The method of Claim 1 wherein the test compound is an antagonist and nuclear receptor activity is measured by the blocking of coactivator binding.

6. The method of Claim 1 wherein said screening is in vitro.

7. The method of Claim 6 wherein said screening is high throughput screening.

8. The method of Claim 1 wherein said test compound is from a library of compounds.

9. The method of Claim 1 wherein said test compound is a small organic molecule, a peptide, or peptidomimetic.

10. The method of Claim 1 which further comprises the step of providing the atomic coordinates of the estrogen receptor a ligand binding domain or portion thereof to a computerized modeling system, prior to said modeling step.

11. The method of Claim 1 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors. retinoid receptors, glucocorticoid receptors.

progestin receptors. mineralocorticoid receptors. androgen receptors, peroxisome receptors and vitamin D receptors.

12. The method of Claim 11 wherein said nuclear receptor is an estrogen receptor.

13. The method of Claim 12 wherein said estrogen receptor is the estrogen receptor .alpha..

14. A method of identifying a compound that modulates ligand binding to a nuclear receptor.
said method comprising:
modeling test compounds that fit spatially into a nuclear receptor ligand binding domain of interest using an atomic structural model of the estrogen receptor a ligand binding domain or portion thereof, screening said test compounds in an assay characterized by binding of a test compound to the binding domain, and identifying a test compound that modulates ligand binding to said nuclear receptor, wherein said atomic structural model comprises atomic coordinates of amino acid residues corresponding to residues of human estrogen receptor a Met343. Leu346, A1a350, G1u353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528.

15. The method of Claim 14 wherein the amino acid residues correspond to residues Met343, Met421, His524, Leu525 and Met528.

16. The method of Claim 14 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

17. The method of Claim 16 wherein said nuclear receptor is an estrogen receptor.

18. The method of Claim 17 wherein said estrogen receptor is the estrogen receptor .alpha..

19. The method of Claim 14 wherein said screening is in vitro.

20. The method of Claim 19 wherein said screening is high throughput screening.

21. The method of Claim 14 wherein said test compound is from a library of compounds.

22. The method of Claim 14 wherein said test compound is an agonist or antagonist of ligand binding.

23. The method of Claim 14 wherein said test compound is a small organic molecule, a peptide, or peptidomimetic.

24. A method for identifying an agonist or antagonist of ligand binding to a nuclear receptor.
said method comprising the steps of:
providing the atomic coordinates of the estrogen receptor a ligand binding domain or portion thereof to a computerized modeling system, wherein said atomic coordinates are of the amino acid residues corresponding to residues of human estrogen receptor a Met343.
Leu346, A1a350, G1u353, Leu384, Leu387. Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528;
modeling compounds which fit spacially into the ligand binding domain; and identifying in an assay for nuclear receptor activity a compound which increases or decreases the activity of the nuclear receptor by binding the ligand binding domain of said nuclear receptor, whereby an agonist or antagonist of ligand binding is identified.

25. The method of Claim 24 wherein the amino acid residues correspond to residues Met343, Met421, His524. Leu525 and Met528.

26. The method of Claim 24 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

27. The method of Claim 26 wherein said nuclear receptor is an estrogen receptor.

28. The method of Claim 27 wherein said estrogen receptor is the estrogen receptor .alpha..

29. A method of modulating nuclear receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a compound that fits spatially and preferentially into a ligand binding domain of a nuclear receptor of interest, where said compound is designed so as to distort at least one amino acid residue corresponding to residues of human estrogen receptor a Met343, Leu346, A1a350, G1u353. Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528.

30. The method of Claim 29 wherein at least one amino acid residue corresponds to residues Met343. Met421, His524, Leu525 and Met528.

31. The method of Claim 29 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors. progestin receptors, mineralocorticoid receptors, androgen receptors.
peroxisome receptors and vitamin D receptors.

32. The method of Claim 31 wherein said nuclear receptor is an estrogen receptor.

33. The method of Claim 32 wherein said estrogen receptor is the estrogen receptor .alpha..

34. A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data is capable of displaying a graphical three-dimensional representation of a molecular complex of a compound bound to a nuclear receptor ligand binding domain comprising structure coordinates of amino acids corresponding to human estrogen receptor a Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 or a homologue of said molecular complex, wherein said homologue comprises a ligand binding domain that has a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5.ANG..

35. The machine-readable data storage medium of Claim 34 wherein the amino acid residues correspond to residues Met343, Met421, His524, Leu525 and Met528.

36. The machine-readable data storage medium of Claim 34 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

37. The machine-readable data storage medium of Claim 36 wherein said nuclear receptor is an estrogen receptor.

38. The machine-readable data storage medium of Claim 37 wherein said estrogen receptor is the estrogen receptor .alpha..

39. The machine-readable data storage medium of Claim 34 wherein said molecular complex is defined by the set of structure coordinates depicted in Appendix 1 or Appendix 2, or a homologue of said molecular complex, said homologue having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5.ANG..

40. A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which, when combined with a second set of machine readable data, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data, wherein: said first set of data comprises a Fourier transform of at least a portion of the structural coordinates selected from the group consisting of coordinates depicted in Appendix 1 or Appendix 2;
and said second set of data comprises an X-ray diffraction pattern of a molecule or molecular complex.

41. The machine-readable data storage medium of Claim 40 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

42. The machine-readable data storage medium of Claim 41 wherein said nuclear receptor is an estrogen receptor.

43. The machine-readable data storage medium of Claim 42 wherein said estrogen receptor is the estrogen receptor .alpha..

44. A cocrystal of a nuclear receptor comprising an agonist bound to the ligand binding domain and a molecule bound to the coactivator binding site of the nuclear receptor, wherein said crystal defracts with at least 2.03.ANG. resolution.

45. The cocrystal of Claim 44 wherein said nuclear receptor is the estrogen receptor .alpha..

46. The cocrystal of Claim 45 wherein said estrogen receptor a is human.

47. The cocrystal of Claim 46 wherein said molecule is peptide.

48. The cocrystal of Claim 47 wherein said peptide comprises a NR-box amino acid sequence or derivative thereof.

49. A cocrystal of a nuclear receptor comprising an antagonist bound to the ligand binding domain of the nuclear receptor, wherein said crystal defracts with at least 1.9.ANG. resolution.

50. The cocrystal of Claim 49 wherein said nuclear receptor is the estrogen receptor .alpha..

51. The cocrystal of Claim 50 wherein said estrogen receptor a is human.

52. A computational method of designing a nuclear receptor ligand where at least one amino acid residue of a nuclear receptor LBD that corresponds to human estrogen receptor a Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528, interacts with at least one first chemical moiety of said ligand, comprising the step of selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety with a structure to either decrease or increase an interaction between said interacting amino acid and said second chemical moiety compared to said interaction between said interacting amino acid and said first chemical moiety.

53. The method of Claim 52 wherein at least one amino acid residue corresponds to residues Met343, Met421, His524, Leu525 and Met528.

54. The method of Claim 52 further comprising determining a change in interaction between said interacting amino acid and said ligand after chemical modification of said first chemical moiety.

55. The method of Claim 52 wherein said chemical modification enhances hydrogen bonding interaction, charge interaction, hydrophobic interaction, Van Der Waals interaction or dipole interaction between said second chemical moiety and said interacting amino acid compared to said first chemical moiety and said interacting amino acid.

56. The method of Claim 52 wherein said chemical modification reduces hydrogen bonding interaction, charge interaction, hydrophobic interaction, Van Der Waals interaction or dipole interaction between said second chemical moiety and said interacting amino acid compared to said first chemical moiety and said interacting amino acid.

57. The method of Claim 52 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralocorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

58. The method of Claim 57 wherein said nuclear receptor is an estrogen receptor.

59. The method of Claim 52 wherein the estrogen receptor is the estrogen receptor .alpha..

60. The method of Claim 59 wherein the ligand is an agonist.

61. The method of Claim 60 wherein the ligand is selected from the group consisting of 17.beta.-estradiol, diethylstilbestrol, moxestrol, mesohexestrol, coumestrol, .DELTA.9-THC, o,p-DDT, zearalenone and kepone.

62. The method of Claim 61 wherein the ligand is 17.beta.-estradiol, and the first chemical moiety is a free carbon of the A' ring located at a position selected from the group consisting of C6.alpha., C7.alpha., C12.alpha., C15.alpha., C16.alpha. and C17.alpha..

63. The method of Claim 59 wherein the ligand is an antagonist.

64. The method of Claim 63 wherein the ligand is selected from the group consisting of ICI
164,384 and EM800.

65. The method of Claim 59 wherein the ligand is a selective estrogen receptor modulator.

66. The method of Claim 65 wherein the ligand is selected from the group consisting of tamoxifen, raloxifene and GW5638.

67. A method of modulating nuclear receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a ligand that fits spatially and preferentially into a ligand binding domain of a nuclear receptor of interest, wherein said ligand is designed by a computational method where at least one amino acid residue of a nuclear receptor ligand binding domain that corresponds to human estrogen receptor a Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528, interacts with at least one first chemical moiety of said ligand, comprising the step of selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety with a structure to either decrease or increase an interaction between said interacting amino acid and said second chemical moiety compared to said interaction between said interacting amino acid and said first chemical moiety.

68. The method of Claim 67 wherein at least one amino acid residue corresponds to residues Met343, Met421, His524, Leu525 and Met528.

69. The method of Claim 67 wherein said ligand is an antagonist.

70. The method of Claim 67 wherein said ligand is an agonist.

71. The method of Claim 70 which further comprises administering a coactivator mimic designed by a computational method where at least one amino acid residue of a nuclear receptor coactivator binding site that corresponds to human estrogen receptor a helix 3 residues Leu354, Val355, Met357, Ile358, Ala361 and Lys362, helix 4 residue Phe367, helix 5 residues Gln375, Val376, Leu379 and Glu380, helix 6 residue Trp383, and helix 12 residues Asp538, Leu539, Glu542, Met543 and Leu544, interacts with at least one first chemical moiety of said coactivator mimic, comprising the step of selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety with a structure to either decrease or increase an interaction between said interacting amino acid and said second chemical moiety compared to said interaction between said interacting amino acid and said first chemical moiety.