AU2003262215A1 - Methods and compounds for modulating nuclear receptor activity - Google Patents

Description

pI

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: The Regents of The University of California and Arch Development Corporation Actual Inventor(s): Andrew K Shiau, Peter J Kushner, David A Agard, Geoffrey L Greene Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHODS AND COMPOUNDS FOR MODULATING NUCLEAR RECEPTOR ACTIVITY Our Ref 707469 POF Code: 333689/193871, 453841 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 1 p la METHODS AND COMPOUNDS FOR MODULATING NUCLEAR RECEPTOR

ACTIVITY

This Application is a divisional application of Australian Patent Application 34571/99, the entire content of which is herein incorporated by reference.

INTRODUCTION

Technical Field 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.

Background 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 promoterdependent 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., New Engl. J. Med. 331:1056-1061 (1994)). The nuclear receptor family also includes receptors for glucocorticoids, androgens, mineralocorticoids, progestins, thyroid hormones, 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/liganddependent molecular switch, and recognizes a variety of compounds diverse in their size, shape and chemical properties. Accordingly, the estrogen hormones exert their physiological effects by binding to the estrogen receptor (Beato, et al., Cell W:\dskadnklspedesDIv of 34571-99.doc WO 99/50658 PCT/US99/06937 83(6):851-857 (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-independent actions..

All ERa ligands bind exclusively to the C-terminal LBD. Some of these ligands.

including the endogenous estrogen. 17p-estradiol (E 2 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.

S 10 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, exhibited 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 2 C WO 99/50658 PCT/US99/06937 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 Cterminal 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 DNA binding, these regions of the LBD have been predicted to form part of a recognition surface, created in the presence ofagonist, 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 E 2 and RAL show that although both ligands bind at the same site within the core of the LBD (Brzozowski. et al., suDra), each of these ligands induces a different conformation of helix 12. Whereas helix 12 in the E 2 -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-CoAl (Onate. et al.. Science 270:1354-1357 (1995)).

GRIPI/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/RAC3/ACTR/AIB /SRC-3 (Anzick. et al..

3 WO 99/50658 PCT/US99/06937 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-I 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.. Endocrinology 137:3594-7 (1996)).

SRC-1 and GRIPI also bind to the agonist-bound LBDs of both the human TR and human ERa using the putative coactivator binding site (Feng, et al., supra).

Members of the p160 family of coactivators such as SRC-1, GRIP 1 /TIF2/SRC-2, and p/CIP/RAC3/ACTR/AIBI/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., supra). 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 pi 60 coactivators contains several NR boxes. The NR boxes within SRC-1, GRIP 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 TRp and the GRIPI NR Box II peptide and biochemical studies of GRIPI binding to TRp 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, 4 hypercholesterolemia, obesity and other conditions. For example, compounds that modulate ERa transcriptional 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 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 coactivatorcoactivator 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 rodeling 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 spatially 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 W:\%iskanklVspecies34571d.doc WO 99/50658 PCT/US99/06937 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 WO 99/50658 PCT/US99/06937 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 ofpeptide. 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 I A is a stereo view of the electron density of the DES-ERa LBD-GRIP1 NR Box II peptide complex and Figure IB is a stereo view of the electron density of the OHT-ERa LBD complex.

Figure 1 is a black and white graphical representation of a figure that was generated using BOBSCRIPT (Esnouf, J. Mol. Graph. Model. 15, 132-4, 112-3 (1997)) and rendered using Raster3D (Merritt, et al., Acta Crvstallogr. 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-GRIPI 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, 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 H5 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 lie 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 7 WO 99/50658 PCT/US99/06937 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 530-551 are depicted as a Ca worm; residues 536-544 are colored magenta. The side chains of Leu 536, Tyr 537. 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 S 10 bound in a hydrophobic groove and those of lie 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 530-511 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 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- 0 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 5A and Figure 5B 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 306-526 of the LBD. Helix 12 from the DES-LBD-coactivator peptide complex is omitted for clarity. Residues 536-551 (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 hydrogen bonds between the e-amino group of Lys 362 and the backbone 8 WO 99/50658 PCT/US99/06937 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 543. and L544=Leu 544. 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 E 2 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 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 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 5. 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 (wihite 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 (hTRP and rTRa) (SEQ ID NO: 5 and 6 and SEQ ID NO: 7 and retinoids (hRARy and hRXRa) (SEQ ID NO: 9 and 10 and SEQ ID NO: 11 and 12), peroxisome (hPPARy) (SEQ ID NO: 13 and 14), vitamin D (hVDR) (SEQ ID NO: 15 and 16), estrogen (hERa) (SEQ ID NO: 17 and 18), glucocorticoid (hGR) (SEQ ID NO: 19 and 20), progestin (hPR) (SEQ ID NO: 21 and 22), mineralocorticoid (hMR) (SEQ ID NO: 23 and 24) and androgen (hAR) (SEQ ID NO: 25 and 26). The boxes represent residues of alpha-helix (H3, H4, H5, H6 and H12); lower case letters and represent hydrophobic and polar residues, respectively. The numbered positions at the top of the table, 280, 281, etc., correspond to hTRp 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 cyclic peptides, peptide analogs, or constrained peptides).

Certain residues within the ERa LBD have been identified that are of particular importance: Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (See Figure 4A). Of these, some have been found to directly or indirectly affect 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 W:\clskank\speciesl34571d.doc WO 99/50658 PCT/US99/06937 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 hTRO. rTRa. hRARy, hGR. hPR. hMR and hAR all have a proline residue. hRXRo has as aspartic acid residue. hPPARy has a histidine residue and hVDR has a threonine residue at positions corresponding to the Tyr 537 residue of hERa. Therefore, selective agonists and antagonists can be designed for the estrogen receptor that interact with Tyr 537.

S 10 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 E 2 In addition, it is expected that ligandinduced 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 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 12. 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 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. Ala350. Glu353. Leu384. Leu387. Leu391. Arg394. Phe404. Met421. Leu428.

11 WO 99/50658 PCT/US99/06937 Gly521. His524. Leu525 and Met528. preferably Met343. Met421. His524. Leu525 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 compound capable of binding to the site. This includes receptor residues having an atom within 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 information 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 threedimensional 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 WO 99/50658 PCT/US99/06937 more residues within the LBD that correspond to the same as or equivalent to) human ERa residues Met343. Leu346. Ala350, Glu353, Leu384. Leu387. Leu391. Arg394. Phe404. Met421.

Leu428. Gly521. His524. Leu525 and Met528. preferably Met343. Met421, His524. Leu525 and Met528. Similarly, another embodiment of the invention 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, Ala350.

Glu353, Leu384. Leu387. Leu391, Arg394, Phe404. Met421. Leu428, Gly521, His524. Leu525 and Met528. preferably Met343, Met421, His524. Leu525 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 alignment 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 Sresidues 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 I hERa M343 M421 F425 H524 L525 M528 hPR L715 F794 1798 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 R396 A397 L401 hRXRa V265 G343 F346 H435 L436 F440 rTRa F215 L292 V296 R384 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 WO 99/50658 PCT/US99/06937 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 the same as or equivalent to) human TR residues of C-terminal helix 3 (Ile280. Thr28 Val283. Va1284, Ala287. and Lys288), helix 4 (Phe293). helix 5 (Gln301, Ile302. Leu305. Lys306). helix 6 (Cys309). and helix 12 (Pro453. Leu454. Glu457, Val458 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 (Ile280. Val283. Val284, and Ala287), helix 4 (Phe293), helix 5 (Ile302 and Leu305), helix 6 (Cys309). and helix 12 (Leu454, Val458 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, Val355, Met357, I1e358. Ala361, and Lys362), helix 4 (Phe367), helix 5 (Gln375, Val376, Leu379, Glu380), helix 6 (Trp383), and helix 12 (Asp538, Leu539, Glu542. 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, Ile358 and Ala361), helix 4 V (Phe367). helix 5 (Val376, Leu379). helix 6 (Trp383), and helix 12 (Leu539. Met543 and Leu544). This corroborates the data presented by Apriletti, et al., suDra, 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 polypeptides 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 WO 99/50658 PCT/US99/06937 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 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 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, Ala350, Glu353. Leu384. Leu387, Leu391. Arg394, :,-:Phe404, Met421, Leu428, Gly521, 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 Sillustration 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 equivalent to) human ERa residues of Met343. Leu346.

Ala350, Glu353. Leu384. Leu387, Leu391. Arg394. Phe404, Met421, Leu428. Gly521. 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 ofTR. 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 16 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 NO: 4) a peptide derived from the NR Box II region of the p160 coactivator GRIP1) 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 2.03A resolution crystal structure of the hERa LBD bound to DES and the coactivator and the 1.9A x-ray crystal structure of the hERa LBD bound to OHT, the crystals diffract with at least 2.03A or 1.9A resolution, respectively.

In yet another aspect of the invention, compounds of interest are discovered, 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, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528, preferably Met343, Met421, His524, Leu525 and Met528.

W:Acska\nklfspedes34571d.doc 17 Compounds of particular interest fit spatially and preferentially into the ligand binding domain. By "fits 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 step 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 tissuespecific 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, 3) 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 physicalchemical 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.

W:dskklnkd.spedesl34571d.doc 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 hERa, Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, 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, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, 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 between 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 W:\ds kankispedes\34571d.doc r WO 99/50658 PCT/US99/06937 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. 2 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.

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. Ala350, Glu353. Leu384, Leu387, Leu391. Arg394. Phe404, Met421. Leu428. Gly521. 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 17p-estradiol is an endogenous ligand for the hERa.

:In the case of estradiol, positions of interest are C6a, C7a, Cl2a, Cl5a. Cl6a and Cl7a.

Modifications at one or more of these free carbons on 17p-estradiol's backbone would affect the ligand's interactions with one or more of the Met343, Leu346, Ala350, Glu353. Leu384. Leu387, SLeu391. Arg394, Phe404, Met421. Leu428, Gly521, 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), A'-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- WO 99/50658 PCT/US99/06937 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 complementarity (DesJalais. et al., J. Med. Chem. 31:722-729 (1988)) or by estimated interaction energy (Meng, et al., J. Comp. 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.

WO 99/50658 PCT/US99/06937 and incorporating any structural data into that iterative design process. For example. one skilled in the an 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" 1 1:29-34 (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.

35:2145-2154 (1992)); and HOOK (available from Molecular Simulations. Burlington. MA).

WO 99/50658 PCT/US99/06937 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 portion(s) of a molecule known to bind to the site. such as a known ligand. These methods include: LUDI (Bohm. J. Com. Aid. Molec. Desien 6:61-78 (1992). available from 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 compoupd 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. 5.500,807; 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 ligand 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.

WO 99/50658 PCT/US99/06937 As an example. in vitro binding assays can be perbormed 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 GRIP 1 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 Prog. 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- 23,804 (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 hormone-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 WO 99/50658 PCT/US99/06937 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 from traditional estrogen replacement therapy. Others include GR-based disorders including Type 11 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, a compound will act as an agonist in one tissue. while acting as an 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, Ala350, Glu353. Leu384, Leu387, Leu391, Arg394. Phe404. Met421, Leu428, Gly521. 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. Ala350. Glu353. Leu384.

WO 99/50658 PCTIUS99/06937 Leu387. Leu391. Arg394. Phe404. Met421. Leu428. Gly521. His524. Leu525 and Met528.

preferably Met343. Met421. His524. Leu525 and Met528. 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 alone, 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. Val355, Met357, 11e358, 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 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/GRIPI peptide complex.

described herein, precisely defines the binding site that would need to be targeted.

WO 99/50658 PCT/US99/06937 As noted above and as exemplified in the Examples. ER LBDs are co-crystallized with a peptide molecule comprising a coactivator GRIPI NR Box II peptide sequence (SEQ ID NO:4) bound to the coactivator binding site and DES with the cocrystal structure refined to a resolution of2.03A 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. having a resolution value less than 3.6A. More preferably the cocrystal structure is refined to greater than 3.4A. 3.2A. 3.0A. 2.8A, 2.6A, 2.4A, 2.2A. 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. having a resolution value less than 3.6A. More preferably the cocrystal structure is refined to greater than 3.4A, 3.2A, 2.8A, 2.6A, 2.4A, 2.2A, 2.0A, even more preferably to a resolution greater than 1.9A.

Crystals are made from purified nuclear receptor LBDs that are usually expressed by a cell culture, such as E. coli. E. coli is often a preferred expression system. The thyroid receptor was successfully expressed in E. coli 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. coli.

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 hormone 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.

WO 99/50658 PCT/US99/06937 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 I 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 I and 2. The Appendix 1 coordinates for the DES-ERa LBD-GRIPI 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 ligand binding domain comprises structure coordinates of amino acids corresponding to hERa Met343. Leu346, Ala350, Glu353. Leu384, Leu387, Leu391, Arg394. Phe404, Met421, Leu428. Gly521, 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 1.5A. 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.

27 WO 99/50658 PCT/US99/06937 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. coli. 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 Endocrinolovg 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, AIBI, RAC3, p/CIP, and GRIPI and its homologues TIF 2 and 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. Cell. Biol.

17:2735-44 (1997) and Proc. Natl. Acad. Sci. USA 93(10):4948-52 (1996)), for GRIPI 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 554 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.

WO 99/50658 PCT/US99/06937 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 licand-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 Nterminus, 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 Sthat preserves the integrity of the protein. Ligand equilibration can be established between 2 and 37C, although the receptor tends to be more stable in the 2-20 0 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 0 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 WO 99/50658 PCT/US99/06937 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: where L is leucine and X is any amino acid (the NR box). The structure of the DES-hERa LBD-GRIPI 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, the coactivator binding site. Further, structural studies of the complex between TRP and the GRIP1 NR box II peptide and biochemical studies of GRIP binding to TRp 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/GRIPI 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. Gin 375 and Glu 542) are highly conserved across the nuclear receptor family (Wurtz. et al.. supra). The side chains of Gin 375 and Leu 379 are predominantly buried even in the absence of GRIP1 binding and appear to form integral parts of WO 99/50658 PCT/US99/06937 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 15A distance between Lys 362 and Glu 542 is well suited to measure off the -I IA 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 TRp 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 TRp (see the Examples, Apriletti, et al.. supra and Feng, et al.. sura 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 (lie 358, Leu 372, Val 376, Leu 379, Leu,5.39 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 Mutations in le 358, Val 376 and Leu 539 abrogate GRIP! binding (see the Examples and Feng, et al., supra). Although these residues are, in general, more poorly conserved across nuclear receptors than either Lys 3,62 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. Opin. 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 GRIP to the LBDs of the ERa, the TRp and the glucocorticoid receptor (GR) with very different efficiencies (Ding, et al., suDra).

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 (le 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 lie 689 as a key receptor binding determinant. In the crystal, only the side chains of the motif leucines and lie 689 extensively contact the LBD in both noncrystallographic symmetry related peptides. Mutation of 31 C WO 99/50658 PCT/US99/06937 lie 689 to alanine reduces the ability of the peptide to inhibit the binding of GRIP1 to ERa by 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 Glu 542 (Figures IA and 3A). The proximity of this negatively charged moiety of Glu 542 to the hydrophobic side chain of lie 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 GRIPI. which each contain a different residue preceding the LXXLL motif (SEQ ID NO: have differing affinities for ERa (Ding, et al., sura; Voegel, et al., EMBO J. 17:507-19 (1998)).

The NR boxes of TIF2, the human homologue of GRIPI, 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 p 60 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 Waals 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., suDra). 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 32 WO 99/50658 PCT/US99/06937 sequence (LXXML versus LXXLL) (SEQ ID NO:2 versus SEQ ID NO: 1) functions as an intramolecular mimic of the coactivator helix (Figure 5 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 antagonistbound 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 E 2 complexes (Figures 3A, 3B and Numerous studies have demonstrated the importance of the OHT side chain in receptor antagonism (Jordan, et al., sunra 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 12 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 540.

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 WO 99/50658 PCT/US99/06937 or E, binding. These different conformations impose different restrictions on the positioning of helix 12.

Helices 3, 8 and 1 in the DES and E 2 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 2 complexes and it ends at Tyr 526 in the OHT complex. Helix 12 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 537 that stabilizes the N-terminus of helix 12 (Figure IB). 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 ~17A over five residues. Although theoretically possible, this conformation would be highly strained and hence unlikely. In contrast, the longer loop connecting helices 1 1 and 12 in the OHT complex allows helix 12 to extend to the static region of the coactivator binding groove.

In the DES and E 2 complexes, helix 12 and the loop connecting helices 11 and 12 pack against helices 3 and 11, whereas they do not in the OHT complex (Figures 2A and 2B and (Brzozowski, et al., suDra). A recently described structure of the E 2 -LBD complex suggests that the longer helices in the DES and E 2 complexes are not dependent upon the interactions helix 12 forms in the agonist-bound conformation (Tanenbaum, et al., suDra). 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 E 2 between various hydrophobic residues from helices 3, 7, 8 and I and the P 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 E 2 structures. As a result, many of the interresidue packing interactions present in the DES and E 2 structures are either absent or altered in the OHT structure (Figure 6D). These structural WO 99/50658 PCT/US99/06937 distortions apparently force the main chain from residues 339 to 341. 421 to 423. and 527 to 530 (which form parts of helices 3. 8 and 11 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 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 12 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 528 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-mi column ofestradiol- Sepharose (Greene. et al.. Proc. Natl. Acad. Sci. USA 77:5115-5119 (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. 250 mM NaSCN (Hegy, et al.. Steroids 61:367-373 (1996)). Protein was eluted with 3 x 10-5 M ligand (either DES or OHT) in 30-100 WO 99/50658 PCT/US99/06937 ml of 50 mM Tris. 1 mM EDTA. I mM DTT and 250 mM NaSCN. pH 8.5. 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 glutathione-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 pSG5-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, and a protease inhibitor cocktail) or with 1 pM of either DES or OHT for 1 hour at 4 0

C.

Extract samples containing thirty pmol of GST-LBD were then incubated with 10 pi 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. 35 S-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 pSG5-GRIP (provided by Michael Stallcup of the University of Southern California) as the template. Immobilized GST-LBDs were incubated for 2.5 hours with 2.5 pj aliquots of crude translation reaction mixture diluted in 300 pi of Trisbuffered saline (TBS). After five washes in TBS containing 0.05% NP-40. proteins were eluted 36 WO 99/50658 PCT/US99/06937 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-GRIP1 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 GRIPI NR Box II peptide (SEQ ID NO:4) for 7-16 hr. Two UL samples of this solution were mixed with equal volume samples of reservoir buffer consisting of 25-27% 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 1 with cell dimensions a=54.09. b-82.22. c=58.04 and P=1 11.34. Two molecules each of the DES-LBD and the coactivator peptide form the asymmetric unit. A 200 pm x 40 pm x 40 pm crystal was transferred to a cryosolvent solution containing 25% PEG 4000. ethylene glycol, 100 mM Tris (pH 200 mM Na Acetate and 10 pM peptide and frozen in ai N stream at -170*C in a rayon loop. Diffraction data from this crystal were measured at 170 0 C using a 300 mm MAR image plate at the Stanford Synchrotron Radiation Laboratory (SSRL) at beamline 7-1 at a wavelength of 1.08A.

-Crystals of the hERa LBD complexed to OHT were obtained by the hanging drop vapor diffusion method. Equal volume aliquots (2 UL) of a solution containing 3.9 mg/mL proteinligand complex and the reservoir solution containing 9% PEG 8000, 6% ethylene glycol, 50 mM HEPES (pH 6.7) and 200 mM NaCI were mixed and suspended over 800 4L of the reservoir solution. Hexagonal plate-like crystals formed after 4-7 days at 21-23 0 C. Both crystal size and quality were improved through microseeding techniques. These crystals belong to the space group P6.22 with cell parameters a=b=58.24A 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% PEG 8000, 25% ethylene glycol. 50 mM HEPES (pH 7.0) and 200 mM NaCI and then flash frozen in liquid N 2 suspended in a rayon loop. Diffraction data were measured at -170 0 C using a 345 mm MAR image plate at SSRL at beamline 9-1 and at a wavelength of 0.98A.

WO 99/50658 PCT/US99/06937 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 cutoff.

Structure Determination and Refinement Initial efforts to determine the structure of the DES-LBD-GRIPl NR Box II peptide complex utilized a low resolution 1A) data set (data not shown). A self-rotation search implemented with POLARRFN ("The CCP4 suite: programs for protein crystallography", Acta Crvstallocr. 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 CC=35.6% after placement of both monomers). Given that the model at this point was both inaccurate 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. Belg. 97:655-667 (1988)) and model refinement in REFMAC (Murshudov. et al., Acta Crvstallogr. 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. Crvst. 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-GRIP 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 P6 5 22.

A translation search in P6 5 22 yielded the correct solution 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 WO 99/50658 PCT/US99/06937 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 maximumlikelihood target (Adams, et al., Proc. Natl. Acad. Sci. USA 94:5018-23 (1997)). Anisotropic scaling and a bulk solvent correction were used and all B-factors were refined isotropically.

Except for the Rr,e 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 306-551. 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-GRIP I NR Box II peptide complex became available when the Rfre of the OHT-LBD model was 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 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 Rf, set contained a random sample of 6.5% of all data. In refinement, all data between 27 and 2.03A (with no a cutoff) were used. The final model was composed of residues 305-549 of monomer A. residues 305-461 and 470-554 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 plot and none were in the disallowed regions.

Figure IA provides a view of a 2Fo-Fc electron density map calculated at 2.03A resolution and contoured at 1.0 a showing the GRIPI NR box II interaction with the LBD. The GRIP NR Box II peptide (SEQ ID NO:4) was omitted from the model prior to map calculation.

lie 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 1B provides a view of a 2Fo-Fc electron density map calculated 39 WO 99/50658 PCT/US99/06937 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 536 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. Biol.

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 GRIP 1, a mouse p 160 coactivator, interacts both in vivo and in vitro with the ERa LBD bound to agonist (Ding. et al., supra), but not with the LBD bound to antagonist (Norris. et al., J.

Biol. Chem. 273:6679-88 (1998)). Mutational studies of GRIPI 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., sunra and Voegel. et al., supra).

Competition assays indicate that a 13 residue GRIPI NR Box II peptide, NH 2

KHKILHRLLQDSS-CO

2 H (SEQ ID NO:4), corresponding to residues 686-698 of GRIP1 (Ding, et al., supra), synthesized by standard solid phase methods, binds specifically to the agonistbound ERa LBD (ICso<0.4pM; 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 GRIPI NR Box II peptide (SEQ ID NO: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 NR Box II peptide (SEQ ID NO:4), buffer alone, or in the presence of either a 2-fold or 10-fold molar excess of the GRIP1 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, ImM 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 WO 99/50658 PCT/US99/06937 characteristic of the full-length protein. These observations suggest that the GRIP NR Box II peptide is a valid model for studying the interaction between GRIP and the ERa LBD.

In order to characterize structurally the interaction between the GRIPI NR Box II peptide and the ERa LBD. recombinant human ERa LBD (residues 297-554) was crystallized bound to both DES and the GRIPI 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-GRIPI NR Box II peptide complex has been refined to a crystallographic R-factor of 19.9% (Rfre,=25.0%) using data to 2.03A resolution. as shown in Figure 1A and Table 2. The structure of the OHT-ERca LBD complex has been refined using data to 1.90A to a crystallographic R-factor of 23.0% (Rfree=26.2%), as shown in Figure IB and Table 2.

Table 2 Summary of Crystallographic Statistics Ligand Data Collection DES OHT Space group P2 1 P6 5 22 Resolution 2.03 1.90 Observations 104189 269253 Unique 30265 23064 Completeness 98.4 99.1 Rsym(%)" 7.8 Average I/al 9.8 16.1 Refinement Number of non-hydrogen atoms 4180 2070 Rcryst (%)b/Rfree 19.9/25.0 23.0/26.1 Bond r.m.s. deviation 0.006 0.006 Angle r.m.s. deviation 1.05 1.05 Average B factor (A 2 34.0 40.4 a Rsym =i I Ii- <li> Zil where <Ii> is the average intensity over symmetry equivalents b RcTyst IFo-F I FoI WO 99/50658 PCT/US99/06937 Example 3 Overall Structure of the DES-LBD-GRIPI NR Box II Peptide Complex The asymmetric unit of the DES-LBD-GRIPI NR Box II peptide complex crystals contains the same noncrystallographic dimer of LBDs that has been observed in the previously determined structures of the LBD bound to both E2 and RAL (Brzozowski. et al.. supra and Tanenbaum. et al.. supra). Beyond the flexible loops between helices 2 and 3 and helices 9 and the two LBDs of the dimer adopt similar structures 0.47A based on Ca positions).

The conformation of each LBD complexed with DES closely resembles that of the LBD bound to E 2 (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. 5/6 and 11 covering the ligand binding pocket (Figure 2A). One GRIPI 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 IA). Residues 687 to 697 from the GRIP I NR Box II peptide, designated peptide A. and residues 686 to 696 from the GRIP1 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 lie 689 to Gin 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-GRIPI 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 538- 546) is colored magenta. Helices 3, 4 and 5 (labeled H3. H4 and H5 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 1000A 2 of predominantly hydrophobic surface area from both molecules. The GRIPI NR Box II peptide binding site is a shallow groove composed of residues Leu 354. Val 355. Ile 358. Ala 361 and WO 99/50658 PCT/US99/06937 Lys 362 from helix 3. Phe 367 and Val 368 from helix 4: Leu 372 from the turn between helices 3 and 4: Gin 375. Val 376. Leu 379 and Glu 380 from helix 5: and Asp 538. Leu 539. Glu 542 and Met 543 from helix 12 (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 GRIP1 NR Box II peptide a helix formed by the side chains of lie 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, Gin 375. Val 376 and Leu 379 (Figure 3A and 3C). In contrast, the side chains of both lie 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 lie 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 1A). 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 e-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 Nterminal 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-carboxylate of Glu 542 and E-amino group of Lys 362 near the ends of the GRIP1 NR Box II peptide helix (Figure 3C).

The side chain carboxylate (y-carboxylate) of Glu 542 hydrogen bonds to the amides of the 43 WO 99/50658 PCT/US99/06937 residues of N-terminal turn of the peptide helix residues 688 and 689 of peptide A: residues 689 and 690 of peptide B) (Figure IA). Similarly. the e-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 GRIPI 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 (lie 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 35 S-labeled GRIP1 in the absence of ligand or in the presence of DES or OHT.

35 S-labeled GRIPI was incubated with either immobilized GST. immobilized wild type GST-hERa LBD, or immobilized mutant GST-LBDs in the absence ofligand or in the presence of DES or OHT. The bound GRIP was quantitated after SDS-PAGE. 1358R. mutant LBD containing a Ile->Arg substitution at residue 358; 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 GRIPI. 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 GRIPI binding in the presence of agonist. Only the wild-type GST-LBD was able to recognize the coactivator in the presence of DES.

Example Agonist Recognition Despite its different shape and larger molecular volume. DES (273A 3 is accommodated within the same binding pocket that recognizes E 2 (252A 3 In its receptor complex. DES is completely encased within the narrower half of the LBD in a predominantly hydrophobic cavity composed of residues from helices 3. 6. 7. 8. 11. and 12 as well as the SI/S2 hairpin (Figures 2A and 4A).

WO 99/50658 PCT/US99/06937 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 2 A ring near helices 3 and 6. Like the aromatic ring of the E 2 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 (Figure 4A) is bound near helices 7, 8 and 11 adjacent to the location of the E 2 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 2 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 E 2 does not. There are unoccupied cavities adjacent to the a face of the B ring and the p face of the C ring of the E 2 (Brzozowski. et al..

sup 1 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 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., Endocrinology 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 E 2 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.. sura, and Tanenbaum. et al., supra). This remarkable adaptability is presumably the result of both relatively large molecular volume of the binding pocket (-500A 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 configurations 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 E 2 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 527 to 530 form parts of helices 3. 8 and WO 99/50658 PCT/US99/06937 11 respectively. In contrast. these regions adopt an extended conformation in the OHT complex (Figures 2A. 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 538 to 546 whereas helix 12 in the OHT complex consists of residues 536 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 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 NO:3 instead of SEQ ID NO: 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 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, Val 355 and lie 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 lie 358, Lys 362. Leu 372. Gin 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 E-amino group hydrogen bonding to the carbonvls of residues 543 and 544 (Figure Given that the capping interaction at the N-terminal turn coactivator helix is formed by a helix 12 residue (Glu 542). the N-terminal turn of helix 12 in the 46

C.

WO 99/50658 PCT/US99/06937 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 537 and interacts with the amide of Tyr 537 through a series of water-mediated hydrogen bonds (Figure 1 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 536 forms van der Waals contacts with Glu 380 and Trp 383 and that of Tvr 537 forms van der Waals contacts with His 373, Val 376 and Glu 380 (Figures lB. 3B and 3D). As a result of these contacts. helix 12 in the OHT complex buries more solvent accessible surface area (-1200A 2 than the NR box peptide in the DES complex.

Example 8 OHT Recounition OHT is bound within the same pocket that recognizes DES, E 2 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 I I (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 P-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 2 D ring end of the binding pocket to adapt to the different structural features of DES and Instead. the residues that contact the B ring (Met 343, Leu 346. Met 421. lie 424, Gly 521. His 524 and Leu 525). 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 actually precludes the side chain of one residue.

47 48 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 524 from helix 11 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 E 2 (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 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 discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.

W;skonkAkspeciesM34571.-99,doc 48a Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

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.

W:cska\nkl\specesU34571.-99doc

C.

C

WO 99/50658 PCT/US99/06937 Appendix 1 Atomic Coordinates for Human ERa Complexed With DES and a GRIPI NR Box II Peptide CRYSTI 54.094 82.217 58.041 90.00 111.33 90.00 P 21 2 ORIGX1 ORIGX2 ORIGX3 SCALE 1 SCALE2 SCALE3 1.000000 0.000000 0.000000 0.018486 0.000000 0.000000

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

CB

C

O

N

CA

N

CA

CB

C

O

N

CA

CB

C

O

N

CA

CB

CG

CDI

CD2

C

O

N

CA

CB

OG

C

O

N

CA

CB

CG

CDI

CD2 0.000000 1.000000 0.000000 0.000000 0.012163 0.000000 SER A SER A SER A SER A SER A LEU A LEU A LEU A LEU A LEU A ALA A ALA A ALA A ALA A ALA A LEU A LEU A LEU A LEU A LEU A LEU A LEU A LEU A SER A SER A SER A SER A SER A SER A LEU A LEU A LEU A LEU A LEU A LEU A 0.000000 0.00000 0.000000 0.00000 1.000000 0.007221 0.000000 0.018497 0.00000 0.00000 0.00000 0.00000 305 305 305 305 305 306 306 306 306 306 307 307 307 307 307 308 308 308 308 308 308 308 308 309 309 309 309 309 309 310 310 310 310 310 310 35.230 -14.787 35.331 -14.303 34.146 -13.984 36.797 -16.033 36.138 -14.713 35.982 -14.313 35.329 -13.950 36.251 -14.256 34.929 -12.478 35.580 -11.638 33.851 -12.176 33.358 -10.810 31.841 -10.795 33.792 -10.204 33.878 -8.984 34.064 -11.062 34.487 -10.598 34.423 -11.745 33.214 -12.688 33.188 -13.513 31.919 -11.898 35.903 -10.037 36.385 -9.445 36.561 -10.219 37.928 -9.743 38.720 -10.750 38.889 -10.283 37.986 -8.373 38.965 -7.637 36.940 -8.038 36.877 -6.759 35.516 -6.596 35.301 -7.188 33.951 -6.728 36.417 -6.755 -1.163 1.289 1.186 0.285 0.061 2.449 3.702 4.878 3.719 3.100 4.434 4.541 4.436 5.866 6.005 6.842 8.156 9.171 9.130 10.406 8.989 8.100 9.066 6.959 6.771 5.934 4.606 6.099 6.249 5.352 4.658 3.974 2.583 2.055 1.650 1.00 73.26 1.00 72.95 1.00 72.46 1.00 74.06 1.00 73.59 1.00 72.21 1.00 71.05 1.00 70.19 1.00 69.57 1.00 69.96 1.00 68.06 1.00 64.88 1.00 65.83 1.00 63.36 1.00 62.73 1.00 62.52 1.00 62.57 1.00 62.81 1.00 64.21 1.00 66.28 1.00 63.80 1.00 61.61 1.00 62.92 1.00 60.50 1.00 58.73 1.00 59.53 1.00 59.47 1.00 57.05 1.00 56.70 1.00 52.69 1.00 48.20 1.00 48.32 1.00 44.94 1.00 46.45 1.00 43.19 c WO 99/50658 PCT/US99/06937 ATOM 36 C LEU A 310 ATOM 37 0 LEU A 310 ATOM 38 N THR A 311 ATOM 39 CA THR A 311 ATOM 40 CB THR A 311 ATOM 41 OGI THR A 311 ATOM 42 CG2 THR A 311 ATOM 43 C THR A 311 ATOM 44 0 THR A 311 ATOM 45 N ALA A 312 ATOM 46 CA ALA A 312 ATOM 47 CB ALA A 312 ATOM 48 C ALA A 312 ATOM 49 0 ALA A 312 15 ATOM 50 N ASP A 313 ATOM 51 CA ASP A 313 ATOM 52 CB ASP A 313 ATOM 53 CG ASP A 313 ATOM 54 ODI ASP A 313 ATOM 55 OD2 ASP A 313 ATOM 56 C ASP A 313 ATOM 57 0 ASP A 313 ATOM 58 N GLN A 314 ATOM 59 CA GLN A 314 ATOM 60 CB GLN A 314 ATOM 61 CG GLN A 314 ATOM 62 CD GLN A 314 ATOM 63 OEI GLN A 314 ATOM 64 NE2 GLN A 314 ATOM 65 C GLN A 314 ATOM 66 0 GLN A 314 ATOM 67 N MET A 315 ATOM 68 CA MET A 315 ATOM 69 CB MET A 315 ATOM 70 CG MET A 315 ATOM 71 SD MET A 315 ATOM 72 CE MET A 315 ATOM 73 C MET A 315 ATOM 74 0 MET A 315 ATOM 75 N VAL A 316 ATOM 76 CA VAL A 316 ATOM 77 CB VAL A 316 ATOM 78 CGI VAL A 316 ATOM 79 CG2 VAL A 316 ATOM 80 C VAL- A 316 ATOM 81 0 VAL A 316 ATOM 82 N SER A 317 ATOM 83 CA SER A 317 37.086 36.605 37.812 38.034 39.313.

39.079 40.464 36.834 36.021 36.726 35.616 35.741 35.561 34.510 36.698 36.752 38. 133 38.323 39.414 37.380 36.422 35.704 36.931 36.666 37.462 38.963 39.700 39.394 40.701 35.176 34.605 34.542 33.115 32.650 31.137 30.443 31.351 32.311 31.453 32.587 31.882 32.395 31.786 32.021 32.092 31.145 33.337 33.682 -5.589 5.609 1.00 46.44 -5.607 6.741 1.00 46.78 -4.576 5.148 1.00 44.36 -3.380 5.949 1.00 42.88 -2.633 5.532 1.00 42.31 -1.936 4.303 1.00 42.50 -3.606 5.350 1.00 46.02 -2.475 5.674 1.00 43.21 -2.776 4.800 1.00 42.12 1.372 6.409 1.00 42.16 -0.444 6.228 1.00 40.10 0.709 7.205 1.00 40.07 0.090 4.799 1.00 41.80 0.074 4.154 1.00 37.81 0.564 4.304 1.00 42.35 1.104 2.953 1.00 42.27 1.703 2.680 1.00 43.74 3.054 3.348 1.00 46.62 3.645 3.205 1.00 51.01 3.529 4.015 1.00 48.89 0.027 1.926 1.00 38.68 0.281 0.959 1.00 38.75 -1.179 2.145 1.00 34.76 -2.277 1.229 1.00 33.55 -3.512 1.643 1.00 36.90 -3.384 1.436 1.00 40.45 -4.610 1.905 1.00 43.13 -5.196 2.935 1.00 43.60 -5.032 1.117 1.00 44.03 -2.595 1.201 1.00 34.95 -2.860 0.140 1.00 32..89 -2.564 2.374 1.00 32.54 -2.848 2.470 1.00 35.46 -2.794 3.926 1.00 37.09 -2.777 4.097 1.00 39.42 -4.426 4.053 1.00 46.55 -5.205 5.397 1.00 45.29 -1.859 1.640 1.00 31.83 -2.247 0.852 1.00 32.10 -0.560 1.830 1.00 32.62 0.470 1.079 1.00 31.09 1.888 1.425 1.00 34.77 2.899 0.461 1.00 34.10 2.246 2.862 1.00 34.40 0.232 -0.414 1.00 33.48 0.266 -1.200 1.00 32.49 -0.027 -0.795 1.00 33.49 -0.280 -2.187 1.00 32.88 (7" WO 99/50658 PCTIUS99/06937

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84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 I11 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 CB SER A OG SER A C SER A O SER A N ALA A CA ALA A CB ALA A C ALA A O ALA A N LEU A CA LEU A CB LEU A CG LEU A CD1 LEU A CD2 LEU A C LEU A O LEU A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N AASP A N BASP A CA AASP A CA BASP A CB AASP A CB BASP A CG AASP A CG BASP A ODI AASP A ODI BASP A OD2 AASP A OD2 BASP A C AASP A C BASP A O AASP A O BASP A N ALA A CA ALA A CB ALA A C ALA A O ALA A N GLU A CA GLU A 317 -317 317 317 318 318 318 318 318 319 319 319 319 319 319 319 319 320 320 320 320 320 320 320 320 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 321 322 322 322 322 323 323 35.165 35.825 32.849 32.279 32.792 32.035 32.156 30.565 29.961 29.997 28.597 28.170 28.076 27.523 27.194 28.340 27.430 29.140 28.972 30.052 29.974 31.060 28.611 29.052 28.230 30.042 .30.041 30.214 30.258 31.537 31.573 31.694 32.770 31.523 33.312 31.988 33.170 29.069 29.123 28.820 28.934 28.374 27.268 27.124 25.946 24.955 25.932 24.713 -0.635 -2.297 0.277 -3.154 -1.396 -2.801 -1.238 -3.880 -2.529 -2.111 -3.676 -2.580 -4.811 -1.579 -3.305 -2.771 -3.642 -3.784 -2.614 -1.791 -2.212 -1.861 -1.576 -0.540 -2.555 0.632 -1.840 1.852 -3.733 0.243 -1.257 -3.020 -1.475 -3.818 -0.195 -3.120 0.756 -4.212 1.839 -4.155 2.899 -3.054 3.940 -3.292 3.562 -3.044 0.040 -5.561 0.271 -6.446 -0.833 -5.720 -0.839 -5.695 -1.559 -6.977 -1.595 -6.925 -2.334 -6.973 -2.374 -6.826 -3.230 -8.195 -1.562 -7.284 -2.733 -9.329 -1.868 -8.366 -4.432 -8.022 -0.622 -6.564 -2.524 -7.275 -2.565 -7.253 -2.861 -8.434 -2.942 -8.411 -2.968 -6.235 -3.902 -6.417 -4.781 -5.175 -3.204 -6.709 -3.857 -7.036 -1.880 -6.596 -1.117 -6.827 1.00 35.77 1.00 42.70 1.00 30.71 1.00 31.14 1.00 29.51 1.00 29.93 1.00 28.56 1.00 31.55 1.00 30.64 1.00 34.13 1.00 32.93 1.00 31.15 1.00 32.27 1.00 32.14 1.00 31.82 1.00 34.41 1.00 35.23 1.00 32.53 1.00 35.33 1.00 33.52 1.00 34.60 1.00 33.69 1.00 31.05 1.00 35.41 1.00 39.16 0.50 36.33 0.50 35.76 0.50 37.71 0.50 37.11 0.50 40.01 0.50 39.41 0.50 41.93 0.50 39.96 0.50 42.11 0.50 43.41 0.50 42.69 0.50 41.33 0.50 37.19 0.50 36.68 0.50 36.87 0.50 36.08 1.00 35.35 1.00 31.59 1.00 30.73 1.00 30.07 1.00 26.53 1.00 27.98 1.00 29.88

C

WO 99/50658 PCT/US99/06937

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132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 CB GLU A CG GLU A CD GLU A OEI GLU A OE2 GLU A C GLU A O GLU A N PRO A CD PRO A CA PRO A CB PRO A CG PRO A C PRO A O PRO A N PRO A CD PRO A CA PRO A CB PRO A CG PRO A C PRO A O PRO A N ILE A CA ILE A CB ILE A CG2 ILE A CG1 ILE A CDI ILE A C ILE A O ILE A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N TYR A CA TYR A CB TYR A CG TYR A CD! TYR A CEI TYR A CD2 TYR A CE2 TYR A CZ TYR A OH- TYR A C TYR A 323 323 323 323 323 323 323 324 324 324 324 324 324 324 325 325 325 325 325 325 325 326 326 326 326 326 326 326 326 327 327 327 327 327 327 327 327 328 328 328 328 328 328 328 328 328 328 328 25.027 24.870 23.463 23.183 22.640 24.010 24.655 22.674 21.774 21.935 20.613 20.626 21.717 21.893 21.335 21.082 21.125 21.258 20.773 19.749 18.873 19.571 18.296 18.502 17.168 19.189 19.301 17.506 17.906 16.392 15.595 14.872 15.778 14.944 16.850 14.598 14.161 14.251 13.303 13 .724 14.587 14.021 14.798 15.962 16.750 16.157 16.917 11.923 0.380 -6.855 1.068 -5.509 0.940 -4.960 -0.056 -4.257 1.836 -5.233 -1.515 -8.123 -1.705 -9.151 -1.659 -8.083 -1.466 -6.935 -2.032 -9.290 -2.598 -8.760 -2.363 -7.258 -0.785 -10.138 0.332 -9.668 -0.959 -11.403 -2.198 -12.161 0.242 -12.211 -0.266 -13.637 -1.695 -13.559 0.830 -11.954 0.165 -11.402 2.081 -12.352 2.762 -12.212 4.282 -12.133 4.992 -12.286 4.632 -10.805 6.120 -10.525 2.408 -13.471 2.758 -14.581 1.703 -13.301 1.279 -14.439 -0.029 -14.104 -1.210 -13.728 -2.462 -13.583 -1.415 -14.805 2.317 -14.935 3.202 -14.194 2.207 -16.210 3.123 -16.814 3.465 -18.245 4.693 -18.314 5.949 -18.518 7.092 -18.509 4.612 -18.110 5.753 -18.098 6.988 -18.297 8.130 -18.265 2.501 -16.827 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 30.98 31.62 31.98 33.10 30.01 30.86 28.86 30.66 31.01 30.29 31.42 33.66 27.46 26.19 27.80 27.35 25.59 24.02 26.00 23.73 24.83 22.11 24.01 25.97 20.75 29.31 32.91 25.72 25.55 25.57 23.80 23.96 19.89 21.19 17.53 27.16 25.98 26.56 24.45 26.72 27.73 28.56 29.10 26.01 30.63 30.07 37.94 24.95 WO 99/50658 PCT/US99/06937

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180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 223 224 225 226 227 O TYR A N SER CA SER A CB SER A OG SER A C SER A O SER A N GLU A CA GLU A CB GLU A C GLU A O GLU A N TYR A CA TYR A CB TYR A CG TYR A CDI TYR A CEI TYR A CD2 TYR A CE2 TYR A CZ TYR A OH TYR A C TYR A O TYR A N ASP A CA ASP A CB ASP A C ASP A O ASP A N PRO A CD PRO A CA PRO A CB PRO A CG PRO A C PRO A O PRO A N THR A CA THR A CB THR A OGI THR A CG2 THR A C THR A O THR A N ARG A CA ARG A CB ARG A C ARG A O ARG A 328 329 329 329 329 329 329 330 330 330 330 331 331 331 331 331 331 331 331 331 331 331 331 332 332 332 332 332 333 333 333 333 333 333 334 334 334 334 334 334 334 335 335 335 335 335 11.774 10.912 9.533 8.661 7.297 9.129 9.908 7.930 7.459 6.031 7.532 7.068 8.124 8.263 9.323 9.202 10.105 9.985 8.174 8.045 8.950 8.814 6.943 6.018 6.868 5.684 5.781 4.356 3.561 4.103 4.962 2.840 3.070 4.101 1.673 1.879 0.457 -0.724 -1.997 1.971 -3.237 -0.864 -1.389 -0.386 -0.377 -0.569 -1.349 -0.919 1.274 -16.846 3.358 -16.800 2.908 -16.837 3.858 -16.020 3721 -16.364 2.947 -18.313 3.397 -19.154 2.469 -18.629 2.482 -20.007 1.968 -20.074 3.924 -20.505 4.841 -19.826 4.126 -21.681 5.470 -22.234 5.482 -23.350 4.347 -24.345 3.284 -24.334 2.228 -25.233 4.327 -15.287 3.276 -26.193 2.232 -26.159 1.191 -27.042 6.043 -22.754 5.301 -23.096 7.372 -22.792 8.092 -23.262 8.321 -24.772 7.410 -22.926 7.116 -23.818 7.144 -21.632 7.418 -20.465 6.497 -2 1.253 6.076 -19.802 7.028 -19.290 7.478 -21.398 8.690 -21.395 6.956 -21.532 7.802 -21.687 6.949 -21.813 6.256 -23.065 7.821 -21.761 8.782 -20.525 8.443 -19.461 10.002 -20.766 11.099 -19.801 12.427 -20.531 10.996 -18.627 10.908 -17.475 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 27.02 25.60 29.45 30.80 33.74 31.30 27.35 32.98 35.10 34.67 40.06 42.65 41.16 42.66 42.54 38.67 34.66 34.89 37.88 34.65 30.73 30.97 46.24 45.38 49.11 52.40 52.86 52.90 53.94 53.63 53.63 53.55 53.78 53.42 52.17 51.19 52.26 54.21 53.90 53.92 54.15 56.34 56.44 58.24 57.96 60.22 56.61 60.70

C

WO 99/50658 PCTIUS99/06937

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228 N 229 CD 230 CA 231 CB 232 CG 233 C 234 0 235 N 236 CA 237 CB 238 CG 239 CDI 240 CD2 241 CEI 242 CE2 243 CZ 244 C 245 0 246 N 247 CA 248 CB 249 OG 250 C 251 0 252 N 253 CA 254 CB 255 CG 256 CD 257 OEI 258 OE2 259 C 260 0 261 N 262 CA 263 CB 264 C 265 0 266 N 267 CA 268 CB 269 OG 270 C 271 0 272 N 273 CA 274 CB 275 CG PRO A PRO A

PROA

PRO A PRO A PRO A PRO A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE A SER A SER A SER A SER A SER A SER A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A ALA A ALA A ALA A ALA A ALA A SER A SER A SER A SER A SER A SER A MET A MET A MET A MET A 336 336 336 336 336 336 336 337 337 337 337 337 337 337 337 337 337 337 338 338 338 338 338 338 339 339 339 339 339 339 339 339 339 340 340 340 340 340 341 341 341 341 341 341 342 342 342 342 -2.667 -3.389 -3.587 -4.911 -4.645 -3.698 -4.340 -3.063 -3.055 -2.063 -0.649 -0.017 0.061 1.305 1.386 2.009 -4.401 -5.250 -4.573 -5.781 -6.477 -6.227 -5.292 -4.090 -6.206 -5.802 -7.015 -6.637 -7.717 -8.471 -7.810 -5.040 -3.862 -5.712 -5.078 -6.055 -3.837 -2.909 -3.836 -2.742 -3.231! -2.211 -1.480 -0.389 -1.626 -0.498 -0.912 0.241 11.015 -18.889 11.117 -20.165 10.915 -17.752 11.456 -18.302 11.809 -19.760 9.468 -17.279 8.644 -17.929 9.170 -16.147 7.821 -15.582 7.732 -14.421 8.011 -14.805 9.168 -14.368 7.113 -15.591 9.429 -14.707 7.364 -15.938 8.525 -15.495 7.338 -15.071 8.127 -14.671 6.022 -15.080 5.385 -14.578 4.594 -15.684 3.206 -15.554 4.439 -13.488 4.186 -13.387 3.916 -12.676 3.012 -11.608 2.521 -10.814 1.680 -9.600 1.652 -8.535 0.656 -8.477 2.625 -7.754 1.821 -12.170 1.641 -11.872 1.010 -12.982 -0.158 -13.574 -0.871 -14.496 0.273 -14.350 -0.515 -14.543 1.535 -14.773 2.133 -15.537 3.454 -16.154 4.130 -16.864 2.376 -14.691 1.913 -15.038 3.115 -13.595 3.396 -12.708 4.396 -11.623 5.218 -11.059 1.00 52.43 1.00 49.06 1.00 49.58 1.00 48.66 1.00 51.33 1.00 49.25 1.00 48.06 1.00 47.90 1.00 46.61 1.00 47.73 1.00 46.27 1.00 46.55 1.00 48.12 1.00 48.09 1.00 47.57 1.00 48.40 1.00 46.15 1.00 48.34 1.00 45.06 1.00 45.12 1.00 44.49 1.00 45.78 1.00 47.04 1.00 44.08 1.00 45.63 1.00 45.40 1.00 45.66 1.00 46.81 1.00 47.56 1.00 47.37 1.00 49.29 1.00 45.23 1.00 46.51 1.00 42.87 1.00 40.24 1.00 41.40 1.00 38.83 1.00 35.58 1.00 35.79 1.00 36.58 1.00 39.01 1.00 36.09 1.00 35.63 1.00 33.20 1.00 35.92 1.00 35.88 1.00 35.96 1.00 38.02

C)

(7 WO 99/50658 PCT/US99/06937

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276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 .291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 SD MET A 342 CE MET A 342 C MET A 342 O MET A 342 N MET A 343 CA MET A 343 CB MET A 343 CG MET A 343 SD MET A 343 CE MET A 343 C MET A 343 O MET A 343 N GLY A 344 CA GLY A 344 C GLY A 344 O GLY A 344 N LEU A 345 CA LEU A 345 CB LEU A 345 CG LEU A 345 CDI LEU A 345 CD2 LEU A 345 C LEU A 345 O LEU A 345 N LEU A 346 CA LEU A 346 CB LEU A 346 CG LEU A 346 CDI LEU A 346 CD2 LEU A 346 C LEU A 346 O LEU A 346 N THR A 347 CA THR A 347 CB .THR A 347 OGI THR A 347 CG2 THR A 347 C THR A 347 O THR A 347 N ASN A 348 CA ASN A 348 CB ASN A 348 CG ASN A 348 ODI ASN A 348 ND2 ASN A 348 C ASN A 348 O ASN A 348 N LEU A 349 -0.308 0.626 -0.011 1.195 -0.957 -0.640 -1.921 -2.667 -1.749 -1.468 0.234 1.159 -0.069 0.688 2.104 3.046 2.257 3.576 3.459 2.765 2.901 3.379 4.433 5.564 3.884 4.595 3.729 3.483 2.623 4.809 5.032 6.181 4.117 4.436 3.164 2.421 2.301 5.366 6.176 5.242 6.092 5.657 6.522 7.616 6.010 7.532 8.453 7.711 6.374 -9.780 7.815 -10.205 2.100 -12.059 1.880 -11.909 1.243 -11.687 -0.034 -11.062 -0.810 -10.751 -0.337 -9.502 -0.507 -7.940 -2.299 -7.886 -0.875 -11.979 -1.558 -11.527 -0.823 -13.272 -1.591 -14.242 -1.085 -14.396 -1.873 -14.463 0.232 -14.471 0.839 -14.608 2.361 -14.753 2.924 -15.995 4.439 -15.999 2.324 -17.257 0.534 -13.383 0.061 -13.505 0.813 -12.205 0.596 -10.947 1.063 -9.783 2.569 -9.682 2.844 -8.463 3.317 -9.587 -0.848 -10.707 -1.102 -10.345 -1.793 -10.891 -3.196 -10.674 -4.058 -10.641 -3.860 -11.849 -3.682 -9.444 -3.734 -11.756 -4.622 -11.496 -3.197 -12.970 -3.617 -14.082 -2.926 -15.385 -3.302 -16.571 -2.799 -16.771 -4.236 -17.391 -3.229 -13.741 -4.027 -13.870 -1.993 -13.288 1.00 44.73 1.00 42.49 1.00 34.17 1.00 33.40 1.00 29.95 1.00 31.96 1.00 31.70 1.00 37.13 1.00 36.00 1.00 32.14 1.00 31.72 1.00 30.26 1.00 29.04 1.00 24.94 1.00 26.01 1.00 28.72 1.00 26.97 1.00 31.15 1.00 30.06 1.00 33.50 1.00 33.52 1.00 33.22 1.00 30.31 1.00 32.80 1.00 27.83 1.00 26.19 1.00 24.51 1.00 26.33 1.00 27.33 1.00 24.89 1.00 25.72 1.00 29.86 1.00 23.80 1.00 23.91 1.00 26.39 1.00 24.57 1.00 23.98 1.00 26.17 1.00 27.44 1.00 25.48 1.00 23.77 1.00 24.59 1.00 29.93 1.00 24.81 1.00 32.61 1.00 22.82 1.00 18.83 1.00 22.58

C!

WO 99/50658 PCT/US99/06937 ATOM 324 CA LEU A ATOM 325 CB LEU A ATOM 326 CG LEU A ATOM 327 CDI LEU A ATOM 328 CD2 LEU A ATOM 329 C LEU A ATOM 330 0 LEU A ATOM 331 N ALA A ATOM 332 CA ALA A ATOM 333 CB ALA A ATOM 334 C ALA A ATOM 335 0 ALA A ATOM 336 N ASP A ATOM 337 CA ASP A ATOM 338 CB ASP A ATOM 339 CG ASP A ATOM 340 ODI ASP A ATOM 341 OD2 ASP A ATOM 342 C ASP A ATOM 343 0 ASP A ATOM 344 N ARG A ATOM 345 CA ARG A ATOM 346 CB ARG A ATOM 347 CG ARG A ATOM 348 CD ARG A ATOM 349 NE ARG A ATOM 350 CZ ARG A ATOM 351 NH1 ARG A ATOM 352 NH2 ARG A ATOM 353 C ARG A ATOM 354 0 ARG A ATOM 355 N GLU A ATOM 356 CA GLU A ATOM 357 CB GLU A ATOM 358 CG GLU A ATOM 359 CD GLU A ATOM 360 OEI GLU A ATOM 361 OE2 GLU A ATOM 362 C GLU A ATOM 363 0 GLU A ATOM 364 N LEU A ATOM 365 CA LEU A ATOM 366 CB LEU A ATOM 367 CG LEU A ATOM 368 CDI LEU A ATOM 369 CD2 LEU A ATOM 370 C LEU A ATOM 371 0 LEU A 349 349 349 349 349 349 349 350 350 350 350 350 351 351 351 351 351 351 351 351 352 352 352 352 352 352 352 352 352 352 352 353 353 353 353 353 353 353 353 353 354 354 354 354 354 354 354 354 9.030 8.929 10.155 11.224 9.726 9.564 10.724 8.705 9.113 7.963 9.568 10.625 8.767 9.093 8.028 8.103 8.217 8.049 10.469 11.219 10.810 12.115 12.120 11.539 11.554 10.592 10.910 12.172 9.962 13.223 14.346 12.909 13.888 13.317 13.295 12.832 11.611 13.686 14.246 15.398 13.246 13.434 12.107 11.160 9.720 11.584 14.500 15.255 -1.507 -12.914 -0.028 -12.536 0.673 -11.953 0.826 -13.017 2.040 -11.415 -2.335 -11.734 -2.749 -11.717 -2.591 -10.756 -3.356 -9.586 -3.441 -8.593 4.757 -9.985 -5.221 -9.554 -5.423 -10.810 -6.772 -11.259 -7.274 -12.239 -8.772 -12.458 -9.196 -13.628 -9.525 -11.464 -6.825 -11.912 -7.773 -11.702 -5.808 -12.697 -5.787 -13.347 -4.785 -14.507 -5.352 -15.797 -4.319 -16.915 -3.245 -16.687 -1.954 -16.641 -1.564 -16.813 -1.049 -16.441 -5.442 -12.350 -5.945 -12.454 -4.587 -11.383 -4.206 -10.376 -3.102 -9.483 -1.718 -10.114 -0.648 -9.129 -0.531 -8.926 0.066 -8.557 -5.423 -9.512 -5.600 -9.104 -6.257 -9.235 -7.452 -8.415 -8.209 -8.270 -7.606 -7.223 -8.013 -7.510 -8.069 -5.839 -8.386 -8.981 -9.007 -8.234 1.00 21.85 1.00 22.00 1.00 23.64 1.00 19.35 1.00 21.97 1.00 22.94 1.00 23.97 1.00 21.67 1.00 21.83 1.00 18.95 1.00 21.90 1.00 24.15 1.00 23.24 1.00 25.87 1.00 27.03 1.00 31.64 1.00 35.06 1.00 36.86 1.00 22.36 1.00 25.15 1.00 23.58 1.00 21.07 1.00 21.02 1.00 20.44 1.00 20.43 1.00 19.85 1.00 19.69 1.00 17.36 1.00 21.88 1.00 22.11 1.00 24.13 1.00 18.66 1.00 19.08 1.00 21.62 1.00 20.97 1.00 23.84 1.00 24.76 1.00 24.95 1.00 20.14 1.00 19.40 1.00 19.54 1.00 21.77 1.00 23.09 1.00 25.00 1.00 23.49 1.00 23.31 1.00 23.21 1.00 22.44

G;

WO 99/50658 WO 9950658PCTIIJS99/06937

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372 N VAL A 355 373 CA VAL A 355 374 GB VAL A 355 375 COI VAL A 355 376 CG2 VAL A 35 5 377 C VAL A 35 5 378 0 VAL A 355, .379 N HIS A 3156 380 CA HIS A 356 381 GB HIS A 356 382 CG HIS A 356 383 CD2 HIS A 356 384 ND1 HIS A 356 385 GEl HIS A 356 386 NE2 HIS A 356 387 C HIS A 356 388 0 HIS A 356 389 N MET A 357 390 CA MET A 357 391 GB MET A 357 3192 CG MET A 357 393 SD MET A 357 394 CE MET A 357 395 C MET A 357 396 0 MET A 357 397 N ILE A 358 398 CA ILE A 358 399 GB ILE A 358 400 CG2 ILE A 358 401 CG1 ILE A 358 402 CDI ILE A 358 403 C ILE A 358 404 0 ILE A 358 405 N ASN A 359 406 CA ASN A 359 407 GB ASN A 359 408 CG ASN A 359 409 ODI ASN A 359 410 ND2 ASN A 359 411 C ASN A 359 412 0 ASN A 359 413 N TRP A 360 414 CA TRY A 360 415 CB TRY A 360 416 CG TRY A 360 417 GD2 TRP A 360 418 CE2 TRY A 360 419 CE3) TRP A 360 14.560 15 .55 1 15.353 16.435 13 .957 16.944 17.857 17.105 18.392 18.384 18.494 17.543 19.704 19.496 18.192 18.702 19.864 17.660 17.837 16.503 16.629 15.051 14.189 18.4 11 19.33 7 17.856 18.314 17.529 18.267 16.125 15.062 19.801 20.569 20.207 2 1.601 21.721 2 1.253 2 1.916 20.102 22.476 23.686 2 1.872 22.634 21.849 22.196 2 1.501 22.147 20-39-2 -8.490 -10 .302 1.00 22.52 -9.343 -10.935 1.00 21.66 -9.365 -12.466 1.00 24.35 -10.214 -13.119 1.00 28.16 -9.886 -12.798 1.00 21.59 -8.811 -10.606 1.00 23.7 4 -9.581 -10.291 1.00 23 .51 -7.489 -10.669 1.00 21.27 -6.861 -10.369 1.00 211.1 -5.390 -10.811 1.00 19.87 -5,205 -12.295 1.00 21.77 -5.048 -13.248 1.00 21.66 -5.177 -12.955 1.00 21.11 -5.011 -14.249 1.00 24.96 -4.931 -14.455 1.00 18.37 -6.947 -8.875 1.00 21.41 -7.111 -8.465 1.00 21.88 -6.843 -8.058 1.00 21.84 -6.906 -6.610 1.00 21.51 -6.668 -5.898 1.00 17.60 -6.5 79 -4.369 1.00 19.36 -6.755 -3.531 1.00 23.64 -5.332 -4.163 1.00 23.13 -8.259 -6.192 1.00 23.69 -8.328 -5.389 1.00 24.41 -9.331 -6.746 1.00 27.14 -10.672 -6.425 1.00 28.79 -11.725 -7.232 1.00 32.4 2 -13.064 -7.220 1.00 3 2.77 -11.880 -6.644 1.00 3 1.94 -12.196 -7.680 1.00 34.85 -10.802 -6.728 1.00 28.75 -11.305 -5.912 1.00 3 )1.60 -10.325 -7.897 1.00 277. 91 -10.401 -8.293 1.00 29.16 -10.172 -9.801 1.00 31. 88 -11.381 -10.599 1.00 39.34 -12.422 -10.612 1.00 41.27 -11.255 -11.253 1.00 38.58 -9.436 -7.510 1.00 30.75 -9.629 -7.4-12 1.00 33.35 -8.400 -6.940 1.00 30.07 -7.451 -6.132 1.00 27.87 -6.150 -5.948 1.00 24.80 -5.392 -4.691 1.00 23 .04 -5.443 -3.438 1.00 19.83 -4.543 -2.564 1.00 22.31 -6.165 2. 972 1.00 20.09 WO 99/50658 PTU9/63 PCT/US99/06937

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O 15 ATOM

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420 CDI 421 NEI 422 CZ2 423 CD3 424 CH2 425' C 426 0 427 N 428 CA 429 CB 430 C 431 0 432 N 433 CA 434 CB 435 CG 436 CD 437 CE 438 NZ 439 C 440 0 441 N 442 N 443 CA 444 CA 445 CB 446 CB 447 CG 448 CG 449 CD 450 CD 451 NE 452 NE 453 CZ 454 CZ TRLP A TRP A.

TRP A TRY A TRY A TRY A TRY A ALA A ALA A ALA A ALA A ALA A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A AARG A BARG A AARG A BARG A AARG A BARG A AARG A BARG A AARG A BARG A AARG A BARG A AARG A BARG A 3,60 360 360 360 .360 360 360 361 361 361 361 361 362 362 362 362 362 362* _362 362 362 363 363 363 363 363 363 363 363 363 363 363 3 63 363 363 363 363 363 363 363 363 363 36 3 364 364 364 364 364 23.2 12 23.187 21.721 19.968 20.635 22.892 23.978' 21.879 2 1.972 20.676 23.161 23.843 23.414 24.530 24.564 23.3 19 23.458 22.369 22.111 25.854 26.880 25.826 25.826 27 .03 5 27.035 27.03 1 27.03 1 26.933 26.930 2 7. 745 27.752 29. 171 27.195 30.086 27.905 29.735 29.205 31.358 27.3 11 27.207 27.207 28.223 28.223 26.215 26.288 24.898 25.036 23.946 -4.488 -4.529 1.00 18.99 .3.974 -325 1.00 21.17 -4.340 1.243 1.00 20.43 -5.965 -1.661 1.00 20.12 -5.057 -0.812 1.00 18.54 -8.099 -4.766 1.00 24.8 8 -7.980 -4.198 1.00 25.00 -8.789 -4.252 1.00 24.08 -9.462 -2.958 1.00 26.06 -10.203 -2.672 1.00 20.2 7 10.433 -2.897 1.00 28.44 -10.531 -1.876 1.00 28.95 -11.144 -3 .992 1.00 3 1.41 -12.097 4.047 1.00 33.33 -12.824 -5.390 1.00 34.81 -13.608 -5.756 -1.00 36.27 -14.178 -7.167 1.00 38.30 -15.193 -7.472 1.00 40.94 -15.322 -8.937 1.00 42.49 -1 1.351 -3.893 1.00 34.17 -11.977 -3.595 1.00 35.40 -10.059 -4.095 0.50 34.23 -10.059 -4.095 0.50- 34.03 -9.254 -3 .987 0.50 33.25 -9.254 -3 .987 0.50 32.83 -8.153 -5.044 0.50 34.67 -8.153 -5.045 0.50 34.20 -8.654 -6.478 0.50 36.32 -8.654 -6.480 0.50' 35.56 -7.775 -7.415 0.50 38.39 -7.781 -7.414 0.50 37.18 -7.793 -7.091 0.50 39.9 8 -7.725 -8.762 0.50 37.39 -7.038 -7.692 0.50 40.54 -7.457 -9.855 0.50 40.02 -6.218 -8.675 0.50 38.13 -7.191 -9.761 0.50 40.42 -7.123 -7.326 0.50 43.19 -7.436 -11.041 0.50 38.91 -8.630 -2.610 0.50 3 3.28 -8.630 -2.610 0.50 32.81 -7.992 -2.344 0.50 34.18 -7.992 -2.345 0.50 33.43 -8.798 -1.740 1.00 33. 12 -8.240 -0.389 1.00 33.63 -8.178 0.292 1.00 3 4.97 -7.608 1.700 1.00 3 5.44 -7.328 -0.532 1.00 36.69 455 NH IAARG A 456 NH IBARG A 457 NH2AARG A 458 NH2BARG A 459 C AARG A 460 C BARG A 461 0 AARG A 462 0 BARG A 463 N VAL A 464 CA VAL A 465 CB VAL A 466 CGI VAL A 467 CG2 VAL A r- WO 99/50658 PCT/US99/06937

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468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 C VAL A O VAL A N PRO A CD PRO A CA PRO A CB PRO A CG PRO A C PROA O PRO A N GLY A CA GLY A C GLY A O GLY A N PHE A CA PHE A CB PHE A CG PHE A CDI PHE A CD2 PHE A CEI PHE A CE2 PHE A CZ PHE A C PHE A O PHE A N VAL A CA VAL A CB VAL A CGI VAL A CG2 VAL A C VAL A O VAL A N ASP A CA ASP A CB ASP A CG ASP A ODI ASP A OD2 ASP A C ASP A O ASP A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N THR A 364 364 365 365 365 365 365 365 365 366 366 366 366 367 367 367 367 367 367 367 367 367 367 367 368 368 368 368 368 368 368 369 369 369 369 369 369 369 369 370 370 370 370 370 370 370 370 371 27.184 26.878 28.306 28.775 29.231 30.110 30.127 28.538 27.692 28.890 28.307 26.991 26.638 26.246 24.960 24.281 22.827 22.401 21.882 21.050 20.535 -9.157 0.428 -10.341 0.603 -8.626 0.935 -7.235 0.793 -9.442 1.733 -8.408 2.430 -7.247 1.475 -10.373 2.720 -9.945 3.507 -11.654 2.654 -12.635 3.554 -13.264 3.138 -14.336 3.635 -12.615 2.236 -13.148 1.783 -12.178 0.808 -12.473 0.581 -13.083 -0.596 -12.176 1.563 -13.400 -0.792 -12.491 1.373 20.118 -13.103 0.196 25.072 -14.519 1.117 24.244 -15.398 1.359 26.088 -14.694 0.276 26.289 -15.965 -0.420 27.386 -15.850 -1.504 26.972 -14.831 -2.550 28.707 -15.457 -0.873 26.664 -17.100 0.533 26.469 -18.274 0.216 27.199 -16.750 1.699 27.579 -17.755 2.688 28:336 -17.106 3.849 29.608 -16.413 3.404 30.121 -15.570 4.167 30.097 -16.709 2.293 26.340 -18.465 3.228 26.360 -19.671 3.475 25.261 -17.714 3.407 24.020 -18.279 3.924 22.980 -17.173 4.110 23.404 -16.015 5.014 22.219 -15.095 5.245 23.931 -16.552 6.332 2'.44) -19.360 3.013 23.773 -19.423 1.829 2. 593 -20.206 3.575 1.00 34.27 1.00 34.95 1.00 36.08 1.00 34.84 1.00 37.82 1.00 34.31 1.00 37.77 1.00 37.61 1.00 37.74 1.00 39.04 1.00 38.27 1.00 39.32 1.00 39.53 1.00 38.60 1.00 36.36 1.00 32.10 1.00 30.12 1.00 28.95 1.00 26.18 1.00 29.42 1.00 27.60 1.00 26.81 1.00 36.82 1.00 36.55 1.00 38.28 1.00 42.34 1.00 41.78 1.00 44.60 1.00 42.23 1.00 43.85 1.00 44.85 1.00 44.93 1.00 44.96 1.00 43.76 1.00 43.04 1.00 44.32 1.00 46.76 1.00 45.89 1.00 48.61 1.00 43.59 1.00 44.24 1.00 41.42 1.00 41.45 1.00 42.25 1.00 38.35 1.00 44.03 1.00 43.63 1.00 44.29 WO 99/50658 PCTIUS99/06937

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516 CA THR A 517 CB THR A 518 OGI THR A 519 CG2 THR 520 C THR A 521 0 THR A 522 N LEU A 523 CA LEU A 524 CB LEU A 525 CG LEU A 526 CDI LEU A 527 CD2 LEU A 528 C LEU A 529 0 LEU A 530 N HIS A 531 CA HIS A 532 CB HIS A 533 CG HIS A 534 CD2 HIS A 535 NDI HIS A 536 CEI HIS A 537 NE2 HIS A 538 C HIS A 539 0 HIS A 540 N ASP A 541 CA ASP A 542 CB ASP A 543 CG ASP A 544 ODI ASP A 545 OD2 ASP A 546 C ASP A 547 0 ASP A 548 N GLN A 549 CA GLN A 550 CB GLN A 551 CG GLN A 552 CD GLN A 553 OEI GLN A 554 NE2 GLN A 555 C GLN A 556 0 GLN A 557 N VAL A 558 CA VAL A 559 CB VAL A 560 CGI VAL A 561 CG2 VAL A 562 C VAL A 563 0 VAL A 371 371 371 371 371 371 372 372 372 372 372 372 372 372 373 373 373 373 373 373 373 373 373 373 374 374 374 374 374 374 374 374 375 375 375 375 375 375 375 375 375 376 376 376 376 376 376 376 21.968 -21.272 2.806 21.293 -22.302 3.730 20.262 -21.663 4.495 22.314 -22.903 4.677 20.923 -20.684 1.864 20.418 -19.585 2.092 20.607 -21.418 0.804 19.624 -20.971 -0.166 19.407 -22.043 -1.237 18.512 -21.690 -2.429 19.005 -20.417 -3.098 18.521 -22.844 -3.420 18.307 -20.644 0.512 17.705 -19.602 0.261 17.849 -21.558 1.382 16.599 -21.353 2.100 16.318 -22.525 3.062 15.114 -22.315 3.934 13.808 -22.621 3.743 15.187 -21.716 5.174 13.979 -21.663 5.709 13.124 -22.206 4.861 16.665 -20.047 2.885 15.677 -19.324 2.971 17.839 -19.738 3.440 18.020 -18.516 4.219 19.287 -18.620 5.073 19.064 -19.425 6.344 17.896 -19.543 6.772 20.052 -19.940 6.912 18.083 -17.277 3.326 17.598 -16.208 3.696 18.688 -17.431 2.152 18.788 -16.339 1.198 19.634 -16.756 -0.001 21.125 -16.570 0.189 21.920 -17.222 -0.922 21.478 -17.267 -2.067 23.097 -17.736 -0.588 17.379 -16.009 0.730 16.990 -14.840 0.653 16.617 -17.056 0.429 15.242 -16.907 -0.027 14.588 -18.286 -0.286 13.093 -18.122 -0.516 15.232 -18.952 -1.485 14.393 -16.159 1.002 13.653 -15.237 0.661 1.00 44.84 1.00 45.65 1.00 46.43 1.00 46.48 1.00 44.93 1.00 44.36 1.00 43.83 1.00 44.62 1.00 47.17 1.00 46.91 1.00 48.73 1.00 51.12 1.00 44.84 1.00 43.25 1.00 43.14 1.00 42.23 1.00 45.38 1.00 51.43 1.00 54.99 1.00 54.26 1.00 53.77 1.00 55.27 1.00 39.78 1.00 37.71 1.00 36.38 1.00 37.21 1.00 38.17 1.00 41.47 1.00 37.09 1.00 44.40 1.00 37.19 1.00 38.13 1.00 33.13 1.00 31.94 1.00 28.81 1.00 31.71 1.00 34.49 1.00 36.09 1.00 40.32 1.00 31.50 1.00 27.42 1.00 30.38 1.00 33.50 1.00 30.57 1.00 33.14 1.00 30.79 1.00 33.80 1.00 34.89 "'i

C

WO 99/50658 PCT/US99106937

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564 N HIS A 565 CA HIS A 566 CB HIS A 567 CG HIS A 568 CD2 HIS A 569 NDI HIS A 570 CEI HIS A 571 NE2 HIS A 572 C HIS A 573 0 HIS A 574 N LEU A 575 CA LEU A 576 CB LEU A 577 CG LEU A 578 CDI LEU A 579 CD2 LEU A 580 C LEU A 581 0 LEU A 582 N LEU A 583 CA LEU A 584 CB LEU A 585 CG LEU A 586 CDI LEU A 587 CD2 LEU A 377 377 377 377 377 377 377 377 377 377 378 378 378 378 378 378 378 378 379 379 379 379 379 379 379 379 380 380 380 380 380 380 380 380 380 381 381 381 381 381 381 382 382 382 382 382 383 383 14.500 -16.568 2.261 1.00 33.35 13.730 -15.941 3.329 1.00 32.81 13.966 -16.694 4.644 1.00 35.24 13.429 -15.989 5.851 1.00 40.15 14.054 -15.495 6.946 1.00 40.86 12.090 -15.703 6.012 1.00 43.08 11.913 -15.062 7.154 1.00 42.44 13.089 -14.922 7.740 1.00 44.85 14.058 -14.454 3.507 1.00 28.63 13.158 -13.619 3.613 1.00 29.20 15.343 -14.125 3.544 1.00 24.41 15.759 -12.738 3.721 1.00 23.21 17.289 -12.650 3.743 1.00 20.98 17.960 -13.190 5.016 1.00 24.22 19.471 -13.041 4.924 1.00 21.07 17.431 -12.446 6.221 1.00 20.24 15.190 -11.827 2.630 1.00 24.78 14.638 -10.766 2.922 1.00 22.09 15.321 -12.242 1.374 1.00 24.13 14.812 -11.447 0.262 1.00 25.02 15.307 -12.025 -1.062 1.00 27.12 16.724 -11.600 -1.437 1.00 24.39 17.299 -12.557 -2.470 1.00 27.58 16.679 -10.178 -1.983 1.00 29.05 13.287 -11.355 0.246 1.00 27.61 12.726 -10.301 -0.062 1.00 26.16 12.616 -12.454 0.576 1.00 25.65 11.154 -12.471 0.592 1.00 26.85 10.640 -13.882 0.871 1.00 29.38 10.718 -14.796 -0.331 1.00 35.58 10.228 -16.194 -0.025 1.00 39.31 10.142 -17.008 -0.967 1.00 42.89 9.927 -16.478 1.153 1.00 39.45 10.604 -11.526 1.649 1.00 25.43 9.551 -10.925 1.469 1.00 27.75 11.324 -11.400 2.753 1.00 25.57 10.907 -10.530 3.843 1.00 26.46 11.570 -11.000 5.149 1.00 31.46 11.305 -9.946 6.623 1.00 45.32 11.262 -9.059 3.589 i.00 24.77 10.516 -8.166 3.975 1.00 25.01 12.377 -8.815 2.903 1.00 22.23 12.855 -7.449 2.681 1.00 21.83 14.319 -7.383 3.095 1.00 21.56 12.705 -6.778 1.311 1.00 19.78 588 C 589 0 590 N 591 CA 592 CB 593 CG 594 CD 595 OEI 596 OE2 597 C 598 0 599 N 600 CA 601 CB 602 SG 603 C 604 0 605 N 606 CA 607 CB 608 C 609. 0 610 N 61.1 CA LEU A LEU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A CYS A CYS A CYS A CYS A CYS A CYS A ALA A ALA A ALA A ALA A ALA A TRP A TRP A 12.996 12.261 12.164 -5.587 1.182 -7.507 0.294 -6.915 -1.036 1.00 17.01 1.00 17.61 1.00 18.06

C

WO 99/50658 PCT/US99/06937

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612 CB TRP 613 CG FRP A 614 CD2 TRP A 615 CE2 TRP A 616 CE3 TRP A 617 CDI TRP A 618 NEI TRP A 619 CZ2 TRP A 620 CZ3 TRP A 621 CH2 TRP A 622 C TRP A 623 0 TRP A 624 N LEU A 625 CA LEU A 626 CB LEU A 627 CG LEU A 628 CDI LEU A 629 CD2 LEU A 630 C LEU A 631 0 LEU A 632 N GLU A 633 CA GLU A 634 CB GLU A 635 CG GLU A 636 CD GLU A 637 OEI GLU A 638 OE2 GLU A 639 C GLU A 640 0 GLU A 641 N ILE A 642 CA ILE A 643 CB ILE A 644 CG2 ILE A 645 CGI ILE A 646 CDI ILE A 647 C ILE A 648 0 ILE A 649 N LEU A 650 CA LEU A 651 CB LEU A 652 CG LEU A 653 CDI LEU A 654 CD2 LEU A 655 C LEU A 656 0 LEU A 657 N MET A 658 CA MET A 659 CB MET A 383 383 383 383 383 383 383 383 383 383 383 383 384 384 384 384 384 384 384 384 385 385 385 385 385 385 385 385 385 386 386 386 386 386 386 386 386 387 387 387 387 387 387 387 387 388 388 388 11.580 10.105 9.049 7.836 9.012 9.506 8.142 6.598 7.780 6.589 11.448 11.972 10.273 9.586 8.125 7.211 7.464 5.750 10.324 10.334 10.949 11.718 12.274 11.292 11.963 12.43 1 12.027 12.890 13.206 13.539 14.685 15.475 16.544 16.185 16.682 14.273 14.993 13.112 12.620 11.359 11.519 10.173 12.589 12.283 12.571 11.677 11.286 10.3 02 -7.928 -2.035 -8.201 -1.919 -7.509 -2.599 -8.138 -2.238 -6.420 -3.482 -9.189 -1.190 -9.159 -1.377 -7.713 -2.724 -5.998 -3.968 -6.647 -3.587 -5.564 -1.170 -4.663 -1.824 -5.396 -0.567 -4.118 -0.719 4.218 -0.258 -3.013 -0.577 -2.485 -1.995 -3.432 -0.410 -3.027 0.051 -1.870 -0.357 -3.404 1.163 -2.462 1.970 -3.154 3.213 -3.237 4.357 -3.676 5.640 -2.799 6.391 -4.897 5.889 -1.934 1.156 -0.743 1.196 -2.842 0.431 -2.484 -0.388 -3.763 -0.807 -3.424 -1.849 -4.338 0.432 -5.766 0.284 -1.645 -1.598 -0.724 -2.004 -1.944 -2.167 -1.173 -3.304 -1.814 -3.882 -3.064 -4.747 -3.406 -5.395 -2.824 -5.808 0.249 -2.838 1.224 -3.530 0.357 -1.660 1.656 -1.121 1.460 0.034 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 20.28 20.50 22.48 20.41 22.06 23.38 22.59 21.98 25.50 23.11 19.18 19.27 18.32 16.38 16.79 18.39 13.91 18.38 18.80 20.90 18.61 19.58 17.43 22.92 25.83 23.69 27.64 19.46 15.04 13.32 15.01 17.43 17.99 20.31 23.97 16.10 17.42 17.61 18.20 17.51 26.37 24.63 21.58 17.60 17.15 17.65 18.49 19.65 WO 99/50658 PCT/US99/06937

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0. 15 ATOM

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660 CG MET A 661 SD MET A 662 CE MET A 663 C MET A 664 0 MET A 665 N ILE A 666 CA ILE A 667 CB ILE A 668 CG2 ILE A 669 CG1 ILE A 670 CDI ILE A 671 C ILE A 672 0 ILE A 673 N GLY A 674 CA GLY A 675 C GLY A 676 0 GLY A 677 N LEU A 678 CA LEU A 679 CB LEU A 680 CG LEU A 681 CDI LEU A 682 CD2 LEU A 683 C LEU A 684 0 LEU A 685 N VAL A 686 CA VAL A 687 CB VAL A 688 CGI VAL A 689 CG2 VAL A 690 C VAL A 691 0 VAL A 692 N TRP A 693 CA TRP A 694 CB TRP A 695 CG TRP A 696 CD2 TRP A 697 CE2 TRP A 698 CE3 TRP A 699 CDI TRP A 700 NEI TRP A 701 CZ2 TRP A 702 CZ3 TRP A 703 CH2 TRP A 704 C TRP A 705 0 TRP A 706 N ARG A 707 CA ARG A 388 388 388 388 388 389 389 389 389 389 389 389 389 390 390 390 390 391 391 391 ,391 391 391 391 391 392 392 392 392 392 392 392 393 393 393 393 393 393 393 393 393.

393 393 .)9_3 393 393 394 394 8.893 7.744 6.163 12.451 12.417 13.482 14.604 15.590 16.362 16.556 17.373 15.333 15.813 15.410 16.049 15.243 15.801 13.920 13.018 11.561 10.480 10.579 9.115 13.208 13.440 13.122 13.282 13.186 13.733 11.739 14.626 14.728 15.652 16.999 17.977 19.287 20.341 21.375 20.512 19.710 20.963 22.566 21.698 22.709 17.082 17.767 16.399 16.412 1.105 -0.435 0.769 0.910 0.908 0.048 2.553 -0.691 3.767 -0.928 1.988 -0.064 2.831 0.331 2.108 1.299 0.998 0.578 3.142 1.889 2.658 3.080 3.322 -0.922 4.453 -0.970 2.477 -1.943 2.895 -3.183 4.021 -3.819 4.994 -4.318 3.888 -3.787 4.887 -4.343 4.420 -4.194 5.497 -4.342 6.156 -5.725 4.868 -4.148 6.216 -3.620 7.255 4.243 6.170 -2.295 7.357 -1.469 6.993 0.042 8.129 0.897 6.712 0.414 8.014 -1.754 9.242 -1.832 7.186 -1.924 7.670 -2.204 6.491 -2.199 6.784 -2.857 7.605 -2.339 7.612 -3.302 8.335 -1.154 6.339 -4.077 6.833 -4.351 8.323 -3.120 9.044 -0.971 9.030 -1.950 8.414 -3.547 9.435 -3.650 7.897 -4.568 8.531 -5.890 1.00 15.12 1.00 18.73 1.00 18.34 1.00 22.62 1.00 22.49 1.00 21.45 1.00 18.54 1.00 19.35 1.00 15.50 1.00 21.95 1.00 15.86 1.00 18.67 1.00 19.75 1.00 20.58 1.00 19.33 1.00 17.48 1.00 21.87 1.00 19.17 1.00 21.50 1.00 18.25 1.00 21.98 1.00 21.39 1.00 17.15 1.00 23.27 1.00 23.60 1.00 23.04 1.00 24.42 1.00 27.38 1.00 30.37 1.00 23.48 1.00 27.55 1.00 27.50 1.00 23.65 1.00 24.76 1.00 22.86 1.00 25.90 1.00 28.09 1.00 29.94 1.00 30.20 1.00 26.55 1.00 30.64 1.00 32.43 1.00 34.58 1.00 36.54 1.00 25.02 1.00 20.97 1.00 23.06 1.00 25.97 WO 99/50658 PTU9/63 PCT/US99/06937

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708 CB ARO A 394 709 CG ARG A 394 710 CD ARG A 394 711 NE ARG A 394 712 CZ ARO A 394 7 13 NHI ARG A 394 714 NH2 ARG A 394 715 C ARG A '394 716 0 ARG A 394 717 N SER A 395 718 CA SER A 395 719 CB SER A 395 720 OG SER A 395 721 C SER A 395 722 0 SER A *395 723 N MET A 396 724 CA MET A 396 725 CB MET A 396 726 CG MET A 396 727 SD MET A 396 728 CE MET A 396 729 C MET A 396 730 0 MET A 396 731 N GLU A 397 73)2 CA GLU A 397 733 CB GLU A 397 734 CG GLU A 397 735 CD GLU A 397 736 OEI GLU A 397 73 7 0E2 GLU A 397 738 C GLU A 397 739 0 GLU A 397 740 N HIS A 398 741 CA HIS A 398 742 CB HIS A 398 743 CG HIS A 398 744 CD2 HIS A 398 745 NDI HIS A 398 746 CEI HIS A 398 747 NE2 HIS A 398 748 C HIS A 398 749 0 HIS A 398 750 N PRO A 399 751 CD PRO A 399 752 CA PRO A 399 7 5.3. CB PRO A 399 754 CG PRO A 399 755 C PRO A 399 15. 776 16.243 15 .830 14.443 14.053 14.944 12.783 15 .622 15 .889 14 .638 13 .776 12.395 11.916 14.3")16 13 .726 15.43 7 16.061 17.466 17.5 85 19.192 20.263 16. 143 15 .637 16.794 16.971 18.184 17.883 19.117 19.2 19 19.980 15 .735 15 .830 14.579 13 .342 12.924 13 .870 13.904 14.940 15.592 14.985 12.2 16 11.282 12.283 13 .328 11.243 11.603 13.050 9.828 7.633 -6.965 6.195 -7.024 5.551 -8.352 5.071 -8.363 3.912 -7.841 3.108 -7.267 3.544 -7.907 9.833 -5.879, 10.729 -6.677 9.924 -4.988 11.104 -4.902 10.696 -4.382 9.530 -5.029 12.240 -4.033 13.324 -3.977 11.986 -3.368 12.954 -2.475 12.483 -2.112 11.919 -0.715 12.262 0.004 11.996 -1.404 14.376 -3.018 15.316 -2.403 14.526 4.166 15.831 -4.790 15.785 -5.729 15.189 -7.096 14.665 -7.810 13.430 -7.990 15.485 -8.196 16.322 -5.554 17.229 -6.376 15.728 -5.280 16.118 -5.950 15.043 -6.956 14.886 -8.104 15.484 -9.318 14.017 -8.074 14.086 -9.220 14.969 -9.993 16.332 -4.944 15.535 -4.864 17.427 4.171 18.467 -4.198 17.709 173 19.101 -2.654 19.267 -2.963 17.663 -3.744 1.00 24.05 1.00 26.05 1.00 22.7 0 1.00 20. 71 1.00 21.26 1.00 20.09 1.00 21.26 1.00 23.4 0 1.00 28.61 1.00 26.65 1.00 27.46 1.00 26.70 1.00 22.95 1.00 3 1.45 1.00 28.11 1.00 33.83 1.00 38.83 1.00 39.47 1.00 41.37 1.00 42.20 1.00 42.84 1.00 40.69 1.00 38.85 1.00 42.19 1.00 44.80 1.00 46.02 1.00 54.42 1.00 59.40 1.00 60.63 1.00 62.71 1.00 42.94 1.00 44.68 1.00 40.82 1.00 -39.21 1.00 39.05 1.00 41.57 1.00 39.2.8 1.00 41.85 1.00 40.88 1.00 42.30 1.00 3 7.04 1.00 36.51 1.00 39.19 1.00 35.36 1.00 37.10 1.00 37.86 1.00 35. 8 3 1.00 '37.02

C

C-

WO 99/50658 PCTIUS99/06937

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A TOMN 756 0 PRO A\ 757 N GLY A* 758 CA GLY A 759 C GLY A.

760 0 GLY A- 761 N LYS A.

762 CA LYS A 763 CB LYSA 764 CG LYSA 765 CD LYS A 766 CE LYS A.

767 NZ LYS A 768 C LYS A 769 0 LYS A 770 N LEU A 771 CA LEU A 772 CB LEU A 773 CG LEU A 774 CDI LEU A 775 CD2 LEU A 76C LEU A 777 0 LEU A 778 N LEU A 779 CA LEU A 780 CB LEU A 781 CG LEU A 782 CDI LEU A 783 CD2 LEU A 784 C LEU A 785 0 LEU A 786 N PHE A 787 CA PHE A 788 CB PHE A 789 CG PHE A 790 CD] PHE A 791 CD2 PHE A 792 CE! PHE A 793 CE2 PHE A 794 CZ PHE A* 795 C PHE A 796 0 PHE A- 797 N ALA A 798 CA ALA A 799 CB ALA A\ 800 C ALA A* 801 0 ALA A 802 N PRO A- 803 CD PRO A 3'99 400 400 400 400 401 401 401 401 401 401 401 401 401 402 402 402 402 402 402 402 402 403 403 403 403 403 403 403 403 404 404 404 404 404 404 404 404 404 404 404 405 405 405 405 405 406 406 9.554 8.938 7.559 7.230 6.063 8.237 7.972 8.235, 8.130 9.096 8.733 7.295 8.768 9.809 8.256 8.889 7.866 7.265 6.126 8.355 9.448 8.704 10.761 11.393 12.825 13.401 14.519 13 .915 11.419 12.42 8 10.306 10.239 8.826 7.850 7.028 7.750 6.116 6.845 6.026 11.232 11.882 11.348 12.271 11.650 12.549 11.770 13.672 14.712 18.249 -4.789 16.954 -3.057 16.865 -3.503 15.706 -4.428 15.344 -4.574 15.112 -5.055 14.007 -5.966 14.430 -7.415 15.927 -7.675 16.353 -8.774 17.721 -9.331 18.027 -9.116 12.746 -5.677 12.776 -5.006 11.635 -6.197 10.334 -6.050 9.294 -5.590 9.555 -4.207 8.583 -3.937 9.416 -3.157 9.948 -7.414 9.836 -8.389 9.770 -7.487 9.400 -8.744 9.937 -8.8 16 10.027 -10.238 11.046 -10.288 8.665 -10.676 7.891 -8.901 7.257 -8.619 7.319 -9.344 5.881 -9.546 5.470 -9.946 5.5 13 -8.816 6.623 -8.63 I 4.444 -7.925 6.668 -7.573 4.481 -6.870 5.595 -6.693 5.507 -10.637 4.464. -10.578 6.383 -1 1.626 6.195 -12.740 5.287 -13' .806 7.578 13.3 17 8.508 -13.109 7.737 -14.032 6.745 14.3 5 1.00 38.52 1.00 33 .58 1.00 32.12 1.00 3 2.43 1.00 33 .21 1.00 31.35 1 .00 30.75 1.00 35.43 1.00 35.15 1.00 36.88 1.00 3 6.71 1.00 3 4.22 1.00 30.97 1.00 27.60 1.00 27.28 1.00 29.07 1.00 22.55 1.00 24.94 1.00 19.32 1.00 2 1.54 1.00 28.78 1.00 29.98 1.00 27.5 7 1.00 27.17 1.00 26.95 1.00 30.42 1.00 30.76 1.00 33.11 1.00 24.78 1.00 24.68 1.00 23.11 1.00 26.93 1.00 27.04 1.00 27.89 1.00 26.20 1.00 23.10 1.00 25.29 1.00 21.01 1.00 22.91 1.00 26.04 1.00 27.27 1.00 28.80 1.00 29.21 1.00 26.89 1.00 30.23 1.00 27.38 1.00 30.05 1.00 26.31 (-i WO 99/50658 PCTIUS99/06937 ATOM 804 ATOM 805 ATOM 806 ATOM 807 ATOM 808 ATOM 809 ATOM 810 ATOM 811 ATOM 812 ATOM 813 ATOM 814 ATOM 815 ATOM 816 ATOM 817 ATOM 818 ATOM 819 ATOM 820 ATOM 821 ATOM 822 ATOM 823 ATOM 824 ATOM 825 ATOM 826 ATOM 827 ATOM 828 ATOM 829 ATOM 830 ATOM 831 ATOM 832 ATOM 833 ATOM 834 ATOM 835 ATOM 836 ATOM 837 ATOM 838 ATOM 839 ATOM 840 ATOM 841 ATOM 842 ATOM 843 ATOM 844 ATOM 845 ATOM 846 ATOM 847 ATOM 848 ATOM 849 ATOM 850 ATOM 851 CA PRO A CB PRO A CG PRO A C PRO A O PRO A N ASN A CA ASN A CB ASN A CG ASN A ODI ASN A ND2 ASN A C ASN A O ASN A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N LEU A CA LEU A CB LEU A CG LEU A CDI LEU A CD2 LEU A C LEU A O LEU A N ASP A CA ASP A CB ASP A CG ASP A ODI ASP A OD2 ASP A C ASP A O ASP A N ARG A CA ARG A CB ARG A 406 406 406 406 406 407 407 407 407 407 407 407 407 408 408 408 408 408 408 408 408 409 409 409 409 409 409 409 409 410 410 410 410 410 410 410 410 411 411 411 411 411 411 411 411 412 412 412 13.977 15.232 15.865 12.820 12.605 12.063 10.935 10.950 10.884 11.189 10.486 9.605 8.549 9.660 8.452 8.141 6.696 5.746 6.406 8.607 8.880 8.441 8.548 9.373 10.023 11.100 10.614 7.132 6.482 6.654 5.297 4.503 4.645 4.026 .3.958 5.207 6.078 4.141 3.933 3.733 2.471 1.570 2.383 2.727 2.033 2.480 1.375 1.260 9.053 -14.604 8.800 -15.438 7.602 -14.776 9.589 -15.436 10.796 -15.507 8.690 -16.053 9.119 -16.865 8.418 -18.228 6.907 -18.121.

6.317 -17.077 6.268 -19.215 8.901 -16.166 8.897 -16.798 8.724 -14.851 8.544 -14.061 7.062 -13.851 6.823 -13.397 7.479 -14.390 5.334 -13.287 9.245 -12.717 8.614 -11.695 10.563 -12.741 11.395 -11.553 12.636 -11.877 13.399 -10.728 12.547 -10.082 14.691 -11.266 11.792 -11.163 12.546 -11.882 11.284 -10.030 11.576 -9.583 10.277 -9.449 9.238 -10.560 7.925 -10.104 9.744 -11.819 12.332 -8.261 12.214 -7.400 13.108 -8.105 13.843 -6.873 15.341 -7.144 15.645 -7.928 14.785 -8.001 16.764 -8.474 13.234 -6.179 12.395 -6.762 13.647 -4.940 13.099 4.169 13.824 -2.825 1.00 32.10 1.00 31.28 1.00 31.44 1.00 32.58 1.00 32.58 1.00 32.86 1.00 32.78 1.00 34.73 1.00 35.37 1.00 30.24 1.00 34.08 1.00 34.90 1.00 36.09 1.00 33.56 1.00 35.59 1.00 33.81 1.00 36.44 1.00 34.14 1.00 32.96 1.00 38.03 1.00 36.38 1.00 37.87 1.00 37.95 1.00 39.52 1.00 42.46 1.00 43.24 1.00 46.05 1.00 37.13 1.00 35.70 1.00 35.29 1.00 33.33 1.00 29.37 1.00 32.75 1.00 29.16 1.00 30.70 1.00 35.14 1.00 36.94 1.00 34.76 1.00 35.40 1.00 40.02 1.00 41.32 1.00 45.03 1.00 45.01 1.00 36.10 1.00 34.08 1.00 35.99 1.00 39.37 1.00 39.75 C- i WO 99/50658 PCT/US99/06937

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852 CG ARG A 853 CD ARG A 854 NE ARG A 855 CZ ARG A 856 NH1 ARG A 857 NH2 ARG A 858 C ARG A 859 0 ARG A 860 N ASN A 861 CA ASN A 862 CB ASN A 863 CG ASN A 864 ODI ASN A 865 ND2 ASN A 866 C 867 0 868 N 869 CA 870 CB 871 CG 872 CD 873 OEI 874 NE2 875 C 876 0 877 N 878 CA 879 C 880 0 881 N 882 CA 883 CB 884 CG 885 CD 886 CE 887 NZ 888 C 889 0 890 N 891 CA 892 CB 893 SG 894 C 895 0 896 N 897 CA 898 CB 899 CGI ASN A ASN A GLN A GLN A GLN A GLN A GLN A GLN A GLN A GLN A GLN A GLY A GLY A GLY A GLY A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A CYS A CYS A CYS A CYS A CYS A CYS A VAL A VAL A VAL A VAL A 412 412 412 412 412 412 412 412 413 413 413 413 413 413 413 413 414 414 414 414 414 414 414 414 414 415 415 415 415 416 416 416 416 416 416 416 416 416 417 417 417 417 417 417 418 418 418 418 0.562 0.454 -0.261 -1.574 -2.3 16 -2.150 0.034 -0.775 -0.198 -1.458 -1.518 -1.739 -2.376 -1.213 1.673 -2.792 -0.600 -0.703 0.585 0.572 1.914 2.591 2.309 -0.970 -1.491 -0.618 -0.836 -2.306 -2.696 -3.129 -4.566 -5.212 -4.761 4.910 -5.992 -5.416 -5.227 -6.339 -4.540 -5.066 -4.062 -3.916 -5.373 -6.220 -4.671 -4.866 -3.525 -3.670 15.168 -2.870 1.00 40.49 15.736 -1.465 1.00 40.65 14.826 -0.577 1.00 37.48 14.855 -0.384 1.00 42.84 15.754 -1.024 1.00 40.82 13.986 0.438 1.00 38.32 13.108 -4.889 1.00 39.80 12.201 -4.706 1.00 39.92 14.119 -5.717 1.00 41.64 14.215 -6.440 1.00 43.19 15.533 -7.210 1.00 46.44 16.718 -6.299 1.00 47.86 16.594 -5.249 1.00 48.05 17.876 -6.687 1.00 49.43 13.044 -7.385 1.00 41.48 12.567 -7.546 1.00 40.50 12.577 -8.010 1.00 42.82 11.448 -8.925 1.00 44.73 11.307 -9.741 1.00 47.52 12.088 -11.049 1.00 50.47 12.713 -11.375 1.00 53.91 13.257 -10.501 1.00 53.68 12.637 -12.641 1.00 56.91 10.163 -8.141 1.00 43.21 9.193 -8.682 1.00 42.33 10.168 -6.860 1.00 41.97 8.992 -6.040 1.00 40.43 8.720 -5.804 1.00 40.80 7.601 -5.472 1.00 37.83 9.748 -5.978 1.00 42.16 9.613 -5.779 1.00 44.34 10.996 -5.704 1.00 45.65 11.819 -4.510 1.00 47.42 13.309 -4.777 1.00 50.97 13.924 -3.898 1.00 53.25 14.764 -2.809 1.00 56.95 8.793 -6.886 1.00 45.33 8.299 -6.714 1.00 46.50 8.648 -8.015 1.00 45.18 7.890 -9.1,48 1.00 46.25 7.902 -10.305 1.00 49.29 9.493 -11.168 1.00 49.59 6.452 -8.752 1.00 47.18 5.794 -9.359 1.00 46.50 5.968 -7.731 1.00 45.07 4.612 -7.232 1.00 42.75 3.841 -7.206 1.00 42.45 2.563 -6.410 1.00 40.22 WO 99/50658 PCT/US99/06937

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900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 CG2 VAL A C VAL A O VAL A N GLU A CA GLU A CB GLU A CG GLU A CD GLU A OEI GLU A OE2 GLU A C GLU A O GLU A N GLY A CA GLY A C GLY A O GLY A N MET A CA MET A CB MET A CG MET A SD MET A CE MET A C MET A O MET A N VAL A CA VAL A CB VAL A CGI VAL A CG2 VAL A C VAL A O VAL A N GLU A CA GLU A CB GLU A CG GLU A CD GLU A OEI GLU A OE2 GLU A C GLU A O GLU A N ILE A CA ILE A CB ILE A CG2 ILE A CGI ILE A CD] ILE A C ILE A O ILE A 418 418 418 419 419 419 419 419 419 419 419 419 420 420 420 420 421 421 421 421 421 421 421 421 422 422 422 422 422 422 422 423 423 423 423 423 423 423 423 423 424 424 424 424 424 424 424 424 -3.071 -5.441 -4.883 -6.559 -7.223 -8.536 -9.010 -10.413 -10.582 -11.347 -6.370 -5.955 -6.129 -5.346 -3.854 -3.088 -3.444 -2.035 -1.799 -0.351 0.806 0.881 -1.474 -0.275 -2.319 -1.823 -2.927 -3.823 -2.279 -1.231 -0.274 -1.803 -1.311 -2.190 -3.588 -4.438 -5.349 -4.200 0.127 1.007 0.369 1.711 1.696 3.1081 0.671 0.810 2.700 3.856 3.538 -8.634 4.714 -5.818 5.400 -4.963 4.036 -5.579 4.073 -4.275 3.282 -4.333 2.751 -2.984 2.168 -3.035 1.059 -3.590 2.820 -2.516 3.552 -3.121 2.393 -3.116 4.419 -2.140 4.049 -0.973 4.258 -1.140 4.105 -0.190 4.623 -2.350 4.825 -2.656 4.607 -4.160 4.754 -4.617 3.611 -3.812 2.294 -5.005 6.180 -2.226 6.294 -1.985 7.205 -2.118 8.520 -1.708 9.607 -1.766 9.535 -0.533 10.982 -1.854 8.498 -0.296 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 38.03 41.46 42.08 40.95 42.51 44.52 50.42 54.38 54.09 57.90 41.11 39.42 40.53 37.61 37.01 32.59 36.21 36.02 32.84 35.82 35.57 32.51 34.93 35.17 33.97 31.29 33.14 30.10 30.08 32.64 28.41 31.53 35.99 40.37 49.41 52.38 56.91 54.53 34.83 31.85 30.17 28.99 30.96 27.20 30.77 34.69 28.21 28.48 9.220 7.670 7.558 6.594 7.129 7.336 8.188 6.652 7.04.3 7.552 6.038 5.488 4.195 3.588 3.230 1.787 6.483 6.551 0.002 0.571 1.935 2.737 3.043 1.795 1.835 0.776 1.886 2.581 1.050 0.929 0.109 0.068 0:725 0.291 0.312 0.73 5 C7' WO 99/50658 PCT/US99/06937

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15 ATOM

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948 N PHE A 949 CA PHE A 950 CB PHE A 951 CG PHE A 952 CDI PHE A 953 CD2 PHE A 954 CEI PHE A 955 CE2 PHE A 956 CZ PHE A 957 C PHE A 958 0 PHE A 959 N ASP A 960 CA ASP A 961 CB ASP A 962 CG ASP A 963 ODI ASP A 964 OD2 ASP A 965 C ASP A 966 0 ASP A 967 N MET A 968 CA MET A 969 CB MET A 970 CG MET A 971 SD MET A 972 CE MET A 973 C MET A 974 0 MET A 975 N LEU A 976 CA LEU A 977 CB LEU A 978 CG LEU A 979 CDI LEU A 980 CD2 LEU A 981 C LEU A 982 0 LEU A 983 N LEU A 984 CA LEU A 985 CB LEU A 986 CG LEU A 987 CDI LEU A 988 CD2 LEU A 989 C LEU A 990 0 LEU A 991 N ALA A 992 CA ALA A 993 CB ALA A 994 C ALA A 995 0 ALA A 425 425 425 425 425 425 425 425 425 425 425 426 426 426 426 426 426 426 426 427 427 427 427 427 427 427 427 428 428 428 428 428 428 428 428 429 429 429 429 429 429 429 429 430 430 430 430 430 2.253 3.119 2.381 2.538 2.619 2.566 2.721 2.668 2.745 3.591 4.757 2.680 2.984 1.721 0.781 -0.432 1.253 4.071 4.974 3.978 4.981 4.567 3.385 3.153 2.173 6.321 7.363 6.285 7.506 7.202 6.910 6.278 8.204 8.148 9.366 7.328 7.837 6.714 6.33 1 5.022 7.449 8.425 9.482 7.734 8.201 7.214 9.577 10.455 7.260 -0.675 8.253 -1.315 8.958 -2.458 8.289 -3.798 9.050 -4.958 6.900 -3.905 8.443 -6.207 6.282 -5.149 7.056 -6.303 9.306 -0.312 9.713 -0.328 9.746 0.552 10.759 1.570 11.102 2.369 12.034 1.613 12.039 1.925 12.758 0.710 10.278 2.532 11.030 2.900 9.022 2.947 8.468 3.856 7.070 4.309 7.072 5.257 5.489 6.080 4.637 4.910 8.410 3.128 8.760 3.689 7.985 1.868 7.892 1.075 7.252 -0.287 5.747 -0.176 5.222 -1.468 5.010 0.131 9.269 0.902 9.416 1.034 10.281 0.628 11.642 0.462 12.571 -0.003 12.411 -1.476 13.139 -1.751 12.952 -2.350 12.166 1.776 12.808 1.793 11.890 2.877 12.333 4.185 11.909 5.265 11.742 4.462 12.409 5.005 1.00 27.68 1.00 27.30 1.00 26.36 1.00 27.22 1.00 27.36 1.00 27.89 1.00 29.63 1.00 27.28 1.00 27.63 1.00 25.66 1.00 26.33 1.00 27.92 1.00 28.88 1.00 32.58 1.00 37.47 1.00 37.72 1.00 36.35 1.00 26.96 1.00 27.20 1.00 25.76 1.00 25.89 1.00 21.17 1.00 24.38 1.00 34.32 1.00 21.03 1.00 22.29 1.00 22.19 1.00 21.75 1.00 22.91 1.00 18.47 1.00 19.24 1.00 16.82 1.00 16.23 1.00 23.98 1.00 23.06 1.00 23.91 1.00 26.29 1.00 27.47 1.00 30.78 1.00 34.75 1.00 31.96 1.00 25.83 1.00 26.42 1.00 26.45 1.00 26.11 1.00 23.13 1.00 25.01 1.00 24.31 WO 99/50658 PCT/US99/06937

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996 N 997 CA 998 CB 999 OGI 1000 CG2 1001 C 1002 0 1003 N 1004 CA 1005 CB 1006 OG 1007 C 1008 0 1009 N 1010 CA 1011 CB 1012 OG 1013 C 1014 0 1015 N 1016 CA 1017 CB 1018 CG 1019 CD 1020 NE 1021 CZ 1022 NHI THR THR A THR AX THR A THR A THR A THR A SER SER A SER A SER A SER A SER A SER A SER A SER ,A SER A SER A SER A ARG A ARG A ARG A ARG A ARG A ARG A ARG A ARG A 431 431 431 431 431 431 431 432 432 432 432 432 432 433 433 433 433 433 433 434 434 434 434 434 434 434 434 434 434 434 435 435 435 435 435 435 435 435 435 435 435 436 436 436 436 436 436 436 9.767 11.046 10.973 9.924 12.291 12.103 13.234 11.736 12.676 12.067 13.084 13.033 14.176 12.045 12.269 10.957 10.175 13.263 14.152 13.105 13.980 13.468 14.331 14.626 15.321 15.935 15.949 16.528 15.413 16.352 15.577 16.90 1 16.777 16.795 16.758 16.847 16.771 16.860 16.821 17.576 18.763 16.812 17.341 16.282 16.846 15.750 14.826 13.530 10.486 4.074 9.825 4.294 8.323 3.962 7.727 4.727 7.633 4.299 10.477 3.429 10.667 3.868 10.819 2.197 11.479 1.301 11.650 -0.093 11.930 -1.039 12.850 1.876 13.294 1.779 13.521 2.459 14.824 3.076 15.387 3.623 15.961 2.591 14.644 4.223 15.473 4.429 13.545 4.959 13.236 6.086 11.994 6.819 11.541 7.983 12.672 8.958 12.169 10.140 12.935 11.034 14.255 10.885 12.381 12.084 13.014 5.605 13.563 6.173 12.206 4.561 11.935 4.000 11.045 2.758 9.563 3.051 9.084 4.359 8.643 2.009 7.709 4.622 7.271 2.262 6.807 3.570 13.253 3.607 13.464 3.871 14.137 2.975 15.429 2.549 16.206 1.756 17.317 0.877 17.960 0.040 16.955 -0.472 16.913 -0.184 1.00 25.25 1.00 22.78 1.00 21.36 1.00 20.27 1.00 19.99 1.00 23.73 1.00 19.60 1.00 24.32 1.00 26.96 1.00 28.70 1.00 33.42 1.00 27.92 1.00 30.78 1.00 28.96 1.00 34.21 1.00 35.07 1.00 42.38 1.00 33.43 1.00 31.94 1.00 31.32 1.00 29.78 1.00 29.84 1.00 32.17 1.00 37.00 1.00 39.44 1.00 44.06 1.00 45.52 1.00 45.01 1.00 29.24 1.00 29.72 1.00 28.95 1.00 30.59 1.00 32.03 1.00 31.88 1.00 35.60 1.00 35.89 1.00 35.36 1.00 32.71 1.00 33.24 1.00 32.73 1.00 31.16 1.00 33.37 1.00 39.13 1.00 40.42 1.00 43.09 1.00 44.53 1.00 48.34 1.00 48.81 ATOM 1023 NH2 ARG A

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1024 C 1025 0 1026 N 1027 CA 1028 CB 1029 CG 1030 CDI 1031 CD2 1032 CEI 1033 CE2 1034 CZ 1035 C 1036 0 1037 N 1038 CA 1039 CB 1040 CG 1041 CD 1042 NE 1043 CZ ARG A ARG A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE A PHE PHE A PHE A ARG A ARG A ARG A ARG ARG ARG A ARG A WO 99/50658 PCT/US99/06937 ATOM 1044 NHI ARG A ATOM 1045 NH2 ARG A

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1046 C 1047 0 1048 N 1049 CA 1050 CB 1051 C 1052 0 1053 N 1054 CA 1055 CB 1056 CG 1057 SD 1058 CE 1059 C 1060 0 1061 N 1062 CA 1063 CB 1064 CG 1065 ODI ARG A ARG A MET A MET A MET A MET A MET A MET A MET A MET A MET A MET A MET A MET A MET A ASN A ASN A ASN A ASN A ASN A 1066 ND2 ASN A 1067 C ASN A 1068 0 ASN A 1069 N LEU A 1070 CA LEU A 1071 CB LEU A 1072 CG LEU A 1073 CDI LEU A 1074 CD2 LEU A 1075 C LEU A 1076 0 LEU A 1077 N GLN A 1078 CA GLN A 1079 CB GLN A 1080 CG GLN A 1081 CD GLN A 1082 OEI GLN A 1083 NE2 GLN A 1084 C GLN A 1085 0 GLN A 1086 N GLY A 1087 CA GLY A 1088 C GLY A 1089 0 GLY A 1090 N GLU A 1091 CA GLU A 436 436 436 436 437 437 437 437 437 438 438 438 438 438 438 438 438 439 439 439 439 439 439 439 439 440 440 440 440 440 440 440 440 441 441 441 441 441 441 441 441 441 442 442 442 442 443 443 12.997 12.769 17.792 18.896 16.936 17.257 16.102 18.550 19.303 18.804 20.011 19.787 18.694 18.747 20.374 21.176 22.321 20.886 2 1.924 23.019 23.933 23.528 25.197 22.552 23.764 21.692 22.161 20.991 21.451 21.957 20.318 23. 146 22.925 24.225 25.255 26.632 26.896 27.040 27.985 26.053 25.100 24.540 25.608 25.528 26.181 25.642 27.340 28.057 17.823 0.619 15.950 -0.687 16.250 3.753 16.789 3.764 16.334 4.766 17.087 5.975 16.998 6.965 16.594 6.626 17.378 7.201 15.285 6.538 14.693 7.117 13.221 7.463 12.938 8.460 11.188 8.880 11.064 9.619 14.756 6.142 14.503 6.522 15.070 4.895 15.118 3.895 16.125 4.243 16.407 3.090 16.295 1.934 16.733 3.372 13.732 3.739 13.581 3.649 12.698 3.704 11.326 3.579 10.344 3.380 8.886 3.209 8.353 4.546 8.032 2.682 11.161 2.435 11.671 1.333 10.450 2.702 10.220 1.699 10.320 2.345 11.669 2.979 12.748 1.939 12.782 1.167 13.659 1.899 8.860 1.038 7.931 1.625 8.752 -0.187 7.503 -0.921 6.350 -0.184 5.245 -0.154 6.603 0.416 5.567 1.150 1.00 47.80 1.00 49.53 1.00 38.10 1.00 41.00 1.00 39.47 1.00 38.20 1.00 39.79 1.00 41.15 1.00 40.20 1.00 39.65 1.00 39.70 1.00 39.90 1.00 41.94 1.00 43.12 1.00 43.73 1.00 38.03 1.00 38.39 1.00 37.64 1.00 35.68 1.00 40.98 1.00 45.09 1.00 47.16 1.00 46.87 1.00 31.06 1.00 29.54 1.00 31.47 1.00 31.63 1.00 33.05 1.00 37.07 1.00 36.18 1.00 32.33 1.00 32.10 1.00 32.76 1.00 32.54 1.00 31.97 1.00 31.75 1.00 35.56 1.00 34.97 1.00 35.51 1.00 35.41 1.00 34.08 1.00 30.73 1.00 32.78 1.00 32.91 1.00 31.87 1.00 33.18 1.00 30.60 1.00 30.85 WO 99/50658 PCT/US99/06937

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1092 CB GLU A 1093 CG GLU A 1094 CD GLU A 1095 OEI GLU A 1096 OE2 GLU A 1097 C GLU A 1098 0 GLU A 1099 N GLU A 1100 CA GLU A 1101 CB GLU A 1102 CG GLU A 1103 CD GLU A 1104 OEI GLU A 1105 OE2 GLU A 1106 C GLU A 1107 0 GLU A 1108 N PHE A 1109 CA PHE A 1110 CB PHE A 1111 CG PHE A 1112 CDI PHE A 1113 CD2 PHE A 1114 CEI PHE A 1115 CE2 PHE A 1116 CZ PHE A 1117 C PHE A 1118 0 PHE A 1119 N VAL A 1120 CA VAL A 1121 CB VAL A 1122 CGI VAL A 1123 CG2 VAL A 1124 C VAL A 1125 0 VAL A 1126 N CYS A 1127 CA CYS A 1128 CB CYS A 1129 SG CYS A 1130 C CYS A 1131 0 CYS A 1132 N LEU A 1133 CA LEU A 1134 CB LEU A 1135 CG LEU A 1136 CDI LEU A 1137 CD2 LEU A 1138 C LEU A 1139 0 LEU A 443 443 443 443 443 443 443 444 444 444 444 444 444 444 444 444 445 445 445 445 445 445 445 445 445 445 445 446 446 446 446 446 446 446 447 447 447 447 447 447 448 448 448 448 448 448 448 448 29.376 30.425 30.310 29.677 30.853 27.206 27.211 26.482 25.619 25.147 26.250 25.748 25.006 26.088 24.403 23.970 23.861 22.688 22.254 21.372 20.034 21.885 19.215 21.079 19.741 22.913 22.083 24.019 24.278 25.522 25.251 26.735 24.467 24.177 24.962 25.155 25.953 27.738 23.781 23.512 22.915 21.568 20.803 21.142 20.328 20.827 20.766 20.006 6.111 1.704 6.378 0.646 7.770 0.066 8.630 0.716 8.003 -1.038 5.048 2.299 3.854 2.595 5.955 2.948 5.589 4.067 6.843 4.797 7.633 5.463 8.944 6.023 9.652 5.304 9.268 7.182 4.813 3.572 3.841 4.191 5.256 2.443 4.633 1.853 5.416 0.610 4.634 -0.316 4.419 -0.004 4.094 -1.489 3.670 -0.855 3.349 -2.342 3.138 -2.023 3.169 1.489 2.316 1.796 2.868 0.822 1.481 0.447 1.360 -0.465 2.046 -1.799 1.968 0.217 0.614 1.694 -0.586 1.680 1.223 2.770 0.503 4.025 1.359 5.011 1.324 4.731 0.178 4.618 -0.960 5.002 1.186 4.680 1.002 5.219 2.324 5.207 3.337 6.303 4.594 6.072 2.760 7.672 -0.038 4.442 -0.803 5.030 1.00 32.74 1.00 36.30 1.00 40.92 1.00 42.27 1.00 46.82 1.00 30.43 1.00 28.11 1.00 30.26 1.00 28.18 1.00 26.32 1.00 29.27 1.00 29.62 1.00 32.00 1.00 29.02 1.00 26.93 1.00 24.78 1.00 27.79 1.00 24.50 1.00 25.40 1.00 23.74 1.00 23.00 1.00 22.37 1.00 22.57 1.00 21.69 1.00 22.25 1.00 22.81 1.00 22.92 1.00 22.46 1.00 22.26 1.00 22.87 1.00 22.57 1.00 22.38 1.00 23.68 1.00 22.91 1.00 22.02 1.00 24.17 1.00 23.95 1.00 28.57 1.00 21.14 1.00 19.37 1.00 19.28 1.00 21.31 1.00 21.90 1.00 26.61 1.00 27.74 1.00 24.03 1.00 21.72 1.00 20.87

C:

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1140 N 1141 CA 1142 CB 1143 CG 1144 CD 1145 CE 1146 NZ 1147 C 1148 0 1149 N 1150 CA 1151 CB 1152 OG 1153 C 1154 0 1155 N 1156 CA 1157 CB 1158 CG2 1159 CG1 1160 CDI 1161 C 1162 0 1163 N 1164 CA 1165 CB 1166 CG2 LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A SER A SER A SER A SER -A SER A SER A ILE A ILE A ILE A ILE A ILE A ILE A ILE A ILE A ILE A ILE A ILE A ILE A 449 449 449 449 449 449 449 449 449 450 450 450 450 450 450 451 451 451 451 451 451 451 451 452 452 452 452 452 452 452 452 453 453 453 453 453 453 453 453 454 454 454 454 454 454 454 454 455 20.929 20.205 20.440 19.438 19.456 20.8 16 20.741 20.629 19.800 2 1.924 22.451.

23.982 24.460 2 1.975 21.728, 2 1.853, 21.385 2 1.452 20.593 22.909 23.1 15 19.952 19.575 19. 152 17.763 17.024 15.720 16.725 16.284 17.725 16.980 18.555 18.589 19.624 19.83 5 18.550 20.948 18.906 18.198 19.966 20.410 2 1.870 22.8 16 24.222 -0.055 -0.997 -0.659 -1.297 -0.613 -0.754 -0.482 -2.436 -3.345 -2.637 3.965 -3.953 -3.975 -4.408 -5.590 -3).449 -3.741 -2.476 -2.65 8 -2.2 10 -0.960 -4.250 -5.184 -3.642 -4.058 -3).145 -3).792 -1.788 -0.707 -5.517 -6.340 -5.844 -7.205 -7.3 16 -8.729 -9.250 -8.694 -8.245 -9.241 -7.997 -8.925 -8.625 -8.584 -8.268 3.119 2.269 0.788 173 -1.542 -2.229 -3.698 2.548 2.552 2.777 3.074 3041 1.702 4.454 4.682 5.369 6.726 7.6 16 8.886 7.999 8.850 6.662 7.369 5.795 5.649 4.627 4.169 5.282 4.306 5.191 5.73 7 4.209 3.679 2.554 1.989 1.364 0.953 4.746 4.891 5.499 6.530 6.878 5.673 6.132 4.952 7.807 8.438 8.167 1.00 21.42 1.00 20.98 1.00 2 1.55 1.00 24.82 1.00 23.33 1.00 23.5 8 1.00 28.77 1.00 20.33 1.00 20.57 1.00 19.25 1.00 21.84 1.00 20.59 1.00 29.78 1.00 21.58 1.00 20.06 1.00 22.20 1.00 22.82 1.00 19. 62 1.00 21.11 1.00 22.20 1.00 24.48 1.00 21.82 1.00 21.72 1.00 20.18 1.00 18.13 1.00 19.72 1.00 18.99 1.00 18.33 1.00 23.25 1.00 19.50 1.00 17.60 1.00 19.23 1.00 21.60 1.00 21.50 1.00 25.06 1.00 25.27 1.00 24.73 1.00 19.41 1.00 20.75 1.00 21.35 1.00 23 .67 1.00 20.69 1.00 24.92 1.00 24.27 1.00 22.84 1.00 26.06 1.00 27.44 1.00 25.01 1167 CGI ILE A 1168 CDI ILE A 1169 C ILE A 1170 0 ILE A 1171 N LEU A 1172 CA LEU A 1173 CB LEU A 1174 CG LEU A 1175 CDI LEU A 1176 CD2 LEU A 1177 C LEU A 1178 0 LEU A 1179 N LEU A 1180 CA LEU A 1181 CB LEU A 1182 CG LEU A 1183 CDI LEU A 1184 CD2 LEU A 1185 C LEU A 1186 0 LEU, A 1.187 N ASN A 22.785 -9.913 19.572 -8.945 19.413 -9.997 19.011 -7.795 (7, WO 99/50658 PCT/US99/06937

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1188 CA 1189 CB 1190 CG 1191 ODI 1192 ND2 1193 C 1194 0 1195 N 1196 CA 1197 CB 1198 OG 1199 C 1200 0 1201 N 1202 CA 1203 C 1204 0 1205 N 1206 CA 1207 CB 1208 CGI 1209 CG2 1210 C 1211 0 ASN A 455 ASN A 455 ASN A 455 ASN A 455 ASN A 455 ASN A 455 ASN A 455 SER A 456 SER A 456 SER A 456 SER A 456 SER A 456 SER A 456 GLY A 457 GLY A 457 GLY A 457 GLY A 457 VAL A 458 VAL A 458 VAL A 458 VAL A 458 VAL A 458 VAL A 458 VAL A 458 18.240 -7.681 9.400 1.00 26.10 18.439 -6.295 10.002 1.00 22.67 17.627 -6.109 11.264 1.00 26.67 17.899 -6.751 12.270 1.00 25.16 16.615 -5.246 11.212 1.00 20.73 16.739 -7.957 9.418 1.00 25.78 16.230 -8.516 10.380 1.00 29.22 16.027 -7.549 8.381 1.00 28.51 14.578 -7.704 8.371 1.00 32.52 14.019 -7.213 7.033 1.00 35.98 14.266 -5.818 6.897 1.00 30.88 14.033 -9.086 8.711 1.00 33.00 13.112 -9.202 9.523 1.00 33.07 14.597 -10.130 8.117 1.00 28.40 14.115 -11.464 8.413 1.00 36.28 15.055 -12.289 9.277 1.00 40.41 14.831 -13.486 9.456 1.00 38.20 16.095 -11.657 9.820 1.00 44.13 17.079 -12.356 10.647 1.00 51.09 18.214 -11.399 11.095 1.00 51.06 17.688 -10.390 12.104 1.00 51.75 19.365 -12.199 11.692 1.00 50.65 16.513 -13.060 11.885 1.00 57.26 17.085 -14.045 12.356 1.00 58.77 15.401 -12.560 12.416 1.00 62.31 14.793 -13.177 13.592 1.00 68.49 14.293 -12.100 14.560 1.00 70.46 15.396 -11.196 15.069 1.00 71.73 15.127 -9.888 15.462 1.00 71.93 16.147 -9.045 15.898 1.00 72.60 16.716 -11.644 15.128 1.00 72.77 17.741 -10.812 15.560 1.00 73.55 17.450 -9.514 15.941 1.00 72.93 18.467 -8.687 16.351 1.00 74.56 13.649 -14.097 13.187 1.00 71.86 13.380 -15.099 13.852 1.00 73.11 12.981 -13.756 12.090 1.00 74.84 11.881 -14.567 11.589 1.00 77.66 11.246 -13.900 10.373 1.00 76.69 12.436 -15.938 11.212 1.00 80.26 11.684 -16.866 10.912 1.00 80.82 13.762 -16.051 11.231 1.00 82.69 14.440 -17.299 10.905 1.00 85.63 15.920 -17.034 10.630 1.00 85.47 14.284 -18.288 12.059 1.00 87.52 14.493 -17.940 13.224 1.00 86.53 13.914 -19.520 11.724 1.00 89.49 13.711 -20.568 12.718 1.00 91.34 1212 N TYR A 459 1213 CA TYR A 459 1214 CB TYR A 459 1215 CG TYR A 459 1216 CDI TYR A 459 1217 CEl TYR A 459 1218 CD2 TYR A 459 1219 CE2 TYR A 459 1220 CZ TYR A 459 1221 OH TYR A 459 1222 C TYR A 459 1223 0 TYR A 459 1224 N THR A 460 1225 CA THR A 460 1226 CB THR A 460 1227 C THR A 460 1228 0 THR A 460 1229 N PHE A 461 1230 CA PHE A 461 1231 CB PHE A 461 1232 C PHE A 461 1233 0 PHE A 461 1234 N LEU A 462 1235 CA LEU A 462 WO 99/50658 PCT/US99/06937

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15 ATOM

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1236 CB 1237 C 1238 0 12 9 N 1240 CA 1241 CB 1242 C 1243 0 1244 N 1245 CA 1246 CB 1247 C 1248 0 1249 N 1250 CA 1251 CB 1252 C 1253 0 1254 N 1255 CA 1256 CB 1257 C 1258 0 1259 N 1260 CA 1261 CB 1262 C 1263 0 1264 N 1265 CA 1266 CB 1267 OG 1268 C 1269 0 1270 N 1271 CA 1272 CB 1273 C 1274 0 1275 N 1276 CA 1277 CB 1278 C 1279 0 1280 N 1281 CA 1282 CB 1283 CG LEU A LEU A LEU A SER A SER A SER A SER A SER A SER A SER A SER A SER A SER A THR A THR A THR A THR A THR A LEU A LEU A LEU A LEU A LEU A LYS A LYS A LYS A LYS A LYS A SER A SER A SER A SER A SER A SER A LEU A LEU A LEU A LEU A LEU A GLU A GLU A GLU A GLU A GLU A GLU A\ GLU A GLU A GLU A 462 462 462 463 463 463 463 463 464 464 464 464 464 465 465 465 465 465 466 466 466 466 466 467 467 467 467 467 468 468 468 468 468 468 469 469 469 469 469 470 470 470 470 470 471 471 471 471 12.961 -21.741 12.087 15.016 -21.060 13.340 16.042 -21.165 12.664 14.966 -21.357 14.635 16.131 -21.855 15.358 16.033 -21.483 16.833 16.189 -23.371 15.200 15.156 -24.034 15.102 17.399 -23.917 15.167 17.577 -25.355 15.015 17.284 -25.769 13.577 18.997 -25.743 15.396 19.815 -26.074 14.535 19.279 -25.699 16.694 20.600 -26.036 17.212 20.952 -27.483 16.863 21.640 -25.085 16.634 21.302 -24.017 16.121 22.907 -25.479 16.723 23.999 -24.665 16.207 25.335 -25.338 16.498 23.829 -24.461 14.706 24.411 -23.545 14.125 23.028 -25.323 14.086 22.772 -25.238 12.653 21.740 -26.287 12.240 22.269 -23.841 12.308 23.032 -22.990 11.849 20.981 -23.610 12.536 20.384 -22.315 12.252 18.901 -22.333 12.620 18.229 -23.378 11.937 21.109 -21.230 13.040 21.264 -20.105 12.565 21.558 -21.579 14.242 22.276 -20.640 15.098 22.595 -21.294 16.436 23.564 -20.174 14.419 24.111 -19.122 14.756 24.044 -20.969 13.466 25.256 -20.638 12.726 25.803 -21.880 12.032 24.920 -19.565 11.697 25.617 -18.556 11.581 23.842 -19.792 10.953 23.396 -18.842 9.945 22.461 -19.526 8.944 23.150 -19.976 7.668 1.00 91.23 1.00 92.05 1.00 91.91 1.00 92.53 1.00 92.96 1.00 91.67 1.00 93.39 1.00 93.44 1.00 93.82 1.00 93.85 1.00 93.74 1.00 93.96 1.00 93.65 1.00 93.91 1.00 93.79 1.00 93.38 1.00 93.27 1.00 93.03 1.00 93.26 1.00 92.34 1.00 91.59 1.00 92.18 1.00 92.67 1.00 91.28 1.00 90.02 1.00 89.93 1.00 88.35 1.00 88.50 1.00 86.02 1.00 84.10 1.00 84.08 1.00 83.03 1.00 83.39 1.00 83.48 1.00 82.04 1.00 80.28 1.00 79.81 1.00 79.18 1.00 78.61 1.00 76.69 1.00 74.84 1.00 74.12 1.00 73.77 1.00 72.94 1.00 72.08 1.00 70.05 1.00 71.52 1.00 72.90 WO-99/50658 PTU9/63 PCTIUS99/06937

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1284 CD GLU A 1285 OEI GLU A 1286 0E2 GLU A 1287 C GLU A 1288 0 GLU A 1289 N LYS A 1290 CA LYS A 1291 CB LYS A 1292 CG LYS A 1293 CD LYS A 1294 CE LYS A 1295 NZ LYS A 1296 C LYS A 1297 0 LYS A 1298 N ASP A 1299 CA ASP A 1300 CB ASP A 1301 CG ASP A 1302 ODI ASP A 1303 0D2 ASP A 1304 C ASP A 1305 0 ASP A 1306 N HIS A 1307 CA HIS A 1308 CB HIS A 1309 CG HIS A 1310 CD2 HIS A 1311 NDI HIS A 1312 CEI HIS A 1313 NE2 HIS A 1314 C HIS A 1315 0 HIS A 1316 N ILE A 1317 CA ILE A 1318 CB ILE A 1319 CG2 ILE A 1320 CGI ILE A 1321 CDI ILE A 1322 C ILE A 1323 0 ILE A 1324 N HIS A 13 25 CA HIS A 1326 CB HIS A 1327 CG HIS A 13)28 CD2 HIS A 1329 NDI HIS A 1 330 CEI HIS A 1331 NE2 HIS A 471 471 471 471 471 472 472 472 472 472 472 472 472 472 473 473 473 473 473 473 473 473 474 474 474 474 474 474 474 474 474 474 475 475 475 475 475 475 475 475 476 476 476 476 476 476 476 476 24.512 -20.586 7.932 1.00 74.01 25.469 -20.258 7.198 1.00 74.22 24.626 -21.395 8.878 1.00 75.18 22.667 -17.692 10.630 1.00 67.33 21.685 -17.165 10.107 1.00 67.77 23.152 -17.319 11.811 1.00 62.63 22.564 16.229 12.578 1.00 57.41 21.697 -16.777 13.713 1.00 58.74 20.683 -15.776 14.243 1.00 60.32Q 19.271 16.342 14.219 1.00 60.73 18.485 -15.909 15.449 1.00 61.78 19.3 52 -15.788 16.658 1.00 60.09 23.662 -15.339 13.150 1.00 53.42 23.631 -14.120 12.978 1.00 50.87 24.628 -15.949 13.830 1.00 47.52 25.73 2 -15.194 14.405 1.00 45.55 26.613 -16.094 15.269 1.00 50.48 26.380 -15.885 16.749 1.00 55.50 2 5.272_ -15.436 17.118 1.00 58.06 27.304 -16.170 17.541 1.00 59.81 26.557 -14.611 13.269 1.00 42.62 27.087 -13.506 13.373 1.00 42.10 26.663 -'15.364 12.180 1.00 38.05 27.416 -14.904 11.026 1.00 37.25 27.429 -15.978 9.941 1.00 35.07 28.036 15.523 8.653 1.00 37.36 29.292 15.113 8.355 1.00 38.86 27.322 -15.452 7.476 1.00 41.31.

28.110 -15.020 6.509 1.00 40.86 29.311 -14.807 7.016 1.00 44.49 26.749 -13.640 10.493 1.00 36.68 27.417 -12.676 10.132 1.00 3 6.48 25.422 -13.652 10.447 1.00 35.93 24.683 -12.499 9.963 1.00 3 6.21 23.174 -12.797 9.868 1.00 3 6.31 22.411 -11.527 9.513 1.00 3 8.19 22.922 -13.874 8.813 1.00 36.97 21.528 -14.454 8.869 1.00 35.59 24.893 -11.322 10.907 1.00 35. 34 25.092 -10.189 10.471 1.00 33 24.857 -11.596 12.206 1.00 35.9 25.031 -10.540 13.193 1.00 3 5.06 24.681 11.062 14.585 1.00 37.30 23 .210 -11.068 14.860 1.00 43.06 22.329 -10.051 15.017 1.00 4 3.93 22.476 -12.230 14.968 1.00 45.60 21.207 11.928 15.177 1.00 47.56 21.091 -10.613 15.211 1.00 46.21

C'

WO 99/50658 PCT/US99/06937

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1332 C HIS A 1333 0 HIS A 1334 N ARG A 1335 CA ARG A 1336 CB ARG A 1337 CG ARG A 1338 CD ARG A 1339 NE ARG A 1340 CZ ARG A 1341 NHI ARG A 1342 NH2 ARG A 1343 C ARG A 1344 0 ARG A 1345 N VAL A 1346 CA VAL A 1347 CB VAL A 1348 CGI VAL A 1349 CG2 VAL A 1350 C VAL A 1351 0 VAL A 1352 N LEU A 1353 CA LEU A 1354 CB LEU A 1355 CG LEU A .1356 CDI LEU A 1357 CD2 LEU A 1358 C LEU A 1359 0 LEU A 1360 N ASP A 1361 CA ASP A 1362 CB ASP A 1363 CG ASP A 1364 ODI ASP A 1365 OD2 ASP A 1366 C ASP A 1367 0 ASP A 1368 N LYS A 1369 CA LYS A 1370 CB LYS A 1371 CG LYS A 1372 CD LYS A 1373 CE LYS A 1374 NZ LYS A 1375 C LYS A 1376 0 LYS A 1377 N ILE A 1378 CA ILE A 1379 CB ILE A 476 476 477 477 477 477 477 477 477 477 477 477 477 478 478 478 478 478 478 478 479 479 479 479 479 479 479 479 480 480 480 480 480 480 480 480 481 481 481 481 481 481 481 481 481 482 482 482 26.438 26.634 27.420 28.796 29.757 29.800 30.782 3 1.780 32.780 32.918 33.643 28.906 29.462 28.369 28.389 27.658 27.672 28.319 27.689 28.216 26.499 25.727 24.474 23.211 22.056 22.864 26.592 26.595 27.324 28.206 28.878 27.990 28.355 26.935 29.283 29.672 29.767 30.794 31.306 32.158 32.894 33.883 34.954 30.260 30.979 28.996 28.421 27.066 -9.966 13.170 -8.774 13.415 -10.805 12.862 -10.331 12.795 -11.506 12.605 -12.459 13.788 -13.599 13.557 -13.675 14.622 -12.811 14.770 -11.803 13.918 -12.955 15.766 -9.361 11.621 -8.268 11.753 -9.766 10.475 -8.930 9.280 -9.605 8.100 -8.678 6.890 -10.933 7.761 -7.610 9.584 -6.536 9.294 -7.702 10.171 -6.516 10.530 -6.912 11.324 -7.229 10.517 -7.503 11.481 -6.063 9.584 -5.582 11.369 -4.370 11.158 -6.158 12.320 -5.388 13.193 -6.305 14.222 -6.602 15.417 -7.505 16.198 -5.944 15.580 -4.699 12.361 -3.562 12.636 -5.394 11.340 4.830 10.477 -5.890 9.512 -6.953 10.188 -7.799 9.157 -6.963 8.350 -6.388 9.215 -3.635 9.696 -2.657 9.463 -3.705 9.291 -2.598 8.545 -2.983 7.915 1.00 35.40 1.00 35.45 1.00 34.07 1.00 34.18 1.00 41.04 1.00 47.61 1.00 55.67 1.00 60.17 1.00 61.98 1.00 64.29 1.00 62.79 1.00 30.77 1.00 33.59 1.00 27.65 1.00 27.07 1.00 28.00 1.00 25.83 1.00 31.66 1.00 26.92 1.00 26.97 1.00 25.74 1.00 27.97 1.00 25.55 1.00 29.01 1.00 27.05 1.00 24.92 1.00 25.39 1.00 27.39 1.00 26.04 1.00 27.32 1.00 26.67 1.00 31.02 1.00 31.50 1.00 32.21 1.00 25.59 1.00 27.15 1.00 25.17 1.00 24.93 1.00 28.42 1.00 35.59 1.00 41.21 1.00 41.48 1.00 43.22 1.00 26.12 1.00 23.73 1.00 25.44 1.00 27.69 1.00 27.59 WO 99/50658 PTU9/63 PCTIUS99/06937

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1380 CG2 ILE A 1381 CGI ILE A 1382 CDI ILE A 1383 C ILE A 1384 0 ILE A 1385 N THR A 1386 CA THR A 1387 CB THR A 1388 OGI THR A 1389 CG2 THR A 1390 C THR A 1391 0 THR A 1392 N ASP A 1393 CA ASP A 1394 CB ASP A 1395 CG ASP A 1396 ODI ASP A 1397 0D2 ASP A 1398 C ASP A 1399 0 ASP A 1400 N THR A 1401 CA THR A 1402 CB THR A 1403 OGI THR A 1404 CG2 THR A 1405 C THR A 1406 0. THR A 1407 N LEU A 1408 CA LEU A 1409 CB LEU A 1410 CG LEU A 1411 CDI LEU A 1412 CD2 LEU A 1413 C LEU A 1414 0 LEU A 1415 N ILE A 1416 CA ILE A 1417 CB -ILE A 1418 CG2 ILE A 1419 CGI ILE A 1420 CDI ILE A 1421 C .ILE A 1422 0 ILE A 1423 N HIS A 1424 CA HIS A 1425 CB HIS A 1426 CG HIS A 1427 CD2 HIS A 482 482 482 4827 482 483 483 483 483 483 483 483 484 484 484 484 484 484 484 484 485 485 485 485 485 485 485 486 486 486 486 486 486 486 486 487 487 487 487 487 487 487 487 488 488 488 488 488 26.470 27.2-74 26.000 28.253 28.3 12 28.046 27.905 27.535 26.181 27.673 29.257 29.331 30.324 3 1.674 32.7 18 -32.629 32.002 .33.185 3 1.930 32.481 31.505 3 1.689 3 1.124 3 1.753 3 1.381 30.994 31.583 29. 74 3 28.973 27.567 26.508 25.210 26.309 29.662 29.745 30.151 30.843 .31.203 -32.255 29.937 29.23 7 32. 125 32.497 32.791 34.031) .34.585 -35.799 35.970 -1.788 7.183 4.131 6.922 -4.838 6.533 -1.408 9.481 -0.256 9.045 -1.690 10.768 -0.632 11.760 -1.192 13.154 -1.658 13.133 -0.111 14.226 0.074 11.858 1.306 11.846 -0.714 11.960 -0.152 12.039 -1.273 12.107 -2.083 13 .394 -1.608 14.366 -3.198 13.434 0.715 10.807 1.812 10.905 0.226 9.645 0.960 8.394 0.166 7.197 -1.123 7.132 0.907 5.898 2.318 8.468 3.354 8.137 2.310 8.915.

3.537 9.027 3.233 9.547 2.921 8.486 2.550 9.183 4.128 7.577 4.519 9.960 5.710 9.669 4.015 11.088 4.857 12.055 4.054 13.332 4.803 14.154 3.813 14.163 5.088 14.624 5.393 11.412 6.554 11.602 4.533 10.649 4.898 9.967 3..691 9.207 3997 8.385 4.089 7.045 1.00 25.97 1.00 23 1.00 21.30 1.00 27.33 1.00 28.55 1.00 25.03 1.00 23.62 1.00 22.18 1.00 25.39 1.00 25.84 1.00 23.04 1.00 23.55 1.00 22.24 1.00 25.48 1.00 26.88 1.00 32.52 1.00 33.68 1.00 34.63 1.00 25.16 1.00 26.05 1.00 28.96 1.00 26.63 1.00 26.12 1.00 24.30 1.00 23.31 1.00 28.90 1.00 27.26 1.00 24.76 1.00 26.19 1.00 27.27 1.00 23.50 1.00 22.03 1.00 21.35 1.00 27.36 1.00 25.87 1.00 27.88 1.00 28.40 1.00 26.74 1.00 27.54 1.00 25.93 1.00 23.42 1.00 28.89 1.00 29.85 1.00 29.71 1.00 34.12 1.00 36.61 1.00 42.74 1.00 -43.12

C

WO 99/50658 PCT/US99/06937

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1428 ND1 HIS 1429 CEI HIS A 1430 NE2 HIS A 1431 C 1432 0 1433 N 1434 CA 1435 CB 1436 CG 1437 CD1 1438 CD', 1439 C 1440 0 1441 N 1442 CA 1.443 CB 1444 CG 1445 SD 1446 CE 1447 C 1448 0 1449 N 1450 CA 1451 CB 1452 C 1453 0 1454 N 1455 CA 1456 CB 1457 CG 1458 CD 1459 CE 1460 NZ 1461 C 1462 0 1463 N 1464 CA 1465 CB 1466 C 1467 0 1468 N 1469 CA 1470 C 1471 0 1472 N 1473 CA 1474 CB 1475 CG HIS A HIS A LEU A LEU A LEU A LEU A ILEU A ~LEU A LEU A LEU A MET A MET A MET A MET A MET A MET A MET A MET A ALA A ALA A ALA A ALA A ALA A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A ALA A ALA A ALA A ALA A ALA A GLY A GLY A GLY A GLY A LEU A LEU A LEU A LEU A 488 488 488 488 488 489 489 489 489 489 489 489 489 490 490 490 490 490 490 490 490 491 491 491 491 491 492 492 492 492 492 492 492 492 492 493 493 493 493 493 494 494 494 494 495 495 495 495 37.034 3 7.9 13 37.293 3' 3.799 .34.577 32.721 32.384! 31.145 3 1.310.

29. 94 5 32.183 32. 124 32.587 3 1.387 31.056 30.000 28.607 27.457 26.321 32.287 32.412 33.184 34.407 35. 168 35 .275 35.865 35.339 36. 122 36. 136 37.490 37.390 38.631 38.357 35.534 36.227 34.254 33.590 32.097 33.816 33.277 34.604 34.903 33.857 33.916 32Z.905 31.876 30. 713 29.540 4.239 8.946 4.466 7.987 4.381 6.825 6.05 1 8.998 7.004 8.955 5.958 S.223 6.992 7.258 6.587 6.464 5.353 5.574 4.856 5. 125 5.701 4.378 8.320 7.954 9.365 7.507 8.274 9.058 9.482 9.801 9.161 10.862 8.940 10.289 8.247 11.496 7.408 10.418 10.108 10.455 11.330 10.517 9.262 10.949 9.730 11.585 8.554 12.185 10.445 10.550 11.487 10.838 9.876 9.347 10.440 8.248 9.477 7.052 8.840 6.744 7.830 -5.595 6.937 5.518 5.577 4.948 11.780 7.809 12.604 7.215 11.992 8.100 13.238 7,728 13.001 7.528 14.305 8.796 15.410 8.707 13.960 9.811 14.904 10.873 15.060 11.965 16.011 12.747 14.138 12.043 14.248 1 3 .068 13.304 12.769 13.901 11.988 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00* 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 43. 13 43.40 45.63 32.74 31.06 33.56 30.78 34.67 34.73 .33.21 35.92 33.97 33.22 31.33 30.61 32.34 30.71 31.14 30.36 32.22 28.25 33.81 39.92 37.22 42.68 45.32 44.39 44.80 46.96 47.20 45.71 45.55 36.28 45.61 46.18 43.75 42.42 40.92 41.78 40.76 41.01 41.63 41.18 38.22 39.53 38.91 .39.20 40.73

C"

WO 99/50658 PCTIUS99/06937

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1476 CDI LEU A 495 1477 CD2 LEU A 495 1478 C LEU A 495 1479 0 LEU A 495 1480 N THR A 496 1481 CA THR A 496 1482 CB THR A 496 1483 OGI THR A 496 1484 CG2 THR A 496 1485 C THR A 496 1486 0 THR A 496 1487 N LEU A 497 1488 CA LEU A 497 1489 CB LEU A 497 1490 CG LEU A 497 1491 CDI LEU A 497 1492 CD2 LEU A 497 1493 C 1494 0 1495 N 1496 CA 1497 CB 1498 CG 1499 CD 1500 OEI 1501 NE2 1502 C 1503 0 1504 N 1505 CA 1506 CB 1507 CG 1508 CD 1509 OEI 1510 NE2 1511 C 1512 0 1513 N 1514 CA 1515 CB 1516 CG 1517 CD 1518 OEI 1519 NE2 1520 C 1521 0 1522 N 1523 CA LEU A 497 LEU A 497 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 498 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 499 GLN A 500 GLN A 500 GLN A 500 GLN A 500 GLN A 500 GLN A 500 GLN A 500 GLN A 500 GLN A 500 HIS A 501 HIS A 501 29.976 28.349 32.461 33.347 31.979 32.462 31.925 30.498 32.315 31.933 31.081 32.429 31.965 32.689 33.714 34.755 32.988 30.455 29.712 30.006 28.586 28.344 26.894 26.712 27.363 25.809 27.776 26.682 28.311 27.603 28.292 28.135 28.930 29.956 28.457 27.529 26.567 28.550 28.577 29.933 31.012 32.371 32.612 33.301 27.459 26.700 27.357 26.327 14.170 10.553 12.943 12.026 13.923 14.431 13.074 14.544 14.604 15.459 14.350 16.812 15.375 17.829 15.263 17.908 16.797 17.434 12.987 17.210 12.427 16.521 12.452 18.319 11.151 18.786 10.760 20.074 9.640 19.896 9.692 21.008 8.305 19.884 11.198 19.026 10.350 18.534 12.202 19.773 12.348 20.062 13.566 20.951 13.796 21.341 15.130 22.015 16.112 21.686 15.176 23.008 12.476 18.773 11.927 18.665 13.196 17.793 13.362 16.524 14.420 15.661 15.840 16.191 16.849 15.389 16.518 14.795 18.089 15.364 12.047 15.753 11.793 15.032 11.214 15.903 9.937 15.216 9.276 15.406 9.839 14.508 9.370 14.930 8.194 15.141 10.324 15.082 9.017 15.711 8.469 14.908 8.864 17.029 8.021 17.631 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 37.80 40.94 36.01 34.85 37.52 35.45 37.55 32.93 36.16 35.67 34.34 34.88 35.67 41.10 45.27 45.09 47.77 33.72 33.20 30.82 31.47 30.51 34.38 38.60 42.92 40.02 30.47 30.85 29.52 30.24 30.20 31.60 31.61 30.66 34.17 29.40 30.04 25.67 29.30 31.52 33.05 34.84 36.47 38.25 27.98 24.84 26.20 27.63

C

WO 99/50658 PCT/US99/06937

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1524 CB HIS A 1525 CG HIS A 1526 CD2 HIS A 1527 ND1 HIS A 1528 CE1 HIS A 1529 NE2 HIS A 1530 C HIS A 1531 0 HIS A 1532 N GLN A 1533 CA GLN A 1534 CB GLN A 1535 CG GLN A 1536 CD GLN A 1537 OEI GLN A 1538 NE2 GLN A 1539 C GLN A 1540 0 GLN A 1541 N ARG A 1542 CA ARG A 1543 CB ARG A 1544 CG ARG A 1545 CD ARG A 1546 NE ARG A 1547 CZ ARG A 1548 NH1 ARG A 1549 NH2 ARG A 501 501 501 501 501 501 501 501 502 502 502 502 502 502 502 502 502 503 503 503 503 503 503 503 503 503 503 503 504 504 504 504 504 504 504 504 505 505 505 505 505 506 506 506 506 506 506 506 26.535 27.892 28.726 28.541 29.716 29.854 24.935 23.998 24.796 23.504 23.554 23.460 23.589 23.632 23.651 23.056 21.913 23.955 23.630 24.772 24.432 25.479 25.072 24.279 23.804 23.962 23.347 22.425 24.143 23.953 24.971 24.781 25.166 25.627 22.541 21.846 22.120 20.784 20.605 19.738 18.754 19.954 19.013 19.502 19.240 20.187 20.704 20.423 7.919 19.145 7.420 19.535 6.540 18.931 7.844 20.676 7.244 20.758 6.448 19.712 8.572 17.348 7.815 17.107 9.892 17.379 10.498 17.119 12.006 17.371 12.378 18.848 13.875 19.089 14.663 18.149 14.268 20.355 10.221 15.685 9.822 15.453 10.429 14.727 10.196 13.326 10.668 12.418 10.563 10.932 11.222 10.056 11.214 8.654 12.126 8.105 13.120 8.840 12.044 6.820 8.716 13.065 8.375 12.321 7.841 13.672 6.406 13.496 5.621 14.323 4.100 14.344 3.505 12.991 3.495 15.444 6.030 13.934 5.288 13.245 6.547 15.083 6.262 15.585 6.868 16.980 6.832 14.628 6.164 14.293 8.066 14.184 8.711 13.277 10.111 12.903 11158 13.975 12.333 13.857 12.614 12.777 13.025 14.968 1.00 27.97 1.00 34.27 1.00 36.10 1.00 31.81 1.00 34.89 1.00 37.46 1.00 24.93 1.00 26.73 1.00 22.79 1.00 26.14 1.00 22.36 1.00 26.19 1.00 28.67 1.00 28.40 1.00 24.72 1.00 26.19 1.00 24.09 1.00 24.88 1.00 25.25 1.00 27.63 1.00 28.75 1.00 27.72 1.00 29.35 1.00 25.84 1.00 27.35 1.00 30.63 1.00 24.53 1.00 25.90 1.00 23.00 1.00 22.60 1.00 25.43 1.00 25.23 1.00 28.52 1.00 22.14 1.00 22.84 1.00 21.51 1.00 20.16 1.00 21.08 1.00 23.57 1.00 20.20 1.00 17.31 1.00 22.11 1.00 21.70 1.00 22.26 1.00 25.84 1.00 32.88 1.00 31.23 1.00 32.97 1550 C 1551 0 1552 N 1553 CA 1554 CB 1555 CG 1556 CDI 1557 CD2 1558 C 1559 0 1560 N 1561 CA 1562 CB 1563 C 1564 0 1565 N 1566 CA 1567 CB 1568 CG 1569 CD 1570 OEI 1571 NE2 ARG A ARG A LEU A LEU A LEU A LEU A LEU A LEU A LEU A LEU A ALA A ALA A ALA A ALA A ALA A GLN A GLN A GLN A GLN A GLN A GLN A GLN A WO 99/50658 PCT/US99/06937

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1572 C GLN A 506 1573 0 GLN A 506 1574 N LEU A 507 1575 CA LEU A 507 1576 CB LEU A 507 1577 CG LEU A 507 1578 CDI LEU A 507 1579 CD2 LEU A 507 1580 C LEU A 507 1581 0 LEU A 507 1582 N LEU A 508 1583 CA LEU A 508 1584 CB LEU A 508 1585 CG LEU A 508 1586 CDI LEU A 508 1587 CD2 LEU A 508 1588 C LEU A 508 1589 0 LEU A 508 1590 N LEU A 509 1591 CA LEU A 509 1592 CB LEU A 509 1593 CG LEU A 509 1594 CDl LEU A 509 1595 CD2 LEU A 509 1596 C LEU A 509 1597 0 LEU A 509 1598 N ILE A 510 1599 CA ILE A 510 1600 CB ILE A 510 1601 CG2 ILE A 510 1602 CGI ILE A 510 1603 CDI ILE A 510 1604 C ILE A 510 1605 0 ILE A 510 1606 N LEU A 511 1607 CA LEU A 511 1608 CB LEU A 511 1609 CG LEU A 511 1610 CDI LEU A 511 1611 CD2 LEU A 511 1612 C LEU A 511 1613 0 LEU A 511 1614 N SER A 512 1615 CA SER A 512 1616 CB SER A 512 1617 OG SER A 512 1618 C SER A 512 1619 0 SER A 512 18.813 17.684 19.905 19.827 21.231 22.026 23.371 21.264 19.090 18.242 19.402 18.755 19.501 20.977 21.642 21.095 17.279 16.498 16.895 15.495 15.347 15.710 15.354 14.989 14.681 13.493 15.343 14.710 15.720 15.208 15.965 14.789 14.210 13.120 14.998 14.633 15.754 17.128 1.8.024 16.996 13.326 12.663 12.963 11.718 11.661 10.315 10.572 9.584 7.881 12.016 7.715 11.550 7.354 11.474 6.537 10.263 6.244 9.725 7.457 9.225 6.994 8.713 8.176 8.130 5.219 10.496 4.825 9.695 4.539 11.592 3.260 11.881 2.535 13.001 2.311 12.678 1.551 13.814 1.542 11.367 3.396 12.239 2.478 12.003 4.530 12.815 4.747 13.173 6.030 13.999 5.858 15.479 7.106 16.263 4.656 16.038 4.841 11.885 4.514 11.854 5.270 10.815 5.397 9.508 5.946 8.464 5.710 7.056 7.438 8.696 8.189 9.288 4.025 9.049 3.906 8.474 2.989 9.323 1.634 8.917 0.656 9.267 1.022 8.692 -0.206 8.724 1.544 7.267 1.181 9.543 0.283 9.025 1.799 10.664 1.471 11.331 2.117 12.720 2.229 13.165 1.994 10.464 1.296 10.236 1.00 23.57 1.00 21.83 1.00 19.98 1.00 22.03 1.00 23.02 1.00 25.80 1.00 27.67 1.00 25.62 1.00 22.35 1.00 19.33 1.00 21.29 1.00 20.72 1.00 22.29 1.00 24.70 1.00 21.37 1.00 27.88 1.00 19.14 1.00 17.80 1.00 19.23 1.00 20.14 1.00 20.28 1.00 21.35 1.00 19.29 1.00 20.84 1.00 21.69 1.00 22.40 1.00 20.22 1.00 20.40 1.00 28.34 1.00 32.54 1.00 28.23 1.00 33.16 1.00 23.21 1.00 21.16 1.00 18.38 1.00 20.10 1.00 21.69 1.00 26.03 1.00 22.68 1.00 26.00 1.00 18.51 1.00 17.40 1.00 18.68 1.00 18.67 1.00 18.58 1.00 27.92 1.00 18.43 1.00 13.91

('I

WO 99/50658 PCTIUS99/06937

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1620 N HIS A 1621 CA HIS A 1622 CB HIS A 1623 CG HIS A 1624 CD2 HIS A 1625 ND1 HIS A 1626 CEI HIS A 1627 NE2 HIS A 1628 C HIS A 1629 0 HIS A 1630 N ILE A 1631 CA ILE A 1632 CB ILE A 1633 CG2 ILE A 1634 CG1 ILE A 1635 CDI ILE A 1636 C ILE A 1637 0 ILE A 1638 N ARO A 1639 CA ARG A 1640 CB ARG A 1641 CG ARG A 1642 CD ARG A 1643 NE ARG A 1644 CZ ARO A 1645 NHI ARG A 1646 NH2 ARG A 1647 C ARG A 1648 0 ARG A 1649 N HIS A 1650 CA HIS A 1651 CB HIS A 1652 CG 'HIS A 1653 CD2 HIS A 1654 NDI HIS A 1655 CEl HIS A 1656 NE2 HIS A 1657 C HIS A 1658 0 HIS A 1659 N MET A 1660 CA MET A 1661 CB MET A 1662 CG MET A 1663 SD MET A 1664 CE MET A 1665 C MET A 1666 0 MET A 1667 N SER A 513 513 513 513 513 513 513 513 513 513 514 514 514 514 514 514 514 514 515 515, 515 515 515 515 515 515 515 515 515 516 516 516 516 516 516 516 516 516 516 517 517 517 517 517 517 517 517 518 10.7 13 9.698 10.013) 9.923 8.863 11.010, 10.624 9.326 9.650 8.575 10.809 10.849 12.3 12 12.349 12.891 14.393 10.112 9.364 10.301 9.585 9.984 9.173 9.823 11.038 11.406 10.654 12.511 8.089 .7.275 7.726 6.3 17 6.126 4.692 3.967 3.830 2.633 2.689 5.708 4.598 6.438 5.925 6.837 6.805 7.670 9.390 5.773 4.791 6.741 3.228 9.982 .3.831 9.124 5.1315 8.894 6.146 10.136 6.744 10.734 6.391 10.949 7.101 11.995 7.328 11.889 3.079 7.790 2.863 7.220 2.662 7.297 1.921 6.038 1.678 5.576 0.602 4.499 2.986 5.019 2.992 4.874 0.590 6.210 0.164 5.328 -0.071 7.347 -1.327 7.564 -1.980 8.889 -3.237 9.213 -4.470 8.606 -4.8 13 9.334 -6.05 1 9.641 -7.080 9.281 -6.254 10.340 -1.020 7.594 -1.759 7.038 0.085 8.237 0.441 8.330 1.702 9.166 2'.101 9.312 3.061 8.691 1.469 10.180 2.022 10.089 2.992 9.191 0.659 6.954 0.216 6.689 1.334 6.073 1.589 4.730 2.576 4.002 3.978 4.631 5.243 3 .701 4.777 3 .962 0.289 3.940 0.101 3224 -0.610 4.086 1.00 18.95 1.00 20.82 1.00 24.36 1.00 32.13 1.00 35.29 1.00 35.00 1.00 3 4.67 1.00 3 )5.82 1.00 19.08 1.00 21.20 1.00 15.58 1.00 16.48 1.00 20.09 1.00 19.55 1.00 22.62 1.00 27.34 1.00 16.40 1.00 17.91 1.00 18.20 1.00 18.05 1.00 18.36 1.00 17.84 1.00 17.94 1.00 26.96 1.00 25.13 1.00 23.49 1.00 32.16 1.00 18.29 1.00 16.22 1.00 19.33 1.00 17.78 [.00 16.84 1.00 18.16 1.00 21.17 1.00 20.70 1.00 21.52 1.00 20.16 1.00 16.63 1.00 18.58 1.00 15.29 1.00 16.58 1.00 18.66 1.00 16.88 1.00 24.08 1.00 14.30 1.00 17.86 1.00 18.25 1.00 17.43 WO 99/M658 WO 9950658PCTIUS99/06937

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1668 CA SER A 1669 CB SER A 1670 00 SER A 1671 C SER A 1672 0 SER A 1673 N ASN A 1674 CA ASN A 1675 CB ASN A 1676 CG ASN A 1677 ODI ASN A 1678 ND2 ASN A 1679 C 1680 0 1681 N 1682 CA 1683 CB 1684 CG 1685 CD 1686 CE 1687 NZ 1688 C 1689 0 1690 N 1691 CA 1692 C 1693 0 1694 N 1695 CA 1696 CB 1697 CO 1698 SD 1699 CE 1700 C 1701 0 1702 N 1703 CA 1704 CB 1705 CG 1706 CD 1707 OEI 1708 0E2 1709 C 1710 0 1711 N 1712 CA 171 3 CB 1714 CG 1715 CD2 ASN A ASN A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A LYS A GLY A GLY A GLY A GLY A MET A MET A MET A MET A MET A MET A MET A MET A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A GLU A HIS A HIS A HIS A HIS A HIS A 518 518 518 518 518 i 19 519 519 519 519 519 519 519 520 520 520 520 520 520 520 520 520 521 521 521 521 522 522 522 522 522 522 522 522 523 523 523 523 523 523 523 523 523 524 524 524 514 524 6.697 7.974 7.834 5.476 4.788 5.204 4.047 3.957 5.046 5.585 5.368 2.761 1.902 2.627 1.449 1.484 1.512 0.656 -0.787 -1.560 1.380 0.316 2.520 .2.561 2.177, 1.426 2.696 2.393 3.170 3.396 4.572 6.125 0.893 0.268 0.32 1 -1.110 -1.555 -0.830 -1.153 -2.225 -0.337 -1.872 -2.8 17 -1.449 -2.093 -1.481 -2.233 -3.227 -1.896 3.403 -2.695 3.680 -4.030 3.227 -2.695 3.854 -3.295 3,.030 -2.697 5159 3-3.418 5.696 3-3.257 7.216 -4.011 7.957 -4.999 7.461 3-3.545 9.163 -2.871 5.079 -3.632 4.631 -1.548 5.078 -0.900 4.512 0.607 4.786 0.996 6.264 0.080 7.133 0.547 7.181 -0.134 8.261 -1.144 3 .005 -1.436 2.467 -1.021 2.332 -1.236 0.897 -2.655 0.536 -2.878 -0.413 -3.619 1.290 -5.027 1.058 -5.898 2.042 -7.308 1 .559 -7.352 0.202 -7.229 1.113 -5.281 1.218 -5.920 0.361 -4.790 2.318 -4.954 2.566 -4.206 3.835 -4.564 5.124 -3.585 6.258 -2.938 6.200 -3.460 7.202 -4.368 1.381 -4.964 0.882 -3.182 0.940 -2.505 173 -1.125 0.37 9 -0.278 -1.355 0.624 -1.172 1.00 18.40 1.00 16.77 1.00 24.23 1.00 17.91 1.00 18.97 1.00 21.82 1.00 21.99 1.00 23.24 1.00 -31. 14 1.00 3 2.50 1.00 29.10 1.00 23.76 1.00 24.48 1.00 20.58 1.00 25.49 1.00 24.73 1.00 32.31 1.00 37.11 1.00 41.56 1.00 42.66 1.00 25.40 1.00 26.44 1.00 22.88 1.00 21.53 1.00 24.79 1.00 25.71 1.00 22.75 1.00 23.40 1.00 25.74 1.00 31.06 1.00 34.06 1.00 29.28 1.00 26.49 1.00 25.47 1.00 24.95 1.00 27.15 1.00 31.08 1.00 38.93 1.00 46.90 1.00 47.40 1.00 47.39 1.00 26.10 1.00 24.25 1.00 24.74 1.00 26.17 1.00 24.64 1.00 3 0.59 1.00 32.15 WO 99/50658 WO 9950658PCTIUS99/06937

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1716 ND] 1717 GEI 1718 NE2 1719 C 1720 0 1721 N 1722 CA 1723 CB 1724 CG 1725 CDI 1726 CD2 1727 C 1728 0 1729 N 1730 CA 1731 CB .1732 CG 1733 CDI 1734 CEI 1735 CD2 1736 CE2 1737 CZ 1738 OH 1739 C 1740 0 1741 N 1742 CA 1743 CB 1744 OG 1745 C 1746 0 1747 N 1748 CA 1749 CB 1750 CG 1751 SD 1752 CE 1753 C 1754 0 1755 N 1756 CA 1757 CB 1758 CG 1759 CD 1760 CE 1761 NZ 1762 C 1763 0 HIS A HIS A HIS A HIS A HIS A LEU A LEU A LEU A LEU A LEU A LEU A LEU A LEU A TYR A TYR A TYR A TYR A TYR A TYR A TYR A TYR A TYR A TYR A TYR A TYR A SER A SER A SER A SER A SER A SER A MET A MET A MET A MET A MET A MET A MET A MET A LYS A LYS A LYS A LYS A LYS A LYS A LYS -A LYS A LYS A 524 524 524 524 524 52 5 52 5 525 525 525 525 525 525 526 526 526 526 526 526 526 526 526 526 526 526 527 527 527 527 527 527 528 528 528 528 528 528 528 528 529 529 529 529 529 529 529 529 529 -2.829 -3.580 1.996 -2.976 -0.8 11 -0.5 94 0.865 1.307 0.734 2.829 -1.497 -2.128 -1.559 -2.397 -2.22 1 -2.849 -2.1 14 -2.698 -4.188 -4.781 -4.029 -4.603 -852 -4.673 -4.158 -5.503 -5.606 -6.954 -5.8 17 -6.883 -4.883 -5.047 -3).898 -3).965 -5.652 -5.553 -5.087 689 -4.443 -4.4 13 -3).550 -2.798 3.548 -2.616 -2.420 829 6. 325 -0.332 -2.713 0.502 -3.326 1.094 -2.413 3-3.294 -1.474 3-3.419 -2.217 3-3.824 -1.746 -4.60 1 -2.955 -5.039 -3 .051 -5.765 -4.32 1 -5.076 -5.562 -5.769 -4.370 -5.822 -2.950 -6.133 -3.957 -6.512 -1..814 -7.698 1.696 -8.350 -0.324 -9.722 -0.229 -10.867 -0.537 -12.136 -0.482 -9.876 0.142 -11.141 0.201 -12.264 -0.113 -13.515 -0.063 -7.298 -1.893 -8.094 -2.349 -6.055 -1.543 -5.523 -1.686 -4.169 -0.979 -378 -0.786 -5.356 -3.172 -5.757 -3.642 -4.755 -3.901 -4.536 -5.331 -3.679 -5.870 -2.206 -5.468 -1.598 -5.273 -0.004 -6.044 -5.871 -6.071 -5.979 -7.137 -6.883 -5.499 -8.213 -6.099 -9.158 -5.261 -10.204 -6.071 -11.520 -6.104 -12.694 -5.856 -12.954 -4.402 -8.768 -6.182 -9.069 -7.266 1.00 27.46 1.00 34.58 1.00 30.50 1.00 28.06 1.00 29.81 1.00 27.07 1.00 29.30 1.00 26.39 1.00 29.34 1.00 29.61 1.00 29.22 1.00 3 1.67 1.00 32.45 1.00 3 6.14 1.00O 40.36 1.00 45.27 1.00 50.62 1.00 54.55 1.00 57.27 1.00 53.48 1.00 55.93 1.00 56.60 1.00 60.70 1.00 42.83 1.00 43.49 1.00 41.55 1.00 44.04 1.00 43.47 1.00 47.51 1.00 44.18 1.00 44.88 1.00 41.79 1.00 44.04 1.00 44.78 1.00 45.37 1.00 51.83 1.00 46.61 1.00 44.29 1.00- 44.02 1.00 46.78 1.00 51.28 1.00 50.87 1.00 50.55 1.00 5 1.25 1.00 53.22) 1.00 53.22 1.00 54.27 1.00 55.50 WO 99/50658 PCT/US99/'06937

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1764 N CYS A 1765 CA CYS A 1766 CB CYS A 1767 SG CYS A 1768 C CYS A 1769 0 CYS A 1770 N LYS A 1771 CA LYS A 1772 GB LYS A 1773 C LYS A 1774 0 LYS A 1775 N ASN A 1776 CA ASN A 1777 GB ASN A 1778 CG ASN A 1779 ODI ASN A 1780 ND2 ASN A 1781 C ASN A 1782 0 ASN A 1783 N VAL A 1784 CA VAL A 1785 GB VAL A 1786 CGI VAL A 1787 CG2 VAL A 1788 C VAL A 1789 0 VAL A 1790 N VAL A 1791 CA VAL A 1792 GB VAL A 1793 CG1 VAL A 1794 CG2 VAL A 1795 C VAL A 1796 0 -VAL A 1797 N PRO A 1798* CD PRO A 1799 CA PRO A 1800 GB PRO A 1801 CG PRO A 1802 C PRO A 1803 0 PRO A 1804 N LEU A 530 530 530 530 530 530 531 531 531 531 531 532 532 532 532 532 532 532 532 533 533 533 533 533 533 533 534 534 534 534 534 534 534 535 535 535 535 535 535 535 536 -6.472 -7.833 -8.333 -7.289 -8.766 -8.569 -9.390 -9.158 -9.073 -9.6 18 -8.179 -7.783 -8.966 -8.750 -8.344 -9.016 -7.247 -7.487 -6.507 -5.954 -6.223 -6.181 -7.574 -4.452 -3.846 -3.852 -2.417 -1.767 -0.300 -1.900 -2.089 -2.519 -1.3 15 -0.749 -0.949 0.011 -0.353 -0.296 0.121 -0.203 0.382 -0.250 -0.686 -1.953 -0.905 1.895.

2.414 -8.901 -5.027 -9.416 -4.961 -9.380 -3.517 -10.304 -2.358 -8.609 -5.858 -9.169 -6.514 -7.293 -5.888 -6.411 -6.713 -4.952 -6.3 17 -6.615 -8.195 -5.928 -9.061 -7.56 1 -8.474 -7.890 -9.840 -8.518 -10.581 -9.985 -10.878 -10.352 -11.983 -10.836 -9.891 -6.710 -10.648 -6.615 -11.850 -5.822 -9.992 -4.656 -10.669 -3.371 -9.865 -2.163 -10.785 -3.467 -9.172 -4.767 -10.907 -3.874 -11.499 -5.863 -10.451 -6.063 -10.621 -6.632 -9.341 -6.950 -9.601 -5.635 -8.200 -7.008 -11.770 -8.164 -11.780 -6.527 -12.755 -5.172 -12.874 -7.373 -13.893 -6.500 -14.697 -5.102 -14.319 -8.664 -13.411 -8.768 -12.254 -9.645 -14.299 -10.926 -13.937 -12.046 14.763 -13.256 -13.938 -12.917 -13.173 -14.449 -14.854 -10.990 -14.081 -11.501 -15.075 1.00 56.71 1.00 58.35 1.00 59.78 1.00 63.19 1.00 59.36 1.00 59.52 1.00 59.24 1.00 60.14 1.00 58.92 1.00 61.48 1.00 61.74 1.00 61.65 1.00 61.60 1.00 62.28 1.00 64.66 1.00 67.08 1.00 62.68 1.00 59.75 1.00 57.50 1.00 59.39 1.00 58.22 1.00 59.20 1.00 59.21 1.00 59.57 1.00 57.86 1.00 60.56 1.00 56.03 1.00 54.11 LOO 54.02 1.00 52.37 1.00 55.70 1.00 54.31 1.00 51.66 1.00 53.54 1.00 54.28 1.00 53.24 1.00 52.71 1.00 53.19 1.00 54.25 1.00 54.56 1.00 53.63 1.00 53.11 1.00 51.88 1.00 51.83 1.00 49.51 1.00 53.43 1.00 52.58 1.00 5 5.33 1805 CA LEU A 536 1806 GB LEU -A 536 1807 CG LEU A 536 1808 CDI LEU A 536 1809 GD2 LEU A 536 1810 C LEU A 536 1811 0 LEU A 536

C',

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1812 N TYR A 1813 CA TYR A 1814 CB TYR A 1815 CG TYR A 1816 CDI TYR A 1817 CEI TYR A 1818 -CD2 TYR A 1819 CE2 TYR A 1820 CZ TYR A 1821 OH TYR A 1822 C TYR A 1823 0 TYR A 1824 N ASP A 1825 CA ASP A 1826 CB ASP A 1827 CG ASP A 1828 ODI ASP A 1829 OD2 ASP A 1830 C ASP A 1831 0 ASP

A

1832 N LEU A 1833 CA LEU A 1834 CB LEU A 1835 CG LEU A 1836 CDI LEU A 1837 CD2 LEU A 1838 C LEU A 1839 0 LEU A 1840 N LEU A 1841 CA LEU A 1842 CB LEU A 1843 CG LEU A 1844 CDI LEU A 1845 CD2 LEU A 1846 C LEU A 1847 0 LEU A 1848 N LEU A 1849 CA LEU A 1850 CB LEU A 1851 CG LEU A 1852 CDI LEU A 1853 CD2 LEU A 1854 C LEU A 1855 0 LEU A 1856 N GLU A 1857 CA GLU A 1858 CB GLU A 1859 CG GLU A 537 537 537 537 537 537 537 537 537 537 537 537 538 538 538 538 538 538 538 538 539 539 539 539 539 539 539 539 540 540 540 540 540 540 540 540 541 541 541 541 541 541 541 541 542 542 542 542 2.601 4.057 4.627 4.33 1 3.623 3.334 4.747 4.462 3.757 3.472 4.401 4.330 4.748 5.055 5.594 4.571 4.931 3.405 5.991 5.620 7.196 8.155 9.419 10.561 10.913 11.758 7.558 7.590 7.011 6.411 5.792 5.124 6.092 4.693 5.337 5.316 4.446 3.378 2.452 1.244 0.476 1.713 3.937 3.472 4.929 5.535 6.73 8 6.396 -10.462 -13.087 -10.501 -13.093 -9.134 -12.709 -8.053 -13.731 -6.905 -13.376 -5.915 -14.317 -8.187 -15.058 -7.202 -16.008 -6.071 -15.631 -5.097 -16.565 -11.562 -12.056 -11.319 -10.856 -12.748 -12.540 -13.896 -11.691 -15.037 -12.554 -15.531 -13.566 -16.373 -14.416 -15.073 -13.511 -13.676 -10.508 -13.964 -9.371 -13.200 -10.766 -12.959 -9.692 -12.323 -10.263 -12.031 -9.292 -13.280 -8.492 -11.538 -10.077 -12.050 -8.614 -12.367 -7.423 -10.917 -9.042 -9.976 -8.111 -8.800 -8.861 -7.774 -7.945 -7.357 -6.838 -6.572 -8.762 -10.660 -7.282 -10.522 -6.063 -11.388 -7.941 -12.101 -7.245 -12.771 -8.255 -11.932 -8.678 -11.476 -7.448 -10.733 -9.485 -13.147 -6.275 -13.254 -5.137 -13.915 -6.723 -14.932 -5.868 -15.566 -6.564 -16.327 -7.831 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 48.72 44.22 44.52 45.18 43.77 45.23 46.91 43.93 46.70 48.35 41.29 41.82 40.34 38.84 43.47 47.67 49.33 48.07 37.28 38.55 33.83 32.80 32.78 30.93 33.81 25.92 31.85 25.63 32.07 31.03 30.56 31.12 29.76 30.85 34.55 31.60 35.64 37.84 38.49 39.80 40.02 40.48 40.10 42.72 38.45 39.59 41.73 48.34 WO 99/50658 PCT/US99/06937

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1860 CD GLU A 1861 QEI GLU A 1862 0 E2 GLU A 1863 C GLU A 1864 0 GLU A 1865 N MET A 1866 CA MET A 1867 CB MET A 1868 CG MET A 1869. SD MET A 1870 CE MET A 1871 C MET A 1872 0 MET A 1873 N LEU A 1874 CA LEU A 1875 CB LEU A 1876 CG LEU A 1877 CD] LEU -A 1878 CD2 LEU A 1879 C LEU A 1880 0 LEU A 1881 N ASP A 1882 CA ASP A 1883 CB ASP A 1884 CG ASP A 1885 ODI ASP A 1886 0D2 ASP A 1887 C ASP A 1888 0 ASP A 1889 N ALA A 1890 CA ALA A 1891 CB ALA A 1892 C ALA A 1893 0 ALA A 1894 N HIS A 1895 CA HIS A 1896 CB HIS A 1897 CG HIS A 1898 CD2 HIS A 1899 ND1 HIS A 1900 CEI HIS A 1901 NE2 HIS A 1902 C HIS A 1903 0 HIS A 1904 N ARO A 1905 CA ARO A 1906 CB ARG A 1907 Co 'ARG A 542 542 542 542 542 543 543 543 543 543 543 543 543 544 544 544 544 544 544 544 544 545 545 545 545 545 545 545 545 546 546 546 546 546 547 547 547 547 547 547 547 547 547 547 548 548 548 548 6.931 -17.747 -7.819 8.049 -17.961 -7.298 6.230 -18.647 -8.331 5.989 -14.299 -4.553 5.567 -14.710 -3.472 6.844 -13.287 -4.663 7.380 -12.580 -3.503 8.242 -11.408 -3.963 9.311 -11.797 -4.953 10.829 12.223 -4.114 12.014 -11.399 -5.151 6.287 -12.064 -2.581 6.413 -12.127 -1.358 5.218 -11.544 -3.175 4.100 -11.013 -2.408 3.087 -10.344 -3.341 1.775 -9.905 -2.688 2.060 -8.886 -1.586 0.854 -9.317 -3.741 3.420 -12.120 -1.614 2.957 -11.899 -0.496 3.367 -13.313 -2.197 2.746 -14.456 -1.539 2.606 -15.617 -2.524 1.703 -15.278 -3 .691 0.697 -14.568 -3.475 1.999 -15.718 -4.824 3.559 -14.898 -0.327 3.004 -15.388 0.657 4.874 14.723 -0.401 5.750 -15.095 0.702 7.180 -14.678 0.395 5.269 -14.424 1.987 5.476 -14.940 3.085 4.622 -13.270 1.838 4.102 -12.520 2.978 4.144 -11.017 2.684 5.489 -10.394 2.896 6.644 -10.506 2.199 5.748 -9.514 3.925 7.004 -9.111 3.853 7.570 -9.698 2.814 2.668 -12.940 3 .306 1.842 -12.120 3707 2.381 -14.224 3.1 33 1.053 -14.758 3.411 0.243 -14.864 2.113) -1.149 14.243 2.186 1.00 52.57 1.00 52.70 1.00 53 .69 1.00 39.94 1.00 40.99 1.00 38.29 1.00 38.11 1.00 37.34 1.00 40.59 1.00 45.64 1.00 42.61 1.00 3 7.94 1.00 39.20 1.00 -39.44 1.00 40.91 1.00 39.88 1.00 42.70 1.00 37.35 1.00 38.4 7 1.00 42.83 1.00 42.73 1.00 46.32 1.00 50.65 1.00 53.67 1.00 57.35 1.00 59.99 1.00- 59.68 1.00 50.74 1.00 49.39 1.00 51.82 1.00 53.12 1.00 53.19 1.00 54.67 1.00 52.32 1.00 56.66 1.00 59.19 1.00 56.70 1.00 54.64 1.00 53.92 1.00 52.17 1.00 52.16 1.00 51.90 1.00 62.77 1 .00' 63.24 1.00 68.37 1.00 72.75 1.00 73.73 1.00 74.04

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1908 CD 1909 NE 1910 CZ 1911 NH 1912 NH 1913 C 1914 0 1915 N 1916 CA 1917 CB 1918 C 1919 0 1920 OX1 HETATM 1921 CP9 HETATM 1922 CP8 SHETATM 1923 CP7 HETATM 1924 CP6 HETATM 1925 CPI HETATM 1926 CP2 HETATM 1927 CP3 HETATM 1928 OP3 HETATM 1929 CP4 HETATM 1930 CP5 HETATM 1931 C7 HETATM 1932 C6 HETATM 1933 C5 HETATM 1934 C4 HETATM 1935 C3 HETATM 1936 03 HETATM 1937 C2 HETATM 1938 CI HETATM 1939 C8 HETATM 1940 C9 HETATM 1941 CL ATOM 1942 CB ATOM 1943 C ATOM 1944 0 ATOM 1945 N ATOM 1946 CA ATOM 1947 N ATOM 1948 CA ATOM 1949 CB ATOM 1950 CG ATOM 1951 CDI ATOM 1952 CD2 ATOM 1953 C ATOM 1954 0 ATOM 1955 N ARG A ARG A ARG A I ARG A SARG A ARG A ARG A LEU A LEU A LEU A LEU A LEU A SLEU A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A DES A CL A SER B SER B SER B SER B SER B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B ALA B 548 548 548 548 548 548 548 549 549 549 549 549 549 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 601 305 305 305 305 305 306 306 306 306 306 306 306 306 307 -1.081 -2.305 -2.478 -1.506 -3.627 1.179 0.197 2.398 2.669 2.971 3.846 4.892 3.708 5.390 5.834 5.038 3.587 2.987 1.597 0.842 -0.506 1.421 2.793 5.671 7.113 7.541 8.889 9.814 11.125 9.423 8.066 4.894 4.959 14.781 12.321 12.672 13.701 12.045 11.875 12.193 12.884 11.884 12.221 13.304 10.965 13.660 14.570 13.293 -12.728 2.297 -12.167 2.863 -10.880 3.149 -10.006 2.919 -10.464 3.662 -16.133 4.061 -16.697 4.549 -16.665 4.063 -17.969 4.653 -18.986 3.557 -17.870 5.619 -17.317 5.215 -18.341 6.769 -3.061 -6.139 -1.989 -5.134 -0.714 -5.236 -0.864 -5.062 -0.978 -3.784 -1.150 -3.684 -1.214 -4.871 -1.419 -4.824 -1.099 -6.143 -0.929 -6.230 0.461 -5.482 0.561 -5.809 0.306 -7.131 0.429 -7.477 0.804 -6.488 0.901 -6.839 1.066 -5.161 0.937 -4.838 1.765 -5.443 2.468 -4.070 -3.035 -17.739 21.086 25.295 22.102 27.548 22.760 27.702 23.521 25.606 22.187 26.251 21.293 28.484 21.133 29.757 21.200 30.913 20.417 32.183 21.144 32.966 20.258 33.027 19.819 29.803 19.654 30.614 18.881 28.933 1.00 74.50 1.00 75.04 1.00 75.59 1.00 75.79 1.00 76.00 1.00 74.94 1.00 75.15 1.00 76.49 1.00 78.14 1.00 77.55 1.00 79.13 1.00 80.40 1.00 79.46 1.00 21.38 1.00 22.41 1.00 21.32 1.00 25.87 1.00 23.92 1.00 29.77 1.00 31.40 1.00 33.36 1.00 27.01 1.00 27.40 1.00 22.39 1.00 21.75 1.00 19.97 1.00 23.81 1.00 21.88 1.00 22.32.

1.00 19.74 1.00 21.25 1.00 21.47 1.00 21.38 1.00 24.10 1.00 64.27 1.00 64.37 1.00 66.90 1.00 63.72 1.00 64.21 1.00 63.09 1.00 60.98 1.00 61.23 1.00 62.23 1.00 62.56 1.00 64.31 1.00 58.39 1.00 58.56 1.00 54.82 WO 99/50658 PTU9/63 PCTIUS99/06937

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1956 CA 1957 CB 1958 C .1959 0 1960 N 1961 CA 1962 CB 1963 CG 1964 CDI 1965 CD2 1966 C 1967 0 1968 N 1969 CA 1970 CB 1971 OG 1972 C 1973 0 1974 N 1975 CA 1976 CB 1977 CG 1978 CDI 1979 CD2 1980 C 1981 0 1982 N 1983 CA 1984 CB 1985 OGI 1986 CG2 1987 C 1988 0 1989 N 1990 CA 1991 CB 1992 C 1993 0 1994 N 1995 CA 1996 CB 1997 CG 1998 ODI 1999 0D2 ALA B ALA B ALA B ALA B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B SER B SER B SER B SER B SER B SER B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B THR B THR B THR B THR B THR B THR B THR B ALA B ALA B ALA B ALA B ALA B ASP B ASP B ASP B ASP B ASP B ASP B 307 307 307 307 308 308 308 .308 -308 308 308 308 309 309 309 309 309 309 310 310 310 310 310 310 310 310 311 311 311 3)11 311 311 311 312 312 312 312 312 313 313 313 313 313 313 313 313 314 13 .97 1 13 .092 15.303 16.196 15.431 16.643 16.413 16.3 15 15.942 15.287 17.874 19.000 17.669 18.796 18.562 17.459 19.072 20.053 18.2 17 18.394 17.205 16.2 16 16.040 14.881 19.691 20.111 20.339 2 1.564 22.434 2 1.724 22.782 21. 145 19.967 22. 106 21.811 23 .077 21.210 20.226 2 1.800 2 1.304 22.258 23.494 24.586 23 .377 19.925 19.056 19.73 3 18.458 17.589 28.861 16.584 218.143 17.719 28.122 16.885 28.274 18.769 27.320 18.983 26.542 20.100 25.526 19.708 24.051 18.239 23.903 20.602 23.375 19.297 27.3 85 19.102 26.932 19.775 28.608 20.100 29.4 75 21.447 30.163 21.379 3 1.046 19.028 3 0.529 19.119 3 1.269 18.012 30.596 16.936 31.569 15.969 .31.499 15.873 32.668 17.219 33.355 15.380 32.138 16.174 31.285 16.070 30.139 15.662 32.326 14.888 32.127 14.824 33.399 14.116 34.420 16.212 3 3.893 13.460 31.790 13.117 31.899 12.628 31. 396 11.237 31.053 10.527 30.577 10.489 3 2.240 9.766 3 2.089 10.665 33.419 9.994 34A.615 10.219 35.788 9.358 35.700 9.858 36.040 8.184 3 5.290 10.520 3 4.971 9.768 35.426 11.819 34.763 12.457 35.046 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 16~00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 50.62 51.30 46.84 45.62 43.46 43.01 4 1.3 2 43. 40.51 39.80 42.11- 44.34 40.88 42.79 41.25 46.67 42.60 44.18 39.44 37.62 38.84 42.43 42.55 39.69 34.11 34.41 34.04 32.34 31.75 36.20 31.05 32. 37 28.16 3 3.23 3 5.63 .34.00 34.29 33.10 33.90 34.19 42.09 44.87 51.57 46.79 31.99 32.03 29.38 29.73 2000 C ASP B 2001 0 ASP B 2002 N GLN B 2003 CA GLN B WO 99/50658 ATOM 2004 CB GLN B ATOM 2005 CG GLN B ATOM 2006 CD GLN B ATOM 2007 QEI GLN B ATOM' 2008 NE2 GLN B ATOM 2009 C GLN B ATOM 2010 0 GLN B ATOM 2011 N MET B ATOM 2012 CA MET B ATOM 2013 CB MET B ATOM 2014 CG MET B ATOM 2015 SD MET B ATOM 2016 CE MET B ATOM 2017 C MET B 15 ATOM 2018 0 MET B ATOM 2019 N VAL B ATOM 2020 CA VAL B ATOM 2021 CB VAL B ATOM 2022 CG1 VAL B ATOM 2023 CG2 VAL B ATOM 2024 C VAL B ATOM 2025 0 VAL B ATOM 2026 N SER B ATOM 2027 CA SER B ATOM 2028 CB SER B AT 'OM 2029 OG SER B ATOM 2030 C SER B ATOM 2031 0 SER B ATOM 2032 N ALA B ATOM 2033 CA ALA B ATOM 2034 CB ALA B ATOM 2035 C ALA B *ATOM 2036 0 ALA B ATOM 2037 N LEU B ATOM 2038 CA LEU B ATOM 2039 CB LEU B ATOM 2040 CG LEU B ATOM 2041 CDI LEU B ATOM 2042 CD2 LEU B ATOM 2043 C LEU B ATOM 2044 0 LEU B ATOM 2045 N LEU B ATOM 2046 CA LEU B ATOM 2047 CB LEU B ATOM 2048 CG LEU B ATOM 2049 CDI LEU B ATOM 2050 CD2 LEU B ATOM 2051 C LEU B PCTIUS99I06937 314 314 314 314 314 314 314 315 315 315 315 315 315 .315 315 316 316 316 316 .316 316 316 317 317 317 317 317 317 318 318 318 318 318 319 319 319 319 319 319 319 319 320 .320 320 320 320 320 320 18.562 18.970 19.213 19.300 19.327 17.409 16.274 17.801 16.900 17.595 16.787 15.252 15.890 16.490 15.302 17.48 1 17.229 18.554 18.272 19.302 16.326 15.397 16.601 15.799 16.358 17.492 14.346 13.434 14.135 12.786 12.850 12.038 10.902 12.695 12.098 13.050 13.264 14. 146 11.918 11.729 10.6 15 12.656 12.399 13.657 14.846 16.053 14.484 11.249 13.966 34.83 2 14.732 36.085 16.208 35.815 16.6-34 34.664 16.995 36.880 11.873 34.116 11.620 34.522 11.657 32.864 11.079 3 1.8 72 11.029 30.509 10.345 29.421 11.220 29.065 12.835 2-8.611 9.665 321.311 9.351 32.396 8.823 32.598 7.447 33.02 7 6.708 33.35 1 5.404 34.096 6.410 32.074 7.389 3 4.258 6.579 3 4.318 8.243 3 5.242 8.268 36.460 9.294 37.45 1 8.771 38.112 8.600 36.154 7.932 36.64 8 9.634 3 5.342 10.049 34.969 11.250 34.022 8.890 34. 30 6 8.598 3 4.648 8.225 33.364 7.102 32.6 52 6.635 31.548 7.622 30. 394 6.995 29.331 8.020 29.803 5.926 33. 564 5.396 33.488 5.516 34.426 4.405 3 5.33 4 4.075 36.145 3.460 -33 .39 8 .3.375 3 6.33')0 2.076 34.895 4.722 36-290 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 32.88 36.47 36.76 38.79 39.72 29.11 28.82 27.27 30.41 30.10 38.02 41.12 39.32 27.99 26.60 27.26 24.54 26.22 29.81 29.75 27.22 25.55 24.40 27.63 31.68 39.97 26.73 25.65 24.19 24.17 21.44 21.63 20.25 23.37 25.42 22.03 20.71 23.60 23.82 27.26 28.91 26.58 26.73 26.87 26.15 28.04 26.96 29.19

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15 ATOM

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2052 0 LEU B 2053 N ASP B 2054 CA ASP B 2055 CB ASP B 2056 CG ASP B 2057 ODI ASP B 2058 0D2 ASP B 2059 C 2060 0 2061 N 2062 CA 2063 CB 2064 C 2065 0 2066 N 2067 CA 2068 CB 2069 CG 2070 CD 2071 0E1 2072 0E2 2073 C 2074 0 2075 N 2076 CD 2077 CA 2078 CB 2079 CG 2080 C 2081 0 2082 N 2083 CD 2084 CA 2085 CB 2086 CG 2087 C 2088 0 2089 N 2090 CA 2091 CB 2092 CG2 2093 CGI 2094 CDI 2095 C 2096 0 2097 N 2098 CA 2099 CB ASP B ASP B ALA B ALA B ALA B ALA B ALA B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B PRO B ILE B ILE B ILE B ILE B ILE B ILE B ILE B ILE B LEU B LEU B LEU B 320 321 321 321 321 321 321 321 321 322 322 322 322 322 323 323 323 323 323 323 323 323 323 324 324 324 324 324 324 324 325 325 325 325 325 325 325 326 326 326 326 .326 326 326 326 .327 327 327 10.449, 11. 160 10. 112 10.494 1 1.407 10.897 12.635 8.742 7.715 8.726 7.469, 7.668 6.9 11 5.810 7.662 7.229 8.196 9.393 8.988 8.852 8.809 5.796 5.409 4.986 5.286 3.607 2.919 4.015 3.6:9 4.590 2.540 1.299 2.520 1.394 0.448 2.270 1.853 2.538 2.301 3.303 3.011 4.729 5.241 0.893 0.632 -0.0 18 -1.399 336 3.849 36.63 1 5.976 36.719 6.371 37.647 7.683 38.336 7.461 39.535 7.058 40.605 7:676 3 9.402 6.494 36.989 6.432 3 7.661 6.650 35.672 6.779 3 4.950 7.668 33 .728 5.420 34.523 5.338 33.979 4.355 34.78 1 3.02 1 34.386 1.982 34.938 1.746 3 4.024 1.134 32.685 1.881 31.692 -0.095 32.624 2.696 34.8 10 2.926 35.951 2.165 33.880 1.806 32.483 1.839 34.242 1.658 32.893 1.137 32.015 0.556 35.060 -0.200 35.028 0.287 35.801 1.068 35.945 -0.940 36.603 -0.691 37.595 0.205 36.854 -2.192 35.776 -2.118 34.617 -334 36.379 -4.620 35.722 -5.688 36.185 -7.018 35.481 -5.209 3 5.900 585 34.533 -5.020 36.149 -5.231 37.332 -5.104 35.188 -5.437 3 5. 493 -4.747 34.493 1.00 2-6.66 1.00 29.72 1.00 31.36 1.00 36.60 1.00 46.11 1.00 46.64 1.00 45.98 1.00 28.29 1.00 27.19 1.00 28.34 1.00 25.55 1.00 24.11 1.00 22.80 1.00 24.54 1.00 20.16 1.00 21.44 1.00 23.72 1.00 23.58 1.00 25.23 1.00 21.74 1.00 25.49 1.00 22.35 1.00 22. 34 1.00 19.10 1.00 19.11 1.00 22.04 1.00 2 1'.96 1.00 24. 13 1.00 23.44 1.00 22.20 1.00 24.88 1.00 26.67 1.00 25.10 1.00 27.09 1.00 26.87 1.00 25.77 1.00 21.69 1.00 24.05 1.00 22.51 1.00 25.81 1.00 23.78 1.00 25.75 1.00 27.78 1.00 23.63 1.00 24.81 1.00 19.44 1.00 17.03 1.00 18.39 WO 99/50658 PCT/US99/06937

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2100 CG LEU B 2101 CDI LEU B 2102 CD2 LEU B 2103 C LEU B 2104 0 LEU B 2105 N TYR B 2106 CA TYR B 2107 CB TYR B 2108 CG TYR B 2109 CDI TYR B 2110 CEI TYR B 2111 CD2 TYR B 2112 CE2 2113 CZ 2114 OH 2115 C 2116 0 2117 N 2118 CA 2119 CB 2120 OG 2121 C 2122 0 2123 N 2124 CA 2125 CB 2126 C 2127 0 2128 N 2129 CA 2130 CB 2131 CG 2132 CDI TYR B TYR B TYR B TYR B TYR B SER B SER B SER B SER B SER B SER B GLU B GLU B GLU B GLU B GLU B TYR B TYR B TYR B TYR B TYR B 327 327 327 327 327 328 328 328 328 328 328 328 328 328 328 328 328 329 329 329 329 329 329 330 330 330 330 330 331 331 331 331 331 331 331 331 331 331 331 331 332 332 332 332 332 332 332 332 -2.201 -3.245 -2.384 -1.662 -0.854 -2.803 -3.202 -3.658 -2.515 -2.118 -1.034 -1.802 -0.716 -0.338 0.739 -4.336 -5.115 -4.420 -5.480 -5.002 -6.091 -6.625 -6.453 -7.792 -8.930 10.134 -8.493 -3.216 34.373 -2.679 33.406 -2.570 35.742 -6.928 35.499 -7.722 35.014 -7.300 36.066 -8.692 36.135 -9.050 37.550 -9.376 38.468 -10.696 38.677 -11.000 39.498 -8.362 39.103 -8.654 39.926 -9.973 40.117 -10.257 40.923 -8.944 35.168 -8.039 34.849 -10.180 34.698 -10.571 33.787 -11.710 32.887 -12.329 32.233 -11.042 34.673 -11.157 35.888 -11.289 34.084 -11.776 34.859 -11.999 33.951 -13.093 35.491 1.00 20.69 1.00 14.87 1.00 14.39 1.00 19.87 1.00 20.90 1.00 20.92 1.00 21.79 1.00 22.91 1.00 24.60 1.00 25.93 1.00 28.10 1.00 29.46 1.00 35.30 1.00 32.59 1.00 37.24 1.00 22.25 1.00 19.77 1.00 25.81 1.00 29.39 1.00 27.65 1.00 28.98 1.00 33.17 1.00 32.52 1.00 38.75 1.00 44.91 1.00 45.63 1.00 48.62 1.00 52.37 1.00 51.75 1.00 55.25 1.00 53.04 1.00 50.70 1.00 47.09 1.00 46.43 1.00 47.52 1.00 43.98 1.00 44.33 1.00 45.31 1.00 60.11 1.00 63.13 1.00 61.60 1.00 63.58 1.00 65.11 1.00 65.32 1.00 63.69 1.00 63.61 1.00 62.86 1.00 62.26 2133 CEI TYR B 2134 CD2 TYR B 2135 CE2 TYR B 2136 CZ TYR B 2137 OH TYR B 2138 C TYR B 2139 0 TYR B 2140 N ASP B 2141 CA ASP B 2142 CB ASP B 2143 CG ASP B 2144 ODI ASP B 2145 OD2 ASP B 2146 C ASP B 2147 0 ASP B -7.739 -13.851 34.882 -8.952 -13.366 36.707 -8.575 -14.596 37.396 -8.538 -14.365 38.911 -9.769 -13.668 39.440 -10.880 -14.400 39.856 -12.035 -13.762 40.292 -9.842 -12.273 39.478 -10.993 -11.625 39.913 -12.086 -12.376 40.314 -13.239 -11.747 40.715 -9.528 -15.743 37.075 -10.748 -15.569 37.066 -8.952 -16.913 36.809 -9.704 -18.124 36.490 -10.637 -17.895 35.298 -11.723 -18.953 35.200 -11.420 -20.136 35.463 -12.876 18.602 34.866 -8.707 -19.227 36.153 -7.853 -19.056 35.287 WO 99/50658 PCT/US99/06937

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2148 N PRO B 2149 CD PRO B 2150 CA PRO B 2151 CB PRO B 2152 CG PRO B 2153 C PRO B 2154 0 PRO B 2155 N THR B 2156 CA THR B 2157 CB THR B 2158 OGI THR B 2159 CG2 THR B 2160 C THR B 2161 0 THR B 2162 N ARG B 2163 CA ARG B 2164 CB ARG B 2165 C ARG B 2166 0 ARG B 2167 N PRO B 2168 CD PRO B 2169 CA PRO B 2170 CB PRO B 2171 CG PRO B 2172 C PRO B 2173 0 PRO B 2174 N PHE B 2175 CA PHE B 2176 CB PHE B 2177 CG PHE B 2178 CDI PHE B 2179 CD2 PHE B 2180 CEI PHE B 2181 CE2 PHE B 2182 CZ PHE B 2183 C PHE B 2184 0 PHE B 2185 N SER B 2186 CA SER B 2187 CB SER B 2188 OG SER B 2189 C SER B 2190 0 SER B 2191 N GLU B 2192 CA GLU B 2193 CB GLU B 2194 CG GLU B 2195 CD GLU B 333 3333 333 333 334 334 334 334 334 334 334 335 335 335 335 335 336 336 336 336 336 336 336 337 337 337 337 337 337 337 337 337 337 337 338 338 338 338 338 338 339 339 339 339 339 -8.811 -20.379 36.833 -9.808 -20.690 37.875 -7.901 -21.503 36.596 -8.015 -22.325 37.874 -9.410 -22.071 38.347 -8.180 -22.340 35.351 -7.384 -23.214 35.007 -9.303 -22.084 34.683 -9.649 -22.832 33.475 -11.065 -22.477 32.975 -11.132 -21.078 32.675 -12.102 -22.817 34.036 -8.634 -22.499 32.388 -8.931 -21.774 31.437 -7.432 -23.043 32.553 -6.324 -22.820 31.633 -5.130 -23.667 32.050 -6.667 -23.086 30.174 -6.302 -22.298 29.298 -7.377 -24.194 29.884 -7.938 -25.227 30.769 -7.698 -24.437 28.471 -8.399 -25.799 28.476 -8.164 -26.372 29.844 -8.602 -23.324 27.954 -9.809 -23.342 28.179 -8.007 -22.350 27.274 -8.764 -21.223 26.742 -7.850 -20.003 26.567 -7.229 -19.517 27.846 -5.846 -19.511 28.002 -8.023 -19.062 28.893 -5.262 -19.059 29.185 -7.449 -18.608 30.079 -6.064 -18.607 30.224 -9.420 -21.535 25.402 -8.962 -22.399 24.658 -10.504 -20.828 25.107 -11.198 -20.981 23.836 -12.713 -20.948 24.035 -13.164 -19.621 24.235 -10.761 -19.761 23.037 -10.143 -18.855 23.591 -11.075 -19.722 21.750 -10.682 -18.579 20.950 -11.146 -18.737 19.501 -10.758 -17.553 18.623 -10.865 -17.852 17.137 1.00 63.96 1.00 64.24 1.00 64.24 1.00 64.70 1.00 65.00 1.00 63.90 1.00 63.70 1.00 63.83 1.00 63.77 1.00 64.63 1.00 65.95 1.00 65.09 1.00 62.62 1.00 60.15 1.00 63.14 1.00 60.70 1.00 58.73 1.00 59.71 1.00 62.33 1.00 55.25 1.00 53.53 1.00 50.10 1.00 49.70 1.00 50.71 1.00 44.54 1.00 44.14 1.00 39.18 1.00 38.25 1.00 36.98 1.00 36.81 1.00 38.89 1.00 35.97 1.00 36.85 1.00 37.15 1.00 38.40 1.00 36.81 1.00 36.26 1.00 35.85 1.00 34.76 1.00 34.85 1.00 33.53 1.00 34.99 1.00 34.32 1.00 33.01 1.00 33.94 1.00 33.79 1.00 39.11 1.00 43.17

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2196 QEI 2197 0E2 2198 C 2199 0 2200 N 2201 CA 2202 CB 2203 C 2204 0 2205 N 2206 CA 2207 CB 2208 00 2209 C 2210 0 2211 N 2212 CA 2213 CB 2214 CG 2215 SD 2216 CE 2217 C 2218 0 2219 N 2220 CA 2221 CB 2222 CO 2223 SD 2224 CE 2225 C 2226 0 2227 N 2228 CA 2229 C 2230 0 2231 N 2232 CA 2233 CB 2234 CG 2235 CDI 2236 CD2 2237 C 2238 0 2239 N 2240 CA 2241 CB 2242 CG 2243 CDI GLU B GLU B GLU B GLU B ALA B ALA B ALA B ALA B ALA B SER B SER B SER B SER B SER B SER B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B MET B GLY B GLY B GLY B GLY B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU -B 339 339 339 339 340 340 340 340 340 341 341 341 341 341 341 342 342 342 342 342 342 342 342 343 343 343 343 343 343 343 343 344 344 344 344 345 345 345 345 345 345 345 345 346 346 346 346 346 -11.990 -17.785 16.600 -9.824 18.152 16.510 -11.265 -17.295 21.531 -10.575 16.283 21.631 -12.535 17.33 9 21.920 13 194 -16.164 22.469 -14.696 -16.412 22.573 -12.639 -15.731 23.826 -12.431 -14.541 24.060 -12.407 -16.691 24.719 -11.882 -16.386 26.044 11.867' 17.643 26.923 -10.851 -18.541 26.515 -10.479 -15.793 25.960 -10.171 -14.824 26.651 -9.631 -16.368 25.114 -8.271 -15.865 24.954 -7.477 -16.758 24.001 -6.038 -16.300 23.802 -4.866 -17.667 23.777 -4.034 -17.341 22.244 -8.322 -14.448 24.385 -7.653 -13.541 24.874 -9.114 -14.278 23.345 -9.262 -12.979 22.712 -10.210 -13.088 21.528 -9.540 -13.618 20.273 -8.325 -12.456 19.609 -9.344 -11.015 19.371 -9.798 -11.966 23.712 -9.360 -10.810 23.728 -10.739 -12.403 24.536 -11.320 -11.526 25.536 -10.313 -11.103 26.592 -10.262 -9.934 26.982 -9.511 -12.048 27.063 -8.520 -11.748 28.083 -7.886 -13.040 '28.600 -8.794 -14.010 29.362 -8.099 -15.357 29.488 -9.122 1 3.44 3 30.736 -7.425 10.822 217.550 -7.037 -9.865 28.212 -6.937 -11.108 26.350 -5.874 10.303 25.763 -5.343 -10.962 24.486 -4.684 12.33)1 24.668 -4.303 -12.916 23 .309 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 45.28 39.19 34.28 33.65 31.12 29.10 33.84 28.98 30.48 26.66 24.26 27.04 .33.84 23.97 21.56 26.83 27.24 30.45 .35.35 44.57 41.37 25.31 26.67 25.75 25.47 23.51 28.86 29.25 28.74 25.37 24.98 23.91 22.43 22.06 20.87 19.36 25.74 26.78 30.04 28.39 29.93 23.24 23.43 21.92 22.71 23 17 20.66 18.75 C7, WO 99/50658 PCT/US99/06937

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2244 CD2 LEU B 2245 C LEU B 2246 0 LEU B 2247 N THR B 2248 CA THR B 2249 CB THR B 2250 OGI THR B 2251 CG2 THR B 2252 C THR B 2253 0 THR B 2254 N ASN B 2255 CA ASN B 2256 CB ASN B 2257 CG ASN B 2258 ODI ASN B 2259 ND2 ASN B 2260 C ASN B 2261 0 ASN B 2262 N LEU B 2263 CA LEU B 2264 CB LEU B 2265 CG LEU B 2266 CDI LEU B 2267 CD2 LEU B 2268 C LEU B 2269 0 LEU B 2270 N ALA B 2271 CA ALA B 2272 CB ALA B 2273 C ALA B 2274 0 ALA B 2275 N ASP B 2276 CA ASP B 2277 CB ASP B 2278 CG ASP B 2279 ODI ASP B 2280 OD2 ASP B 2281 C ASP B 2282 0 ASP B 2283 N ARG B 2284 CA ARG B 2285 CB ARG B 2286 CG ARG B 2287 CD ARG B 2288 NE ARG B 2289 CZ ARG B 2290 NHI ARG B 2291 NH2 ARG B 346 346 346 347 347 347 347 347 347 347 348 348 348 348 348 348 348 348 349 349 349 349 349 349 349 349 350 350 350 350 350 351 351 351 351 351 351 351 351 352 352 352 352 352 352 352 352 352 -3.464 -6.304 -5.540 -7.516 -7.987 -9.152 -10.218 -8.676 -8.426 -8.358 -8.884 -9.293 -10.008 -10.342 -9.478 -11.647 -8.035 -8.014 -6.984 -5.724 -4.716 -3.297 -3.323 -2.370 -5.31 -4.738 -5.067 -4.529 -4.587 -5.272 -4.650 -6.600 -7.409 -8.902 -9.785 -9.660 10.604 -7.064 -6.963 -6.894 -6.552 -6.728 -8.189 -8.323 -8.010 -7.187 -6.579 -6.980 -12.188 25.553 -8.873 25.458 -7.935 25.695 -8.699 24.937 -7.357 24.608 -7.388 23.60 1 -8.190 24.123 -7.955 22.262 -6.590 25.853 -5.357 25.883 -7.314 26.874 -6.667 28.114 -7.642 29.056 -7.022 30.398 -6.746 31.216 -6.764 30.625 -6.120 28.798 -4.991 29.271 -6.931 28.832 -6.516 29.446 -7.674 29.434 -7.316 29.889 -6.904 31.356 -8.504 29.672 -5.307 28.718 -4.322 29.349 -5.391 27.391 -4.308 26.578 -4.690 25.095 -2.988 26.805 -1.926 26.904 -3.053 26.857 -1.856 27.074 -2.202 27.041 -0.974 26.858 -0.292 25.824 -0.682 27.754 -1.228 28.415 -0.009 28.534 -2.056 29.438 -1.509 30.742 -2.571 31.833 -2.819 32.189 -3.882 33.279 -5.222 32.785 -6.075 33.387 -5.741 34.516 -7.275 32.864 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 20.84 22.99 22.07 20.53 21.89 21.65 19.65 22.01 23.60 20.31 22.27 23.99 22.32 28.26 27.14 27.02 19.48 18.26 19.07 20.37 18.21 18.24 12.44 21.28 19.92 16.56 16.67 17.11 14.15 17.92 18.71 17.51 16.57 18.97 21.80 24.62 22.78 16.81 15.75 13.97 16.09 15.78 17.93 19.84 21.36 21.18 20.51 28.51 WO 99/50658 WO 9950658PCT/US99/06937 ATOM 2292 C ARG B ATOM 2293 0 ARG B ATOM 2294 N GLU B ATOM 2295 CA GLU B ATOM 2296 CB GLU B ATOM 2297 CG GLU B ATOM 2298 CD GLU B ATOM 2299 OEI GLU B ATOM 2300 0E2 GLU B ATOM 2301 C GLU B ATOM 2302 0 GLU B ATOM 2303 N LEU B ATOM 2304 CA LEU B ATOM 2305 CB LEU B 15 ATOM 2306 CG LEU B ATOM 2307 CDI LEU B ATOM 2308 CD2 LEU B ATOM 2309 C LEU B ATOM 2310 0 LEU B ATOM 2311 N VAL B ATOM 2312 CA VAL B ATOM 2313 CB VAL B ATOM 2314 CG1 VAL B ATOM 2315 CG2 VAL B ATOM 2316 C VAL B ATOM 2317 0 VAL B ATOM 2318 N HIS B ATOM 2319 CA HIS B ATOM 2320 CB HIS B ATOM 2321 CG HIS B ATOM 2 322 CD2 HIS B ATOM 2323 NDI HIS B ATOM 2324 CEI HIS B ATOM 2325 NE2 HIS B ATOM 2326 C HIS B ATOM 2327 0 HIS B ATOM 2328 N MET B ATOM 2329 CA MET B ATOM 2330 CB MET B ATOM 2331 CG MET B ATOM 2332 SD MET B ATOM 2333 CE MET B ATOM 2334 C MET B ATOM 2335 0 MET B ATOM 2336 N ILE B ATOM 2337 CA ILE B ATOM 2338 CB ILE B ATOM 2339 CG2 ILE B 352 352 353 353 353 353 353 353 353 353 353 354 354 354 354 354 354 354 354 355 355 355 355 355 355 355 356 356 356 356 356 356 356 356 356 356 357 357 357 357 357 357 .357 357 358 358 .358 358 5.12 3 -4.83 5 -4.23 1 -2.838 -1.990 1.554 -0.620 -1.099 0.599 -2.729 -1.872 -3).594 -31.556 -4.616 -4.174 -5.373 -3).069 -3).747 -3123 -4.600 -4.844 -5.925 -6.070 -7.254 -3.533 -3.158 -2.826 -1.559 -1.110 -2.0 18 -3).128 -1.838 -2.802 -3).598 -0.479 0.424 -0.566 0.428 0.239 1.149 0.747 0.746 0.3 16 1.319 -0.909 -1.122~ -2.63 4 -2.879 -0.975 3 0.728 0.057 3 1.339 -1.665 30.019 -1.228 29.935 -2.243 29.168 -31.456 29.973 -4.355 29.176 -5.078 28.275 -4.324 29.442 0.119 29.219 0.939 29.540 0.335 28.235 1.575 27.472 1.534 26.360 0.750 25.112 0.509 24.189 1.531 24.384 2.805 28.361 3.850 28.141 2.682 29.369 3.791 30.279 3.429 31.327 4.561 32.344 3.187 30.639 4.161 30.986 5.328 31.049 3. 160 31.499 3.418 32.177 2.174 32.945 1.818 34.085 1.045 34.135 2.312 35.358 1.860 36.145 1.088 35.426 3.861 31.184 4.614 31.547 3.413 29.931 3.830 28.939 3.099 27.604 3.631 26.476 3.014 24.826 1.222 25.122 5.334 28.699 6.031 28.560 5.839 28.659 7.263 28.423 7.577 28.287 9.080 28.450 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 15.81 15.61 15.45 16.59 14.64 18.2 3 22.72 21.94 24.41 15.85 13.76 12.93 15.33 16.44 17.03 16.70 14.52 12.78 14.28 12.60 16.78 16.84 19.88 19.33 19.17 17.30 19.68 20.64 2 1.03 22.88 21.70 19.24 18.84 17.92 19.67 19.61 14.92 15.13 13.94 14.71 17.75 15.21 14.94 17.02 18.01 19.77 23.11 25.00

C

WO 99/50658 PCTIUS99/06937 ATOM 2340 CGI ILE B ATOM 2341 CD1 ILE B ATOM 2342 C ILE B ATOM 2343 0 ILE B ATOM 2344 N ASN B ATOM 2345 CA ASN B ATOM 2346 GB ASN B ATOM 2347 CG ASN B ATOM 2348 ODI ASN B ATOM 2349 ND2 ASN B ATOM 2350 C ASN B ATOM 2351 0 ASN B ATOM 2352 N TRP B ATOM 2353 CA TRP B 15 ATOM 2354 GB TRP B ATOM 2355 CG TRP B ATOM 2356 CD2 TRP B ATOM 2357 CE2 TRY B ATOM 2358 CE3 TRY B ATOM 2359 CDI TRY B ATOM 2360 NEI TRY B ATOM 2361 CZ2 TRY B ATOM 2362 CZ3 TRY B ATOM 2363 CH2 TRY B ATOM 2364 C ATOM -2365 0 ATOM 2366 N ATOM 2367 CA ATOM 2368 GB ATOM 2369 C ATOM 2370 0 ATOM 2371 N ATOM 2372 CA ATOM 2373 GB ATOM 2374 G ATOM 2375 CD ATOM 2376 CE ATOM 2377 NZ ATOM 2378 C ATOM 2379 0 ATOM 2380 N ATOM 2381 CA ATOM 2382 GB ATOM 2383 CG ATOM 2384 CD ATOM 2385 NE ATOM 2386 CZ ATOM 2387 NHI 358 358 358 358 -359 359 359 359 -359 359 359 359 360 360 360 360 .360 .360 360 360 .360 360 360 -360 360 360 361 361 361 361 361 .362 362 362 .362 362 362 .362 362 .362 363 36 3 363 363 363 363 363 3 63 TRY B TRY B ALA B ALA B ALA B ALA B ALA B LYS B3 LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B -3.137 7.105 26.913" -4.600 6.653 26.890 -0.501 8.100 29.550 0.080 9.153 29.299 -0.619 7.631 30.790 -0.029 8.341 31.924 -0.480 7.726 33.224 -1.831 8.171 33.649 -2.42 1 9.069 3.3.04 2 -2.364 7.549 34.691 1.473 8.306 31.837 2.152 9.285 32.149 1.995 7.149 -31.438 3.439 6.965 31.310 3.754 5.524 30.878 5.085 5.363 -30.176 5.310 5.308 28.756 6.698 5.129 28.561 4.475 5.392 27.633 6.306 5.221 30.762 7.283 5.078 29.800 7.272 5.032 27.288 5.045 5.296 26.363 6.431 5.115 26.202 3.979 7.939 30.273 4.991 8.606 30.497 3.295 8.012 29.135 3.708 8.900 28.051 2.682 8.855 26.921 3.883 10.336 28.552 4.858 11.005 28.210 2.932 10.794 29.361 2.966 12.139 29.923 1.741 12.363 30.811 0.426 12.417 30.064 -0.563 13.304 -30.805 -1.620 12.490 31.512 -2.873 13.276 3 1.664 4.223 12.379 30.757 4.661 13.517 30.922 4.805 11.302 31.278 5.996 11.414 312.109 5.887 10.457 33.298 4.650 10.704 34.158 4.569 9.745 35.344 4.477 8.344 34.928 3.395 7.582 35.080 2.300 8.081 3 5.64 8 1.00 24.19 1.00 20.17 1.00 22.93 1.00 23.33 1.00 22.34 1.00 23.24 1.00 25.10 1.00 32.65 1.00 32.98 1.00 33.8 7 1.00 24.77 1.00 24.19 1.00 20.82 1.00 19.29 1.00 18.59 1.00 18.21 1.00 14.38 1.00 13.42 1.00 15.52 1.00 13.34 1.00 16.05 1.00 16.84 1.00 15.11 1.00 16.12 1.00 20.13 1.00 17.26 1.00 19.34 1.00 22.01 1.00 19.53 1.00 22.39 1.00 19.57 1.00 21.96 1.00 26.45 1.00 29.79 1.00 33.57 1.00 36.83 1.00 36.89 1.00 39.07 1.00 27.77 1.00 26.93 1.00 26.61 1.00 27.74 1.00 28.93 1.00 36.07 1.00 42.83 1.00 49.79 1.00 51.48 1.00 52.17

G

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WO 99/50658 PCT/US99/06937 ATOM 2388 NH2 ARG B

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2389 C 2390 0 2391 N 2392 CA 2393 CB 2394 CG1 2395 C02 2396 C 2397 0 2398 N 2399 CD 2400 CA 2401 CB 2402 CG 2403 C 2404 0 2405 N 2406 CA 2407 C 2.408 0 2409 N 2410 CA 2411 CB 2412 CG 2413 CDI 2414 CD2 2415 CEI 2416 CE2 2417 CZ 2418 C 2419 0 2420 N 2421 CA ARG B ARG B VAL B VAL B VAL B VAL B VAL B VAL. B VAL B PRO B PRO B PRO B PRO B PRO B PRO B PRO B GLY B GLY B GLY B GLY B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B VAL B VAL B 363 363 363 364 364 364 364 364 364 364 365 365 365 365 365 365 365 366 366 366 366 367 367 367 367 367 367 367 367 367 367 367 368 368 368 368 368 368 368 369 369 369 369 369 369 369 369 370 3.405 7.308 8.374 7.231 8.431 8.116 9.267 7.860 8.925 8.219 10. 141 11.061 10.719 12. 189 12.170 10.546 11.056 9.821 9.612 8.241 7.791 7.564 6.250 5.745 4.629 3.3 13 4.897 2.2 72 3.867 2.553 5.178 4.458 5.049 4.020 3.8 17 2.944.

5.157 4.328 3.450 5.572 5.950 7.466 8.2 13 9.409 7.604 5.248 5.13 1 4.776 6.316 34.668 11.190 31.367 11.183 3 1.975 11.009 30.053 10.823 29.248 10.048 27.947 10.184 26.968 8.560 28.268 12.241 28.923 13.023 28.285 12.591 29.375 11.726 30.137 13.919 29.138 13.739 29.507 12.671 30.545 14.464 27.726 13.897 26.766 15.570 27.609 16.182 26.310 15.969 25.700 16.779 24.886 14.895 26.096 14.593 25.542 13.244 26.058 12.671 25.239 12.771 25.669 12.025 24.033 12.2 33 24.914 11.486 23.272 11.588 23.711 15.646 25.781 16.001 24.854 16.143 27.009 17.151 27.277 17.412 28.795 16.320 29.392 17.495 29.508 18.482 26.598 19.330 26.457 18.665 26.175 19.904 25.503 19.963 25.309 20.169 26.615 19.807 26.684 20.693 27.572 19.997 24.149 21.074 23.571 18.859 23.653 1.00 40.24 1.00 25.80 1.00 29.36 1.00 24.2 8 1.00 21.87 1.00 21.84 1.00 15.85 1.00 16.24 1.00 28.14 1.00 24.24 1.00 28.57 1.00 30.58 1.00 32.16 1.00 32.70 1.00 33. 1.00 32.2 1.00 37.04 1.00 34.09 1.00 32.54 1.00 33.46 1.00 33.73 1.00 31.08 1.00 28.60 1.00 25.96 1.00 22.75 1.00 22.62 1.00 22.29 1.00 25.63 1.00 20.82 1.00 25.50 1.00 26.79 1.00 23.37 1.00 31.26 1.00 35.71 1.00 35.98 1.00 37.64 1.00 35.81 1.00 35.87 1.00 3 7.71 1.00 35.49 1.00 36.54 1.00 39.79 1.00 44.33 1.00 48.45 1.00 43.27 1.00 34.49 1.00 3)4.51 1.00 30.97 2422 CB VAL B 2423 CGI VAL B 2424 CG2 VAL B 2425 C VAL B 2426 0 VAL B 2427 N ASP B 2428 CA ASP B 2429 CB ASP B 2430 CG ASP B 2431 ODI ASP B 243 2 0D2 ASP B 2433 C ASP B 2434N 0 ASP B 2435 N LEU B

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WO 99/50658 PCT/US99/06937

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2436 CA LEU B 370 2437 CB LEU B 370 2438 CG LEU B 370 2439 CDI LEU B 370 2440 CD2 LEU B 370 2441 C LEU B 370 2442 0 LEU B 370 2443 N THR B 371 2444 CA THR B 371 2445 CB THR B 371 2446 OGI THR B 371 2447 CG2 THR B 371 2448 C THR B 371 2449 0 THR B 371 2450 N LEU B 372 2451 CA LEU B 372 2452 CB LEU B 372 2453 CG LEU B 372 2454 CDi LEU B 372 2455 CD2 LEU B 372 2456 C LEU B 372 2457 0 LEU B 372 2458 N HIS B 373 2459 CA HIS B 373 2460 CB HIS B 373 2461 CG HIS B 373 2462 CD2 HIS B 373 2463 NDI HIS B 373 2464 CEI HIS B 373 2465 NE2 HIS B 373 2466 C HIS B 373 2467 0 HIS B 373 2468 N ASP B 374 2469 CA ASP B 374 2470 CB ASP B 374 2471 CG ASP B 374 2472 ODI ASP B 374 2473 0D2 ASP B 374 2474 C ASP B 374 2475 0 ASP B 374 2476 N GLN B 375 2477 CA GLN B 375 2478 CB GLN B 375 2479 CG GLN B 375 2480 CD GLN B 375 2481 OE1 GLN B 375 2482 NE2 GLN B 375 2483 C GLN B 375 4.086 4.145 5.522 5.353 6.316 2.628 2.066 2.011 0.602 0.150 0.284 0.991 -0.208 0.300 -1.461 -2.323 -3.722 -4.715 -4.231 -6.105 -2.437 -2.417 -2.564 -2.685 -2.844 -2.503 -3.293 -1.205 -1.210 -2.465 -1.468 -1.610 -0.275 0.950 2.178 2.433 3.195 1.874 1.029 1.432 0.642 0.667 0.213 1.164 0.623 -0.044 0.895 -0.259 18.809 22.370 17.389 21.799 16.733 21.688 15.242 21.400 17.396 20.574 19.218 22.521 19.151 23.611 19.645 21.425 20.014 21.474 20.690 20.163 19.763 19.080 21.930 19.878 18.726 21.666 17.624 21.431 18.863 22.087 17.702 22.303 18.147 22.737 17.006 22.960 16.147 24.126 17.562 23.246 16.863 21.034 15.629 21.078 17.548 19.905 16.888 18.614 17.935 17.503 17.430 16.132 17.105 15.079 17.220 15.715 16.787 14.465 16.708 14.056 16.012 18.337 14.878 17.897 16.541 18.589 15.783 18.350 16.678 18.535 17.577 17.333 18.557 17.478 17.305 16.246 14.592 19.303 13.494 18.908 14.814 20.556 13.749 21.547 14.270 22.901 15.236 23.563 15.691 24.890 14.953 25.602 16.953 25.236 12.630 21.104 1.00 29.80 1.00 27.27 1.00 28.07 1.00 30.38 1.00 22.82 1.00 28.04 1.00 29.71 1.00 28.70 1.00 30.31 1.00 31.96 1.00 29.49 1.00 29.98 1.00 30.59 1.00 27.10 1.00 27.65 1.00 30.86 1.00 30.11 1.00 32.80 1.00 34.10 1.00 31.16 1.00 31.77 1.00 27.06 1.00 31.30 1.00 31.35 1.00 34.30 1.00 41.27 1.00 42.50 1.00 43.69 1.00 48.87 1.00 43.72 1.00 28.29 1.00 30.21 1.00 28.85 1.00 28.28 1.00 31.33 1.00 39.07 1.00 40.60 1.00 38.64 1.00 29.05 1.00 24.26 1.00 24.52 1.00 27.37 1.00 26.66 1.00 29.74 1.00 33.13 1.00 32.82 1.00 33.98 1.00 24.52 WO 99/50658 WO 9950658PCTIUS99/06937 ATOM 2484 0 GLN B ATOM 2485 N VAL B ATOM 2486 CA VAL B ATOM 2487 CB VAL B ATOM 2488 CG1 VAL B ATOM 2489 CG2 VAL B ATOM 2490 C VAL B ATOM 2491 0 VAL B ATOM 2492 N HIS B ATOM 2493 CA HIS B ATOM 2494 CB HIS B ATOM 2495 CG HIS B ATOM 2496 CD2 HIS B ATOM 2497 NDI HIS B ATOM 2498 CEI HIS B ATOM 2499 NE2 HIS B ATOM 2500 C HIS B ATOM 2501 0 HIS B ATOM 2502 N LEU B ATOM 2503 CA LEU B ATOM 2504 CB LEU B ATOM 2505 CG LEU B ATOM 2506 CDl LEU B ATOM 2507 CD2 LEU B ATOM 2508 C LEU B ATOM 2509 0 LEU B ATOM 2510 N LEU B ATOM 2511 CA LEU B ATOM 2512 CB LEU B ATOM 2513 CG LEU B ATOM 2514 CDI LEU B ATOM 2515 CD2 LEU B ATOM 2516 C LEU B ATOM 2517 0 LEU B ATOM 2518 N GLU B ATOM 2519 CA GLU B ATOM 2520 CB GLU B ATOM 2521 CG GLU B ATOM 2522 CD GLU B ATOM 2523 OEI GLU B ATOM 2524 0E2 GLU B ATOM 2525 C GLU B ATOM 2526 0 GLU B ATOM -2527 N ACYS B ATOM 2528 N BCYS B ATOM 2529 CA ACYS B ATOM 2530 CA BCYS B ATOM 2531 CB ACYS B 375 376 376 376 376 376 376 376 377 377 377 377 377 377 377 377 377 377 -378 378 378 378 -378 .378 378 378 379 379 379 379 379 379 379 379 380 380 380 -380 .380 380 380 380 380 .381 381 381 381 381 0.074 -1.426 -2.409 -3.718 -4.572 -4.486 -1.852 -1.949 -1.251 -0.689 -0.078 0.535 1.828 -0.2 17 0.588 1.833 0.365 0.32 1 1.307 2.365 3.363 4.230 5.104 5.094 1.832 2.262 0.888 0.317 -0.526 0.292 -0.578 0.85 1 -0.518 -0.476 1.273 -2.086 -2.994 -4.182 -5.070 -6.206 -4.631 -1.210 -1.586 -0.039 -0.035 0.860 0.875 1.870 11.451 21.221 13.013 20.599 12.055 20.140 12.760 19.717 11.823 18.877 13.192 20.954 11.257 18.965 10.032 18.938 11.953 18.007 11.284 16.843 12.306 15.886 11.690 14.667 11.559 14.287 11.086 13.683 10.607 12.750 10.882 13.093 10.237 17.210 9.109 16.719 10.609 18.072 9.691 18.474 10.402 19.388 11.489 18.736 12.148 19.796 10.885 17.638 8.433 19.161 7.320 18.859 8.610 20.077 7.486 20.795 7.989 2 1.968 8.353 23.214 9.092 24.211 7.075 23.842 6.605 19.872 5.377 19.968 7.222 18.971 6.435 18.049 7.3 50 17.222 7.874 18.007 8.789 17.188 9.066 1 7.625 9.230 16.110 5.594 17.117 4.491 16.722 6.113 16.772 6.113 16.779 5.384 15.887 5.407 15.884 6.342 15.248 1.00 23 .56 1.00 21.87 1.00 23.44 1.00 22.09 1.00 24.14 1.00 16.96 1.00 24.15 1.00 22.26 1.00 25.85 1.00 25.68 1.00 25.27 1.00 3 0.63 1.00 31.03 1.00 35.05 1.00 33.12 1.00 3 1.06 1.00 24.37 1.00 21.47 1.00 19.24 1.00 20.09 1.00 18.64 1.00 22.15 1.00 22.51 1.00 20.68 1.00 18.91 1.00 17.52 1.00 18.25 1.00 18.60 1.00 16.77 1.00 17.90 1.00 15.84 1.00 22.09 1.00 20.17 1.00 18.11 1.00 19.40 1.00 20.19 1.00 22.43 1.00 25.30 1.00 29.44 1.00 31.70 1.00 31.75 1.00 18.92 1.00 19.83 0.75 17.41 0.25 17.76 0.75 20.19 0.25 17.50 0.75 24.20 WO 99/50658 PCT/US99/06937 ATOM 2532 CB BCYS B ATOM 2533 SG ACYS B ATOM 2534 SG BCYS B ATOM 2535 C ACYS B ATOM 2536 C BCYS B ATOM 2537 0 ACYS B ATOM 2538 0 BCYS B ATOM 2539 N ALA B ATOM 2540 CA ALA B ATOM 2541 CB ALA B ATOM 2542 C ALA B ATOM 2543 0 ALA B ATOM 2544 N TRP B ATOM 2545 CA TRP B ATOM 2546 CB TRP B ATOM 2547 CG TRP B ATOM 2548 CD2 TRP B ATOM 2549 CE2 ATOM 2550 CE3 ATOM 2551 CDI ATOM 2552 NEI ATOM 2553 CZ2 ATOM 2554 CZ3 ATOM 2555 CH2 ATOM 2556 C ATOM 2557 0 ATOM 2558 N ATOM 2559 CA ATOM 2560 CB ATOM 2561 CG ATOM 2562 CDI ATOM 2563 CD2 ATOM 2564 C ATOM 2565 0 ATOM 2566 N ATOM 2567 CA ATOM 2568 CB ATOM 2569 CG ATOM 2570 CD ATOM 2571 OEI ATOM 2572 OE2 ATOM 2573 C ATOM 2574 0 ATOM 2575 N ATOM 2576 CA TRP B TRP B TRP B TRP B TRP B TRP B TRP B TRP B TRP B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B ILE B ILE B 381 381 381 381 381 381 381 382 382 382 382 382 383 383 383 383 383 383 383 383 383 383 383 383 383 383 384 384 384 384 384 384 384 384 385 385 385 385 385 385 385 385 385 386 386 386 386 386 1.830 1.167 3.048 1.626 1.689 1.737 1.904 2.134 2.955 4.135 2.356 3.070 1.074 0.487 -1.009 -1.871 -2.493 -3.226 -2.506 -2.236 -3.051 -3.963 -3.243 -3.960 0.701 0.982 0.568 0.773 0.181 0.173 -0.352 -0.707 2.262 2.627 3.116 4.565 5.336 5.297 6.162 7.381 5.622 4.963 5.788 4.389 4.723 4.173 4.374 4.910 6.406 15.226 7.518 14.060 5.656 14.128 4.269 16.592 4.305 16.561 3.161 16.069 3.241 15.982 4.560 17.785 3.602 18.530 4.364 19.143 2.702 19.607 1.852 20.142 2.855 19.916 2.089 21.013 2.410 21.160 1.775 20.129 0.483 20.198 0.309 19.003 -0.542 21.155 2.312 18.933 1.439 18.250 -0.853 18.733 -1.702 20.888 -1.844 19.686 0.579 21.020 0.010 22.077 -0.087 19.879 -1.532 19.903 -2.200 18.656 -3.735 18.720 4.240 20.089 -4.259 17.586 -1.861 20.034 -2.833 20.690 -1.046 19.414 -1.260 19.509 -0.179 18.739 -0.312 17.207 0.738 16.520 0.500 16.358 1.808 16.149 -1.161 20.987 -1.942 21.463 -0.213 21.690 -0.019 23.108 1.326 23.614 1..451 25.130 2.476 22.907 0.25 0.75 0.25 0.75 0.25 0.75 0.25 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 16.63 33.54 10.36 20.59 19.19 19.16 19.25 19.04 20.27 18.68 16.82 13.37 15.30 15.80 16.63 19.93 20.80 19.27 21.32 18.59 23.67 21.55 20.29 19.03 17.35 13.92 14.07 15.98 12.19 12.97 10.65 17.84 14.64 13.78 14.96 13.79 15.34 15.38 23.97 21.03 22.19 15.79 15.04 13.32 14.06 15.36 15.97 17.95 ATOM 2577 CB ILE B ATOM 2578 CG2 ILE B ATOM 2579 CG I ILE B

C,

WO 99/50658 PCTIUS99/06937

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2580 CDI ILE B 2581 C ILE B 2582 0 ILE B 21583 N LEU B 2584 CA LEU B 2585 CB LEU B 2586 CG LEU B 2587 CDI LEU B 2588 CD2 LEU B 2589 C LEU B 2590 0 LEU B 2591 N MET B 2592 CA MET B 2593 CB MET. B 2594 CG MET B 2595 SD MET B 2596 CE MET B 2597 C MET B 2598 0 MET B 2599 N ILE B 2600 CA ILE B 2601 CB ILE B 2602 CG2 ILE B 2603 CG I ILE B 2604 CDI ILE B 2605 C ILE B 2606 0 ILE B 2607 N GLY B 2608 CA GLY B 2609 C GLY B 2610 0 GLY B 2611 N LEU B 2612 CA -LEU B 2613 CB LEU B 2614 CG LEU B 2615 CDI LEU B 2616 CD2 LEU B 2617 C LEU B 2618 0 LEU B 2619 N VAL B 2620 CA VAL B 2621 CB VAL B 2622 CGI- VAL B 2623 CG2 VAL B 2624 C VAL B 2625 0 VAL B 2626 N TRP B 2627 CA TRP B 386 386 386 387 387 387 387 387 387 387 387 388 388 388 388 388 388 388 388 389 389 389 389 389 389 389 389 390 390 390 390 391 391 391 391 391 391 391 391 392 -392 392 392 -392 -392 392 3 9 3 393 4.118 4.227 4.905 3.038 2.5 16 1.070 -0.031 -1.371 -0.075 3.39 1 3.712 3.785 4.602 4.673 3.403 3.364 1.906 6.004 6.460 6.707 8.044 8.836 8.330 10.325 11.228 7.950 8.844 6.855 6.681 6.444 6.989 5.623 5.334 4.332 4.157 3.580 3.232 6.649 7.002 7.378 8.649 9.288 10.751 8.520 9.6 15 10.336 9.617 10.492 3.768 22.874 -1.164 23.99 3 -1.560 24.941 -1.675 23.709 -2.791 24 .478 -3.097 24.080 -2.113 24.486 -2.628 23.972 -1.966 26.002 -4.013 24.180 -4.792 25.076 -4.178 22.921 -5.329 22.547 -5.460 2 1.026 -6.066 20.453 -6.193 18.675 -7.225 18.511 -5.332 23.133 -6.366 2363 -4.203 23).074 -4.209 23 634 -2.911 23.322 -1.746 24.158 -3.164 23.602 -1.972 23.357 -4.446 25.147 -5.044 25.739 -4.007 25.761 -4.219 27.189 -5.702 27.463 -6.282 28.403 -6.325 26.628 -7.743 26.775 -8.179 25.699 -9.689 25.457 -10.351 26.699 -9.913 24.268 -8.518 26.625 -9.352 ,27.465 -8.215 25.557 -8.868 25.278 -8.281 24.005 -8.687 23 .920 -8.773 22.76 7 -8.707 26.450 -9.637 26.811 -7.522 2 7.046 -7.241 28.171 1.00 1.00 1.00 1.00 1.00 1.00 21.12 14.97 19.60 15.18 15.98 17.15 1.00 17.77 1.00 15.38 1.00 14.69 1.00 14.03 1.00 16.43 1.00 16.67 1.00 14.83 1.00 13.91 1.00 17.23 1.00 14.97 1.00 20.19 1.00 21.50 1.00 15.34 1.00 15.59 1.00 14.95 1.00 12.81 1.00 17.24 1.00 15.65 1.00 14.30 1.00 18.72 1.00 13.99 1.00 14.87 1.00 18.54 1.00 16.54 1.00 16.15 1.00 18.91 1.00 19.55 1.00 20.91 1.00 19.41 1.00 20.70 1.00 20.31 1.00 18.66 1.00 18.71 1.00 19.51 1.00 23.77 1.00 24.63 1.00 19.94 1.00 22.80 1.00 19.36 1.00 22.10 1.00 23.20 (7* (3, WO 99/50658 PCT/US99/06937

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2628 CB TRP B 2629 CG TRP B 2630 CD2 TRP B 2631 CE2 TRY B 2632 CE3 TRP B 2633 CDI TRP B 2634 NEI TRP B 2635 CZ2 TRP B 2636 CZ3 TRP B 2637 CH2 TRP B 2638 C TRP B 2639 0 TRP B 2640 N ARG B 2641 CA ARG B 2642 CB ARG B 2643 CG ARG B 2644 CD ARG B 2645 NE ARG B 2646 CZ ARG B 2647 NHI ARG B 2648 NH2 ARG B 2649 C 2650 0 2651 N 2652 CA 2653 CB 2654 OG 2655 C 2656 0 2657 N 2658 CA 2659 CB 2660 CG 2661 SD 2662 CE 2663 C 2664 0 2665 N 2666 CA 2667 CB 2668 CG 2669 CD 2670 OEI 2671 OE2 2672 C 2673 0 2674 N 2675 CA ARG B ARG B SER B SER B SER B SER B SER B SER B MET B MET B MET B MET B MET B MET B MET B MET B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B 393 393 393 393 393 393 393 393 393 393 393 393 394 394 394 394 394 394 394 394 394 394 394 395 395 395 395 395 395 396 396 396 396 396 396 396 396 397 397 397 397 397 397 397 397 10.388 11.056 12.453 12.624 13.578 10.452 11.387 13.876 14.829 14.964 10.208 11.128 8.952 8.680 7.365 6.259 5.026 3.817 3.327 3.944 2.229 8.695 8.657 8.767 8.805 8.206 6.832 10.239 10.458 11.206 12.620 13.479 14.155 15.149 16.675 12.983 13.828 12.348 12.604 12.153 12.983 13.483 13.380 13 .975 11.878 12.021 I 1.100 10.347 -5.773 28.578 -5.479 29.895 -5.591 30.193 -5.208 31.545 -5.976 29.449 -5.046 31.044 4.881 32.037 -5.200 32.171 -5.968 30.072 -5.582 31.423 -8.114 29.388 -8.717 29.944 -8.189 29.819 -9.003 30.990 -8.601 31.667 -8.149 30.759 -7.727 31.574 -7.937 30.786 -7.059 29.915 -5.902 29.722 -7.347 29.220 -10.502 30.713 -11.294 31.648 -10.880 29.438 -12.289 29.041 -12.473 27.638 -12.136 27.619 -12.831 29.031 -14.030 28.854 -11.938 29.210 -12.307 29.205 -11.063 29.423 -10.569 28.171 -9.127 28.491 -9.849 28.998 -13.353 30.250 -14.215 30.011 -13.266 31.410 -14.206 32.492 -13.605 33.821 -12.422 34.271 -12.587 35.686 -11.621 36.470 -13.688 36.013 -15.528 32.273 -16.459 33.061 -15.609 31.202 -16.823 30.914 1.00 19.22 1.00 22.53 1.00 20.36 1.00 25.65 1.00 22.12 1.00 23.02 1.00 24.91 1.00 23.00 1.00 23.98 1.00 23.20 1.00 24.36 1.00 23.04 1.00 21.29 1.00 22.43 1.00 23.97 1.00 26.16 1.00 20.86 1.00 19.54 1.00 20.58 1.00 17.41 1.00 16.82 1.00 21.78 1.00 23.44 1.00 17.10 1.00 25.08 1.00 19.47 1.00 21.73 1.00 26.29 1.00 23.75 1.00 30.79 1.00 35.07 1.00 33.84 1.00 36.88 1.00 40.96 1.00 39.67 1.00 35.88 1.00 34.52 1.00 36.19 1.00 39.24 1.00 44.38 1.00 54.05 1.00 56.78 1.00 60.90 1.00 60.82 1.00 36.65 1.00 35.84 1.00 32.14 1.00 29.48 GLU B- 397 HIS B 398 HIS B 398 WO 99/50658 WO 9950658PCT/US99/06937

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2676 CB HIS B 398 2677 CG HIS B 39 8 2678 CD2 HIS B 398 2679 NDI HIS B 398 2680 CEI HIS B 398 2681 NE2 HIS B 398 2682' C HIS B 398 2683 0 HIS B 398 2684 N PRO B 399 2685 CD PRO B 399 2686 CA PRO B 399 21687 GB PRO B 399 2688 CG PRO B 399 2689 C PRO B 399 2690 0 PRO B 399 2691 N GLY B 400 2692 CA GLY B 400 2693 C GLY B 400 2694 0 GLY B 400 2695 N LYS B 401 2696 CA LYS B 401 2697 CB LYS B 401 2698 CG LYS B 401 2699 CD LYS B 401 2700 CE LYS B 401 2701 NZ LYS B 401 2702 C LYS B 401 2703 0 LYS B 401 2704 N LEU B 402 2705 CA LEU B 402 2706 CB LEU B 402 2707 CG LEU B 402 2708 CDI LEU B 402 2709 CD2 LEU B 402 2710 C LEU B 402 2711 0 LEU B 402 2712 N LEU B 403 2713 CA LEU B 403 2714 CB LEU B 403 2715 CG LEU B 403 2716 CDI LEU B 403 21717 CD2 LEU B 403 2718 C LEU B 403 2719 0 LEU B 403 2720 N PHE B 404 2721 CA PHE B 404 2722 CB PHE B 404 2723 CG PHE B 404 8.863 -16.567 31.178 8.582 -16.111 32.574 8.215 -16.801 33.678 8.727 -14.799 32.972 8.462 -14.701 3 4.262 8.148 -15.902 34.714 10.556 -17.317 29.492 9.637 -17.291 28.672 11.771 -17.801 29.186 12.926 17.922 30.096 12.079 -18.300 27.845 13.434 -18.988 28.016 14.062 -18.284 29.170 11.009 -19.246 27.319 10.552' -20.137 28.035 10.601 -19.035 26.071 9.588 -19.884 25.466 8.161 -19.537 25.849 7.220 -20.153 25.356 7.996 -18.554 26.727 6.668 '18.139 27.165 6.435 -18.563 28.619 6.476 -20.069 28.879 6.181 -20.353 30.349 6.073 -21.847 30.635 7.177 -22.611 29.989 6.493 -16.622 27.060 7.465 -15.872 27.035 5.241 -16.181 26.995 4.929 14.759 26.925 4.088 -14.449 25.689 4.798 14.673 24.360 3.821 -14.395 23.211 6.011 -13.760 24.277 4.147 -14.399 28.179 3.024 -14.880 28.381 4.743 -13.559 29.019 4.099 -13.148 30.259 5.155 -12.856 31.332 4.639 -12.682 .32.766 5.519 -13.450 33.728 4.626 -11.213 33.138 3.219 -11.918 -30. 0 43 3.638 -10.787 30.291 2.003 -12.145 29.565 1.066 11.053 29.340 -0.199 -11.598 28.687 -0.026 .111.897 27.227 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 29.87 31.80 29.12 33.27 32.19 .33.48 25.95 27.47 29.09 29.93 27.40 32.09 30.81 29.76 29.18 27.45 26.93 26.73 28.36 25.50 23.45 28.50 28.58 35.47 38.59 42.39 21.78 21.45 23.45 21.37 18.47 16.89 21.23 23.15 19.66 18.05 19.54 20.21 23.16 29.54 32.67 32.38 20.42 1 9.18 21.44 21.69 17.26 19.75 WO 99/50658 PCT/US99/06937 ATOM 2724 CDI PHE B ATOM 2725 CD2 PHE B ATOM. 2726 CEI ATOM 2727 CE2 ATOM 2728 CZ ATOM 2729 C ATOM 2730 0 ATOM 2731 N ATOM 2732 CA ATOM 2733 CB ATOM 2734 C ATOM 2735 0 ATOM 2736 N ATOM 2737 CD 1 5 ATOM 2738 CA ATOM 2739 CB ATOM 2740 CG ATOM 2741 C ATOM 2742 0 ATOM 2743 N ATOM 2744 CA ATOM 2745 CB ATOM 2746 CG ATOM 2747 ODI ATOM 2748 ND2 ATOM 2749 C ATOM 2750. 0 ATOM 2751 N ATOM 2752 CA ATOM 2753 CB ATOM 2754 CG ATOM 2755 CDI ATOM 2756 CD2 ATOM 2757 C ATOM 2758 0 ATOM 2759 N ATOM 2760 CA ATOM 2761 CB ATOM 2762 CG ATOM 2763 CDI ATOM 2764 CD2 ATOM 2765 C ATOM 2766 0 ATOM 2767 N ATOM 2768 CA ATOM 2769 CB ATOM 2770 CG ATOM 2771 CDI PHE B PHE B PHE B PHE B PHE B ALA B ALA B ALA B ALA B ALA B PRO B PRO B PRO B PRO B PRO B PRO B PRO B ASN B ASN B ASN B ASN B ASN B ASN B ASN B ASN B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B 404 404 404 404 404 404 404 405 405 405 405 405 406 406 406 406 406 406 406 407 407 407 407 407 407 407 407 408 408 408 408 408 408 408 408 409 409 409 409 409 409 409 409 410 410 410 410 410 0.364 -13.167 26.801 -0.210 -10.897 26.280 0.572 -13.434 25.447 -0.007 -11.148 24.924 0.386 -12.418 24.503 0.768 -10.403 30.685 0.656 -9.177 30.804 0.670 -11.247 31.702 0.424 -10.814 33.066 -1.074 -10.603 33.304 0.959 -11.926 33.962 1.133 -13.061 33.517 1.246 -11.612 35.230 1.129 -10.294 35.878 1.765 -12.632 36.148 1.899 -11.882 37.475 2.017 -10.431 37.068 0.876 -13.873 36.259 1.368 -14.967 36.538 -0.426 -13.713 36.039 -1.345 -14.852 36.109 -2.553 -14.526 36.986 -3.327 -13.328 36.486 -2.851 -12.574 35.635 -4.528 -13.140 37.019 -1.820 -15.231 34.714 -2.859 -15.870 34.548 -1.059 -14.816 33.708 -1.387 -15.124 32.327 -2.247 -14.030 31.699 -2.815 -14.464 30.341 -3.702 -15.692 30.546 -3.598 -13.330 29.694 -0.113 -15.316 31.514 0.247 -14.465 30.695 0.553 -16.426 31.759 1.786 -16.774 31.065 2.786 -17.355 32.058 4.186 -17.703 31.562 4.773 -16.551 30.770 5.066 -18.018 32.758 1.401 -17.805 30.009 0.921 -18.892 30.340 1.604 -17.465 28.746 1.228 -18.361 27.660 0.192 -17.672 26.762 -1.047 -17.080 27.452 -1.770 -16.135 26.501 1.00 17.90 1.00 17.04 1.00 19.88 1.00 18.47 1.00 16.45 1.00 21.95 1.00 22.99 1.00 21.12 1.00 22.43 1.00 24.69 1.00 22.40 1.00 21.67 1.00 25.60 1.00 23.65 1.00 25.91 1.00 27.04 1.00 26.56 1.00 25.12 1.00 28.92 1.00 23.53 1.00 24.09 1.00 24.08 1.00 26.72 1.00 22.65 1.00 26.46 1.00 26.91 1.00 28.68 1.00 27.28 1.00 27.23 1.00 26.61 1.00 27.51 1.00 28.75 1.00 25.48 1.00 27.56 1.00 26.86 1.00 27.54 1.00 31.96 1.00 31.88 1.00 37.72 1.00 39.57 1.00 41.72 1.00 31.53 1.00 32.67 1.00 29.58 1.00 31.55 1.00 29.83 1.00 28.55 1.00 26.92

C)

QN

WO 99/50658 PCTIUS99/06937 ATOM 2772 CD2 LEU B

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-4 ATOM

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35 ATOM

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2773 C LEU B 2774 0 LEU B 2775 N ASP B 2776 CA ASP B 2777 CB ASP B 2778 CG ASP B 2779 ODI ASP B 2780 0D2 ASP B 2781 C ASP B 2782 0 ASP B 2783 N ARG B 2784 CA ARG B 2785 CB ARG B 2786 CG ARG B 2787 CD ARG B 2788 NE ARG B 2789 CZ ARG B 2790 NHI ARG B 2791 NH2 ARO B 2792 C ARG B 2793 0 ARG B 2794 N ASN B 2795 CA ASN B 2796 CB ASN B 2797 CG ASN B 2798 ODI ASN B 2799 ND2 ASN B 410 410 410 411 411 411 411 411 411 411 411 412 412 412 412 412 412 412 412 412 412 412 413 413 413 413 413 413 413 413 414 414 414 414 414 414 414 414 414 415 415 415 415 416 416 416 416 416 -1.979 2.397 3.427 2.238 3.275 3.657 2.476 1.773 2.254 2.74 5 1.549 3.635 3.259 4.488 4.361 5.644 5.540 4.64 9 3.777 4.63 2 2.107 1.287 2.041 0.974 1.170 2.017 2.309 2.4 18 0. 383 -1.349 -0.447 -1.685 -1.558 -1.528 -1.293 -0.176 -2.349 -2.052 -3.195 -1.077 -1.350 -2.184 -2.918 -2.070 -2.819 -2.398 -0.973 -0.405 -18.200 27.891 18.83 9 26.814 -18.170 26.726 -20.01 3 26.206 -20.562 2 5.33 6 -21.990 25.752 -22.943 25.749 -23.035 24.719 -23.603 26.786 -20.55 1 23.909 -20.34 1 23.686 -20. 777 22.949 -20.763 21.541 -2 1.083 20.675 -22.314 19.799 -22.552 19.012 -22.099 17.626 -22.559 16.753 -23.490 17.115 -22.091 15.515 -21.712 21.217 -21.427 20.343 -22.834 21.923 -23.798 21.688 -25.035 22.570 -26.100 21.901 -26.022 20.704 -27.104 22.671 -23.168 21.982 -23.372 2 1.247 -22.397 23.063 -21.741 2-3.449 -2 1.172 24.863 -22.242 25.948 -21.667 27.327 -21.277 27.666 -21.606 28.131 -20.63 8 22.463 -20.204 22.409 -20.190 2 1.682 -19.160 20.697 -19.725 19.562 -19.000 18.887 -21.031 19.354 -21.707 18.299 -23 177 18.201 -23 .407 17.736 -24.668 .18.369 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 30.49 33.88 36.49 38.80 38.39 44.53 44.90 45.70 50.54 .38.57 36.48 36.85 -38.32, 38.69 40.05 42.98 40.95 41.11 44.01 41.28 37.64 .36.51 35.32 36.68 37.54.

43.56 46.11 47.04 34.01 32.43 32.85 .31.91 33.17 32.31 34.63 33).23 34.56 29.57 31.32 .30.96 34.27 35.27 33-.20 35.28 38.26 38.00 40.05 44.10 2800 C 2801 0 2802 N 2803 CA 2804 CB 2805 CG 2806 CD 2807 OEI 2808 NE2 2809 C 2810 0 2811 N 2812 CA 2813 C 2814 0 2815 N 2816 CA 2817 C B 2818 CG 2819 C D ASN B ASN B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLY B GLY B GLY B GLY B LYS B LYS B LYS B LYS B LYS B

(I

WO 99/50658 PCT/US99/06937

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2820 CE 21821 NZ 2822 C 2823 0 2824 N 2825 CA 2826 CB 2827 SG 2828 C 2829 0 2830 N 2831 CA 2832 CB 2833 CG1 2834 CG2 2835 C 2836 0 2837 N 2838 CA 2839 CB 2840 CG 2841 CD 2842 OEI 2843 0E2 2844 C 2845 0 2846 N 2847 CA 2848 C 2849 0 2850 N 2851 CA 2852 CB 2853 CG 2854 SD 2855 CE 2856 C 2857 0 2858 N 2859 CA 2860 CB 2861 CG1 LYS B LYS B LYS B LYS B CYS B CYS B CYS B CYS B CYS B CYS B VAL B VAL B VAL B VAL B VAL B VAL B VAL B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLY B GLY B GLY B GLY B MET B MET B MET B MET B MET B MET B MET B MET B VAL B VAL B VAL B VAL B 416 416 416 416 417 417 417 417 417 417 418 418 418 418 418 418 418 419 419 419 419 419 419 419 419 419 420 420 420 420 421 421 421 421 421 421 421 421 422 422 422 422 422 422 422 4 2 3 423 423 0.306 -25.541 17.346 1.286 -24.760 16.542 -4.321 -21.645 18.559 -5.121 -21.790 17.638 -4.698 -21.430 19.817 -6.106 -21.371 20.196 -6.218 -21.226 21.717 -5.674' -22.710 2 2.6 12 -6.899 1-20.277 19.491 -8.127 -20.296 19.485 -6.195 -19.316 18.906 -6.838 -18.236 18.163 -6.525 -16.850 18.775 -6.831 -15.763 17.765 -7.350 -16.630 20.036 -6.241 -18.317 16.764 -5.020 -18.323 16.611 -7.084 -18.388 15.740 -6.554 -18.500 14.390 -7.681 -18.722 13.380 -8.597 -17.538 13.166 -9.477 -17.723 11.946 -9.157 -18.605 11.119 -10.484 -16.993 11.813 -5.717 -17.289 13.997 -6.156 -16.144 14.123 -4.501 -17.562 13.535 -3.594 -16.506 13.122 -2.722 -15.955 14.240 -1.745 -15.246 13.975 3. 0 52 -16.285 15.486 -2.289 -15.780 16.625 -3.108 -15.922 17.914 -2.469 -15.270 19.124 -2.124 -13.494 18.872 -3.697 -12.800 19.233 -0.912 -16.416 16.821 0.022 -15.751 17.269 -0.766 -17.694 16.484 0.524 -18.338 16.675 0.482 -19.835 16.273 0.514 -19.992 14.753 1.659 -20.555 16.897 1.669 -17.640 15-935 2.788 -17.571 16.441 1.402 17.11 3 14.747 2.454 -16.435 13.997 1.963 -16.050 12.596 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 41.85 45,.63 36.93 38.36 37.10 -36.46 39.01 43.81 35.19 33.92 36.04 34.59 34.87 35.32 33.65 34.17 32.73 33.44 34.52 36.21 44.19 48.47 51.04 48.91 32.89 31.09 32.84 34.37 35.30 35.94 30.08 29.22 22.54 23.82 28.40 24.67 29.67 29.76 30.63 29.90 35.74 37.64 3 1.68 28.64 26.15 28.70 31.34 36.21 2862 CG2 VAL B 2863 C VAL B 2864 0 VAL B 2865 N GLU B 2866 CA GLU B 2867 -CB GLU B Gi

C

WO 99/50658 PCT/US99/06937

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2868 CG 2869 CD 2870 OEI 2871 OE2 2872 C 2873 0 2874 N 2875 CA 2876 CB 2877 CG2 2878 CGI 2879 CDI 2880 C 2881 0 2882 N 2883 CA 2884 CB 2885 CG 2886 CDI 2887 CD2 2888 CEI 2889 CE2 2890 CZ 2891 C 2892 0 2893 N 2894 CA 2895 CB 2896 CG 2897 ODI 2898 OD2 2899 C 2900 0 2901 N 2902 CA 2903 CB 2904 CG 2905 SD 2906 CE 2907 C 2908 0 2909 N 2910 CA 2911 CB 2912 CG 2913 CDI 2914 CD2 2915 C GLU B GLU B GLU B GLU B GLU B GLU B ILE B ILE B ILE B ILE B ILE B ILE B ILE B ILE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B PHE B ASP B ASP B ASP B ASP B ASP B ASP B ASP B ASP B MET B MET B MET B MET B MET B MET B MET B MET B LEU B LEU B LEU B LEU B LEU B LEU B LEU B 423 423 423 423 423 423 424 424 424 424 424 424 424 424 425 425 425 425 425 425 425 425 425 425 425 426 426 426 426 426 426 426 426 427 427 427 427 427 427 427 427 428 428 428 428 428 428 428 0.502 -16.376 12.325 0.250 -17.865 12.144 -0.746 -18.368 12.706 1.045 -18.530 11.442 2.928 -15.186 14.744 4.119 -14.870 14.759 2.001 -14.478 15.378 2.381 -13.279 16.111 1.134 -12.435 16.452 1.492 -11.315 17.425 0.584 -11.817 15.160 -0.895 -11.514 15.187 3.153 -13.673 17.370 4.152 -13.037 17.725 2.708 -14.746 18.023 3.370 -15.236 19.223 2.650 -16.479 19.768 1.580 -16.183 20.795 1.287 -17.112 21.792 0.843 -15.001 20.747 0.273 -16.871 22.724 -0.174 -14.749 21.676 -0.459 -15.684 22.663.

4.817 -15.610 18.885 5.741 -15.292 19.636 5.023 -16.281 17.754 6.378 -16.685 17.377 6.364 -17.510 16.090 5.992 -18.965 16.335 6.242 -19.467 17.455 5.448 -19.600 15.409 7.302 -15.489 17.198 8.465 -15.526 17.593 6.788 -14.429 16.591 7.597 -13.234 16.382 6.836 -12.228 15.520 6.864 -12.559 14.038 6.011 -11.341 13.024 4.363 -11.532 13.581 7.945 -12.616 17.732 9.073 -12.180 17.950 6.968 -12.597 18.634 7.157 -12.033 19.968 5.812 -11.964 20.706 4.852 -10.887 20.179 3.443 -11.155 20.687 5.324 -9.505 20.631 8.159 -12.856 20.767 1.00 45.83 1.00 46.71 1.00 45.97 1.00 50.05 1.00 30.57 1.00 26.59 1.00 26.19 1.00 26.23 1.00 29.33 1.00 30.91 1.00 29.09 1.00 30.51 1.00 24.22 1.00 21.05 1.00 21.71 1.00 18.85 1.00 22.98 1.00 22.17 1.00 25.47 1.00 26.30 1.00 24.33 1.00 25.03 1.00 26.44 1.00 20.00 1.00 21.15 1.00 19.87 1.00 23.20 1.00 26.53 1.00 34.28 1.00 35.24 1.00 31.49 1.00 21.84 1.00 21.55 1.00 20.12 1.00 21.02 1.00 18.53 1.00 27.92 1.00 32.84 1.00 33.63 1.00 17.42 1.00 22.09 1.00 20.47 1.00 20.13 1.00 17.58 1.00 18.41 1.00 11.95 1.00 17.80 1.00 20.68 WO 99/50658 PCT/US99/06937

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2916 0 LEU B 2917 N LEU B 2918 CA LEU B 2919 CB LEU B 2920 CG LEU B 2921 CDI LEU B 2922 CD2 LEU B 2923 C LEU B 2924 0 LEU B 2925 N ALA B 2926 CA ALA B 2927 CB ALA B 2928 C ALA B 2929 0 ALA B 2930 N THR B 2931 CA THR B 2932 CB THR B 2933 OG THR B 2934 CG2 THR B 2935 C 2936 0 2937 N 2938 CA 2939 CB 2940 OG 2941 C 2942 0 2943 N 2944 CA 2945 CB 2946 OG 2947 C 2948 0 2949 N 2950 CA 2951 CB 2952 CG 2953 CD 2954 NE 2955 CZ 2956 NHI THR B THR B SER B SER B SER B SER B SER B SER B SER B SER B SER B SER B SER B SER B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B 428 429 429 429 429 429 429 429 429 430 430 430 430 430 431 431 431 431 431 431 431 432 432 432 432 432 432 433 433 433 433 433 433 434 434 434 434 434 434 434 434 434 434 434 435 435 435 435 9.028 -12.305 21.445 8.037 -14.178 20.679 8.938 -15.082 21.382 8.470 -16.532 21.211 7.189 -16.839 21.997 6.551 18.123 21.494 7.537 16.944 23.475 10.361 -14.936 20.865 11.318 -14.968 21.638 10.495 -14.770 19.554 11.808 -14.609 18.947 11.677 -14.596 17.432 12.467 -13.315 19.440 13.670 -13.277 19.713 11.670 -12.258 19.567 12.183 -10.974 20.021 11.128 -9.866 19.863 10.572 -9.936 18.547 11.762 -8.489 20.073 12.603 -11.037 21.480 13.595 -10.429 21.879 11.844 -11.773 22.280 12.169 -11.906 23.693 11.055 -12.661 24.423 11.404 -12.888 25.776 13.491 -12.660 23.820 14.305 -12.377 24.701 13.691 -13.628 22.932 14.914 -14.421 22.928 14.790 -15.575 21.938 14.761 -16.808 22.625 16.104 -13.550 22.548 17.204 -13.701 23.087 15.878 -12.641 21.607 16.926 -11.739 21.165 16.437 -10.912 19.977 17.428 -9.868 19.493 18.694 -10.502 18.919 19.654 -9.479 18.516 20.965 -9.673 18.418 21.492 -10.861 18.696 21.750 -8.671 18.048 17.328 -10.827 22.326 18.515 -10.612 22.569 16.337 -10.297 23.039 16.600 -9.422 24.186 15.278 -8.972 24.825 14.656 -7.758 24.183 1.00 20.45 1.00 20.35 1.00 19.82 1.00 23.13 1.00 21.85 1.00 25.39 1.00 24.91 1.00 20.74 1.00 21.02 1.00 21.40 1.00 22.77 1.00 21.11 1.00 22.40 1.00 20.62 1.00 21.09 1.00 22.67 1.00 23.77 1.00 23.84 1.00 21.78 1.00 21.98 1.00 19.85 1.00 24.24 1.00 26.96 1.00 28.00 1.00 30.31 1.00 27.67 1.00 23.78 1.00 29.27 1.00 31.96 1.00 30.84 1.00 38.26 1.00 31.47 1.00 28.43 1.00 29.55 1.00 29.40 1.00 31.56 1.00 36.76 1.00 37.76 1.00 39.50 1.00 44.17 1.00 43.17 1.00 43.05 1.00 29.15 1.00 28.82 1.00 24.88 1.00 25.74 1.00 26.53 1.00 30.94 2957 NH2 ARG B 2958 C ARG B 2959 0 ARG B 2960 N PHE B 2961 CA PHE B 2962 CB PHE B 2963 CG PHE B

CG

riC WO 99/50658 PCT/US99/06937 ATOM 2964 CDI PHE B ATOM 2965 CD2 PHE B

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2966 CE] 2967 CE.

2968 CZ 2969 C 2970 0 2971 N 2972 CA 2973 CB 2974 CG 2975 CD 2976 NE 2977 CZ 2978 NHi 2979 NH2 2980 C 2981 0 2982 N 2983 N 2984 CA 2985 CA 2986 CB 2987 CB 2988 CG 2989 CG 2990 SD 2991 SD 2992 CE 2993 CE 2994 C 2995 C 2996 0 2997 0 2998 N 2999 CA 3000 CB 3001 CG 3002 SD 3003 CE 3004 C 3005 0 3006 N 3007 CA 3008 CB 3009 CG 3010 ODI 3011 ND2 PHE B PHE B PHE B PHE B PHE B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B ARG B AMET B BMET B AMET B BMET B AMET B BMET B AMET B BMET B AMET B BMET B AMET B BMET B AMET B BMET B AMET B BMET B MET B MET B MET B MET B MET B MET B MET B MET B ASN B ASN B ASN B ASN B ASN B ASN B 435 435 435 435 435 435 435 436 436 436 436 436 436 436 436 436 436 436 437 437 437 437 437 437 437 437 437 437 437 437 437 437 437 437 438 438 438 438 438 438 438 438 439 439 439 439 439 439 15.118 13.592 14.529 12.997 13.468 17.426 18.414 16.999 17.675 16.898 17.232 16.135 15.646 14.433 13.578 14.074 19.110 20.057 19.269 19.252 20.591 20.547 20.489 20.348 20.179 21.605 20.354 21.247 22.155 21.837 21.498 21.487 22.702 22.699 20.913 21.674 20.930 21.161 20.425 21.693 21.877 22.686 21.120 21.199 22.592 22.624 21.584 23.801 -7.271 22.966 -7.108 24.797 -6.155 22.372 -5.989 24.208 -5.516 22.995 -10.184 25.233 -9.675 25.764 -11.405 25.528 -12.253 26.503 -13.569 26.662 -14.358 27.915 -15.367 28.260 -16.085 27.086 -15.923 26.557 -15.061 27.097 -16.620 25.486 -12.531 26.048 -12.397 26.823 -12.921 24.789 -12.906 24.781 -13.212 24.253 -13.206 24.183 -13.646 22.788 -13.595 22.714 -15.127 22.592 -13.594 21.861 -16.099 24.109 -13.937 20.115 -16.194 24.259 -15.632 19.976 -11.993 24.366 -12.005 24.289 -12.123 24.594 -12.162 24.438 -10.809 24.215 -9.560 24.298 -8.437 23.578 -8.364 22.093 -6.849 21.462 -5.657 21.943 -9.122 25.738 -8.240 26.013 -9.721 26.646 -9.359 28.038 -9.524 28.598 -9.480 30.080 -9.620 30.724 -9.260 30.666 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 32.65 33.60 36.84 34.96 31.64 25.39 22.59 24.58 30.25 33.32 38.17 37.27 43.92 46.68 45.59 46.25 29.82 28.76 30.27 31.41 31.98 33.77 31.34 35.88 33.62 40.47 35.21 46.79 33.20 43.22 33.33 34.45 33.54 34.43 32.07 32.48 29.74 36.73 38.21 35.91 28.81 30.13 27.14 27.34 34.85 38.58 42.99 41.14 r., WO 99/50658 PCT/US99/06937

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0" ATOM

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3012 C 3013 0 3014 N 3015 CA 3016 CB 3017 CG 3018 CDI 3019 CD2 3020 C 3021 0 3022 N 3023 CA 3024 CB 3025 CG 3026 CD 3027 OEI 3028 NE2 3029 C 3030 0 3031 N 3032 CA 3033 C 3034 0 3035 N 3036 CA 3037 CB 3038 CG 3039 CD 3040 OEI 3041 OE2 3042 C 3043 0 3044 N 3045 CA 3046 CB 3047 CG 3048 CD 3049 OEI 3050 OE2 3051 C 3052 0 3053 N 3054 CA 3055 CB 3056 CG 3057 CDI 3058 CD2 3059 CEI ASN B ASN B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLN B GLY B GLY B GLY B GLY B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B GLU B PHE B PHE B PHE B PHE B PHE B PHE B PHE B 439 439 440 440 440 440 440 440 440 440 441 441 441 441 441 441 441 441 441 442 442 442 442 443 443 443 443 443 443 443 443 443 444 444 444 444 444 444 444 444 444 445 445 445 445 445 445 445 20.745 21.396 19.625 19.061 17.761 17.087 17.958 15.704 18.782 18.131 19.268 19.060 20.250 21.572 21.610 21.539 21.703 17.789 17.303 17.266 16.058 16.217 15.290 17.387 17.635 18.960 19.005 19.701 19.343 20.607 17.662 17.265 18.128 18.182 19.046 20.545 21.340 20.817 22.488 16.758 16.377 15.987 14.600 13.989 12.483 11.746 11.802 10.346 -7.903 28.212 -7.106 28.891 -7.564 27.573 -6.214 27.633 -6.157 26.818 -4.786 26.740 -3.843 25.923 -4.914 26.111 -5.785 29.074 -6.504 29.830 -4.609 29.452 4.099 30.807 -3.231 31.234 -3.956 31.228 -5.028 32.279 -4.772 33.473 -6.288 31.823 -3.265 30.883 -2.768 29.866 -3.105 32.096 -2.327 32.293 -0.873 31.885 -0.279 31.341 -0.293 32.141 1.102 31.778 1.590 32.378 1.525 33.895 0.270 34.402 -0.841 33.948 0.394 35.252 1.278 30.262 2.328 29.747 0.253 29.552 0.302 28.093 -0.834 27.545 -0.617 27.705 -1.869 27.393 -2.978 27.629 -1.746 26.914 0.155 27.552 0.822 26.597 -0.730 28.176 -0.969 27.792 -2.067 28.675 -2.055 28.709 -2.386 27.575 -1.694 29.872 -2.359 27.592 1.00. 26.24 1.00 19.76 1.00 24.90 1.00 25.04 1.00 22.36 1.00 26.33 1.00 28.33 1.00 24.81 1.00 24.71 1.00 26.96 1.00 25.54 1.00 25.82 1.00 30.41 1.00 30.50 1.00 32.75 1.00 36.52 1.00 31.09 1.00 26.93 1.00 25.40 1.00 24.56 1.00 22.82 1.00 24.19 1.00 20.21 1.00 22.92 1.00 23.33 1.00 24.26 1.00 32.31 1.00 37.68 1.00 35.23 1.00 42.47 1.00 23.08 1.00 21.80 1.00 21.16 1.00 22.60 1.00 20.89 1.00 23.24 1.00 22.11 1.00 20.89 1.00 25.49 1.00 21.06 1.00 23.73 1.00 19.01 1.00 19.44 1.00 18.12 1.00 18.13 1.00 18.34 1.00 16.59 1.00 17.15

C,

WO 99/50658 PCT/US99/06937

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3060 CE2 PHE B 3061 CZ PHE B 3062 C PHE B 3063 0 PHE B 3064 N VAL B 3065 CA VAL B 3066 CB VAL B 3067 CGI VAL B 3068 CG2 VAL B 3 069 C VAL B 3070 0 VAL B 3071 N CYS B 3072 CA CYS B 3073 CB CYS B 3074 SG CYS B 3075 C CYS B 3076 0 CYS B 3077 N LEU B 3078 CA LEU B 3079 CB LEU B 3080 CG LEU B 3081 CDI LEU B 3082 CD2 LEU B 3083 C 3084 0 3085 N 3086 CA 3087 CB 3088 CG 3089 CD 3090 CE 309.1 NZ 3092 C 3093 0 3094 N 3095 CA 3096 CB 3097 OG 3098 C 3099 0 3100 N 3101 CA 3102 CB LEU B LEU B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B SER B SER B SER B SER B SER B SER B ILE B ILE B ILE B 445 445 445 445 446 446 446 446 446 446 446 447 447 447 447 447 447 448 448 448 448 448 448 448 448 449 449 449 449 449 449 449 449 449 450 450 450 450 450 450 451 451 451 451 451 451 451 451 10.406 9.674 13.758 13.008 13.872 13.074 13.165 12.574 14.598 13.450 12.596 14.723 15. 161 16.682 17.538 14.537 13.988 14.623 14.072 14.328 15.730 15.722 16. 167 12.573 12.078 11.849 10.405 9.796 8.285 7.730 8.201 7.159 10.058 9.103 10.837 10.591 11.440 10.859 10.921 10.279 11.926 12.305 13.564 13.724 14.804 16.083 11.142 10.820 -1.662 29.903 -1.997 28.755 0.304 27.888 0.617 26.966 1.044 28.986 2.269 29.112 2.895 30.531 1.923 _31.551 3.251 30.879 3.295 28.051I 4.028 27.561 3.335 27.674 4.255 216.635 4.224 26.512 5.134 27.798 3.826 25.301 4.643 24.563 2.533 25.006 1.994 23.767 0.490 23.684 0.009 23.301 -1.522 23.169 0.658 21-986 2.249 23.652 2.633 22.590 2.037 24.745 2.232 2 4.733 1.745 26.047 1.861 26*.115 0.952 27.193 1.380 28.580 1.088 29.593 3.696 24.486 3.996 23.769 4.610 25.059 6.032 24.849 6.866 25.815 6.868 27.108 6.418 23.405 7.292 22.821 5.768 22.828 6.063 21.450 5.268 2 1.025 5.298 19.505 5.897 .21.676 5.711 210.527 6.464 19.608 1.00 21.99 1.00 16.01 1.00 15.87 1.00 20.27 1.00 15.90 1.00 16.78 1.00 18.32 1.00 21.14 1.00 21.04 1.00 17.91 1.00 19.37 1.00 18.81 1.00 17.34 1.00 19.33 1.00 23.60 1.00 18.09 1.00 17.52 1.00 15.60 1.00 16.67 1.00 14.82 1.00 23.57 1.00 21.61 1.00 18.92 1.00 15.98 1.00 18.91 1.00 -17.94 1.00 16.66 1.00 16.45 1.00 16.12 1.00 19.09 1.00 17.04 1.00 17.25 1.00 18.78 1.00 14.84 1.00 14.50 1.00 17.11 1.00 2 1.20 1.00 30.66 1.00 17.84 1.00 18.82 1.00 16.88 1.00 17.11 1.00 16.69 1.00 19.31 1.00 18.96 1.00 18.98 00 18.09 1.00 17.07 3103 CG2 ILE B 3104 CGI ILE B 3 105 CD1 ILE B 3106 C ILE B _3107 0 ILE B -j WO 99/50658 PCT/US99/06937

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3108 N ILE B 3109 CA ILE B 3110 CB ILE B 3111 CG2 ILE B 3112 CG1 ILE B 3113 CDI ILE B 3114 C ILE B 3115 0 ILE B 3116 N LEU B 3117 CA LEU B 3118 CB LEU B 3119 CG LEU B 3120 CDI LEU B 3121 CD2 LEU B 3122 C LEU B 3123 0 LEU B 3124 N LEU B 3125 CA LEU B 3126 CB LEU B 3127 CG LEU B 3128 CDI LEU B 3129 CD2 LEU B 3130 C LEU B 3131 0 LEU B 3132 N ASN B 3133 CA ASN B 3134 CB ASN B 3135 CG ASN B 3136 ODI ASN B 3137 ND2 ASN B 3138 C ASN B 3139 0 ASN B 3140 N SER B 3141 CA SER B 3142 CB SER B 3143 OG SER B 3144 C SER B 3145 0 SER B 3146 N GLY B 3147 CA GLY B 3148 C GLY B 3149 0 GLY B 3150 N VAL B 3151 CA VAL B 3152 CB VAL B 3153 CGI VAL B 3154 CG2 VAL B 3155 C VAL B 452 452 452 452 452 452 452 452 453 453 453 453 453 453 453 453 454 454 454 454 454 454 454 454 455 455 455 455 455 455 455 455 456 456 456 456 456 456 457 457 457 457 458 458 458 458 458 458 10.505 9.373 8.804 7.464 9.763 9.449 8.271 7.733 7.943 6.903 6.736 5.792 4.388 5.816 7.198 6.320 8.434 8.789 9.959 9.735 11.046 8.658 9.120 8.941 9.566 9.951 11.147 11.576 12.106 11.343 8.925 8.790 8.224 7.260 6.402 7.212 6.385 6.323 5.716 4.879 5.510 4.851 6.789 7.486 8.950 9.827 9.463 7.483 4.571 20.786 4.137 19.976 2.775 20.477 2.496 19.831 1.635 20.107 0.323 20.805 5.195 20.024 5.586 18.992 5.665 21.222 6.680 21.374 7.061 22.850 8.228 23.163 7.881 22.704 8.538 24.667 7.941 20.566 8.458 19.879 8.428 20.636 9.653 19.933 10.347 20.653 10.699 22.130 11.170 22.749 11.777 22.259 9.494 18.449 10.431 17.673 8.311 18.042 8.093 16.651 7.149 16.584 6.871 15.161 7.749 14.496 5.648 14.686 7.580 15.655 8.127 14.564 6.514 16.023 5.873 15.135 4.894 15.939 3.818 16.390 6.774 14.272 6.588 13.055 7.750 14.872 8.627 14.076 9.973 13.765 10.850 13.214 10.130 14.092 11.396 13.879 11.310 14.373 10.650 13.324 12.699 14.701 11.982 12.464 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 18.13 16.77 17.40 14.33 15.36 17.76 17.47 16.50 16.06 17.17 16.23 17.60 16.94 17.17 19.33 21.37 17.68 20.93 24.33 26.16 24.82 23.79 20.75 21.33 20.54 19.46 18.58 17.64 18.40 15.06 22.77 21.94 25.90 24.76 26.91 26.24 26.52 29.22 22.07 25.19 28.59 28.31 31.65 38.50 36.24 38.50 39.84 46.3 0 r c; WO 99/50658 PCT/US99/06937

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3156 0 VAL B 3157 N TYR B 3158 CA TYR B 3159 CB TYR B 3160 CG TYR B 3161 CDI TYR B 3162 CEI TYR B 3 163 CD2 TYR B 3164 CE2 TYR B 3165 CZ TYR B 3166 OH TYR B .3167 C TYR B 3168 0 TYR B 3169 N THR B 3170 CA THR B 3171 CB THR B 3172 OGI THR B 3173 CG2 THR B .3174 C THR B 3175 0 THR B 3176 N PHE B 3177 CA PHE B .3178 CB PHE B 3179 CG PHE B 3180 CDI PHE B 3181 CD2 PHE B 3182 CEl PHE B 3183 CE2 PHE -B .3184 CZ PHE B 3185 C PHE B 3186 0 PHE B 3187 CB GLU B 3188 C GLU B 3189 0 GLU B 3190 N GLU B 3191 CA GLU B 3192 N GLU B 3193 CA GLU B 3194 CB GLU B 3195 CG GLU B 3196 CD GLU B 3197 OEI GLU B 3198 0E2 GLU B 3199 C GLU B 3200 0 GLU B 3201 N LYS B 3 202 CA LYS B 3203 CB LYS B 458 459 459 459 459 459 459 459 459 459 459 459 459 460 460 460 460 460 460 460 461 461 461 461 461 461 461 461 461 461 461 470 470 470 470 470 471 471 471 471 471 471 471 471 471 472 472 472 7.567 7.393 7.385 8.233 9.673 10.284 11.591 10.4 14 11.726 12.305 13.593 5.976 5.629 5.166 3.783 3.178 1.890 3.040 2.94 5 1.7 15 3.625 2.969 3.977 4.235 3.200 5.5 17 3.438 5.765 4.722 1.787 1.775 7.873 8.95 8 9.887 9.096 9.060 7.823 7.596 6.118 5.742 5.062 3.829 5.763 8.487 8.897 8.785 9.639 9.578 13.201 12.302 11.138 11.442 11.640 10.069 10.740 9.170 10.680 9.611 11.786 10.203 11.725 10.662 9.510 9.486 9.439 9.943 10.548 10.532 10.477 11.009 11.753 9.514 12.750 8.874 10.730 9.768 10.702 9.309 9.283 9.464 9.235 8.836 8.916 10.938 11.700 10.107 11.641 10.099 12.620 10.788 13.637 11.607 14.720 12.012 14.789 13.492 14.609 14.404 15.025 13.975 14.662 15.775 15.080 15.344 14.897 16.245 14.286 10.896 14.279 9.645 23.789 14.718 21.731 15.650 21.518 16.432 22.235 13.227 22.830 14.595 21.037 15.665 19.956 16.617 19.54.3 16.604 18.544 15.516 19.198 14.327 19.398 14.378 19.511 1 3 .340 18.756 16.292 18.021 17.189 18.565 15.009 17.461 14.581 17.293 13.060 1.00 47.67 1.00 50.45 1.00 57.07 1.00 57.05 1.00 59.29 1.00 60.93 1.00 61.86 1.00 59.46 1.00 59.67 1.00 60.84 1.00 61.39 1.00 61.22 1.00 62.89 1.00 65.15 1.00 67.76 1.00 68.02 1.00 67.03 1.00 67.31 1.00 70.14 1.00 72.35 1.00 72.64 1.00 75.05 1.00 75.47 1.00 74.32 1.00 73.98 1.00 75.22 1.00 74.02 1.00 74.50 1.00 74.10 1.00 76.78 1.00 77.08 1.00 80.19 1.00 79.30 1.00 78.21 1.00 80.22 1.00 80.03 1.00 78.31 1.00 75.83 1.00 76.70 1.00 78.42 1.00 79.69 1.00 80.26 1.00 80.72 1.00 73".13 1.00 73 .86 1.00 69.65 1.00 64.40 1.00 63.78 WO 99/50658 PTU9163 PCTIUS99/06937

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3 5 ATOM

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3204 CG LYS B 3205 CD LYS B 3206 CE LYS B 3207 NZ LYS B 3208 C LYS B 3209 0 LYS B 3210 N ASP B -3211 CA ASP B 3212 CB ASP B 3213 C ASP B 3214 0 ASP B .3215 N HIS B 3216 CA HIS B 3217 CB HIS B 3218 CG HIS B 3219 CD2 HIS B 3220 NDI HIS B 3221 CEI HIS B 3222 NE2 HIS B -3223 C HIS B -3224 0 HIS B -3225 N ILE B 3226 CA ILE B 3227 CB ILE B 3228 CG2 ILE B 3229 CGI ILE B 3230 CD1 ILE B 3231 C ILE B 3232 0 ILE B 3233 N HIS B 3234 CA HIS B 3235 CB HIS B 3236 CG HIS B 3237 CD2 HIS B 3238 NDI HIS B 3239 CEl HIS B 3240 NE2 HIS B 3241 C HIS B 3242 0 HIS B 3243 N ARG B -3244 CA ARG B 3245 CB ARG B 3246 CG ARG B 3247 CD ARG B 3248 NE ARO B 3249 CZ ARG B 3250 NHI ARG B 3251 NH2 ARG B 472 472 472 472 472 472 473 473 473 473 473 474 474 474- 474 474 474 474 474 474 474 475 475 475 475 475 475 475 475 476 476 476 476 476 476 476 476 476 476 477 477 477 477 477 477 477 477 477 8.343 8.544 7.379 6.475 11.071 11.848 11.413 12.745 12.923 ]2.923 13.959 11.898 11.923 10.652 10.458 11.095 9.510 9.572 10.526 12.030 12.834 11.214 11.222 10.105 10.390 8.770 7.598 12.575 13.112 13.121 14.421 14.782 14.132 13 .723 13.816 13 .238 13.170 15.506 16.442 15.387 16.361 16. 144 16.3 22 16.552 12.566 16.002 11.161 16.368 10.249 15.212 9.990 17.749 15.014 16.833 15.287 19.033 15.076 19.451 15.488 20.940 15.242 19.138 16.970 18.619 17.385 19.449 17.758 19.203 19.196 19.761 19.847 19.32-6 21.267 19.688 22.406 18.395 21.638 18.202 22.943 18.975 23.434 17.707 19.471 17.273 2 0.298 16.923 18.773 15.475 18.943 14.822 18.110 13.335 17.911 14.998 18.832 14.410 18.094 14.898 18.532 14.023 19.207 15.375 17.429 14.886 16.992 15.481 15.637 14.781 14.486 13.498 14.342 15.419 13.306 14.560 12.484 13.387 13.089 15.213 18.022 14.436 18.208 16.365 18.684 16.754 19.703 18.214 20.121 19.2 12 18.9 82 1.00 64.49 1.00 63.81 1.00 64.90 1.00 63.97 1.00 61.03 1.00 60.28 1.00 56.84 1.00 51.69 1.00 50.36 1.00 49.18 1.00 46.85 1.00 45.35 1.00 43.65 1.00 43.70 1.00 43.86 1.00 44.12 1.00 46.60 1.00. 45.29 1.00 47.96 1.00 42.38 1.00 42.83 1.00 38.86 1.00 -36.5 3 1.00 36.56 1.00 36.17 1.00 35.81 1.00 41.77 1.00 33.72 1.00 3 1.50 1.00 3 3.65 1.00 33.31 1.00 37.3 0 1.00 43.64 1.00 45.25 1.00 48.37 1.00 48.87 1.00 48.11 1.00 31.20 1.00 27.25 1.00 30.64 1.00 30.09 1.00 33.46 1.00 40.74 1.00 45.91 1.00 51.37 1.00 53 .68 1.00 53.04 1.00 51.79 16.274 20.64 9 19.479 17.514 21.020 20.155 18.375 21.927 19.702 18.140 22.567 18.560 19.480 22. 18 5 20.389 c) Q fl WO 99/50658 PCT/US99/06937

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3 252 C ARO B 3253 0 ARG' B 3254 N VAL B 3255 CA VAL B 3 256 CB VAL B 3257 CGI VAL B 3258 CG2 VAL B 3259 C VAL B 3260 0 VAL B 3261 N LEU B 3262 CA LEU B 3263 CB LEU B 3264 CG LEU B 3265 CDI LEU B 3266 CD2, LEU B 3267 C LEU B 3268 0 LEU B 3269 N ASP B 3270 CA ASP B 3271 CB ASP B 3272 CG ASP B 3273 ODI ASP B 3274 0D2 ASP B 3 275 C ASP B 3276 0 ASP B 3277 N LYS B 3278 CA LYS B 3279 CB LYS B 3280 CG LYS B 3281 CD LYS B 3282 CE LYS B 3283 NZ LYS B 3284 C LYS B 3285 0 LYS B 3286 N ILE B 3287 CA ILE B 3288 CB ILE B 3289 CG2 ILE B 3290 CGI ILE B 3291 CD1 ILE B 3292 C ILE B 3293 0 ILE B 3294 N THR B 3295 CA THR B .3296 CB THR B 3297 OGI THR B 3298 CG2 THR B 3299 C THR B 477 477 478 478 478 478 478 478 478 479 479 479 479 479 479 479 479 480 480 480 480 480 480 480 480 481 481 481 481 481 481 481 481 481 482 482 482 482 482 482 482 482 483 483 483 483 4 83 483 16.232 17.233 14.999 14.780 13.286 13.088 12.781 15.284 15.9 19 15.021 15.456 14.992 13.575 13.23 1 13.495 16.975 17.506 17.675 19. 141 19.692 19.773 19.857 19.757 19.590 20.551 18.887 19.2 13 18.262 18.962 18.780 20. 120 21. 177 19.124 19.95 1 18.124 17.98 1 16.655 16.580 15.479 14. 136 19. 135 19.621 19.569 20.701 2 1.030 19.890 22.203 21.913 15.835 20.925 15.387 21.486 15.558 21.338 14.685 22. 48 2 14.613 22.861 13.646 24.022 15.996 23.243 13.294 22.112 12.613 22.927 12.889 20.870 11.584 20.379 11.372 18.930 10.798 18.756 10.689 17.274 9.440 19.420 11.471 20.453 10.416 20.778 12.560 20.143 12.566 20.198 13.889 19.649 13.914 18.129 12.836 17.499 15.022 17.563 12.406 21.656 11.697 21.956 13.077 22.560 13.010 23.980 13.898 24.785 14.788 25.804 14.260 27.219 13.928 27.865 14.922 27.511 11.575 24.495 11.145 25.305 10.830 24.027 9.452 24.472 8.828 24.015 7.370 24.491 9.606 24.602 9.209 23.991 8.6 16 23.947 7.722 24.640 8.896 22.722 8.176 22.141 8.662 20.695 8.475 19.85 1 7.882 20.116 8.441 23.035 1.00 26.97 1.00 27.34 1.00 23.70 1.00 24.79 1.00 24.83 1 .00 26.23 1.00 28.26 1.00 26. 1.00 24.28 1.00 22.92 -1.00 2 1.96 1.00 22.63 1.00 20.82 1.00 22.53 1.00 23.08 1.00 21.90 1.00 23.11 1.00 23.65 1.00 24.29 1.00 26.88 1.00 33.32 1.00 35.44 1.00 32.44 1.00 24.13 1.00 24.88 1.00 25.18 J .00 26.78 1.00 31.37 1.00 43.84 1.00 46.08 1.00 50.99 1.00 54.35 1.00 26.87 1.00 20.37 1.00 23.26 1.00 21.07 1.00 19.80 1.00 17.40 1.00 17.16 1.00 19.43 1.00 20.21 1.00 25.55 1.00 21.89 1.00 22.67 1.00 23.34 1.00 27.33 1.00 24.46 1.00 23.51 WO 99/50658 WO 9950658PCTIUS99/06937

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3300 0 THR B .3301 N ASP B ~3302 CA ASP B 3303 GB ASP B 3304 CG ASP B 3305 ODI ASP B 3306 0D2 ASP B 3307 C ASP B 3308 0 ASP B 3309 N THR B 3 310 CA THR B 3311 GB THR B 3312 OGI THR B 3313 CG2 THR B 3314 C THR B 3315 0 THR B 3316 N LEU B 3317 CA LEU B 3318 GB LEU B 3319 CG LEU B 3320 CD1 LEU B 3321 CD2 LEU B 3322 C 3323 0 3324 N 3325 CA 3326 GB 3327 CG2 3328 CGI 33 29 CDI 3330 C '331. 0 3332 N 3333 CA 3334 GB 3335 CG 3336 CD2 -3337 NDI 3338 GEl 3339 NE2 3340 C 3341 0 3342 N 3,343 CA 3344 GB 3345 G LEU B LEU B ILE B ILE B ILE B ILE B ILE B ILE B ILE B ILE B HIS B HIS B HIS B HIS B HIS B HIS B HIS B HIS B HIS B HIS B.

LEU B LEU B LEU B LEU B 483 484 484 484 484 484 484 484 484 485 485 485 485 485 485 485 486 486 486 486 486 486 486 486 487 487 487 487 487 487 487 487 488 488 488 488 488 488 488 488 488 488 489 489 489 489 489 489 221.650 22.119 23.237 23.201 23.504 23.982 23.256 23. 125 24. 125 21.899 21.670 20.203 19.878 19.993 22.017 22.574 21.686 21.969 2 1.346 19.878 19.295 19.763 23.477 23.984 24.191 25.640 26.207 2 7. 725 25.857 26.538 26.275 2 7.200 25.755 26.251 25.450 25.8 18 25.245 26.869 26.927 25.953 26. 123 27.07 1 24.949 24.715 23.298 22.158 20.827 22.143 7.520 23.381 9.703 23.404 10.058 24.276 11.546 24.652 12.464 23 .485 11.984 22.437 13.681 23.627 9.249 25.* 567 8.780 26.'103 9.096 26.066 8.365 27.307 8.52 1 27.763 9.914 27.830 7.896 2 9. 133 6.881 27.188 6.284 28.115 6.290 26.045 4.881 25.792 4.452 24.464 4.031 24.533 4.003 23 123 2.658 25.196 4.634 25.742 3.681 26.334 5.490 25.022 5.345 24.913 6.379 23.899 6.522 24.051 5.936 22.470 4.646 22.02 1 5.518 26.307 4.794 26.671 6.456 27.081 6.720 28.431 7.871 29.041 8.196 30.455 7.838 31.629 9.025 30.779 9.164 32.091 8.453 32.630 5.463 29.292 5.054 29.967 4.850 29.266 3.642 30.040 3.127 29.788 3.909 30.445 3.516 29.799 3.616 31.949 1.00 27.01 1.00 22.88 1.00 24.93 1.00 28.69 1.00 29.19 1.00 29.63 1.00 3 2.02 1.00 24.40 1.00 25.60 1.00 20.16 1.00 22.28 1.00 24.64 1.00 24.28 1.00 23.32 1.00 22.13 1.00 23.30 1.00 23.08 1.00 22.26 1.00 20.93 1.00 24.92 1.00 21.96 1.00 23.90 1.00 24.12 1.00 24.02 1.00 24.53 1.00 25.16 1.00 25.57 1.00 24.54 1.00 25.63 1.00 25.68 1.00 23.60 1.00 23.65 1.00 21.75 1.00 26.07 1.00 26.99 1.00 33.06 1.00 32.79 1.00 36.45 1.00 35.93 1.00 3 3.88 1.00 26.85 1.00 28.52 1.00 28.00 1.00 25.94 1.00 27.07 1.00 3 1.71 1.00 .28.08 1.00 29.30 3346 CDI LEU B 3347 CD2 LEU B

G

G7 WO 99/50658 PCT/US99/06937

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3348 C 3.349 0 3350 N 3351 CA -3352 CB 3353 CG 3354 SD 3 355 CE 3356 C 3357 0 3358 N 3359 CA 3360 CB 3361 C 3362 0 3363 N 3364 CA 3365 CB 3366 CG 3367 CD 3368 CE' 3369 NZ 3370 C 3371 0 3372 N 3373 CA 3374 CB 3375 C 3376 0 3377 N 3378 CA 3379 C 3380 0 3381 N 3382 CA 3383 CB 3384 CG 3385 CD] 3386 CD2 3387 C 3388 0 3389 N 3390 CA 3391 CB LEU B LEU B MET B MET B MET B MET B MET B MET B MET B MET B ALA B ALA B ALA B ALA B ALA B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B ALA B ALA B ALA B ALA B ALA B GLY B GLY B GLY B GLY B LEU B LEU B LEU B LEU B LEU B LEU B LEU B LEU B THR B THR B THR B 489 489 490 490 490 490 490 490 490 490 491 491 491 491 491 492 492 492 492 492 492 492 492 492 493 493 493 493 493 494 494 494 494 495 495 495 495 495 495 495 495 496 496 496 496 496 496 496 25.718 26.241 25.978 26.900 26.775 25.418 25.208 23 .461 28.341 29.109 28.7 13 30.074 30.299 30.250 1.194 29.3 16 29.354 28.110 28.4 12 27.242 26.299 26.395 29.453 30.090 28.835 28.867 27.7 19 30.201 30.402 31.102 32.405 32.639 33.663 3 1.7 12 .31.859 3 0.4 94 29.610 29.3 15 28.307 32.829 32.855 33 .628 34.567 35.5 11 34.753 36.228 .33.770 32.580 2.561 29.642 1.832 30.486 2.453 28.345 1.438 27.857 1.306 26.336 0.776 25.895 0.739 24.106 0.412 24.022 1.743 28.247 0.833 28.574 3.018 28.207 3.394 28.577 4.882 28.335 3.053 30.056 2.361 30.438 3.523 30.878 3267 32.309 3.849 32.976 4.797 34.123 4.887 35.084 6.013 34.698 7.184 35.618 1.771 32.619 1.382 33.593 0.935 31.788 -0.510 31.998 -1.181 31.245 -1.156 31.606 -2.356 31.819 -0.372 31.020 -0.903 30.656 -1.360 29.230 -1.989 28.950 -1.056 28.326 -1.452 26.925 -1.415 26.216 -2.675 26.256 -3.058 27.700 -2.416 25.501 -0.515 26.202 0.688 26.468 -1.064 25.291 -0.243 24.529 -1.095 23.665 -1.758 22.641 -2.122 24.515 0.652 23.590 0.433 2 3.38 0 1.00 26.84 1.00 20.86 1.00 23.82 1.00 26.38 1.00 27.29 1.00 2 1.68 1.00 26.30 1.00 19.66 1.00 26.42 1.00 24.76 1.00 26.67 1.00 30.73 1.00 26.66 1.00 32.08 1.00 34.66 1.00 33.17 1.0 ,0 32.82 1.00 36.38 1.00 38.68 1.00 41.41 1.00 47.57 1.00 50.76 1.00 34.08 1.00 3)4.31 1.00 3)2.03 1.00 30.70 1.00 2 8.8 0 1.00 33.75 1.00 30.53 1.00 33.50 1.00 33.171 1.00 34.40 1.00 33. 13 1.00 31. 76 1.00 30.57 1.00 -30.67 1.00 29.59 1.00 26.60 1.00 27.52 1.00 30. 5 3 1.00 28.14 1.00 28.03 1.00 29.06 1.00 29.40 1.00 30.29 1.00 28.12 1.00 30.12 1.00 29.74 3392 OGI THR B 3393 CG2 THR B 3394 C THR B 3395 0 THR B

'I

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3396 N LEU B 3397 CA LEU B 3398 CB LEU B 3399 CG LEU B 3400 CDI LEU B 3401 CD2 LEU B 3402 C LEU B 3403 0 LEU B 3404 N GLN B 3405 CA GLN B 3406 CB GLN B 3407 CG GLN B 3408 CD GLN B 3409 OE1 GLN B 3410 NE2 GLN B 3411 C GLN B 3412 0 GLN B 3413 N GLN B 3414 CA GLN B 3415 CB GLN B 3416 CG GLN B 3417 CD GLN B 3418 OEI GLN B 3419 NE2 GLN B 3420 C GLN B 3421 0 GLN B 3422 N GLN B 3423 CA GLN B 3424 CB GLN B 3425 CG GLN B 3426 CD GLN B 3427 OEI GLN B 3428 NE2 GLN B 3429 C GLN B 3430 0 GLN B 3431 N HIS B 3432 CA HIS B 3433 CB HIS B 3434 CG HIS B 3435 CD2 HIS B 3436 NDI HIS B 3437 CEI HIS B 3438 NE2 HIS B 3439 C HIS B 3440 0 HIS B 3441 N GLN B 3442 CA GLN B 3443 CB GLN B 497 497 497 497 497 497 497 497 498 498 498 498 498 498 498 498 498 499 499 499 499 499 499 499 499 499 500 500 500 500 500 500 500 500 500 501 501 501 501 501 501 501 501 501 501 502 502 502 34.430 33.762 34.768 35.209 36.120 33.992 33.095 31.967 33.798 33.289 34.411 33.967 34.965 35.737 34.953 32.112 31.167 32.173 31.093 31.501 32.537 32.913 33.306 32.797 29.842 28.715 30.062 28.989 29.564 29.958 30.812 30.559 31.831 28.151 26.923 28.790 28.004 28.791 29.988 30.122 31.224 32.066 31.422 27.451 26.369 28.165 27.698 28.785 1.654 23.018 2.567 22.104 3.564 21.529 4.719 22.434 5.659 21.652 5.469 22.942 1.800 20.967 2.105 20.574 0.797 20.447 -0.009 19.348 -0.876 18.771 -1.796 17.645 -2.912 17.374 -3.298 18.254 -3.437 16.153 -0.888 19.774 -1.076 19.009 -1.434 20.986 -2.281 21.487 -2.935 22.815 -4.056 22.669 -4.687 23.995 -3.997 24.937 -6.004 24.074 -1.430 21.693 -1.910 21.554 -0.160 22.020 0.793 22.256 2.107 22.782 2.073 24.252 3.262 24.641 4.386 24.207 3.021 25.463 1.074 21.015 0.949 21.053 1.465 19.915 1.739 18.724 2.577 17.697 1.896 17.105 0.710 16.465 2.505 17.042 1.724 16.389 0.628 16.028 0.457 18.123 0.457 17.531 -0.648 18.317 -1.926 17.804 -2.996 17.953 1.00 30.44 1.00 28.54 1.00 31.14 1.00 33.58 1.00 31.42 1.00 35.08 1.00 27.35 1.00 24.03 1.00 26.17 1.00 26.32 1.00 27.25 1.00 32.67 1.00 38.39 1.00 36.78 1.00 33.18 1.00 25.70 1.00 25.35 1.00 24.01 1.00 25.34 1.00 28.38 1.00 29.13 1.00 30.80 1.00 33.62 1.00 30.64 1.00 25.70 1.00 26.22 1.00 23.09 1.00 23.53 1.00 26.17 1.00 27.71 1.00 29.32 1.00 28.48 1.00 25.07 1.00 24.24 1.00 24.40 1.00 23.08 1.00 26.92 1.00 32.00 1.00 36.97 1.00 40.32 1.00 37.88 1.00 38.81 1.00 41.21 1.00 25.91 1.00 20.13 1.00 24.94 1.00 21.88 1.00 24.62 WO 99/50658 ATOM 3444 CG GLN B ATOM 3445 CD GLN B ATOM 3446 OEI GLN B ATOM 3447 NE2 GLN B ATOM 3448 C GLN B ATOM 3449 0 GLN B ATOM 3450 N ARG B ATOM 3451 CA ARG B ATOM 3452 CB ARG B ATOM 3453 CG ARG B ATOM 3454 CD ARG B ATOM 3455 NE ARG B ATOM 3456 CZ ARG B ATOM 3457 NH! ARG B ATOM 3458 NH2 ARG B ATOM 3459 C ARG B ATOM 3460 0 ARG B ATOM 3461 N LEU B ATOM 3462 CA LEU B ATOM 3463 CB LEU B ATOM 3464 CG LEU B ATOM 3465 CDI LEU B ATOM 3466 CD2 LEU B ATOM 3467 C LEU B ATOM 3468 0 LEU B ATOM 3469 N ALA B ATOM 3470 CA ALA B ATOM 3471 CB ALA B ATOM 3472 C ALA B ATOM 3473 0 ALA B ATOM 3474 N GLN B ATOM 3475 CA GLN B ATOM 3476 CB GLN B ATOM 3477 CG GLN B ATOM 3478 CD GLN B ATOM 3479 OEI GLN B ATOM 3480 NE2 GLN B ATOM 3481 C GLN B ATOM 3482 0 GLN B ATOM 3483 N LEU B ATOM 3484 CA LEU B ATOM 3485 CB LEU B ATOM 3486 CG LEU B ATOM 3487 CDI LEU B ATOM 3488 CD2 LEU B PCT/US99/06937 502 502 502 502 502 502 503 503 503 503 503 503 503 503 503 503 503 504 504 504 504 504 504 504 504 505 505 505 505 505 506 506 506 506 506 506 506 506 506 507 507 507 507 507 507 507 507 508 29.796 -3.001 16.797 30.843 -4.109 16.902 30.716 -5.033 17.705 31.882 -4.018 16.078 26.428 -2.341 18.554 25.464 -2.807 17.944 26.421 -2.159 19.874 25.259 -2.523 20.678 25.602 -2.519 22.180 24.451 -3.022 23.077 24.853 -3.110 24.550 23.743 -3.546 25.395 23.329 -4.807 25.497 23.933 -5.765 24.809 22.303 -5.110 26.280 24.102 -1.558 20.409 22.945 -1.968 20.351 24.414 -0.276 20.239 23.375 0.714 19.969 23.972 2.117 19.855 22.983 3.173 19.344 21.930 3.449 20.427 23.729 4.448 18.955 22.659 0.357 18.667 21.433 0.478 18.566 23.428 -0.085 17.676 22.859 -0.473 16.396 23.973 -0.745 15.382 21.986 -1.716 16.562 20.871 -1.774 16.041 22.497 -2.706 17.293 21.772 -3.955 17.513 22.590 -4.893 18.409 23.798 -5.551 17.727 24.819 -6.070 18.736 24.564 -6.084 19.943 25.977 -6.499 18.245 20.421 -3.672 18.166 19.396 -4.233 17.766 20.433 -2.800 19.171 19.219 -2.418 19.884 19.548 -1.455 21.030 20.182 -2.011 22.313 20.203 -0.916 23.360 19.415 -3.213 22.816 18.212 -1.730 18.971 17.036 -2.070 18.964 18.678 -0.745 18.214 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 26.55 27.06 28.49 21.90 22.39 22.24 20.54 22.04 22.51 23.34 22.18 19.62 19.88 16.40 19.71 19.05 18.87 20.19 19.33 16.25 20.35 17.97 20.86 21.22 19.28 18.55 18.20 18.45 19.54 17.63 20.30 19.48 21.75 20.85 26.18 21.83 25.39 21.39 20.87 19.52 23.04 22.82 26.12 29.33 27.80 22.19 23.00 21.53 ATOM 3489 C ATOM 3490 0 ATOM 3491 N LEU B LEU B LEU B

N

WO 99/50658 PCT/US99/06937

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3492 CA LEU B 3493 CB LEU B 3494 CG LEU B 3495 CDI LEU B 3496 CD2 LEU B 3497 C LEU B 3498 0 LEU B 3499 N LEU B 3500 CA LEU B 3501 CB LEU B 3502 CG LEU B 3503 CDI LEU B 3504 CD2 LEU B 3505 C LEU B 3506 0 LEU B 3507 N ILE B 3508 CA ILE B 3509 CB ILE B 3510 CG2 ILE B 3511 CGI ILE B 3512 CDI ILE B 3513 C ILE B 3514 0 ILE B 3515 N LEU B 3516 CA LEU B 3517 CB LEU B 3518 CG LEU B 3519 CDI LEU B 3520 CD2 LEU B 3521 C LEU B 3522 0 LEU B 3523 N SER B 3524 CA SER B 3525 CB SER B 3526 OG SER B 3527 C SER B 3528 0 SER B 3529 N HIS B 3530 CA HIS B 3531 CB HIS B 3532 CG HIS B 3533 CD2 HIS B 3534 NDI HIS B 3535 CEI HIS B 3536 NE2 HIS B 3537 C HIS B 3538 0 HIS B 3539 N ILE B 508 508 508 508 508 508 508 509 509 509 509 509 509 509 509 510 510 510 510 510 510 510 510 511 511 511 511 511 511 511 511 512 512 512 512 512 512 513 513 513 513 513 513 513 513 513 513 514 17.797 18.535 18.934 19.566 17.724 17.235 16.118 18.00 17.511 18.603 19.645 20.697 18.965 16.302 15.409 16.264 15.148 15.448 14.162 16.383 17.429 13.852 12.767 13.961 12.772 13.147 13.607 13.404 12.830 12.112 10.915 12.901 12.355 13.484 13.079 11.454 10.373 11.899 11.141 12.013 13.063 12.980 14.378 15.061 14.235 9.895 8.846 10.012 0.006 17.332 1.236 16.805 2.218 17.913 3.446 17.301 2.611 18.725 -0.831 16.183 -0.597 15.728 -1.813 15.713 -2.657 14.631 -3.597 14.145 -2.891 13.278 -3.888 12.829 -2.248 12.082 -3.462 15.095 -3.759 14.303 -3.796 16.380 -4.562 16.912 -5.041 18.361 -5.435 19.075 -6.260 18.308 -6.301 19.419 -3.746 16.846 -4.308 16.759 -2.421 16.867 -1.574 16.774 -0.100 16.981 0.262 18.406 1.751 18.652 -0.549 19.425 -1.771 15.397 -1.578 15.242 -2.161 14.401 -2.408 13.072 -2.644 12.074 -3.550 11.062 -3.638 13.154 -3.683 12.545 -4.625 13.929 -5.860 14.115 -6.916 14.790 -7.475 13.886 -8.364 12.868 -7.066 13.932 -7.678 12.981 -8.472 12.32.1 -5.602 14.958 -6.192 14.704 -4.744 15.942 1.00 20.60 1.00 17.57 1.00 17.67 1.00 20.04 1.00 18.49 1.00 21.17 1.00 21.88 1.00 21.89 1.00 22.81 1.00 22.65 1.00 29.11 1.00 25.69 1.00 27.92 1.00 23.32 1.00 23.36 1.00 23.36 1.00 20.99 1.00 28.60 1.00 28.10 1.00 26.57 1.00 30.14 1.00 17.65 1.00 16.11 1.00 18.12 1.00 16.95 1.00 22.66 1.00 22.13 1.00 25.29 1.00 25.08 1.00 16.65 1.00 17.09 1.00 15.83 1.00 18.66 1.00 17.62 1.00 32.77 1.00 18.54 1.00 17.01 1.00 15.54 1.00 17.67 1.00 19.03 1.00 27.06 1.00 28.40 1.00 28.92 1.00 30.75 1.00 30.08 1.00 15.35 1.00 14.83 1.00 13.35 c WO 09/50658 PCT/US99106937

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3540 CA ILE B 3541 CB ILE B 354 0 L B 3543 CGI ILE B 3544 CDI ILE B 3545 CD ILE B -3546 0 ILE B 3547 N ARG B 3548 CA ARG B .3549 CB ARG B 3550 CG ARG B 3551 CD ARG B 3552 NE ARG B 3553 CZ ARG B 3554 NHI ARO B 3555 NH2 ARG B 3556 C ARG B 3557 0 ARO B 3558 N HIS B 3559 CA HIS B 3560 CB HIS B 3561 CG HIS B 3562 CD2 HIS B 3563 NDI HIS B 3564 CEl HIS B 3565 NE2 HIS B 514 514 514 514 514 514 514 515 515 515 515 515 515 515 515 515 515 515 516 516 516 516 516 516 516 516 516 516 517 517 517 517 517 517 517 517 518 518 518 518 518 518 519 519 519 519 51.9 519 8.865 9.295 8.06 7 10.093 10.691 7.797 6.606 8.224 7.280 8.0 10 7.080 6.407 7.220 6.734 5.424 7.569 6.545 5.332 7.298 6.743 7.861 7.405 7.060 7.258 6.839 6.711 5.685 4.5 96 5.999 5.049 5.701 6.790 7.380 8.104 .3.789 2.688 3.954 2.827 3.3 16 2.234 1.906 0.688 2.4 74 1.622 2.432 2.700 1.839 3.891 -4.417 16.776 -3.53 4 17.967 -2.918 18.650 -4.397 18.962 -3.641 20.115 3-3.717 15.923 -3.972 16.078 -2.823 15.030 -2.138 14.150 -1.173 13.214 -0.454 12.23 4 0.749 12.891 1.948 12.716 3.175 12.547 3.393 12.522 4.182 12.374 -3.182 13.304 -3.093 13.087 -4.171 12.827 -5.237 11.997 -6.176 11.533 -7.223 10.568 -8.521 10.754 -6.978 9.220 -8.078 8.619 -9.028 .9.526 -6.028 1 2.759 -6.303 12.240 -6.396 13.997 -7.162 14.801 -7.587 16.114 -8.638 15.917 -9.320 17.470 -7.'879 18.226 -6.368 15.080 -6.924 15.148 -5.060 15.247 -4.186 15.505 -2.765 15.835 -1.840 15.843 -4.147 14.284 -4.247 14.417 -4.006 13.091 -3.953 11.907 -3.509 10.698 -2.029 10.729 -1.258 11.150 1.618 10.307 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 15.48 20.02 12.84 22.87 29.62 15.16 16.61 16.33 17.54 20.15 21.47 26.05 24.91 24.61 22.46 23.15 16.60 14.51 18.50 17.26 18.14 24.87 26.64 2 1.82 28.42 24.47 16.87 14.81 16.48 15.39 21.05 20.76 23.96 20.45 16.23 16.02 13.32 16.34 17.48 17.46 14.73 19.16 14.52 15.35 19.21 20.58 26.36 19.62 3566 C 3567 0 3568 N 3569 CA 3570 CB 3571 CG 3572 SD 3573 CE 3574 C 3575 0 3576 N 3577 CA 3578 CB 3579 OG 3580 C 3581 0 3582 N 3583 CA 3584 CB 3585 CG 3586 ODI 3587 ND2 HIS B HIS B MET B MET B MET B MET B MET B MET B MET B MET B SER B SER B SER B SER B SER B SER B ASN B ASN B ASN B ASN B ASN B ASN B r" WO 99/50658 PTU9163 PCr[US99/06937

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3588 C ASN B 3589 0 ASN B 3590 N LYS B 3591 CA LYS B 3592 CB LYS B 3593 CG LYS B 3594 CD LYS B 3595 CE LYS B 3596 NZ LYS B 3597 C LYS B 3598 0 LYS B 3599 N GLY B 3600 CA GLY B 3601 C GLY B 3602 0 GLY B 3603 N MET B 3604 CA MET B 3605 CB MET B 3606 CG MET B 3607 SD MET B 3608 CE MET B 3609 C MET B 3610 0 MET B 3611 N GLU B 3612 CA GLU B 3613 CB GLU B 3614 CG GLU B 3615 CD GLU B 3616 OEI GLU B 3617 0E2 GLU B 3618 C GLU B 3619 0 GLU B 3620 N HIS B 3621 CA HIS B 3622 CB HIS B 3623 CG HIS B 3624 CD2 HIS B 3625 NDI HIS B 3626 CEI HIS B 3627 NE2 HIS B 3628 C HIS B -3629 0 HIS B 3630 N LEU B 3631 CA LEU B .3632 CB LEU B 3633 CG LEU B 3 634 CDI LEU B 3635 CD2 LEU B 519 519 520 520 520 520 520 520 520 520 520 521 521 521 521 522 522 522 522 522 522 522 522 523 523 523 523 523 523 523 523 523 524 524 524 524 524 524 524 524 524 524 525 525 525 525 525 525 0.911 -0.265 1.608 0.992 2.038 3.03 7 2.507 2. 186 1.43 5 -0.099 -1.183 0.191 0. 792 -2.000 -3.128 -1.766 -2.852 -2.276 -3).190 -3.199 -1.659 -3.794 -5.022 205 -3.968 -3.031 -2.224 -1.095 -0.131 -1.169 -4.812 -5.993 -4.187 -4.846 -3.824 -4.378 -4.308 -5.107 -5.461 -4.989 -5.996 -7.061I 777 -6.786 -6.2 17 -7.164 -7.*763 -6.414 -5.280 11.658 -5.299 11.297 -6.387 11.885 -7.699 11.717 -8.801 11.872 -8.849 10.728 -9.663 9.558 -8.778 8.364 -9.526 7.312 -7.868 12.769 -8.358 12.478 -7.455 13.998 -7.569 15.058 -6.674 14.833 -7.060 15.125 -5.467 14.326 -4.527 14.042 -3.212 13.516 -2.018 13.707 -1.477 15.417 -0.605 15.475 -5.119 12.989 -5.008 13.097 -5.731 11.966 -6.357 10.889 -6.946 9.830 -5.935 9.030 -6.597 8.239 -5.894 7.857 -7.825 7.999 -7.482 11.465 -7.616 11.147 -8.287 12.326 -9.428 12.952 -10.245 13.743 -11.509 14.321 -12.792 13.892 -11.537 15.490 -12.780 15.757 -13.561 14.803 -9.025 13.870 -9.656 13.860 -7.977 14.655 -7.492 15.588 -6.358 16.444 -5.778 17.498 -6.922 18.321 -4.793 18.399 1.00 16.74 1.00 20.58 1.00 18.60 1.00 20.04 1.00 25.44 1.00 31.68 1.00 42.56 1.00 45.61 1.00 46.00 1.00 18.88 1.00 21.75 1.00 17.83 1.0 16.19 1.00 16.59 1.00 16.57 1.00 17.48 1.00 18.25 1.00 21.27 1.00 26.97 1.00 30.35 1.00 29.8 6 1.00 18.68 1.00 18.80 1.00 18.22 1.00 23.41 1.00 28.74 1.00 3 4.42 1.00 45.58 1.00 49.48 1.00 45.97 1.00 23.98 1.00 22.08 1.00 23.4 6 1.00 26.20 1.00- 27.2 6 1.00 30.91 1.00 30.90 1.00 28.87 1.00 30.4 1.00 29.19 1.00 27.69 1.00 25.00 1.00 23.84 1.00 25.77 1.00 22.22 1.00 26.81 1.00 23.32 1.00 18.95 (7) WO 99/50658 WO 9950658PCT/US99/06937

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3636 C LEU B 3637 0 LEU B -3638 N TYR B 3639 CA TYR B 3640 CB TYR B 3641 CG TYR B 364 CDI TYR B 3643 CEI TYR B 3644 CD2 TYR B 3645 CE2 3646 CZ 3647 OH 3648 C 3649 0 3650 N 3651 CA 3652 CB 3653 OG 3654 C 3655 0 3656 N 3657

CA

3658 CB 3659 CG 3660 SD 3661 CE 3662 C 3663 0 3664 N 3665 CA 3666 CB 3667 CG 3668 CD 3669 CE 3670 NZ 3671 C 3672 0 3673 N 3674 CA 3675 CB 3676 SG 3677 C 3678 0 3679 N -3680 CA TYR B TYR B TYR B TYR B TYR B SER B SER B SER B SER B SER B SER B MET B MET B MET B MET B MET B MET B MET B MET B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B LYS B CYS B CYS B CYS B CYS B CYS B CYS B LYS B LYS B 2;-5 525 526 526 526 526 526 526 526 526 526 526 526 526 527 527 527 527 527 527 528 528 528 528 528 528 528 528 529 529 529 529 529 529 529 529 529 530 530 530 530 530 530 531 531 531 5311 531 -8.013 -9.154 -7.764 -8.819 -8.20 1 -9.183 10.058 -10.943 -9.2 18 10.098 -10.955 -11.810 -9.577 -10.793 -8.849 -9.460 -8.377 -8.94 5 -10.339 -11.446 -9.840 -10.574 -9.682 -8.651 -9.359 -10.265 -11.800 -12.835 -11.673 -12.781 -12.323 -13.436 -13.114 -13.734 -15.221 -13.857 -15.049 -13.407 14.286 -13 .460 -13.369 -15.065 -16.274 -14.360 -14.980 -13.907 -15.844 16.62'3 -6.995 14.842 -7.247 15.249 -6.271 13.757 -5.726 12.918 -4.818 11.854 -4.223 10-878 -3.211 11.267 -2.636 10.357 -4.651 9.552 -4.083 8.634 -3.077 9.043 -2.504 8.129 -6.880 12.265 -6.829 12.11 3 -7.926 11.889 -9.095 11.266 -10.048 10.749 -11.222 10.196 -9.813 12.288 -10.261 11.973- -9.916 13.517 -10.572 14.589 -10.743 15.820 -11.859 15.699 -13.427 15.134 -13.915 16.579 -9.747 14.953 -10.293 15.331 -8.429 14.850 -7.533 15.149 -6.079 15.027 -5.043 15.114 -3.852 14.224 -2.564 14.74 1 -2.569 14.634 -7.840 14.116 -7.877 14.424 -8.083 12.889 -8.409 11.773 -8.535 10.491 -7.034 9.504 -9.692 12.016 -9.741 11.807 -10.733 12.447 -12.023 12.728 -13.091 12.927 -11.907 1 3 .977 -12.804 14.296 1.00 26.84 1.00 26.73 1.00 26.86 1.00 3 0.89 1.00 3 4.31 1.00 43.50 1.00 47.66 1.00 48.85 1.00 48.52 1.00 52.43 1.00 51.67 1.00 57.01 1.00 30.90 1.00 31.48 1.00 31.39 1.00 33.73 1.00 34.13 1.00 43.67 1.00 34.34 1.00 33.42 1.00 31.66 1.00 29.77 1.00 32.96 1.00 33.47 1.00 38.28 1.00 36.01 1.00 29.42 1.00 28.65 1.00 30.64 1.00 31.80 1.00 32.86 1.00 36.42 1.00 41.74 1.00 43.45 1.00 46.51 1.00 36.60 1.00 34.04 1.00 40.04 1.00 44.58 1.00 50.64 1.00 67.65 1.00 42.88 1.00 40.15 1.00 41.92 1.00 42.60 1.00 44.77 1.00 44.43 1.00 44.09 3681 CB LYS B -3682 C LYS B 3683 0 LYS B WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3684 N ASN B 3685 CA ASN B 3686 CB ASN B 3687 CG ASN B 3688 ODI ASN B 3689 ND2 ASN B 3690 C ASN B 3691 0 ASN B 3692 N VAL B 3693 CA VAL B 3694 CB VAL B 3695 CGI VAL B 3696 CG2 VAL B 3697 C VAL B 3698 0 VAL B 3699 N VAL B 3700 CA VAL B 3701 CB VAL B 3702 CGI VAL B 3703 CG2 VAL B 3704 C VAL B 3705 0 VAL B 3706 N PRO B 3707 CD PRO B 3708 CA PRO B 3709 CB PRO B 3710 CG PRO B 3711 C PRO B 3712 0 PRO B 3713 N LEU B 3714 CA LEU B 3715 CB LEU B 3716 CG LEU B 3717 CDI LEU B 3718 CD2 LEU B 3719 C LEU B 3720 0 LEU B 3721 N, TYR B 3722 CA TYR B 3723 CB TYR B 3724 CG TYR B 3725 CDI TYR B 3726 CEI TYR B 3727 CD2 TYR B 3728 CE2 TYR B 3729 CZ TYR B 3730 OH TYR B 3731 C TYR B 532 532 532 532 532 532 532 532 533 533 533 533 533 533 533 534 534 534 534 534 534 534 535 535 535 535 535 535 535 536 536 536 536 536 536 536 536 537 537 537 537 537 537 537 537 537 537 537 -15.678 -16.437 -17.833 -18.526 -19.729 -17.771 -16.557 -17.655 -15.434 -15.471 -14.170 -13.661 -13.107 -15.670 -15.894 -15.596 -15.765 -14.630 -13.324 -15.021 -15.752 -15.026 -16.575 -17.529 -16.608 -17.846 -18.004 -15.338 -14.786 -14.881 -13.675 -12.829 -12.219 -11.344 -11.398 -14.036 -15.024 -13.231 -13.494 -12.618 -12.849 -13.923 -14.174 -12.022 -12.262 -13.340 -13.582 -13.262 -10.793 14.685 -10.496 15.893 -10.003 15.506 -9.271 16.633 -9.424 16.837 -8.471 17.375 -11.657 16.882 -11.994 17.321 -12.264 17.243 -13.371 18.190 -14.219 18.120 -14.263 16.683 -13.644 19.045 -12.835 19.611 -13.602 20.548 -11.511 19.755 -10.849 21.049 -11.259 22.038 -10.575 21.658 -10.910 23.463 -9.329 20.857 -8.808 20.008 -8.597 21.625 -9.078 22.640 -7.135 21.492 -6.729 22.288 -7.809 23.298 -6.494 22.049 -6.963 23.040 -5.426 21.409 -4.732 21.851 -4.314 20.647 -5.433 19.798 -4.822 18.714 -6.370 20.676 -3.498 22.666 -2.829 22.383 -3.194 23.676 -2.032 24.505 -2.071 25.750 -3.327 26.543 -3.431 27.421 -4.609 28.118 -4.435 26.379 -5.620 27.072 -5.699 27.940 -6.872 28.624 -0.761 23.709 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 44.98 44.10 45.14 46.54 50.62 46.07 43.34 41.42 43.45 44.06 45.56 45.67 44.16 43.24 44.21 40.44 37.80 36.38 34.35 39.34 37.97 39.45 37.81 38.74 36.79 36.98 39.77 33.95 34.93 33.42 33.40 29.31 30.06 30.85 28.96 30.50 29.91 28.69 29.89 32.50 39.46 41.90 45.72 47.39 49.93 48.80 53.90 27.09 WO 99/50658 ATOM 3732 0 TYR B ATOM 3733 N ASP B ATOM 3734 CA ASP B ATOM 3735 CB ASP B ATOM 3736 CG ASP B ATOM 3737 ODI ASP B ATOM 3738 OD2 ASP B ATOM 3739 C ASP B ATOM 3740 0 ASP B ATOM 3741 N LEU B ATOM 3742 CA LEU B ATOM 3743 CB LEU B ATOM 3744 CG LEU B ATOM 3745 CDI LEU B ATOM 3746 CD2 LEU B ATOM 3747 C LEU B ATOM 3748 0 LEU B ATOM 3749 N LEU B ATOM 3750 CA LEU B ATOM 3751 CB LEU B ATOM 3752 CG LEU B ATOM 3753 CDI LEU B ATOM 3754 CD2 LEU B ATOM 3755 C LEU B ATOM 3756 0 LEU B ATOM 3757 N LEU B ATOM 3758 CA LEU B ATOM 3759 CB LEU B ATOM 3760 CG LEU B ATOM 3761 CD1 LEU B ATOM 3762 CD2 LEU B ATOM 3763 C LEU B ATOM 3764 0 LEU B ATOM 3765 N GLU B ATOM 3766 CA GLU B ATOM 3767 CB GLU B ATOM 3768 CG GLU B ATOM 3769 CD GLU B ATOM 3770 OEI GLU B ATOM 3771 OE2 GLU B ATOM 3772 C GLU B ATOM 3773 0 GLU B ATOM 3774 N MET B ATOM 3775 CA MET B ATOM 3776 CB MET B ATOM 3777 CG MET B ATOM 3778 SD MET B ATOM 3779 CE MET B

QC)

PCT/US99/06937 537 538 538 538 538 538 538 538 538 539 539 539 539 539 539 539 539 540 540 540 540 540 540 540 540 541 541 541 541 541 541 541 541 542 542 542 542 542 542 542 542 542 543 543 543 543 543 543 -12.518 -13.909 -13.830 14.748 -16.227 -17.052 -16.562 -12.447 -12.120 -11.637 -10.312 -9.567 -8.116 -8.051 -7.564 -9.484 -8.862 -9.487 -8.743 -8.909 -8.188 -6.679 -8.473 -9.241 -8.449 -10.559 -11.164 -12.686 -13.410 -14.910 -13.136 -10.697 -10.359 -10.694 -10.248 -10.250 -11.166 -11.138 -12.223 -10.028 -8.826 -8.530 -7.945 -6.552 -5.749 -5.812 -5.373 -3.585 -0.757 22.729 0.315 24.141 1.598 23.461 2.598 24.164 2.285 23.940 2.613 24.819 1.707 22.882 2.217 23.261 2.626 22.147 2.309 24.313 2.911 24.150 2.991 25.496 3.511 25.469 4.892 24.838 3.569 26.895 2.127 23.127 2.716 22.249 0.803 23.239 -0.048 22.319 -1.528 22.701 -2.554 21.821 -2.303 21.828 -3.952 22.327 0.169 20.891 0.293 19.964 0.206 20.726 0.419 19.413 0.429 19.527 -0.808 18.999 -0.671 19.273 -0.971 17.508 1.751 18.842 1.845 17.666 2.781 19.680 4.106 19.270 5.050 20.468 6.245 20.347 7.105 21.597 7.385 22.144 7.494 22.034 4.010 18.724 4.492 17.634 3.388 19.499 3.237 19.107 2.591 20.247 3.338 21.579 5.084 21.467 4.971 21.349 1.00 26.15 1.00 26.12 1.00 25.27 1.00 28.85 1.00 33.90 1.00 32.68 1.00 38.26 1.00 25.18 1.00 26.41 1.00 20.76 1.00 19.65 1.00 17.48 1.00 16.46 1.00 16.43 1.00 15.57 1.00 16.75 1.00 20.36 1.00 18.23 1.00 18.05 1.00 16.38 1.00 19.81 1.00 19.27 1.00 18.00 1.00 21.50 1.00 20.41 1.00 22.40 1.00 23.27 1.00 25.12 1.00 36.53 1.00 30.98 1.00 31.93 1.00 22.46 1.00 26.29 1.00 23.96 1.00 26.91 1.00 30.84 1.00 37.20 1.00 39.98 1.00 39.92 1.00 38.96 1.00 27.90 1.00 29.32 1.00 26.41 1.00 23.53 1.00 24.60 1.00 26.46 1.00 29.45 1.00 25.43 WO 99/50658 CIJ9/63 PCTIUS99/06937

ATOM

ATOM

ATOM

3780 C 3781 0 3782 N MET B 543 MET B 543 LEU B 544 ATOM 3783 CA LEU B ATOM 3784 CB LEU B ATOM 3785 CG LEU B ATOM 3786 CDI LEU B ATOM 3 787 CD2 LEU B ATOM 3788 C LEU B ATOM 3789 0 LEU B ATOM 3790 N ASP B ATOM 3791 CA ASP B ATOM 3792 CB ASP B ATOM 3793 CG ASP B ATOM 3794 ODI ASP B ATOM 3795 0D2 ASP B ATOM 3796 C ASP B ATOM 3797 0 ASP B ATOM 3798 N ALA B ATOM 3799 CA ALA B ATOM 3800 CB ALA B ATOM 3801 C ALA B ATOM 3802 0 ALA B ATOM 3803 N HIS B ATOM 3804 CA HIS B ATOM 3805 GB HIS B ATOM 3806 CG HIS B ATOM 3807 CD2 HIS B ATOM 3808 NDI HIS B ATOM 3809 GEl HIS B ATOM 3810 NE2 HIS B ATOM 3811 C HIS B ATOM 3812 0 HIS B ATOM 3813 N ARG B ATOM 3814 CA ARG B ATOM 3815 GB ARG B ATOM 3816 C ARG B ATOM 3817 0 ARG B ATOM 3818 N LEU B ATOM 3819 CA LEU B ATOM 3820 GB LEU B ATOM 3821 C LEU B ATOM 3822 0 LEU B ATOM 3823 OXT LEU B HETATM 3824 CP9 DES B HETATM 3825 CP8 DES B HETATM 3826 CP7 DES B HETATM 3827 CP6 DES B 544 544 544 544 544 544 544 545 545 545 545 545 545 545 545 546 546 546 546 546 547 547 547 547 547 547 547 547 547 547 548 548 548 548 548 549 549 549 549 549 549 600 600 600 600 -6.403 -5.535 -7.254 -7.202 -8.069 -8.274 -6.956 -9.330 -7.672 -7.036 -8.787 -9.338 -10.668 -11.818 -12.858 -11.676 -8.382 -8.443 -7.506 -6.543 -5.646 -5.697 -5.189 -5.555 -4.773 -3.991 -2.796 -2.698 -1.502 -0.659 -1.360 -5.649 -5.178 -6.9 19 -7.843 -8.522 -8.886 -8.580 -10.116 -11.204 -12.478 -11.449 -11.451 -11.634 -4.547 -3.163 -2.897 -3).719 2.407 17.832 2.686 17.004 1.394 17.673 0.522 16.499 0.721 16.719 -1.632 15.502 -2.294 15.136 -2.680 15.803 1.252 15.250 1.181 14.195 1.961 15.372 2.702 14.244 3.346 14.637 2.370 14.565 2.624 15.211 1.342 13.863 3.762 13.711 4.120 12.532 4.272 14.572 5.280 14.141 5.693 15.306 4.731 12.996 5.490 12.170 3.410 12.943 2.767 11.892 1.576 12.457 1.968 13.269 2.553 14.486 1.755 12.840 2.193 13.760 2.681 14.768 2.286 10.735 2.152 9.606 2.020 11.019 1.55 1 9.993 0.267 10.452 2.619 9.681 3.812 9.672 2.186 9.422 3.109 9.112 2.327 8.799 4.069 10.275 5.297 10.036 3.579 11.412 -6.077 22.000 -6.365 21.467 -7.853 21.381 -8.551 20.374 1.00 25.80 1.00 23.59 1.00 27.74 1.00 26.32 1.00 26.75 1.00 28.12 1.00 26.36 1.00 27.00 1.00 26.97 1.00 24.25 1.00 30.37 1.00 32.34 1.00 36.61 1.00 42.73 1.00 47.39 1.00 46.96 1.00 3 1.27 1.00 30.53 1.00 29.02 1.00 31.21 1.00 30.98 1.00 32.14 1.00 33.78 1.00 32.27 1.00 37.73 1.00 35.83 1.00 34.54 1.00 30.23 1.00 34.23 1.00 36.72 1.00 3 1.48 1.00 43.69 1.00 46.04 1.00 48.35 1.00 54.74 1.00 54.66 1.00 59.94 1.00 62.81 1.00 64.81 1.00 67.59 1.00 68.06 1.00 69.12 1.00 68.96 1.00 70.70 1.00 18.55 1.00 17.72 1.00 21.17 1.00 22.05

G

c0 WO 99/50658 PCT/US99/06937 HETATM 3828 CP1 DES HETATM 3829 CP2 DES

B

B

HETATM 3830 CP3 HETATM 3831 OP3 HETATM 3832 CP4 HETATM 3833 CP5 HETATM 3834 C7 HETATM 3835 C6 HETATM 3836 C5 HETATM 3837 C4 HETATM 3838 C3 HETATM 3839 03 HETATM 3840 C2 HETATM 3841 Cl HETATM 3842 C8 HETATM 3843 C9 HETATM 3844 Cl HETATM 3845 04 HETATM 3846 03 HETATM 3847 C2 HETATM 3848 CI HETATM 3849 04 HETATM 3850 03 HETATM 3851 C2 ATOM 3852

CB

ATOM 3853

C

ATOM 3854 0 ATOM 3855

N

ATOM 3856

CA

ATOM 3857

N

ATOM 3858

CA

ATOM 3859

CB

ATOM 3860

C

ATOM 3861 0 ATOM 3862

N

ATOM 3863 CA

I

ATOM 3864 CB I ATOM 3865 CG2

I

ATOM 3866 CGI

I

ATOM 3867 CDI

I

ATOM 3868 C

I]

ATOM 3869 0

I]

ATOM 3870 N

L

ATOM 3871 CA

L

ATOM 3872 CB

L

ATOM 3873 CG

L

ATOM 3874 CDi

L

ATOM 3875 CD2

L]

DES B DES B DES B DES B DES B DES B DES B DES B DES B DES B DES B DES B DES B DES B CBM B CBM B CBM B CBM B CBM B CBM B CBM B CBM B HIS C HIS C HIS C HIS C HIS C LYS C LYS C LYS C LYS C LYS C LE C LE C LE C LE C LE C LE C LE C LE C EU C EU C EU C 6 EU C 6 EU C 6 EU C 6 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 600 417 417 417 417 530 530 530 530 687 687 687 687 687 688 688 688 688 688 689 689 689 689 689 589 589 589 590 i90 90 90 90 90 -3.4C -4.23 -5.38 -6.24 -5.71 -4.87 -1.99 -1.33 -2.05- -1.43 -0.07 0.509 0.669 0.035 -1.642 -0.440 -4.997 -4.789 -4.798 -5.468 -15.278 -15.852 -15.832 -14.207 9.818 10.133 11.204 7.944 9.424 9.533 10.101 8.980 11.050 12.253 10.511 11.326 10.496 11.334 9.229 8.406 12.513 13.616 12.288 13.362 12.812 13.835 14.575 13.128 )5 -8.481 18.998 9 -9.095 18.063 8 -9.771 18.509 4 -10.339 17.600 8 -9.858 19.860 7 -9.240 20.791 8 -8.460 22.190 0 -7.834 23.325 4 -7.642 24.522 S -7.072 25.634 7 -6.685 25.542 -6.113 26.655 -6.866 24.353 -7.440 23.241 -9.903 21.942 -10.009 20.998 -22.994 25.273 -24.187 25.003 -22.559 26.552 -21.960 24.264 -5.124 10.243 -5.086 9.064 -4.291 11.201 -5.886 10.628 -20.030 -2.211 -20.267 -4.689 -20.840 -4.472 -19.563 -3.758 -19.484 -3.586 -20.281 -5.875 -20.999 -7.009 -21.540 -7.901 -20.127 -7.827 -20.379 -7.858 -19.103 -8.482 -18.212 -9.306 -17.057 -9.889 -16.286 -10.902 -17.603 -10.551 1 -16.550 -11.258 1 -17.611 -8.560 1 -17.550 -9.097 1 -17.162 -7.329 1 -16.570 -6.534 1 -16.058 -5.199 1 -15.501 -4.206 1 -14.324 -4.831 1.

-15.078 -2.926 1.

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 21.32 21.61 24.89 24.94 24.08 24.67 16.67 15.39 1.01 1.0( 1.01 1.0( I .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 I .C 1.00 .00 .00 .00 .00 .00 .00 .00 .00 .00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 .00 .00 .00 .00 .00 .00 .00 .00 ,00 ,00 0 17.62 0 16.16 20.04 S15.55 S18.94 S15.20 S17.61 11.63 55.80 55.56 56.04 57.04 87.39 87.68 86.22 87.65 63.34 63.49 63.87 65.42 64.86 62.00 60.81 61.76 57.47 57.64 55.74 53.09 53.83 54.55 52.90 50.45 50.82 51.28 48.01 47.33 42.51 40.67 39.95 38.77 WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3876 C LEU C 690 3877 0 LEU C 690 3878 N HIS C 691 3879 CA HIS C 691 3880 CB HIS C 691 3881 CG HIS C 691 3882 CD2 HIS C 691 3883 NDI HIS C 691 3884 CEI HIS C 691 3885 NE2 HIS C 691 3886 C HIS C 691 3887 0 HIS C 691 3888 N ARG C 692 3889 CA ARG C 692 3890 CB ARG C 692 3891 CG ARG C 692 3892 CD ARG C 692 3893 NE ARG C 692 3894 CZ ARG C 692 3895 NHI ARG C 692 3896 NH2 ARG C 692 3897 C ARG C 692 3898 0 ARG C 692 3899 N LEU C 693 3900 CA LEU C 693 3901 CB LEU C 693 3902 CG LEU C 693 3903 CDI LEU C 693 3904 CD2 LEU C 693 3905 C LEU C 693 3906 0 LEU C 693 3907 N LEU C 694 3908 CA LEU C 694 3909 CB LEU C 694 3910 CG LEU C 694 3911 CDI LEU C 694 3912 CD2 LEU C 694 3913 C LEU C 694 3914 0 LEU C 694 3915 *N GLN C 695 3916 CA GLN C 695 3917 CB GLN C 695 3918 CG GLN C 695 3919 CD GLN C 695 3920 OEI GLN C 695 3921 NE2 GLN C 695 3922 C GLN C 695 3923 0 GLN C 695 14.445 -17.615 -6.282 15.643 -17.340 -6.393 14.001 -18.818 -5.939 14.886 -19.946 -5.675 14.042 -21.203 -5.460 14.655 -22.195 -4.526 15.503 -23.227 -4.751 14.392 -22.202 -3.173 15.053 -23.195 -2.605 15.733 -23.833 -3.540 15.824 -20.162 -6.861 17.048 -20.153 -6.717 15.222 -20.350 -8.032 15.949 -20.586 -9.271 14.955 -20.832 -10.410 15.575 -20.826 -11.797 14.528 -21.048 -12.874 14.375 -19.878 -13.732 13.218 -19.260 -13.951 12.108 -19.706 -13.378 13.171 -18.197 -14.746 16.873 -19.434 -9.639 18.047 -19.644 -9.956 16.338 -18.217 -9.607 17.125 -17.039 -9.945 16.249 -15.784 -9.881 15.781 -15.245 -11.239 15.219 -16.389 -12.079 14.728 -14.170 -11.037 18.318 -16.904 -9.006 19.382 -16.426 -9.402 18.135 -17.329 -7.761 19.204 -17.272 -6.775 18.634 -17.415 -5.362 18.222 -16.128 -4.643 17.456 -16.474 -3.371 19.453 -15.307 -4.317 20.172 -18.417 -7.058 21.370 -18.320 -6.776 19.634 -19.498 -7.619 20.416 -20.685 -7.959 19.477 -21.853 -8.304 19.548 -23.010 -7.311 18.454 -24.053 -7.490 18.262 -24.928 -6.653 17.720 -23.969 -8.608 21.330 -20.414 -9.149 22.517 -20.740 -9.116 1.00 48.87 1.00 46.71 1.00 51.36 1.00 53.35 1.00 58.64 1.00 62.94 1.00 64.95 1.00 65.49 1.00 68.18 1.00 68.77 1.00 52.19 1.00 47.53 1.00 52.37 1.00 52.90 1.00 54.04 1.00 57.52 1.00 58.25 1.00 61.43 1.00 64.32 1.00 63.22 1.00 65.93 1.00 53.09 1.00 53.06 1.00 50.73 1.00 49.53 1.00 49.56 1.00 49.78 1.00 50.30 1.00 48.79 1.00 48.38 1.00 46.35 1.00 46.74 1.00 49.41 1.00 45.20 1.00 40.19 1.00 41.65 1.00 35.91 1.00 54.15 1.00 53.55 1.00 57.44 1.00 62.46 1.00 61.95 1.00 61.49 1.00 62.78 1.00 63.33 1.00 60.37 1.00 65.13 1.00 65.87

G,

WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

'ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3924 N 3925 CA 3926 CB 3927 CG 3928, ODI 3929 0 D 2 3930 C 3931 0 3932 N 3933 CA 3934 CB 3935 C 3936 0 3937 OXT 3938 CB 3939 C 3940 0 3941. N 3942 CA 3943 N 3944 CA 3945 CB 3946 CG 3947 CD2 ASP C ASP C ASP C ASP C ASP C ASP C ASP C ASP C SER C SER C SER C SER C SER C SER C LYS D LYS D LYS D LYS D LYS D HIS D HIS D HIS D HIS D HIS D 3948 NDI HIS D 696 696 696 696 696 696 696 696 697 697 697 697 697 697 686 686 686 686 686 687 687 687 687 687 687 687 687 687 687 688 688 688 688 688 688 688 688 688 689 689 689 689 689 689 689 689 690 690 20.761 21.492 20.801 20.127 20.637 19.086 22.951 23.245 23.859 25.291 26.0 19 25.841I 26.286 25.8 18 -14.070 -13.682 -12.629 -12.910 -13.976 -14.6 17 14.447 -15.806 -15.713 -15.4 18 .15.911 -15.741 -15.441 -13.691 -14.099 -12.593 -11.784 -10.446 -10.513 -9.123 -9.162 -7.894 -11.506 -11.271 -11.549 -11.255 -11.438 -10.725 12.927 -13.308 -9.790 -9.405 -8.985 -7.563 -19.824 -10. 19' -19.500 -11.42( 18.3 48 -12.151 -18.792 13.43 -18.455 14.52 1 -19.478 13.342 -19.132 -11.169 -18.115 -10.541 -19.967 -11.668 -19.741 -11.507 -21.076 -11.3 77 -18.960 -12.696 -17.809 -12.489 -19.510 -13.820 13.661 16.843 14.418 19.199 14.738 19.759 15.796 17.283 14.872 17.769 13.676 19.787 13.176 21.144 12.984 21.828 12.336 23.177 11.064 23.539 13.030 24.352 12.215 25.378 11.016 24.912 11.849 21.163 10.878 20.524 11.816 21.909 10.611 22.038 10.773 21.299 10.595 19.780 10.716 19.152 10.529 17.640 10.970 16.986 10.378 23.517 11.326 24.266 9.122 23.942 8.806 25.328 7.301 25.607 6.912 26.899 6.971 25.721 5.679 25.03 1 9.193 25.541 9.649 26.611 9.021 24.496 9.348 24.549 7 1.00 67.67 1.00 70.66 1 1.00 71.06 1.00 71.70 1 .00 72.47 1.00 71.41 1.00 72.41 1.00 72.56 1.00 74.67 1.00 76.45 1.00 76.00 1.00 78.44 1.00 79.20 1.00 80.07 1.00 50.28 1.00 51.59 1.00 50.42 1.00 50.43 1.00 50.62 1.00 49.91 1.00 51.28 1.00 54.12 1.00 60.06 1.00 61.05 1.00 62.39 1.00 62.76 1.00 63.46 1 .00 49.55 1.00 50.84 1.00 44.00 1.00 40.31 1.00 41.42 1.00 42.76 1.00 3 8.66 1.00 38.28 1.00 3 1.5 8 1.00 3 6.70 1.00 3338 1.00 33.06 1.00 28.70 1.00 310.88 1.00 31.45 1.00 32.57 1.00 297 1.00 27.64 1.00 25.54 1 .00 24.25 1.00 26.63 3949 CEI 3950 NE2 3951 C 3952 0 3953 N 3954 CA 3955 CB 3956 CG 3957 CD 3958 CE 3959 NZ 3960 C 3961 0 3962 N 3963 CA 3964 CB 3965 CG2 3966 CGI 3967 CDI 3968 C 3969 0 .3970 N 3971 CA HIS D HIS D HIS D HIS D LYS D LYS D LYS D LYS D LYS D LYS D LYS D LYS D LYS D ILE D ILE D ILE D ILE D ILE D ILE D ILE D ILE D LEU D LEU D r"

N

WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

3972 CB LEU D 690 3973 CG LEU D 690 3974 CDI LEU D 690 3975 CD2 LEU D 690 3976 C LEU D 690 3977 0 LEU D 690 3978 N HIS D 691 3979 CA HIS D 691 3980 CB HIS D 691 3981 CG HIS D 691 3982 CD2 HIS D 691 3983 NDI HIS D 691 3984 CEI HIS D 691 3985 NE2 HIS D 691 3986 C HIS D 691 3987 0 HIS D 691 3988 N ARG D 692 3989 CA ARG D 692 3990 CB ARG D 692 3991 CG ARG D 692 3992 CD ARG D 692 3993 NE ARG D 692 3994 CZ ARG D 692 3995 NHI ARG D 692 3996 NH2 ARG D 692 3997 C ARG D 692 3998 0 ARG D 692 3999 N LEU D 693 4000 CA LEU D 693 4001 CB LEU D 693 4002 CG LEU D 693 4003 CD1 LEU D 693 4004 CD2 LEU D 693 4005 C LEU D 693 4006 0 LEU D 693 4007 N LEU D 694 4008 CA LEU D 694 4009 CB LEU D 694 4010 CG LEU D 694 4011 CDI LEU D 694 4012 CD2 LEU D 694 4013 C LEU D 694 4014 0 LEU D 694 4015 N GLN D 695 4016 CA GLN D 695 4017 CB GLN D 695 4018 CG GLN D 695 4019 CD GLN D 695 -6.903 -5.433 -4.595 -4.956 -7.344 -6.408 -8.206 -8.107 -9.156 -8.903 -7.750 -9.920 -9.407 -8.091 -8.338 -7.602 -9.371 -9.691 -10.959 -11.255 12.502 -13.618 -14.498 -14.392 -15.483 -8.548 -8.139 -8.030 -6.943 -6.674 -7.844 -7.575 -8.043 -5.670 -4.948 -5.395 -4.207 -3.948 -3.118 -3.230 -1.666 -4.336 -3.339 -5.570 -5.820 -7.022 -6.772 -7.943 9.021 23.200 9.387 22.992 8.772 24.108 8.898 21.616 10.823 24.902 11.165 25.625 11.694 24.383 13.125 24.665 13.907 23.861 13.935 22.386 14.000 21.679 13.906 21.458 13.953 20.242 14.010 20.347 13.373 26.159 14.120 26.802 12.742 26.703 12.912 28.114 12.134 28.472 12.129 29.963 11.327 30.290 12.198 30.647 12.677 29.774 12.371 28.486 13.464 30.188 12.451 29.011 13.167 29.929 11.259 28.737 10.705 29.536 9.254 29.116 8.300 29.391 6.932 28.778 8.171 30.894 11.539 29.440 11.700 30.428 12.080 28.257 12.906 28.062 13.126 26.572 12.080 25.825 12.332 24.324 12.148 26.275 14.270 28.742 14.889 29.102 14.733 28.915 16.032 29.528 16.694 28.862 17.071 27.422 17.764 26.795 1.00 22.83 1.00 25.47 1.00 24.03 1.00 20.87 1.00 26.64 1.00 28.34 1.00 27.77 1.00 29.16 1.00 30.89 1.00 37.09 1.00 41.39 1.00 41.65 1.00 44.64 1.00 41.94 1.00 26.65 1.00 24.50 1.00 25.70 1.00 29.11 1.00 30.84 1.00 41.63 1.00 48.83 1.00 54.50 1.00 59.37 1.00 60.97 1.00 59.07 1.00 28.30 1.00 26.50 1.00 24.87 1.00 27.17 1.00 28.45 1.00 30.40 1.00 34.79 1.00 32.02 1.00 25.96 1.00 27.01 1.00 25.33 1.00 27.22 1.00 24.61 1.00 22.20 1.00 21.13 1.00 21.34 1.00 32.40 1.00 31.55 1.00 36.93 1.00 43.18 1.00 40.48 1.00 37.99 1.00 35.86 WO 99/50658 PCT/US99/06937 ATOM 4020 OEI GLN D 695 -7.863 18.895 26.342 1.00 38.84 ATOM 4021 NE2 GLN D 695 -9.082 17.060 26.757 1.00 31.62 ATOM 4022 C GLN D 695 -6.049 16.009 31.034 1.00 48.74 ATOM 4023 0 GLN D 695 -6.119 17.065 31.660 1.00 51.25 ATOM 4024 N ASP D 696 -6.175 14.818 31.611 1.00 54.01 ATOM 4025 CA ASP D 696 -6.398 14.702 33.047 1.00 62.23 ATOM 4026 CB ASP D 696 -6.217 13.238 33.485 1.00 63.97 ATOM 4027 CG ASP D 696 -7.527 12.467 33.475 1.00 67.72 ATOM 4028 ODI ASP D 696 -8.528 12.996 32.941 1.00 68.11 ATOM 4029 OD2 ASP D 696 -7.552 11.333 34.003 1.00 68.95 ATOM 4030 C ASP D 696 -5.456 15.622 33.840 1.00 65.60 ATOM 4031 0 ASP D 696 -4.312 15.189 34.134 1.00 68.33 ATOM 4032 OXT ASP D 696 -5.874 16.755 34.140 1.00 69.20 HETATM 4033 0 HOH 1 16.153 -0.605 -4.425 1.00 17.11 HETATM 4034 0 HOH 2 16.570 -5.304 -16.560 1.00 21.44 HETATM 4035 0 HOH 3 18.526 0.742 -4.495 1.00 23.43 HETATM 4036 0 HOH 4 13.647 -2.187 8.588 1.00 25.82 HETATM 4037 0 HOH 5 9.778 -5.825 2.509 1.00 20.58 HETATM 4038 0 HOH 6 17.072 -3.605 -8.015 1.00 18.38 HETATM 4039 0 HOH 7 24.920 -1.689 -2.780 1.00 25.74 HETATM 4040 0 HOH 8 7.321 -5.649 5.061 1.00 24.11 HETATM 4041 0 HOH 9 25.976 -3.535 15.158 1.00 26.78 HETATM 4042 0 HOH 10 15.088 -7.006 -15.192 1.00 19.64 HETATM 4043 0 HOH 11 14.070 0.925 -5.953 1.00 20.55 HETATM 4044 0 HOH 12 18.008 3.407 -6.654 1.00 32.30 HETATM 4045 0 HOH 13 31.949 -8.393 13.487 1.00 30.64 HETATM 4046 0 HOH 14 19.625 -2.804 -4.279 1.00 24.45 HETATM 4047 0 HOH 15 11.741 1.079 -21.140 1.00 25.87 HETATM 4048 0 HOH 16 25.067 13.951 14.153 1.00 31.07 HETATM 4049 0 HOH 17 15.501 1.323 -10.393 1.00 21.01 HETATM 4050 0 HOH 18 13.880 3.349 -11.482 1.00 24.28 HETATM 4051 0 HOH 19 17.591 0.979 -8.828 1.00 35.26 HETATM 4052 0 HOH 20 23.682 -2.041 -0.314 1.00 37.90 HETATM 4053 0 HOH 21 15.754 9.496 11.841 1.00 39.44 HETATM 4054 0 HOH 22 -4.943 7.574 -3.066 1.00 37.67 HETATM 4055 0 HOH 23 6.877 0.354 -15.982 1.00 36.92 HETATM 4056 0 HOH 24 15.806 -4.002 8.671 1.00 30.38 HETATM 4057 0 HOH 25 17.185 -3.158 -5.321 1.00 28.89 HETATM 4058 0 HOH 26 17.572 9.249 17.009 1.00 30.15 HETATM 4059 0 HOH 27 24.096 -2.929 11.604 1.00 31.37 HETATM 4060 0 HOH 28 22.324 -5.871 -11.980 1.00 32.74 HETATM 4061 0 HOH 29 27.547 -12.361 -0.801 1.00 36.61 HETATM 4062 0 HOH 30 11.173 13.442 -2.719 1.00 35.41 HETATM 4063 0 HOH 31 15.438 -9.527 5.483 1.00 29.88 HETATM 4064 0 HOH 32 9.946 -6.564 5.983 1.00 35.05 HETATM 4065 0 HOH 33 7.599 11.680 -15.261 1.00 38.68 HETATM 4066 0 HOH 34 20.112 10.503 -5.109 1.00 42.66 HETATM 4067 0 HOH 35 15.972 10.343 14.897 1.00 41.73 WO 99/50658 PCT/US99/06937 HETATM 4068 0 HOH 36 22.401 -5.914 -9.527 1.00 28.08 HETATM 4069 0 HOH 37 16.128 -0.899 -8.109 1.00 33.13 HETATM 4070 0 HOH 38 3.581 15.655 -3.706 1.00 41.37 HETATM 4071 0 HOH 39 31.900 13.545 21.339 1.00 37.79 HETATM 4072 0 HOH 40 20.058 -7.530 14.119 1.00 47.51 HETATM 4073 0 HOH 41 34.634 6.668 15.632 1.00 29.24 HETATM 4074 0 HOH 42 17.968 10.511 -9.085 1.00 44.60 HETATM 4075 0 HOH 43 23.258 -17.325 -4.088 1.00 44.10 HETATM 4076 0 HOH 44 4.034 -1.472 27.521 1.00 15.22 HETATM 4077 0 HOH 45 -5.943 -0.018 36.088 1.00 21.11 HETATM 4078 0 HOH 46 6.084 -1.509 29.478 1.00 19.51 HETATM 4079 0 HOH 47 9.762 1.061 15.621 1.00 27.74 HETATM 4080 0 HOH 48 1.804 0.717 17.260 1.00 20.97 HETATM 4081 0 HOH 49 0.929 0.421 30.281 1.00 19.64 HETATM 4082 0 HOH 50 9.627 4.271 31.231 1.00 19.02 HETATM 4083 0 HOH 51 2.121 -0.261 13.654 1.00 26.09 HETATM 4084 0 HOH 52 20.060 10.275 17.711 1.00 25.49 HETATM 4085 0 HOH 53 -6.786 0.736 33.483 1.00 22.34 HETATM 4086 0 HOH 54 2.751 -4.136 27.760 1.00 19.93 HETATM 4087 0 HOH 55 5.994 -4.079 31.292 1.00 32.27 HETATM 4088 0 HOH 56 19.416 16.921 21.645 1.00 25.54 HETATM 4089 0 HOH 57 4.833 2.325 29.006 1.00 19.00 HETATM 4090 0 HOH 58 -7.638 -8.931 37.809 1.00 24.79 HETATM 4091 0 HOH 59 28.442 -4.673 21.875 1.00 24.32 HETATM 4092 0 HOH 60 1.094 -4.893 32.100 1.00 24.27 HETATM 4093 0 HOH 61 0.905 -7.306 32.783 1.00 21.33 HETATM 4094 0 HOH 62 3.396 -2.971 32.306 1.00 26.13 HETATM 4095 0 HOH 63 10.363 4.576 28.391 1.00 33.43 HETATM 4096 0 HOH 64 19.551 -6.473 16.597 1.00 35.38 HETATM 4097 0 HOH 65 -2.888 -19.627 15.665 1.00 27.99 HETATM 4098 0 HOH 66 -7.275 -9.745 31.077 1.00 27.00 HETATM 4099 0 HOH 67 10.189 3.580 16.510 1.00 24.19 HETATM 4100 0 HOH 68 2.741 0.716 28.382 1.00 16.48 HETATM 4101 0 HOH 69 23.522 -4.323 13.943 1.00 27.48 HETATM 4102 0 HOH 70 17.133 8.133 19.686 1.00 32.24 HETATM 4103 0 HOH 71 -0.295 4.535 35.884 1.00 33.42 HETATM 4104 0 HOH 72 9.519 10.828 34.842 1.00 29.38 HETATM 4105 0 HOH 73 6.291 14.878 29.070 1.00 28.21 HETATM 4106 0 HOH 74 -1.721 6.480 13.381 1.00 49.91 HETATM 4107 0 HOH 75 10.091 -15.427 26.194 1.00 24.17 HETATM 4108 0 HOH 76 5.029 7.461 17.718 1.00 18.91 HETATM 4109 0 HOH 77 3.758 2.086 14.306 1.00 28.28 HETATM 4110 0 HOH 78 -1.390 -18.739 33.183 1.00 41.11 HETATM 4111 0 HOH 79 12.703 -8.687 32.119 1.00 36.21 HETATM 4112 0 HOH 80 22.270 -6.451 14.844 1.00 33.21 HETATM 4113 0 HOH 81 1.458 4.605 34.026 1.00 23.59 HETATM 4114 0 HOH 82 1.759 -2.158 30.374 1.00 28.78 HETATM 4115 0 HOH 83 6.153 -21.372 23.188 1.00 31.14 WO 99/50658 PCT/US99/06937 HETATM 4116 0 HOH 84 36.525 0.463 20.792 1.00 45.26 HETATM 4117 0 HOH 85 13.832 9.696 13.792 1.00 33.12 HETATM 4118 0 HOH 86 31.166 6.635 24.924 1.00 35.19 HETATM 4119 0 HOH 87 8.844 -10.389 34.180 1.00 48.80 HETATM 4120 0 HOH 88 9.581 -6.956 34.136 1.00 42.95 HETATM 4121 0 HOH 89 -1.563 15.887 27.596 1.00 39.35 HETATM 4122 0 HOH 90 -5.286 10.345 32.757 1.00 35.20 HETATM 4123 0 HOH 91 15.035 0.607 13.339 1.00 29.53 HETATM 4124 0 HOH 92 -10.984 -1.500 30.272 1.00 29.84 HETATM 4125 0 HOH 93 -7.239 -0.271 -1.207 1.00 48.98 HETATM 4126 0 HOH 94 18.022 -4.902 34.286. 1.00 35.28 HETATM 4127 0 HOH 95 29.347 -6.319 19.920 1.00 37.20 HETATM 4128 0 HOH 96 -14.309 -19.369 20.945 1.00 30.23 HETATM 4129 0 HOH 97 31.496 4.614 18.716 1.00 38.79 HETATM 4130 0 HOH 98 26.567 9.759 25.629 1.00 29.72 HETATM 4131 0 HOH 99 2.848 14.531 1.134 1.00 38.08 HETATM 4132 0 HOH 100 -9.373 5.699 -7.953 1.00 53.23 HETATM 4133 0 HOH 101 -10.137 -0.553 -6.742 1.00 47.72 HETATM 4134 0 HOH 102 10.558 -10.363 15.403 1.00 40.97 HETATM 4135 0 HOH 103 21.079 17.166 18.929 1.00 32.40 HETATM 4136 0 HOH 104 25.810 -5.921 22.506 1.00 37.69 HETATM 4137 0 HOH 105 22.493 -1.311 34.465 1.00 49.94 HETATM 4138 0 HOH 106 19.317 10.977 38.703 1.00 40.60 HETATM 4139 0 HOH 107 4.479 13.951 3.045 1.00 45.33 HETATM 4140 0 HOH 108 20.418 19.353 34.044 1.00 42.18 HETATM 4141 0 HOH 109 -3.065 8.936 14.062 1.00 38.41 HETATM 4142 0 HOH 110 26.856 -4.674 -10.940 1.00 55.67 HETATM 4143 0 HOH 111 2.032 -6.387 5.614 1.00 42.23 HETATM 4144 0 HOH 112 0.601 0.228 -17.268 1.00 40.57 HETATM 4145 0 HOH 113 4.903 13.488 -14.050 1.00 47.72 HETATM 4146 O HOH 114 3.986 16.140 -0.960 1.00 40.66 HETATM 4147 0 HOH 115 12.968 -19.561 2.741 1.00 40.76 HETATM 4148 0 HOH 116 7.170 15.583 2.599 1.00 43.69 HETATM 4149 0 HOH 117 -1.966 10.606 3.572 1.00 52.63 HETATM 4150 0 HOH 118 29.030 10.644 6.707 1.00 42.54 HETATM 4151 0 HOH 119 0.468 4.354 8.374 1.00 38.69 HETATM 4152 0 HOH 120 29.086 17.119 19.272 1.00 45.51 HETATM 4153 0 HOH 121 24.614 17.609 20.174 1.00 53.55 HETATM 4154 0 HOH 122 -15.318 0.362 26.686 1.00 36.77 HETATM 4155 0 HOH 123 -3.857 -24.786 28.325 1.00 39.64 HETATM 4156 O HOH 124 21.728 22.178 31.983 1.00 43.73 HETATM 4157 0 HOH 125 31.650 -7.370 21.642 1.00 40.53 HETATM 4158 0 HOH 126 25.421 10.436 21.161 1.00 32.31 HETATM 4159 0 HOH 127 10.317 -9.457 12.998 1.00 37.77 HETATM 4160 0 HOH 128 22.723 14.887 15.427 1.00 47.90 HETATM 4161 0 HOH 129 6.702 9.556 37.596 1.00 47.81 HETATM 4162 O HOH 130 27.987 13.557 7.167 1.00 41.15 HETATM 4163 0 HOH 131 30.798 16.499 7.588 1.00 58.47 WO 99/50658 PCT/US99/06937 HETATM 4164 0 HOH 132 10.071 -0.571 -20.393 1.00 38.79 I-ETATM 4165 0 HOH 139.562 8.33 4 -21.392 1.00 36.80 HETATM 4166 0 HOH 134 6.712 6.058 8.822 1.00 37.43 HETATM 4167 0 HOH 135 5.927 8.454 10.594 1.00 42.34 S HETATM 4168 0 HOH 136 4. 472 6.306 10.973 1.00 37.35 HETATM 4169 0 HOH 1 37 6.792 7.721 7.051 1.00 4 7.23 HETATM 4170 0 HOH 138 2 4.5 1 3 11.582 33.724 1.00 45.55 HETATM 4171 0 HOH 139 -2.528 -20.361 12.354 1.00 52.13 HETATM 4172 0 HOH 140 -7.864 7.706 19.248 1.00 47.82 HETATM 4173 0 H0H 141 11.577 -16.962 24.398 1.00 39.4 3 HETATM 4174 0 HOH 142 18.087 12.263 -5.507 1.00 3-3.3 6 HETATM 4175 0 HOH 143 -6.816 -14.190 10.674 1.00 51.32 HETATM 4176 0 HOH 144 -7.377 -16.701 33.528 1.00 57.11 H4ETATM 4177 0 HOH 145 -5.379 -20.107 32.689 1.00 43.01 HETATM 4178 0 HOH 146 8.766 -7.947 -16.274 1.00 49.96 HETATM 4179 0 HOH 147 10.946 -7.937 -18.142 1.00 55.67

END

7.

WO 99/50658 PCT/US99/06937 Appendix 2 Atomic Coordinates for Human ERa Complexed With OHT CRYST1 58.242 58.242 277.467 90.00 90.00 120.00 P 65 2 2 12 ORIGXI 1.000000 0.000000 ORIGX2 0.000000 1.000000 ORIGX3 0.000000 0.000000 SCALE1 0.017170 0.009913 SCALE2 0.000000 0.019826 SCALE3 0.000000 0.000000 ATOM I CB LEU 306 ATOM 2 C LEU 306 ATOM 3 0 LEU 306 ATOM 4 N LEU 306 ATOM 5 CA LEU 306 ATOM 6 N ALA 307 ATOM 7 CA ALA 307 ATOM 8 CB ALA 307 ATOM 9 C ALA 307 ATOM 10 0 ALA 307 ATOM 11 N LEU 308 ATOM 12 CA LEU 308 ATOM 13 CB LEU 308 ATOM 14 CG LEU 308 ATOM 15 CDI LEU 308 ATOM 16 CD2 LEU 308 ATOM 17 C LEU 308 ATOM 18 0 LEU 308 ATOM 19 N SER 309 ATOM 20 CA SER 309 ATOM 21 CB SER 309 ATOM 22 OG SER 309 ATOM 23 C SER 309 ATOM 24 0 SER 309 ATOM 25 N LEU 310 ATOM 26 CA LEU 310 ATOM 27 CB LEU 310 ATOM 28 CG LEU 310 ATOM 29 CDI LEU 310 ATOM 30 CD2 LEU 310 ATOM 31 C LEU 310 ATOM 32 0 LEU 310 ATOM 33 N THR 311 ATOM 34 CA THR 311 ATOM 35 CB THR 311 0.000000 0.00000 0.000000 0.00000 1.000000 0.00000 0.000000 0.00000 0.000000 0.00000 0.003604 0.00000 6.638 11.502 7.381 10.684 6.407 11.020 6.369 9.128 7.232 10.330 8.609 10.605 8.891 10.912 10.318 10.501 8.692 12.393 8.451 12.770 8.789 13.228 8.638 14.668 9.298 15.402 10.637 14.822 10.474 14.189 11.694 15.920 7.190 15.130 6.935 16.307 6.246 14.208 4.828 14.544 4.034 13.896 4.071 12.479 4.261 14.095 3.166 14.507 5.016 13.257 4.591 12.749 5.651 11.811 5.586 10.333 5.530 10.200 6.809 9.610 4.330 13.865 4.993 14.905 3.352 13.641 3.017 14.604 1.527 14.554 3.989 1.00 61.20 6.231 1.00 61.47 6.905 1.00 62.09 4.588 1.00 62.32 4.754 1.00 61.30 6.730 1.00 60.52 8.125 1.00 58.77 8.465 1.00 59.70 8.429 1.00 57.51 9.574 1.00 57.64 7.400 1.00 55.82 7.573 1.00 56.62 6.406 1.00 57.48 5.948 1.00 59.17 4.569 1.00 60.38 5.933 1.00 58.46 7.710 1.00 56.51 7.961 1.00 55.58 7.546 1.00 57.04 7.657 1.00 56.46 6.514 1.00 56.79 6.588 1.00 57.23 9.003 1.00 56.13 9.398 1.00 55.17 9.706 1.00 54.31 11.004 1.00 53.55 11.582 1.00 54.40 11.189 1.00. 56.49 9.676 1.00 57.06 11.739 1.00 57.28 12.003 1.00 53.18 11.984 1.00 53.17 12.874 1.00 51.71 13.912 1.00 49.93 14.275 1.00 48.96 WO 99/50658 PTU9/63 PCT/US99/06937 ATOM 36 ATOM 3 7 ATOM 38 ATOM 39 ATOM 40 ATOM 41 ATOM 42 ATOM 43 ATOM 44 ATOM 45 ATOM 46 ATOM 47 ATOM 48 ATOM 49 15 ATOM 50 ATOM 51 ATOM 52 ATOM 53 ATOM 54 ATOM 55 ATOM 56 ATOM 57 ATOM 58 ATOM 59 ATOM 60 ATOM 61 ATOM 62 ATOM 63 ATOM 64 ATOM 65 ATOM 66 ATOM 67 ATOM 68 ATOM 69 ATOM 70 ATOM 71 ATOM 72 ATOM 73 ATOM 74 ATOM 75 ATOM 76 ATOM 77 ATOM 78 *ATOM 79 ATOM 80 ATOM 81 ATOM 82 ATOM 83.

OGI THR 311 CG2 THR 311 C THR 311 O THR 311 N ALA 312 CA ALA 312 CB ALA 3 12 C ALA 312 O ALA 312 N ASP 313 CA ASP 313 CB ASP 313 CG ASP 313 ODI ASP 3)13 0D2 ASP 313 C ASP 313 O ASP 313 N GLN 314 CA GLN 314 CB GLN 314 CG GLN 314 CD GLN 314 QEI GLN 314 NE2 GLN. 314 C GLN 314 O GLN 314 N MET 315 CA MET 315 CB MET 315 CG MET 315 SD MIET 315 CE MET 315 C MET 315 O MET 315 N VAL 316 CA VAL 316 CB VAL 316 CGI VAL 316 CG2 VAL 316 C VAL 316 O VAL 3 16 N SER 317 CA SER 317 CB SER 317 00 SER 317 C SER 317 O SER 317 N ALA 318 1.242 13.311' 14.930 1.00 47.20 0.666 14.688 13.027 1.00 50.99 3.815 14.201 15.145 10 88 4.371 13.103) 15.197 1.00 46.66 3.857 15.078 16.141 1.00 48.76 4.590 14.798 17.369 1.00 47.75 4.359 15.910 18.378 1.00 47.06 4.171 13.460 17.964 1.00 47.41 5.009 12.609 18.262 1.00 45.52 2.868 13.275 18.143 1.00 47.58 2.367 12.032 18.714 1.00 47.63 0.848 12.100 18.879 1.00 51.96 0.430 12.872 20.118 1.00 56.21 1.314 13.234 20.929 1.00 56.38 -0.785 13.117 20.282 1.00 59.15 2.745 10.846 17.835 1.00 43.93 2.959 9.741 18.330 1.00 44.77 2.826 11.081 16.53 1 1.00 44.52 3.182 10.02 8 15.588 1.00 44.73 2.849 10.464 14.156 1.00 45.05 1.534 9.886 13.626 1.00 48.47 0.982 10.646 12.428 1.00 50.37 1.649 11.515 11.856 1.00 49.38 -0.248 10.318 12.043 1.00 51.74 4.673 9.722 15.707 1.00 43.26 5.100 8.580 15.555 1.00 43.93 5.459 10.757 15.980 1.'00 42.29 6.901 10.606 16.130 1.00 41.26 7.565 11.9815 16.224 1.00 42.43 9.082 11.939 16.356 1.00 42.34 9.906 11.190 14.925 1.00 46.22 9.547 12.408 13.680 1.00 37.32 7.218 9.791 17.379 1.00 38.89 8.002 8.841 17.335 1.00 40.02 6.599 10.165 18.491 1.00 37.65 6.819 9.476 19.756 1.00 39.56 6.023 10.136 20.897 1.00 39.22 6.245 9.373 22.192 1.00 44.43 6.446 11.583 21.059 1.00 41.04 6.404 8.012 19.664 1.00 40.04 7.141 7.117 20.077 1.00 37.86 5.215 7.767 19.127 1.00 41.90 4.733 6.400 18.997 1.00 41.68 3.311 6. 402 18.415 1.00 43.85 3.225 5.631 17.230 1.00 49.38 5.696 5.60,1 18.1 14 1.00 39.72 6.011 4.446 18.407 1.00 40.21 6.182 6.220 17.043 1.00 38.35 -(7 WO 99/50658 PCTIUS99/06937

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84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 CA ALA 318 CB ALA 318 C ALA 318 O ALA 318 N LEU 319 CA LEU 319 CB LEU 319 CG LEU 319 CDI LEU 319 CD2 LEU 319 C LEU 319 O LEU 319 N LEU 320 CA LEU 320 CB LEU 320 CG LEU 320 CDI LEU 320 CD2 LEU 320 C LEU 320 O LEU 320 N ASP 321 CA ASP 321 CB ASP 321 CG ASP 321 ODI ASP 321 OD2 ASP 321 C ASP 321 O ASP 321 N ALA 322 CA ALA 322 CB ALA 322 C ALA 322 O ALA 322 N GLU 323 CA GLU 323 CB GLU 323 CG GLU 323 CD GLU 323 OE1 GLU 323 OE2 GLU 323 C GLU 323.

O GLU 323 N PRO 324 CD PRO 324 CA PRO 324 CB PRO 324 CG PRO 324 C PRO 324 7.114 7.485 8.375 8.820 8.938 10.161 10.660 11.136 11.714 12.182 9.965 10.779 8.879 8.567 7.239 7.236 5.876 8.334 8.466 8.971 7.812 7.613 6.669 5.206 4.901 4.357 8.911 9.030 9.878 11.153 11.772 12.148 13.219 11.799 12.704 12.042 12.209 13.657 14.313 14.134 13.205 12.425 14.527 15.522 15.158 16.63 3 16.811 14.940 5.540 6.448 5.137 3.992 6.089 5.854 7.174 8.264 9.440 7.693 4.826 3.916 4.982 4.067 4.467 5.582 5.634 5.332 2.642 1.697 2.504 1.210 1.372 1.318 1.422 1.172 0.565 -0.661 1.395 0.905 1.954 0.513 -0.020 0.768 0.460 0.768 2.210 2.569 3.173 2.245 -0.978 -1.931 -1.151 -0.069 -2.474 -2.166 -0.807 -3.162 16.153 14.986 16.920 16.844 17.664 18.438 19.040 18.071 18.857 17.140 19.549 19.729 20.297 21.387 22.049 23.099 23.802 24.112 20.843 21.443 19.696 19.053 17.860 18.255 19.464 17.346 18.568 18.533 18.193 17.686 16.776 18.769 18.473 20.022 21.117 22.459 22.899 23.200 22.326 24.309 21.110 20.999 21.225 21.345 21.240 21.003 21.610 22.583 1.00 36.96 1.00 37.92 1.00 38.31 1.00 33.94 1.00 36.92 1.00 38.56 1.00 40.86 1.00 41.25 1.00 44.30 1.00 42.61 1.00 38.33 1.00 33.91 1.00 37.39 1.00 41.55 1.00 38.47 1.00 44.81 1.00 44.96 1.00 43.36 1.00 41.11 1.00 41.87 1.00 43.94 1.00 44.77 1.00 48.39 1.00 52.39 1.00 53.56 1.00 55.81 1.00 44.37 1.00 44.67 1.00 40.75 1.00 37.81 1.00 38.07 1.00 35.52 1.00 36.11 1.00 35.61 1.00 36.39 1.00 35.09 1.00 37.93 1.00 37.29 1.00 34.21 1.00 38.02 1.00 38.01 1.00 38.37 1.00 36.03 1.00 36.69 1.00 36.42 1.00 35.75 1.00 35.46 1.00 35.75

C

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132 0 PRO 324 133 N PRO 325 134 CD PRO 325 135 CA PRO 325 136 CB PRO 32 5 137 CG PRO 325 138 C PRO 325 139 0 PRO 325 140 N ILE 326 141 CA ILE 326 142 CB ILE 326 143 CG2 ILE 326 144 'CG I ILE 326 145 CDI ILE 326 146 C ILE 326 147 0 ILE 326 148 N LEU 327 149 CA LEU 327 150 CB LEU 327 151 CG LEU 327 152 CDI LEU 327 153 CD2 LEU 327 154 C LEU 327 155 0 LEU 327 156 N TYR 328 157 CA TYR 328 158 CB TYR 328 159 CG TYR 32 8 160 CDI TYR 328 161 CEI TYR 328 162 CD2 TYR 328 163 CE2 TYR 328 164 CZ TYR 328 165 OH TYR 328 166 C TYR 328 167 0 TYR 328 168 N SER 329 169 CA SER 329 170 CB SER 329 171 OG SER 329 172 C SER 329 173 0 SER 329 174 N GLU 330 175 CA GLU 330 176 CB GLU 330 177 CG GLU 330 178 CD GLU 330 179 OE1 GLU 330 14.6 16 15.134 15.530 14.942 14.753 15.589 16.132 17.237 15.899 16.975 16.458 17.557 15.987 16.035 17.567 16.875 18.840 19.493 20.528 19.978 2 1.068 18.775 20.156 20.393 20.445 2 1.087 20.409 19.194 19.253 18.152 17.996 16.880 16.973 15.896 22.529 22.884 23.359 24.767 25.526 26.787 24.835 23.980 25.845 25.992 26.423 25.278 25.765 25.909 -4.48 5 -5.386 -5.208 -6.652 -6.743 -5.070 -4.723 -5.322 -5.265 -4.891 -5.110 431 -2.747 -6.668 -7.634 -6.784 -8.083 -8.135 -7.800 -7.993 -8.688 -8.438 -7.578 -9.725 -10.229 -11.520 -11.272 -11.398 -11.114 -10.862 -10.574 -10.702 -10.397 -10.520 -10.744 -10.496 10.800 -10.342 10.965 -12.317 -13.0218 -12.811 14.242 14.524 -14.870 -15.405 -16.640 23 .580 22.631I 2 1.534 23.889 23.439 22.200 24.824 24.399 26. 106 27.075 28.473 29.504 28.466 29.8 15 27. 103 27.427 26. 74 5 26.716 25.587 24.196 23.139 23.891 28.030 28.891 28.18 1 29.38 1 29.842 30.686 32.071 32 .864 30.110 30.899 32.274 33.071 29.067 27.9 10 30. 103 29.962 31.204 3 1.282 29.832 30.363 29.128 28.928 27.484 26.542 25. 198 25.062 1.00 34.97 1.00 315.24 1.00 37.02 1.00 34.65 1.00 35.8 3 1.00 3 4.88 1.00 3 4.51 1.00 29.92 1.00 333.62 1.00 35.02 1.00 38.11 1.00 38.70 1.00 40.48 1.00 42.96 1.00 34.14 1.00 34.88 1.00 29.64 1.00 29.54 1.00 27.76 1.00 29.02 1.00 28.76 1.00 31.26 1.00 31.21 1.00 30.12 1.00 30.99 1.00 30.95 1.00 33.38 1.00 33.05 1.00 31.92 1.00 3 6.01 1.00 36.05 1.00 3 7.27 1.00 3 7.66 1.00 44.66 1.00 33.66 1.00 34.78 1.00 33.97 1.00 37.29 1.00 36.51 1.00 37. 1 3 1.00 40.43 1.00 40.11I 1.00 41.40 1.00 47.43 1.00 48.64 1.00 50.20 1.00 53.25 1.00 53.27 c WO 99/50658 PCT/US99/06937

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O 15 ATOM

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180 OE2 GLU 330 181 C GLU 330 182 0 GLU 330 183 N TYR 331 184 CA TYR 331 185 CB TYR 331 186 CG TYR 331 187 CDI TYR 331 188 CEI TYR 331 189 CD2 TYR 331 190 CE2 TYR 331 191 CZ TYR 331 192 OH TYR 331 193 C TYR 331 194 0 TYR 331 195 N ASP 332 196 CA ASP 332 197 CB ASP 332 198 CG ASP 332 199 ODI ASP 332 200 OD2 ASP 332 201 C ASP 332 202 0 ASP 332 203 N PRO 333 204 CD PRO 333 205 CA PRO 333 206 CB PRO 333 207 CG PRO 333 208 C PRO 333 209 0 PRO 333 210 N THR 334 211 CA THR 334 212 CB THR 334 213 OGI THR 334 214 CG2 THR 334 215 C THR 334 216 0 THR 334 217 N ARG 335 218 CA ARG 335 219 CB ARG 335 220 C ARG 335 221 0 ARG 335 222 N PRO 336 223 CD PRO 336 224 CA PRO 336 225 CB PRO 336 226 CG PRO 336 227 C PRO 336 26.004 -14.590 26.999 -14.852 28.207 -14.741 26.498 -15.493 27.373 -16.130 28.092 -15.078 27.239 -14.460 26.656 -13.205 25.864 -12.630 27.010 -15.128 26.219 -14.563 25.648 -13.314 24.855 -12.753 26.603 -17.080 25.393 -16.942 27.320 -18.045 26.719 -19.026 27.681 -20.194 26.961 -21.516 27.575 -22.564 25.781 -21.505 26.393 -18.371 27.292 -18.073 25.096 -18.148 23.945 -18.509 24.677 -17.521 23.165 -17.333 22.866 -17.611 25.010 -18.419 25.129 -17.964 25.160 -19.704 25.475 -20.697 24.929 -22.080 25.571 -22.513 23.423 -22.012 26.982 -20.804 27.432 -21.323 27.759 -20.308 29.214 -20.360 29.835 -20.500 29.757 -19.113 29.100 -18.071 30.968 -19.207 31.820 -20.408 31.601 -18.086 32.982 -18.621 32.829 -20.097 31.701 -16.828 24.280 29.893 29.696 30.942 31.921 32.774 33.860 33.682 34.676 35.065 36.066 35.864 36.839 32.823 33.002 33.387 34.281 34.500 34.648 34.351 35.060 35.619 36.406 35.896 35.053 37.154 36.993 35.556 38.332 39.468 3 8.037 39.050 38.645 37.439 38.411 39.269 40.289 38.313 38.421 37.030 39.123 39.148 39.702 39.713 40.410 40.783 40.779 39.561 1.00 51.80 1.00 49.67 1.00 50.11 1.00 53.62 1.00 58.16 1.00 59.55 1.00 63.08 1.00 64.50 1.00 65.99 1.00 63.52 1.00 65.60 1.00 67.20 1.00 67.40 1.00 59.05 1.00 59.22 1.00 61.62 1.00 64.20 1.00 65.99 1.00 68.11 1.00 69.54 1.00 67.40 1.00 63.33 1.00 63.90 1.00 63.64 1.00. 64.35 1.00 63.52 1.00 63.53 1.00 64.15 1.00 63.29 1.00 63.28 1.00 64.26 1.00 66.09 1.00 66.90 1.00 68.06 1.00 67.57 1.00 65.67 1.00 64.77 1.00 65.65 1.00 66.60 1.00 66.74 1.00 67.09 1.00 67.31 1.00 67.62 1.00 67.30 1.00 67.42 1.00 66.43 1.00 67.52 1.00 68.26 WO 99/50658 PCT/US99/06937

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228 0 229 N 230 CA 231 CB 232 CG 233 CDI 234 CD2 235 CE1 236 CE2 237 CZ 238 C 239 0 240 N 241 CA 242 CB 243 OG 244 C 245 0 246 N 247 CA 248 CB 249 CG 250 CD 251 OEI 252 OE2 253 C 254 0 255 N 256 CA 257 CB 258 C 259 0 260 N 261 CA 262 CB 263 OG 264 C 265 0 266 N 267 CA 268 CB 269 CG 270 SD 271 CE 272 C 273 0 274 N 275 CA PRO 336 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 PHE 337 SER 338 SER 338 SER 338 SER 338 SER 338 SER 338 GLU 339 GLU 339 GLU 339 GLU 339 GLU 339 GLU 339 GLU 339 GLU 339 GLU 339 ALA 340 ALA 340 ALA 340 ALA 340 ALA 340 SER 341 SER 341 SER 341 SER 341 SER 341 SER 341 MET 342 MET 342 MET 342 MET 342 MET 342 MET 342 MET 342 MET 342 MET 343 MET 343 31.996 31.460 31.529 30.818 31.219 30.632 32.191 31.006 32.573 31.980 32.985 33.336 33.825 35.248 35.957 35.547 35.931 36.951 35.368 35.930 35.279 35.996 35.382 34.786 35.496 35.770 36.722 34.562 34.246 32.767 35.096 35.634 35.215 35.972 36.839 37.184 34.957 34.090 35.052 34.121 34.449 33.228 31.791 31.999 34.124 33.063 35.307 35.395 16.895 -15.681 14.408 -13.323 -11.924 -11.287 -11.245 -9.993 -9.950 -9.323 -14.013 -13.487 -14.273 -13.947 14.487 -15.818 -14.504 13.972 -15.573 -16.215 -17.585 -18.740 -20.089 -20.220 -21.020 -15.385 -15.216 -14.874 -14.083 -13.709 -12.824 -12.270 12.388 -11.188 -11.439 -10.226 -10.087 -10.248 -8.978 -7.875 -6.723 -6.089 -7.201 -7.881 -7.365 -7.121 -7.204 -6.708 38.371 40.183 39.480 40.294 39.921 38.833 40.653 38.479 40.306 39.217 39.245 38.189 40.241 40.172 41.414 41.679 38.924 38.475 38.369 37.183 36.971 37.656 37.318 36.227 38.144 35.910 35.144 35.694 34.507 34.523 34.326 35.287 33.076 32.736 31.497 30.846 32.444 31.589 33.166 32.960 33.912 34.560 34.631 36.239 31.516 30.938 30.930 29.558 1.00 69.04 1.00 69.49 1.00 71.39 1.00 72.31 1.00 73.21 1.00 72.82 1.00 73.43 1.00 73.28 1.00 73.00 1.00 72.90 1.00 71.38 1.00 71.56 1.00 71.53 1.00 70.98 1.00 70.43 1.00 69.59 1.00 71.20 1.00 71.35 1.00 70.20 1.00 69.48 1.00 71.07 1.00 72.60 1.00 74.26 1.00 73.51 1.00 76.44 1.00 68.15 1.00 68.99 1.00 64.41 1.00 60.69 1.00 61.17 1.00 57.00 1.00 57.46 1.00 52.15 1.00 46.53 1.00 48.64 1.00 46.48 1.00 43.52 1.00 39.92 1.00 41.24 1.00 42.46 1.00 45.61 1.00 52.39 1.00 57.92 1.00 56.18 1.00 40.22 1.00 39.23 1.00 38.72 1.00 38.50

G)

WO 99/50658 PCT/US99/06937 ATOM 276 ATOM 277 ATOM 278 ATOM 279 ATOM 280 ATOM 281 ATOM 282 ATOM 283 ATOM 284 ATOM 285 ATOM 286 ATOM 287 ATOM 288 ATOM 289 1 15 ATOM 290 ATOM 291 ATOM 292 ATOM 293 ATOM 294 ATOM 295 ATOM 296 ATOM 297 ATOM 298 ATOM 299 ATOM 300 ATOM 301 ATOM 302 ATOM 303 ATOM 304 ATOM 305 ATOM 306 ATOM 307 ATOM 308 ATOM 309 ATOM 310 ATOM 311 ATOM 312 ATOM 313 ATOM 314 ATOM 315 ATOM 316 ATOM 317 ATOM 318 ATOM 319 ATOM 320 ATOM 321 ATOM 322 ATOM 323 CB MET 343 CG MET 343 SD MET 343 CE MET 343 C MET 343 O MET 343 N GLY 344 CA GLY 344 C GLY 344 O GLY 344 N LEU 345 CA LEU 345 CB LEU 345 CG LEU 345 CDI LEU 345 CD2 LEU 345 C LEU 345 O LEU 345 N LEU 346 CA LEU 346 CB LEU 346 CG LEU 346 CDI LEU 346 CD2 LEU 346 C LEU 346 O LEU 346 N THR 347 CA THR 347 CB THR 347 OGI THR 347 CG2 THR 347 C THR 347 O THR 347 N ASN 348 CA ASN 348 CB ASN 348 CG ASN 348 ODI ASN 348 ND2 ASN 348 C ASN 348 O ASN 348 N LEU 349 CA LEU 349 CB LEU 349 CG LEU 349 CDI LEU 349 CD2 LEU 349 C LEU 349 36.838 37.022 36.032 36.113 34.880 34.368 35.017 34.533 33.015 32.359 32.459 31.011 30.665 30.942 30.537 30.164 30.430 29.479 31.021 30.569 31.317 31.091 31.815 29.614 30.732 29.869 31.839 32.086 33.472 34.481 33.666 31.036 30.516 30.737 29.757 29.767 28.646 27.549 28.920 28.361 27.558 28.078 26.782 26.650 25.376 24.140 25.392 26.638 -6.318 -5.749 4.260 -3.358 -7.741 -7.384 -9.020 -10.072 -10.063 -10.233 -9.860 -9.804 -9.631 -10.774 -10.357 -11.998 -8.614 -8.757 -7.443 -6.217 -5.016 -4.767 -3.498 -4.644 -6.250 -5.765 -6.816 -6.911 -7.501 -6.604 -7.707 -7.804 -7.486 -8.926 -9.868 -11.161 -12.117 -12.078 -12.970 -9.251 -9.477 -8.467 -7.811 -7.148 -6.328 29.216 27.804 27.427 28.987 28.561 27.501 28.902 28.024 28.047 27.019 29.238 29.415 30.902 31.883 33.297 31.449 28.633 27.868 28.843 28.193 28.771 30.269 30.668 30.581 26.682 25.955 26.212 24.781 24.497 24.982 23.004 24.122 23.049 24.768 24.242 25.065 24.662 25.220 23.683 24.262 23.353 25.298 25.421 26.795 27.050 1.00 41.15 1.00 40.31 1.00 45.23 1.00 40.45 1.00 35.36 1.00 35.51 1.00 35.53 1.00 33.41 1.00 31.74 1.00 29.58 1.00 32.89 1.00 34.95 1.00 37.56 1.00 43.03 1.00 41.57 1.00 42.80 1.00 33.71 1.00 30.29 1.00 30.20 1.00 32.00 1.00 28.16 1.00 29.84 1.00 29.98 1.00 33.97 1.00 30.70 1.00 29.13 1.00 30.47 1.00 30.93 1.00 29.97 1.00 35.40 1.00 33.58 1.00 31.97 1.00 30.75 1.00 29.31 1.00 32.63 1.00 31.64 1.00 39.14 1.00 41.91 1.00 42.05 1.00 29.02 1.00 32.76 1.00 28.74 1.00 28.58 1.00 26.56 1.00 33.67 1.00 28.82 1.00 33.11 1.00 28.07 -7.199 26.840 -5.779 28.471 -6.762 24.319

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ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

324 0 325 N 326 CA 327 GB 328 C 329 0 330 N 31 CA 332 GB 333 CG 334 ODI 33 D2 336 C 337 0 338 N 339 CA 340 GB 341 CG .342 CD 343 NE 344 CZ 345 NHI 346 NH2 347 C 348 0 349 N .350 CA 351 GB -352 CG 353 CD 354 OEI 355 0E2 356 C 357 0 358 N -359 CA -360 GB -361 CG -362 CDI 363 CD2 364 C 365 0 366 N 367 GA .368 GB 369 CG1 .370 CG2 371 C LEU 349 ALA 350 ALA 350 ALA 350 ALA 350 ALA 350 ASP 351 ASP 351 ASP 351 ASP 351 ASP 351 ASP 351 ASP 351 ASP 351 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 ARG 352 GLU 353 GLU 353 GLU 353 GLU 353 GLU 353 GLU 353 GLU 353 GLU 353 GLU 353 LEU 354 LEU 354 LEU 354 LEU 354 LEU 354 LEU 354 LEU 354 LEU 354 VAL 355 VAL 355 VAL 355 VAL 355 VAL 355 VAL 355 25.6 16 27.675 -7.668 28.972 27.468 26.649 28.2 13 28.093 29.036 30.498 31.354 30.789 26.661 26.193 25.968 24.593 24. 148 24.567 24. 128 24.898 24.364 23.050 25.144 23.642 22.702 23.896 23.045 23.461 23. 147 23.425 24. 564 22.506 23. 131 22.169 24.296 24.522 25.952 26.372 26.243 27.794 23.559 23 ).074 23.291 22.386 22.259 21.423 23.649 21.020 -6.703 -5.941 -4.886 -4.094 -5.461 -4.958 -6.509 -7.143 -8.345 -7.940 -8.831 -6.738 -7.600 -7.458 -8.150 -8.602 -9.534 -10.991 -1 1.911 -11.675 -11.363 -11.251 -1 1.148 -7.411 -7.426 -6.3 70 -5.178 -4.204 -4.669 -3.587 -3.534 -2.789 -4.456 -3.826 -4.540 -3.872 -4.121 -3.257 -1.774 -3.607 -4.300 -3.475 -5.598, -6.125 -7.655' -8.205 -8.282' -5.4991 23.629 24.157 23.148 23.209 2 1.750 20.983 21.420 20. 112 20.0 10 19.978 20. 148 19.784 19.813 18.687 20.811 20.605 21.752 21.532 22.666 23.879 25.054 25.177 26. 104 20.502 19.708 21.291 21.261 22.365 23.771 24.795 25.304 25.085 19.920 19.467 19.293 18.0 17 17.543 16.351 16.722 15.962 16.926 16. 152 16.854 15.844 15.975 14.834 15.998 16.035 1.00 25.22 1.00 28.50 1.00 28.46 1.00 28.12 1.00 28.75 1.00 30.90 1.00 27.20 1.00 29.75 1.00 34.16 1.00 37.5 0 1.00 37.55 1.00 350 1.00 30.52 1.00 27.77 1.00 27.18 1.00 26.21 1.00 26.52 1.00 311.03 1.00 29.80 1.00 30.44 1.00 31.68 1.00 31.18 1.00 32.03 1.00 27.16 1.00 26.65 1.00 274.30 1.00 26.39 1.00 24.91 1.00 27.93 1.00 30.71 1.00 30.09 1.00 30.53 1.00 24.27 1.00 28.71 1.00 26.61 1.00 26.62 1.00 26.36 1.00 29.24 1.00 26.59 1.00 28.88 1.00 27.72 1.00 24.00 1.00 28.82 1.00 29.45 1.00 31.76 1.00 3.3.55 1.00 31.36 1.00 27.71

C

WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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ATOM

ATOM

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372 0 VAL 355 373 N HIS 356 374 CA HIS 356 375 CB HIS 356 376 CG HIS 356 377 CD2 HIS 356 378 NDI HIS 356 379 CEI HIS 356 380 NE2 HIS 356 381 C HIS 356 382 0 HIS 356 383 N MET 357 384 CA MET 357 385 CB MET 357 386 CG MET 357 387 SD MET 357 388 CE MET 357 389 C MET 357 390 0 MET 357 391 N ILE 358 392 CA ILE 358 393 CB ILE 358 394 CG2 ILE 358 395 CGI ILE 358 396 CDI ILE 358 397 C ILE 358 398 0 ILE 358 399 N ASN 359 400 CA ASN 359 401 CB ASN 359 402 CG ASN 359 403 ODI ASN 359 404 ND2 ASN 359 405 C ASN 359 406 0 ASN 359 407 N TRP 360 408 CA TRP 360 409 CB TRP 360 410 CG TRP 360 411 CD2 TRP 360 412 CE2 TRP 360 413 CE3 TRP 360 414 CDI TRP 360 415 NEI TRP 360 416 CZ2 TRP 360 417 CZ3 TRP 360 418 CH2 TRP 360 419 C TRP 360 20.382 20.580 19.291 18.936 18.602 19.352 17.363 17.364 18.559 19.300 18.272 20.457 20.526 21.902 22.011 23.732 24.140 20.256 19.619 20.757 20.553 21.204 20.759 22.728 23.299 19.055 18.519 18.379 16.945 16.434 16.739 17.045 16.673 16.224 15.261 16.706 16.102 16.703 16.522 17.493 16.888 18.819 15.399 15.609 17.558 19.488 18.853 16.312 -5.039 -5.473 -4.906 -5.231 -6.675 -7.700 -7.208 -8.499 -8.823 -3.398 -2.812 -2.765 -1.322 -0.789 0.736 1.290 0.672 -1.011 -0.003 -1.874 -1.721 -2.888 -2.860 -2.799 -1.469 -1.721 -0.817 -2.748 -2.861 -4.101 -5.374 -5.329 -6.508 -1.634 -1.163 -1.104 0.087 0.347 1.747 2.801 3.954 2.883 2.284 3.611 5.180 4.106 5.232 1.296 15.080 17.288 17.627 19.079 19.307 19.779 19.018 19.304 19.767 17.412 17.100 17.574 17.369 17.766 17.699 17.859 19.514 15.898 15.569 15.020 13.576 12.789 11.334 12.874 12.451 13.310 12.662 13.814 13.638 14.363 13.627 12.437 14.320 14.149 13.530 15.264 15.842 17.228 17.707 17.657 18.204 17.205 18.264 18.566 18.3 10 17.309 17.858 14.926 1.00 29.61 1.00 27.76 1.00 28.35 1.00 31.12 1.00 35.93 1.00 33.95 1.00 36.62 1.00 33.33 1.00 32.16 1.00 28.25 1.00 28.99 1.00 25.31 1.00 24.63 1.00 23.61 1.00 24.66 1.00 27.30 1.00 23.62 1.00 24.83 1.00 26.78 1.00 26.25 1.00 30.33 1.00 33.86 1.00 33.68 1.00 36.89 1.00 39.10 1.00 32.20 1.00 32.02 1.00 33.12 1.00 33.35 1.00 37.59 1.00 44.38 1.00 47.35 1.00 42.48 1.00 32.74 1.00 31.39 1.00 27.92 1.00 29.47 1.00 27.66 1.00 30.40 1.00 27.54 1.00 29.42 1.00 28.37 1.00 27.75 1.00 30.84 1.00 27.74 1.00 24.49 1.00 25.09 1.00 27.90 WO 99/50658 PCTIUS99/06937 ATOM -420 0 ATOM 421 N ATOM 4 22 CA ATOM 423 CB ATOM 424 C ATOM 425 0 ATOM 426 N ATOM 427 CA ATOM 428 CB ATOM 429 CG ATOM 430 CD ATOM 431 CE ATOM 432 NZ ATOM 433 C 15 ATOM 434 0 ATOM -435 N ATOM 436 CA ATOM 437 CB ATOM 438 CG ATOM 439 CD ATOM 440 NE ATOM 441 CZ ATOM 442 NHI TRP 360 ALA 361 ALA 361 ALA 361 ALA 361 ALA 361 LYS 362 LYS 362 LYS 362 LYS 362 LYS 362 LYS 362 LYS 362 LYS 362 LYS 362 ARO 363 ARG 363 ARO 36 3 ARG 363 ARG 363 ARG 363 ARO 363 ARG 363 ATOM 443 NH2 ARO 363 ATOM 444 C ARG 363 ATOM 445 0 ARG 363 ATOM 446 N VAL 364 ATOM 447 CA VAL 364 ATOM 448 CB VAL 364 ATOM 449 COI VAL 364 ATOM 450 C02 VAL 364 ATOM 451 C VAL 364 ATOM 452 0 VAL 364 ATOM 453 N PRO 365 ATOM 454 CD PRO 365 ATOM 455 CA PRO 365 ATOM 456 CB PRO 365 ATOM 457 CG PRO 365 ATOM 458 C PRO 365 ATOM 459 0 PRO 365 ATOM 460 N GLY 366 ATOM 461 CA GLY 366 ATOM 462 C GLY 366 ATOM 463 0 GLY 366 ATOM 464 N PHE 367 ATOM 465 CA PHE 367 ATOM 466 CB PHE 367 ATOM 467 CG PHE 367 15.3 60 17.559 17.894 19.346 17.006 16.531 16.795 15.981 16.0 12 17.252 17.547 18.852 19.178 14.545 13.821 14. 134 12.770 12.17 8 12.169 11.468 10.161 9.3 14 9.642 8.143 12.654 11.567 13.785 13.804 15.231 15.293 15.641 1 3 .360 14.028 12.225 11.359 11.724 10.608 10. 135 12.756 13.430 12.878 13.816 15.168 15.858 15.554 16.860 17. 138 18.544 2.002 1.520 2.637 2.539 2.685 3.746 1.526 1.443 0.016 -0.281 1.774 -2.046 -3.507 1.872 2.168 1.921 2.3 13 1.307 -0.110 -1.086 -0.586 -1.262 -2.467 -0.729 3.743 4.199 4.442 5.836 6.271 7.779 5.571 6.591 6.531 7.3 10 7.492 8.050 8.9 18 8.157 8.878 9.726 8.624; 9.371 8.722, 9.035' 7.814: 7.164" 6.291 5.7713 14.581 1.00 14.523 1.00 13.645 1.00 13.220 '1.00 12.403 1.00 12.011 1.00 11.783 1.00 10.581 1.00 10.023 1.00 9.198 1.00 9.136 1.00 8.389 1.00 8.288 1.00 10.815 1.00 9.859 1.00 12.079 1.00 12.409 1.00 13.391 1.00 12.827 1.00 13.746 1.00 14.158 -1.00 14.929 1.00 15.374 1.00 15.261 1.00 12.943 1.00 13.303 1.00 13.002 1.00 13.431 1.00 13.827 1.00 13.995 1.00 15.113 1.00 12.171 1.00 11.146 1.00 12.234 1.00 13.413 1.00 11.069 1.00 11.645 1.00 12.842 1.00 10.321 1.00 10.907 1.00 9.023 1.00 8.212 1.00 8.007 1.00 7.034 1.00 8.901 1.00 8.787 1.00 10.016 1.00 10.080 1.00 28.83 28.25 29.20 28.89 31.08 31.30 30.93 34.15 33.67 39.40 43.60 47.06 50.34 35.81 37.95 34.23 36.04 36.71 40.36 42.17 45.19 49.41 48.02 51.54 37.40 38.22 35.66 34.06 33.87 31.08 31.30 33.19 -33.04 34.69 34.19 35.96 -36.59 -39.59 37.19 40.29 34.78 33.54 34.26 37.15 3.13 l 32.04 30.22) 30.6 2: WO99/50658 PCT/US99/06937 ATOM 468 CDI PHE 367 ATOM 469 CD2 PHE 367 ATOM 470 CEI PHE 367 ATOM 471 CE2 PHE 367 ATOM 472 CZ PHE 367 ATOM 473 C PHE 367 ATOM 474 0 PHE 367 ATOM 475 N VAL 368 ATOM 476 CA VAL 368 ATOM 477 CB VAL 368 ATOM 478 CG1 VAL 368 ATOM 479 CG2 VAL 368 ATOM 480 C VAL 368 ATOM 481 0 VAL 368 O 15 ATOM 482 N ASP 369 ATOM 483 CA ASP 369 ATOM 484 CB ASP 369 ATOM 485 CG ASP 369 ATOM 486 ODI ASP 369 ATOM 487 OD2 ASP 369 ATOM 488 C ASP 369 ATOM 489 0 ASP 369 ATOM 490 N LEU 370 ATOM 491 CA LEU 370 ATOM 492 CB LEU 370 ATOM 493 CG LEU 370 ATOM 494 CDI LEU 370 ATOM 495 CD2 LEU 370 ATOM 496 C LEU 370 ATOM 497 0 LEU 370 ATOM 498 N THR 371 ATOM 499 CA THR 371 ATOM 500 CB THR 371 ATOM 501 OGI THR 371 ATOM 502 CG2 THR 371 ATOM 503 C THR 371 ATOM 504 0 THR 371 ATOM 505 N LEU 372 ATOM 506 CA LEU 372 ATOM 507 CB LEU 372 ATOM 508 CG LEU 372 ATOM 509 CDI LEU 372 ATOM 510 CD2 LEU 372 ATOM 511 C LEU 372 ATOM 512 0 LEU 372 ATOM 513 N HIS 373 ATOM 514 CA HIS 373 ATOM 515 CB HIS 373 18.827 19.589 20. 33 20.896 21.171 17.033 18.073 16.027 16.123 15.076 15.543 13.717 15.965 16.156 15.608 15.465 14.700 13.254 12.686 12.681 16.855 17.038 17.838 19.229 20.020 19.523 20.315 19.693 19.884 19.341 21.052 21.793 22.979 23.880 22.5114 22.373 22.536 22.702 23.273 23.518 24.362 23.690 24.534 24.587 24.813 25.442 26.729 27.506 4.446 6.601 3.950 6.1212 4.791 6.333 6.405 5.541 4.718 3.584 2.447 4.113 5.523 4.992 6.798 7.646 8.929 8.671 7.672 9.472 8.010 8.43111 7.841 8.153 8.339 9.395 9.275 10.792 7.043 5.943 7.333 6.336 6.944 7.523 8.002 5.315 5.591 4.141 3.073 1.841 0.704 0.145 -0.383 3.548 3.374 4.159 4.656 5.282 9.751 1.00 31.94 10.485 1.00 29.20 9.828 1.00 28.30 10.568 1.00 28.12 10.240 1.00 25.41 7.524 1.00 31.46 6.883 1.00 32.30 7.165 1.00 35.20 5.959 1.00 38.98 5.945 1.00 40.61 6.843 1.00 41.48 6.390 1.00 41.60 4.673 1.00 40.06 3.579 1.00 41.66 4.798 1.00 38.65 3.621 1.00 37.15 3.954 1.00 39.89 4.302 1.00 45.59 3.806 1.00 46.34 5.074 1.00 49.13 3.136 1.00 34.91 1.995 1.00 34.25 4.016 1.00 31.76 3.705 1.00 28.08 5.003 1.00 28.81 6.000 1.00 28.74 7.299 1.00 30.81 5.404 1.00 29.77 2.893 1.00 31.25 2.784 1.00 31.78 2.331 1.00 28.86 1.569 1.00 32.90 0.818 1.00 33.44 1.766 1.00 34.59 -0.178 1.00 32.63 2.539 1.00 35.31 3.733 1.00 3 1.27 2.015 1.00 34.34 2.822 1.00 35.46 1.944 1.00 37.73 2.515 1.00 42.43 3.757 1.00 45.60 1.455 1.00 44.29 3.444 1.00 36.95 4.643 1.00 35.57 2.627 1.00 35.68 3.099 1.00 36.60 1.935 1.00 44.01 WO 99/50658 PTU9/63 PCT/US99/06937 ATOM 516 CG HIS 373 ATOM 517 CD2 HIS 373 ATOM 518 NDI HIS 373 ATOM 519 CEI HIS 373 ATOM 520 NE2 HIS 373 ATOM 521 C HIS 3 73 ATOM 522 0 HIS 373 ATOM 523 N ASP 374 ATOM 524 CA ASP 374 ATOM 525 CB ASP 374 ATOM 526 CG ASP 3774 ATOM 527 ODI ASP 374 ATOM 528 OD2 ASP 374 ATOM 529 C ASP 374 ATOM 530 0 ASP 374 ATOM 531 N GLN 375 ATOM 532 CA GLN 375 ATOM 533 CB GLN 375 ATOM 534 CG GLN 375 ATOM 535 CD GLN 375 ATOM 536 OEI GLN 375 ATOM 537 NE2 GLN 375 ATOM 538 C GLN 375 ATOM 539 0 GLN 375 ATOM 540 N VAL 376 ATOM 541 CA VAL 376 ATOM 542 CB VAL 376 ATOM 543 CG1 VAL 376 ATOM 544 CG2 VAL 376 ATOM 545 C VAL 376 ATOM 546 0 VAL 376 ATOM 547 N HIS 377 ATOM 548 CA HIS 377 ATOM 549 CB HIS 377 ATOM 1550 CG HIS 377 ATOM 551 CD2 HIS 377 ATOM 552 NDI HIS 377 ATOM 553 CEI HIS 377 ATOM 554 NE2 HIS 377 ATOM 555 C HIS 377 ATOM 556 0 HIS 377 ATOM 557 N LEU 378 ATOM 558 CA LEU 378 ATOM 559 CB LEU 378 ATOM 560 CG LEU 378 ATOM 561 CDI LEU 378 ATOM 562 CD2 LEU 378 ATOM 5 63 C LEU 378 28.538 29.857 28.246 29.339 30.33 )1 26.575 27.350 25.580 25.342 24.354 25.018 26.264 24.291 24.805 25.152 23.944 23.403 22.424 21. 101 20.2 19 20.155 19.541 24.556 24.585 25.504 26.659 27.531 28.812 26. 745 27.526 27.953 27.785 28.602 28.792 29.508 29.073 30.846 31.201 30. 144 27.983 28.677 26.678 26.015 24.542 24.291 22.778 24.911 26.120 6.280 6.138 7.613 8.248 7.376 5.669 5.650 6.549 7.541 8.603 9.672 9.744 10.440 6.8 76 7.27 5 5.877 5.157 4.077 4.616 3.514 2.426 3.785 4.50,2 4.513 3.938 3.2811 2.597 2.071 1.469 4.285 4.0219 5.428 6.457 7.63 9 8.791 10.017 8.740 9.8 84 10.677 6.954 7.102 7.206 7.695 8.001 9.180 9.353 10.458 6.695 2.360 2.636 2.56 1 2.945 2.999 4.244 5.201 4.148 5.196 4.713 3.860 3.842 3.199 6.472 7.587 6.3 09 7.454 6.993 6.484 5.940 6.510 4.827 8.214 9.442 7.475 8.071 7.003 7.635 6.341 8.82 1 9.948 8.19 1 8.814 7.864 8.488 8.863 8.823 9.377 9.4 13 10.114 11.115 10. 107 11.315 11.027 10.073 9.869 10.642 12.459 1.00 50.69 1.00 54.69 1.00 53.77 1.00 57.09 1.00 57.23 1.00 3 6.22 1.00 3 3.05 1.00 32.03 1.00 3 0.76 1.00 30. 12 1.00 35.83 1.00 34.39 1.00 35.39 1.00 30.33 1.00 27.04 1.00 25.71 1.00 26.68 1.00 29.70 1.00 29.16 1.00 35.87 1.00 30.97 1.00 34.51 1.00 25.51 1.00 28.14 1.00 26.62 1.00 29.24 1.00 29.66 1.00 28.29 1.00 29.90 1.00 30.87 1.00 30.09 1.00 28.05 1.00 28.68 1.00 3 0.26 1.00 33.89 1.00 34.99 1.00 37.01 1.00 34.79 1.00 3 4.95 1.00 25.13 1.00 25.93 1.00 24.58 1.00 26.40 1.00 26.29 1.00 28.06 1.00 27.66 1.00 .30.08 1.00 28.55 WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 0

N

CA

LEU 378 LEU 379 LEU 379 CB LEU 379 CG LEU 379 CD] LEU 379 CD2 LEU 379 C LEU 379 O LEU 379 N GLU 380 CA GLU 380 CB GLU 380 CG GLU 380 CD GLU 380 OEI GLU 380 OE2 GLU 380 C GLU 380 O GLU 380 N ACYS 381 N BCYS 381 CA ACYS 381 CA BCYS 381 CB ACYS 381 CB BCYS 381 SG ACYS 381 SG BCYS 381 C ACYS 381 C BCYS 381 O ACYS 381 O BCYS 381 N ALA 382 CA ALA 382 CB ALA 382 C ALA 382 O ALA 382 N TRP 383 CA TRP 383 CB TRP 383 CG TRP 383 CD2 TRP 383 CE2 TRP 383 CE3 TRP 383 CDI TRP 383 NEI TRP 383 CZ2 TRP 383 CZ3 TRP 383 CH2 TRP 383 C TRP 383 26.379 25.919 26.000 25.401 23.875 23.248 23.563 27.430 27.653 28.402 29.786 30.730 32.172 33.080 32.869 34.004 30.218 31.056 29.637 29.645 29.969 29.993 29.621 29.766 30.698 30.227 29.237 29.211 29.812 29.724 27.974 27.140 25.785 26.913 26.374 27.311 27.026 27.669 29.130 29.797 31.182 29.360 30.102 31.342 32.133 30.305 31.674 27.356 7.075 5.414 4.388 3.073 3.023 1.943 2.759 4.176 3.979 4.236 4.054 4.036 3.785 3.471 4.048 2.646 5.159 4.937 6.339 6.352 7.466 7.481 8.781 8.814 9.192 10.312 7.422 7.498 7.730 7.940 7.012 7.015 7.587 5.755 5.837 4.602 3.354 2.172 2.054 1.347 1.484 0.609 2.578 2.239 0.909 0.039 0.191 3.309 13.605 12.153 13.182 12.667 12.845 11.963 14.312 13.670 14.866 12.762 13.173 11.968 12.380 11.210 10.120 11.386 14.133 15.010 13.965 13.980 14.826 14.847 14.122 14.115 12.732 15.059 16.162 16.159 17.206 17.187 16.128 17.318 16.948 18.131 19.234 17.615 18.318 17.580 17.762 18.803 18.579 19.912 16.965 17.446 19.420 20.745 20.496 19.802 1.00 24.76 1.00 24.29 1.00 27.03 1.00 28.53 1.00 30.29 1.00 33.04 1.00 29.45 1.00 27.18 1.00 25.95 1.00 25.86 1.00 27.58 1.00 30.36 1.00 37.98 1.00 45.23 1.00 42.99 1.00 45.79 1.00 27.50 1.00 26.67 0.75 24.89 0.25 25.79 0.75 24.12 0.25 24.86 0.75 25.96 0.25 25.62 0.75 31.63 0.25 25.40 0.75 22.07 0.25 23.97 0.75 21.97 0.25 23.99 1.00 23.41 1.00 22.83 1.00 25.50 1.00 25.39 1.00 23.09 1.00 25.98 1.00 23.80 1.00 22.52 1.00 24.42 1.00 27.31 1.00 28.24 1.00 27.37 1.00 24.58 1.00 27.35 1.00 28.76 1.00 28.09 1.00 29.77 1.00 23.54

C;

C;

-WO 99/50658 PCTIUS99/06937 ATOM 612 0 ATOM 613 N ATOM 614 CA ATOM 615 CB ATOM 616 CG ATOM 617 CDI ATOM 618 CD2 ATOM 619 C ATOM 620 0 ATOM 621 N ATOM 622 CA ATOM 623 CB ATOM 624 CG ATOM 625 CD ATOM 626 OEI ATOM 627 0E2 ATOM 628 C ATOM 629 0 ATOM 630 N ATOM 631 CA ATOM 632 GB ATOM 633 C02 ATOM 634 CG1 ATOM 635 CDI ATOM 636 C ATOM 637 0 ATOM 638 N ATOM 639 CA ATOM 640 CB ATOM 641 CG ATOM 642 CDI ATOM 643 CD2 ATOM 644 C ATOM 645 0 ATOM 646 N ATOM 647 CA ATOM 648 GB ATOM 649 CG ATOM 650 SD ATOM 651 CE ATOM 652 C ATOM 653 0 ATOM 654 N ATOM 655 CA ATOM 656 GB ATOM 657 CG2 ATOM 658 CGI ATOM 659 CDI TRY 383 LEU 384 LEU 384 LEU 384 LEU 384 LEU 384 LEU 384 LEU 384 LEU 384 GLU 385 GLU 385 GLU 385 GLU 385 GLU 385 GLU 385 GLU 385 GLU 385 GLU 385 ILE 386 ILE 386 ILE 386 ILE 386 ILE 386 ILE 386 ILE 386 ILE 386 LEU 387 LEU 387 LEU 387 LEU 387 LEU 387 LEU 387 LEU 387 LEU 387 MET 388 MET 388 MET 388 MET 388 MET 388 MET 388 MET 388 MET 388 ILE 389 ILE 389 ILE 389 ILE 389 ILE 389 ILE 389 26.526 2-8.542 28.864 30.369 30.824 30.273 32.336 28.075 27.706 27.807 27.0 11 26.86 1 28.115 27.882 27.374 28.188 25.616 25.022 25. 101 23.779 23.328 22.009 23.085 22.994 23.766 22.823 24.810 24.868 26.096 26.070 27.297 24.791 24.944 24.287 25.751 25.924 27.088 28.440 29.726 31.139.

24.660 24.341 23 .93 5 22.729 22.132 21.41 3 2'1.185 20.43 1 2.866 3.765 3.713 3.890 3.645 2.3 05 3.648 4.732 4.458 5.909 6.895 8.177 9.020 10.256 11.256 10.2 19 6.292 6.438 5.6 17 4.995 4.455 3.647 5.651 5.297 3.897 3.8 18 3.071 2.030 1.132 0.194 -0.709 -0.631 2.660 2.204 .3.713 4.385 5.378 4.7.2 5.992 5.041 5.094 5.026 5.775 6.440 7.439 6.705 8.402 9.383 20.584 20.211 21.640 2 1.883 23.336 23.853 23.398 22.453 23 .595 2 1.885 22.6 12 2 1.797 2 1.705 20.860 21.401 19.658 22.836 23.902 21.8 12 21.896 20.498 20.618 19.561 18.078 22.961 23.746 23.020 24.051 23.864 22.654 22.705 22.652 25.438 26.386 25.554 26.835 26.761 26.743 26.736 27.078 27.321 28.505 26.436 26.905 25.852 24.706 26.584 25.683 1.00 22.90 1.00 20.37 1.00 22.41 1.00 24.98 1.00 27.33 1.00 29.71 1.00 26.07 1.00 19.44 1.00 23.24 1.00 20.80 1.00 21.3 2 1.00 21.91 1.00 21.61 1.00 29.53 1.00 30.54 1.00 29.97 1.00 22.26 1.00 22.26 1.00 22.03 1.00 22.74 1.00 22.88 1.00 23.85 1.00 25.05 1.00 26.42 1.00 22.50 1.00 24.75 1.00 22.25 1.00 22.95 1.00 24.61 1.00 23.21 1.00 25.36 1.00 26.29 1.00 26.22 1.00 23.55 1.00 23.92 1.00 24.26 1.00 23.87 1.00 24.08 1.00 27.70 1.00 21.74 1.00 23.33 1.00 25.58 1.00 24.62 1.00 24.03 1.00 27.01 1.00 23 .98 1.00 25.49 1.00 25.45 1 WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 C ILE 389 O ILE 389 N GLY 390 CA GLY 390 C GLY 390 O GLY 390 N LEU 391 CA LEU 391 CB LEU 391 CG LEU 391 CDI LEU 391 CD2 LEU 391 C LEU 391 O LEU 391 N VAL 392 CA VAL 392 CB VAL 392 CGI VAL 392 CG2 VAL 392 C VAL 392 O VAL 392 N. TRP 393 CA TRP 393 CB TRP 393 CG TRP 393 CD2 TRP 393 CE2 TRP 393 CE3 TRP 393 CDI TRP 393 NEI TRP 393 CZ2 TRP 393 CZ3 TRP 393 CH2 TRP 393 C TRP 393 O TRP 393 N ARG 394 CA ARG 394 CB ARG 394 CG ARG 394 CD ARG 394 NE ARG 394 CZ ARG 394 NHI ARG 394 NH2 ARG 394 C ARG 394 O ARG 394 N SER 395 CA SER 395 21.694 20.938 21.679 20.753 21.13 3 20.275 22.433 22.955 24.476 25.206 24.717 26.709 22.603 22.156 22.817 22.506 22.923 22.329 24.442 21.013 20.621 20.191 18.732 18.066 16.605 15.516 14.336 15.419 16.057 14.696 13.073 14.162 13.007 18.256 17.460 18.738 18.288 18.492 19.914 19.929 21.282 21.864 21.208 23.098 18.911 18.445 19.954 20.603 5.401 5.631 4.247 3.201 2.719 2.521 2.547 2.091 1.937 1.656 0.332 1.619 3.070 2.669 4.355 5.369 6.770 7.854 6.870 5.327 5.345 5.241 5.186 5.046 4.670 5.499 4.725 6.821 3.459 3.486 5.233 7.326 6.531 4.051 4.275 2.837 1.729 0.389 0.009 -1.132 -1.561 -1.350 -0.715 -1.784 1.697 0.966 2.492 2.564 27.349 28.294 26.687 27.090 28.482 29.348 28.699 29.983 29.899 31.210 31.793 30.958 31.104 32.186 30.850 31.851 31.353 32.237 31.372 32.165 33.327 31.125 31.280 29.906 29.953 30.369 30.264 30.824 29.618 29.801 30.597 31.155 31.039 32.191 33.109 31.957 32.787 32.065 31.764 30.748 30.417 29.239 28.281 29.022 34.180 35.048 34.395 35.701 1.00 26.54 1.00 22.58 1.00 27.14 1.00 28.42 1.00 29.67 1.00 29.21 1.00 26.06 1.00 29.23 1.00 28.37 1.00 30.81 1.00 25.73 1.00 25.25 1.00 30.84 1.00 29.19 1.00 28.91 1.00 28.86 1.00 30.08 1.00 32.32 1.00 28.52 1.00 28.42 1.00 30.38 1.00 28.23 1.00 29.70 1.00 30.09 1.00 33.50 1.00 31.76 1.00 38.11 1.00 32.56 1.00 34.31 1.00 34.36 1.00 37.93 1.00 35.24 1.00 37.77 1.00 32.07 1.00 32.12 1.00 31.90 1.00 36.63 1.00 36.41 1.00 36.50 1.00 36.34 1.00 33.97 1.00 31.61 1.00 32.42 1.00 29.81 1.00 36.69 1.00 37.07 1.00 33.63 1.00 35.69 (1 WO 99/50658 PCT/US99/06937 ATOM 708 CB SER 395 ATOM 709 OG SER 395 ATOM 710 C SER 395 ATOM 711 0 SER 395 ATOM 712 N MET 396 ATOM 713 CA MET 396 ATOM 714 CB MET 396 ATOM 715 CG MET 396 ATOM 716 SD MET 396 ATOM 717 CE MET 396 ATOM 718 C MET 396 ATOM 719 0 MET 396 ATOM 720 N GLU 397 ATOM 721 CA GLU 397 ATOM 722 CB GLU 397 ATOM 723 CG GLU 397 ATOM 724 CD GLU 397 ATOM 725 OEI GLU 397 ATOM 726 0E2 GLU 397 ATOM 727 C GLU 397 ATOM 728 0 GLU 397 ATOM 729 N HIS 398 ATOM 730 CA HIS 398 ATOM 731 CB HIS 398 ATOM 732 CG HIS 398 ATOM 733' CD2 HIS 398 ATOM 734 NDI HIS 398 ATOM 735 CE] HIS 398 ATOM 736 NE2 HIS 398 -ATOM 737 C HIS 398 ATOM 738 0 HIS 398 ATOM 739 N PRO 399 ATOM 740 CD PRO 399 ATOM 741 CA PRO 399 ATOM 742 CB PRO 399 ATOM 743 CG PRO 399 ATOM 744 C PRO 399 ATOM 745 0 PRO 399 ATOM 746 N GLY 400 ATOM 747 CA GLY 400 ATOM 748 C GLY 400 ATOM 749 0 GLY 400 ATOM 750 N LYS 401 ATOM 751 CA LYS 401 ATOM 752 CB LYS 401 ATOM 753 CG LYS 401 ATOM 754 CD *LYS 401 ATOM 755 CE LYS 401 22.112 22.696 20.010 20.389 19.076 18.431 17.275 17.481 15.962 14.988 17.906 18.125 17.2 15 16.645 15.296 14. 166 13.195 13.660 11.972 17.548 17.071 18.851 19.8 13 20.271 19.187 18.750 18.374 17.482 17.688 20.999 22.121 20.755 19.443 2 1.785 2 1.127 19.660 23.086 23.078 24.202 25.506 25.907 2 7.02 7 25.012 25.315 24,562 24.633 24.288 24.459 2.784 35.540 1.00 3 2.94 1.811 34.688 1.00 32.37 3.713 36.531 1.00 36.44 3.916 37.687 1.00 38.68 4.449 35.937 1.00 36.46 5.588 36.589 1.00 43.08 6.104 35.725 1.00 43.87 7.507 35.176 1.00 46.18 8.278 34.581 1.00 49.58 8.298 3 6.065 1.00 53.58 5.303 37.992 1.00 46.18 6.089 3 8.913 1.00 46.34 4.180 3 8.152 1.00 49.39 3.821 39.444 1.00 52.12 .3.130 39.246 1.00 55.34 4.073 38.873 1.00 58.86 3.448 37.891 1.00 63.28 2.925 3 6.854 1.00 64.68 3.475 38.155 1.00 65.39 2.933) 40.283 1.00 52.75 2.187 41.139 1.00 53.96 3.014 40.040 1.00 50.25 2.220 40. 792 1.00 49.34 1.018 39.963 1.00 52.04 0.017 39.721 1.00 53.95 -1.022 40.472 1.00 53.92 0.054 38.608 1.00 55.91 -0.917 38.685 1.00 55.53 -1.585 39.806 1.00 55.81 3.084 41.196 1.00 47.44 2.887 40.730 1.00 44.91 4.049 42.096 1.00 46.45 4.300 42.721 1.00 47.27 4.968 42.586 1.00 45.35 5.631 43.793 1.00 47.40 5.561 43.504 1.00 47.72 4.270 42.958 1.00 44.70 3.233 43.627 1.00 46.46 4.840 42.509 1.00 41.57 4.281 42.813 1.00 3 9.84 3.047 42.022 1.00 37.8 2.560 42.176 1.00 40.48 2.537 41.180 1.00 36.39 1.344 40.390 1.00 34.47 0.130 40.947 1.00 36.12 -0.007 42.466 1.00 .39.3 0 -1.429 42.903 1.00 44.38 -1.605 44.408 1.00 46.68

G

Gr-) WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803

NZ

C

0

N

CA

CB

CG

CDI

CD2

C

0

N

CA

CB

CG

CD]

CD2

C

0

N

CA

CB

CG

CDI

CD2

CEI

CE2

CZ

C

0

N

CA

CB

C

0

N

CD

CA

CB

CG

C

0

N

CA

CB

CG

ODI

ND2 LYS 401 LYS 401 LYS 401 LEU 402 LEU 402 LEU 402 LEU 402 LEU 402 LEU 402 LEU 402 LEU 402 LEU 403 LEU 403 LEU 403 LEU 403 LEU 403 LEU 403 LEU 403 LEU 403 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 PHE 404 ALA 405 ALA 405 ALA 405 ALA 405 ALA 405 PRO 406 PRO 406 PRO 406 PRO 406 PRO 406 PRO 406 PRO 406 ASN 407 ASN 407 ASN 407 ASN 407 ASN 407 ASN 407 24.968 24.969 24.141 25.612 25.358 26.661 27.278 28.623 26.312 24.755 25.367 23.552 22.873 21.361 20.551 20.584 19.128 23.255 22.543 24.383 24.834 26.201 27.305 27.794 27.848 28.816 28.864 29.350 23.809 23.625 23.138 22.104 22.745 21.309 21.785 20.088 19.356 19.303 17.985 17.922 19.997 19.698 20.924 21.652 21.582 22.232 22.345 22.660 -2.969 1.485 2.308 0.663 0.658 0.847 2.242 2.310 3.277 -0.686 -1.727 -0.658 -1.880 -1.693 -2.991 -3.637 -2.689 -2.218 -1.870 -2.893 -3.256 -3.929 -2.998 -3.033 -2.078 -2.160 -1.205 -1.242 -4.181 -4.175 -4.967 -5.910 -7.172 -6.237 -5.995 -6.779 -7.102 -7.101 -7.654 -7.153 -8.084 -8.112 -8.877 -9.847 11.243 -11.306 -10.296 -12.503 44.747 38.911 -38.531 38.086 36.648 35.867 36.029 35.310 35.482 36.292 36.535 35.735 35.335 35.434 35.415 36.806 34.998 33.899 32.956 33.733 32.403 32.493 32.926 34.228 32.030 34.638 32.423 33.727 31.756 30.538 32.594 32.163 31.598 33.429 34.535 33.288 32.053 34.490 33.935 32.519 35.433 36.626 34.902 35.712 35.083 33.711 33.009 33.319 1.00 53.37 1.00 32.34 1.00 31.16 1.00 28.52 1.00 29.06 1.00 29.26 1.00 24.67 1.00 27.47 1.00 24.93 1.00 30.43 1.00 31.36 1.00 31.07 1.00 32.96 1.00 33.86 1.00 39.29 1.00 43.62 1.00 41.32 1.00 30.06 1.00 31.63 1.00 29.19 1.00 28.93 1.00 30.05 1.00 30.78 1.00 32.91 1.00 32.75 1.00 34.73 1.00 30.68 1.00 31.43 1.00 30.80 1.00 28.09 1.00 30.25 1.00 29.78 1.00 29.97 1.00 31.95 1.00 32.36 1.00 34.40 1.00 35.81 1.00 36.41 1.00 35.38 1.00 36.49 1.00 37.32 1.00 38.34 1.00 36.69 1.00 38.85 1.00 39.69 1.00 44.10 1.00 37.78 1.00 45.74 WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 C ASN 407 O ASN 407 N LEU 408 CA LEU 408 CB LEU 408 CG LEU 408 CDI LEU 408 CD2 LEU 408 C LEU 408 O LEU 408 N LEU 409 CA LEU 409 CB LEU 409 CG LEU 409 CDI LEU 409 CD2 LEU 409 C LEU 409 O LEU 409 N LEU 410 CA LEU 410 CB LEU 410 CG LEU 410 CDI LEU 410 CD2 LEU 410 C LEU 410 O LEU 410 N ASP 411 CA ASP 411 CB ASP 411 CG ASP 411 ODI ASP 411 OD2 ASP 411 C ASP 411 O ASP 411 N ARG 412 CA ARG 412 CB ARG 412 CG ARG 412 CD ARG 412 NE ARG 412 CZ ARG 412 NHI ARG 412 NH2 ARG 412 C ARG 412 o ARG 412 N ASN 413 CA ASN 413 CB ASN 413 23.100 23.965 23.364 24.713 25.449 26.972 27.525 27.578 24.670 24.646 24.644 24.606 23.392 23.164 22.848 22.014 25.894 26.178 26.676 27.931 29.106 29.457 30.972.

28.949 27.946 27.361 28.610 28.717 28.490 29.655 29.537 30.680 30.088 30.933 30.295 31.554 31.601 30.971 31.644 33.071 33.827 33.291 35.120 32.771 33.628 32.844 33.969 33.719 -9.435 -10.256 -8.149 -7.631 -7.720 -7.609 -8.775 -7.587 -6.187 -5.248 -6.034 4.733 4.658 -3.382 -2.233 -3.603 -4.566 -5.358 -3.544 -3.296 -3.354 4.660 4.728 -5.872 -1.944 -0.970 -1.890 -0.640 -0.874 -1.578 -1.849 -1.861 -0.016 -0.610 1.181 1.905 3.090 4.364 5.580 5.615 6.708 7.866 6.645 1.026 0.866 0.469 -0.375 -0.980 35.874 36.178 35.671 35.799 34.459 34.550 35.354 33.158 36.286 35.491 37.607 38.257 39.184 39.993 39.058 40.976 39.060 39.960 38.727 39.423 38.442 37;716 37.554 38.484 40.132 39.652 41.281 42.025 43.528 44.210 45.426 43.553 41.779 41.107 42.321 42.171 43.138 42.614 43.219 42.912 42.985 43.356 42.682 42.429 41.561 43.633 44.021 45.403 1.00 38.12 1.00 39.81 1.00 37.80 1.00 36.89 1.00 36.09 1.00 35.08 1.00 39.15 1.00 36.85 1.00 40.55 1.00 38.29 1.00 39.50 1.00 41.00 1.00 43.69 1.00 47.35 1.00 47.09 1.00 49.38 1.00 41.80 1.00 41.00 1.00 39.23 1.00 40.45 1.00 41.59 1.00 44.87 1.00 45.41 1.00 47.02 1.00 40.67 1.00 40.22 1.00 41.57 1.00 42.69 1.00 44.44 1.00 46.70 1.00 51.44 1.00 48.79 1.00 43.70 1.00 38.48 1.00 46.78 1.00 49.97 1.00 51.28 1.00 54.77 1.00 54.61 1.00 56.53 1.00 61.90 1.00 63.48 1.00 61.21 1.00 50.29 1.00 51.02 1.00 51.94 1.00 53.15 1.00 55.88 WO 99/50658 PCT/US99/06937 ATOM 852 ATOM 853 ATOM 854 ATOM 855 ATOM 856 ATOM 857 ATOM 858 ATOM 859 ATOM 860 ATOM 861 ATOM 862 ATOM 863 ATOM 864 ATOM 865 ATOM 866 ATOM 867 ATOM 868 ATOM 869 ATOM 870 ATOM 871 ATOM 872 ATOM 873 ATOM 874 ATOM 875 ATOM 876 ATOM 877 ATOM 878 ATOM 879 ATOM 880 ATOM 881 ATOM 882 ATOM 883 ATOM 884 ATOM 885 ATOM 886 ATOM 887 ATOM 888 ATOM 889 ATOM 890 ATOM 891 ATOM 892 ATOM 893 ATOM 894 ATOM 895 ATOM 896 ATOM 897 ATOM 898 ATOM 899 CG ASN 413 ODI ASN 413 ND2 ASN 413 C ASN 413 O ASN 413 N GLN 414 CA GLN 414 CB GLN 414 CG GLN 414 CD GLN 414 OEI GLN 414 NE2 GLN 414 C GLN 414 O GLN 414 N GLY 415 CA GLY 415 C GLY 415 O GLY 415 N LYS 416 CA LYS 416 CB LYS 416 CG LYS 416 CD LYS 416 CE LYS 416 NZ LYS 416 C LYS 416 O LYS 416 N CYS 417 CA CYS 417 CB CYS 417 SG CYS 417 C CYS 417 O CYS 417 N VAL 418 CA VAL 418 CB VAL 418 CG1 VAL 418 CG2 VAL 418 C VAL 418 O VAL 418 N GLU 419 CA GLU 419 CB GLU 419 CG GLU 419 CD GLU 419 OEI GLU 419 OE2 GLU 419 C GLU 419 33.654 33.697 33.551 34.235 35.386 33.173 33.326 31.991 31.645 30.203 29.296 29.973 33.850 34.654 33.398 33.849 35.350 36.023 35.877 37.305 37.634 38.121 37.078 37.404 36.225 38.159 39.361 37.538 38.270 37.951 38.592 38.015 38.632 37.111 36.817 35.326 34.971 35.072 37.739 37.799 38.463 39.403 40.149 39.385 40.179 40.432 40.546 38.761 0.073 1.276 -0.375 -1.480 1.743 -2.129 -3.198 -3.904 -4.933 -5.376 -4.536 -6.664 -2.630 -3.265 -1.430 -0.806 -0.582 -0.748 -0.211 0.041 0.262 1.663 2.439 2.448 2.079 -1.105 0.946 -2.257 -3.414 -4.642 -4.549 -3.736 -4.653 -2.994 -3.226 -2.917 -1.503 -3.121 -2.362 -1.140: -3.012 -2.328 -3.351 -3.779 -4.722 -5.870 -4.313'1 -1.281 46.496 46.223 47.742 43.0 13 42.659 42.547 41.573 41.343 42.391 42.336 42.402 42.199 40.259 39.578 39.910 38.680 38.689 37.671 39.851 40.011 41.491 41.823 42.613 44.100 44.933 39.472 39.269 39.238 38.741 39.602 41.301 37.270 36.720 36.631 35.218 34.879 35.284 33.391 34.355 34.512 33.450 32.570 31.710 30.468 29.584 30.011 28.462 31.662 1.00 57.99 1.00 58.27 1.00 57.90 1.00 53.95 1.00 53.67 1.00 55.33 1.00 55.42 1.00 55.44 1.00 56.07 1.00 57.40 1.00 60.22 1.00 57.27 1.00 55.51 1.00 56.16 1.00 57.07 1.00 58.51 1.00 61.10 1.00 59.47 1.00 62.77 1.00 65.49 1.00 66.04 1.00 68.71 1.00 70.98 1.00 71.84 1.00 71.95 1.00 66.41 1.00 67.15 1.00 67.33 1.00 68.16 1.00 70.88 1.00 76.09 1.00 67.54 1.00 68.48 1.00 64.67 1.00 59.97 1.00 59.60 1.00 59.13 1.00 54.85 1.00 58.37 1.00 55.44 1.00 56.02 1.00 54.28 1.00 57.57 1.00 60.87 1.00 63.34 1.00 64.90 1.00 63.18 1.00 52.05 1' WO 99/50658 PCT/1US99/06937 ATOM 900 ATOM 901 ATOM 902 ATOM 903 ATOM 904 ATOM 905 ATOM 906 ATOM 907 ATOM 908 ATOM 909 ATOM 910 ATOM 911 ATOM 912 ATOM 913 ATOM 914 ATOM 915 ATOM 916 ATOM 917 ATOM 918 ATOM 919 ATOM 920 ATOM 921 ATOM 922 ATOM 92 3 ATOM 924 ATOM 925 ATOM 926 ATOM 927 ATOM 928 ATOM 929 ATOM 930 ATOM 931 ATOM 932 ATOM 933 ATOM 934 ATOM 935 ATOM 936 ATOM 937 ATOM 938 ATOM 939 ATOM 940 ATOM 941 ATOM 942 ATOM 943 ATOM 944 ATOM 945 ATOM 946 ATOM 947 GLU 419 N GLY 420 CA GLY 420 C GLY 420 0 GLY 420 N MET 421 CA MET 421 CB MET 421 CO MET 421 SD MET 421 CE MET 421 C MET 421 0 MET 421 N VAL 422 CA VAL 422 CB VAL 422 CG1 VAL 422 CG2 VAL 422 C VAL 422 VAL 422 N GLU 423 CA GLU 423 CB GLU 423 CO GLU 423 CD GLU 423 OEI GLU 423 0E2 GLU 423 C GLU 423 0 GLU 423 N ILE 42 4 CA ILE 424 CB ILE 424 CG2 ILE 424.

CGI ILE 424 CDI ILE 424 C ILE 424 0 ILE 424 N PHE 425 CA PHE 425 CB PHE 425 CG PHE 425 CD1 PHE 425 CD2 PHE 425 CE 1 PHE 425 CE2 PHE 425 CZ PHE 425 C PHE 425 0 PHE 425 37.665 39.465 38.983 37.895 37.4 17 37.5 03 36.449 35.306 34.590 32.927 32.003 _36.923 36. 113 38.232 38.757 40.285 40.595 40.8 13 38.056 37.691 37.846 37. 192 37.909 39.4 11 40.096 39.539 4 1.188 35.704 34.88 1 35.345 .33.949 _33.803 _34.639 3 4.204 33.857 32.890 3 1.729 .33.261 .32.257 32.903 31.948 31.124 31.881 30.244 .,1.010 30.189 3 1.594 30.368 -1.481 -0.165 0.908 1.767 2.705 1.471 1.248 1.327 0.635 0.102 1.699 3.059 3.5 12 3.256 4.019 4.248 5.086 4.920 5.3 72 5.783 6.055 7.356 8.338 8.467 9.158 10. 156 8.703 7.337 7.955 6.617 6.643 6.087 6.936 4.617 3.955 6.035 6.443 5.091, 4.520 3.529 2.496 2.783 1.230 1.8 14, 0.256, 0.549, 5.649 5.77t 3 1.131 31.491 _30.642 3 1.254 30.619 32.488 33. 123 33-554 .32.396 32.843 32.766 34.312 35.111 34.430 35.557 35.433 34.206 36.696 35.689 36.783 34.570 34.616 33 .684 33. 893 32.719 32.205 3 2.3 06 34.250 34.919 33.197 32.771 31.347 30.395 31.296 29.978 33.685 33.632 34.542 35.447 36.423 36.959 38.048 36.381 .38.563 36.88 1 37.973 3 6.240 36.276 1.00 49.82 1.00 49.45 1.00 46.22 1.00 44.55 1.00 42.08 1.00 43.41 1.00 42.48 1.00 42.34 1.00 38.22 1.00 38.56 1.00 35.54 1.00 41.64 1.00 3 9.77 1.00 43.42 1.00 44.79 1.00 46.54 1.00 48.25 1.00 46.24 1.00 44.09 1.00 44.12 1.00 42.07 1.00 40.24 1.00 44.02 1.00 50.04 1.00 55.64 1.00 56.66 1.00 58.02 1.00 35.77 1.00 33.20 1.00 36.16 1.00 31.63 1.00 3 3.58 1.00 3 3.48 1.00 34.46 1.00 34.67 1.00 28.89 1.00 26.49 1.00 29.26 1.00 29.87 1.00 31.26 1.00 32.17 1.00 33.70 1.00 3 0.64 1.00 32.60 1.00 31.55 1.00 33.34 1.00 30.17 1.00 26.71 C WO 99/50658 PCTIUS99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

AT OM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

948 N ASP, 426 949 CA ASP 426 950 CB ASP 426 951 CG ASP 426 952 ODI ASP 426 953 0D2 ASP 426 954 C ASP 426 955 0 ASP 426 956 N MET 427 957 CA MET 427 958 CB MET 427 959 CG MET 427 960 SD MET 427 961 CE MET 427 962 C MET 427 963 0. MET 427 964 N LEU 428 965 CA LEU 428 966 CB LEU 428 967 CG LEU 428 968 CD1 LEU 428 969 CD2 LEU 428 970 C LEU 428 971 0 LEU 428 972 N LEU 429 973 CA LEU 429 974 CB LEU 429 975 CG LEU 429 976 CDI LEU. 429 977 CD2 LEU 429 978 C LEU 429 979 0 LEU 429 980 N ALA 430 981 CA ALA 430 982 CB ALA 430 983 C ALA 430 984 0 ALA 430 985 N THR 431 986 CA THR 431 987 CB THR 431 988 OGI THR 431 989 CG2 THR 431 990 C THR 431 991 0 THR 431 992 N SER 432 993 CA SER 432 994 CB SER 432 995 OG SER 432 32.4 15 -31.893 33.031 33.455 -32.767 -34.480 -31.133 30. 154 31.585 30.919 3 1.744 33.032 33 .962 35.409 29.526 28.536 29.451 28.173 28.379 29.039 29.678 27.995 27.210 26.04 1 27.701 26.859 27.675 28.078 28.96 1 26.825 26.3 19 25.143 27. 193 26.806 28.0 17 25.696 24.753 25.802 24.786 25.207 26.569 24.321 23.462 22.402 23.520 22.308 22.639 21.454 6.4 83 7.587 8.291 7.546 6.574 7.934 8.592 9.175 8.797 9.736 9.912 10.680 10.78 3 11.75 3 9.202 9.947 7.902 7.292 5.824 5.682 4.303 5.927 7.412 7.74 3 7.147 7.251 6.884 5.415 5.264 4.573 8.681 8.901i 9.656 11.059 11.951 11.3 87 12. 107 10.854 11 .105 10.533 10.893 11.087 10.481, 11.099: 9.253 8.5731 7.177i 6.412" 36.870 37.661I 38.401 39.655 40.038 40.256 36.806 -37.257 35.572 34.675 33.407 33.608 32.077 3 2.643 34.324 34.302 34.057 3)3.730 33.332 3 1.957 3 1.782 30.894 34.9 16 34. 743 36. 126 .37.323 38.571 38.757 39.995 38 .903 37.466 37.769- 37.237 37.332 37.078 36.344 36.674 35. 128 34.112 .32.737 32.465 3 1.634 34.530 34.397 .35.037 35.480 36.008 36. 136 1.00 29.45 1.00 3 2.29 1.00 33.49 1.00 39.42 1.00 38.35 1.00 39.58 1.00 29.02 1.00 31.34 1.00 30.69 1.00 28.63 1.00 26.83 1.00 31.41 1.00 34.87 1.00 44.60 1.00 28.70 1.00 25.01 1.00 25.13 1.00 27.60 1.00 28.00 1.00 26.99 1.00 27.80 1.00 25.33 1.00 29.59 1.00 27.07 1.00 30.40 1.00 30.59 1.00 .31.76 1.00 3 2.43 1.00 31.60 1.00 34.66 1.00 3 0.46 1.00 28.40 1.00 3 1.34 1.00 29.83 1.00 3 1.29 1.00 31.04 1.00 30.79 1.00 30.30 1.00 28.81 1.00 30.55 1.00 31.88 1.00 25.63 1.00 29.49 1.00 26.18 1.00 28.11 1.00 29.78 1.00 33.11 1.00 36.92 r WO 99/50658 PCTIUS99/06937

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996 C 997 0 998 N 999 N 1000 CA 1001 CA 1002 CB 1003 CB 1004 OG 1005 OG 1006 C 1007 C 1008 0 1009 0 1010 N 1011 CA 1012 CB 1013 CG 1014 CD 1015 NE 1016 CZ 1017 NH1 SER 432 SER 432 ASER 433 BSER 433 ASER 433 BSER 433 ASER 433 BSER 433 ASER 433 BSER 433 ASER 433 BSER 433 ASER 433 BSER 433 ARG 434 ARG 434 ARG 434 ARG 434 ARG 434 ARG 434 ARG 434 ARG 434 1018 NH2 ARG 434 1019 C ARG 434 1020 0 ARG 434 1021 N PHE 435 1022 CA PHE 435 1023 CB PHE 435 1024 CG PHE 435 1025 CDI PHE 435 1026 CD2 PHE 435 1027 CEI PHE 435 1028 CE2 PHE 435 1029 CZ PHE 435 1030 C PHE 435 1031 0 PHE 435 1032 N ARG 436 1033 CA ARG 436 1034 CB ARG 436 1035 CG ARG 436 1036 CD ARG 436 1037 NE ARG 436 1038 CZ ARG 436 1039 NHI ARG 436 1040 NH2 ARG 436 1041 C ARG 436 1042 0 ARG 436 1043 N MET 437 21.651 20.433 22.476 22.474 22.002 21.985 23.185 23.145 22.823 23.785 21.299 21.295 20.257 20.264 21.867 21.300 22.239 21.670 21.559 21.158 20.488 20.132 20.175 19.937 18.996 19.831 18.563 18.727 19.240 19.459 19.521 19.953 20.016 20.233 17.527 16.361 17.968 17.094 17.844 16.942 17.648 18.982 20.119 20.099 21.283 16.576 15.382 17.477 9.399 9.576 9.901 9.906 10.715 10.717 11.097 11.104 12.090 9.953 11.971 11.976 12.373 12.391 12.579 13.788 14.354 15.528 16.787 17.944 18.995 19.049 19.998 13.491 14.266 12.371 11.963 10.634 10.779 12.035 9.649 12.164 9.768 11.029 11.780 12.135 11.216 10.982 10.215 9.590 8.459 8.841 8.361 7.472 8.770 12.302 12.458 13.252 36.589 36.613 37.496 37.500 38.605 38.608 39.502 39.529 40.443 40.053 38.091 38.092 38.612 38.622 37.054 36.470 35.400 34.625 35.479 34.680 35.149 36.428 34.337 35.873 36.053 35.158 34.549 33.796 32.386 31.824 31.623 30.521 30.322 29.775 35.657 35.496 36.777 37.924 39.012 40.068 40.810 41.275 40.777 39.790 41.266 38.493 38.730 38.706 1.00 31.49 1.00 30.09 0.75 32.09 0.25 31.10 0.75 35.68 0.25 32.21 0.75 37.18 0.25 31.45 0.75 44.09 0.25 29.52 0.75 35.01 0.25 32.88 0.75 35.34 0.25 33.42 1.00 33.38 1.00 34.19 1.00 33.89 1.00 38.30 1.00 37.91 1.00 37.78 1.00 41.06 1.00 40.70 1.00 38.78 1.00 33.48 1.00 30.54 1.00 34.68 1.00 35.02 1.00 34.96 1.00 37.63 1.00 42.03 1.00 41.24 1.00 43.11 1.00 40.59 1.00 40.63 1.00 35.49 1.00 34.78 1.00 38.27 1.00 40.67 1.00 40.70 1.00 44.98 1.00 48.09 1.00 50.16 1.00 52.19 1.00 49.34 1.00 51.85 1.00 40.40 1.00 41.49 1.00 40.02 C'i" (7 WO 99/50658 PCT/US99/06937

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1044 CA MET 437 1045 CB MET 437 1046 C MET 437 1047 0 MET 437 1048 N MET 438 1049 CA MET 438 1050 CB MET 438 1051 CG MET 438 1052 SD MET 438 1053 CE MET 438 1054 C MET 438 1055 0 MET 438 1056 N ASN 439 1057 CA ASN 439 1058 CB ASN 439 1059 CG ASN 439 1060 ODI ASN 439 1061 ND2 ASN 439 1062 C 1063 0 1064' N 1065 CA 1066 CB 1067 CG 1068 CDI 1069 CD2 1070 C 1071 0 1072 N 1073 CA 1074 CB 1075 CG 1076 CD 1077 OEI 1078 NE2 1079 C 1080 0 1081 N 1082 CA 1083 C 1084 0 1085 N 1086 CA 1087 CB 1088 CG 1089 CD 1090 OEI 1091 OE2 ASN 439 ASN 439 LEU 440 LEU 440 LEU 440 LEU 440 LEU 440 LEU 440 LEU 440 LEU 440 GLN 441 GLN 441 GLN 441 GLN 441 GLN 441 GLN 441 GLN 441 GLN 441 GLN 441 GLY 442 GLY 442 GLY 442 GLY 442 GLU 443 GLU 443 GLU 443 GLU 443 GLU 443 GLU 443 GLU 443 17.090 18.329 16.099 15.111 16.367 15.510 16.237 17.352 17.999 16.698 14.221 13.305 14.155 12.981 11.762 10.566 10.721 9.365 12.725 11.637 13.749 13.655 14.999 15.022 14.890 16.297 12.587 12.518 11.763 10.696 9.43 1 8.912 8.362 7.268 9.119 11.099 11.923 10.500 10.792 10.599 11.381 9.556 9.269 7.956 6.723 6.483 5.619 7.159 14.546 15.427 15.221 15.805 15.127 15.732 15.793 16.794 16.862 17.748 14.964 15.451 13.759 12.919 13.556 12.620 11.400 13.189 12.744 13.037 12.274 12.052 11.576 11.467 12.862 10.795 11.024 9.967 11.328 10.420 11.211 12.063 11.227 10.668 11.132 9.565 9.976 8.378 7.468 8.112 7.877 8.925 9.603 10.379 9.488 9.008 8.123 9.515 39.245 39.440 38.299 38.734 37.001 35.988 34.651 34.601 32.943 32.096 35.783 35.125 36.337 36.174 36.847 36.887 36.964 36.829 34.677 34.172 33.972 32.532 31.987 30.462 29.869 29.999 32.196 32.826 31.197 30.785 30.443 31.592 32.729 32.629 33.818 29.585 28.763 29.494 28.401 27.043 26.123 26.918 25.661 25.764 25.879 27.302 27.498 28.225 1.00 41.02 1.00 40.29 1.00 40.81 1.00 42.46 1.00 39.02 1.00 40.11 1.00 38.16 1.00 41.52 1.00 43.94 1.00 39.96 1.00 37.72 1.00 36.82 1.00 38.81 1.00 40.77 .1.00 44.52 1.00 48.29 1.00 48.48 1.00 50.23 1.00 39.36 1.00 37.76 1.00 37.65 1.00 35.22 1.00 34.70 1.00 35.45 1.00 35.24 1.00 35.30 1.00 36.48 1.00 37.36 1.00 36.82 1.00 38.51 1.00 38.23 1.00 42.46 1.00 44.91 1.00 47.31 1.00 44.06 1.00 38.48 1.00 35.80 1.00 36.03 1.00 37.72 1.00 36.88 1.00 33.72 1.00 36.59 1.00 37.13 1.00 41.57 1.00 47.76 1.00 53.96 1.00 57.66 1.00 56.13 WO 99/50658 PCTIUS99/06937

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1092 C GLU 443 1093 0 GLU 443 1094 N GLU 444 1095 CA GLU 444 1096 CB GLU 444 1097 CG GLU 444 1098 CD GLU 444 1099 OEI GLU 444 1100 0E2 GLU 444 1101 C GLU 444 1102 0 GLU 444 1103 N PHE 445 1104 CA PHE 445 1105 GB PHE 445 1106 CG PHE 445 1107 CDI PHE 445 1108 CD2 PHE 445 1109 CEI PHE 445 1110 CE2 PHE 445 1111 CZ PHE 445 1112 C PHE 445 1113 0 PHE 445 1114 N VAL 446 1115 CA VAL 446 1116 GB VAL 446 1117 CG1 VAL 446 1118 CG2 VAL 446 1119 C VAL 446 1120 0 VAL 446 1121 N CYS 447 1122 CA CYS 447 1123 GB CYS 447 1124 SG CYS 447 1125 C CYS 447 1126 0 CYS 447 1127 N LEU 448 1128 CA LEU 448 1129 GB LEU 448 1130 CG LEU 448 1131 CDI LEU 448 1132 CD2 LEU 448 1133 C LEU 448 1134 0 LEU 448 1135 N LYS 449 1136 CA LYS 449 1137 GB LYS 449 1138 CG LYS 449 1139 CD LYS 449 10.408 10.759 10.984 12.097 12.332 11.169 11.383 11.800 11.132 13 .356 14.085 13.590 14.753 14.703 15.667 17.036 15.205 17.933 16.095 17.460 14.850 15.924 13.739 13.787 12.478 12.3 18 11.265 14.099 14.78 1 13.6 19 13.9 19 13.156 11.389 15.420 16.063 15.969 17.392 17.733 17.248 17.807 17.688 18.245 19.207 17.905 18.673 18.135 19.134 18.737 10.551 10.704 11.179 12.095 12.924 13.845 14.610 13.993 15.834 11.305 11.670 10.2 15 9.357 8.139 7.047 7.201 5.863 6.195 4.848 5.015 8.885 8.947 8.415 7.943 7.193 5.939 8.092 9.064 8.837 10.275 11.394 12.653 12.591 11.677 11.885 11.686 11.938 11.932 13.135 13.042 14.434 10.902 11.252 9.621 8.570 7.185 6.052 4.789 25.311 24. 145 26.331 26. 126 27.388 27.732 29.023 30.026 29.036 25.770 24.842 26.50 1 26.276 27.203 26.828 27.030 26.266 26.675 25.908 26.113 24.829 24.22 1 24.266 22.889 22.478 23.343 22.607 2 1.900 20.904 22. 166 2) 1.272 21.693 2 1.309 2 1.328 20.302 22.53 8 22.729 24.220 215.040 26.454 24.376 22.008 21.327 2-1162 2 1.506 2 1.900 2 1.694 22.459 1.00 35.27 1.00 33.85 1.00 32.09 1.00 3 3.92 1.00 3 4.97 1.00 38.28 1.00 38.11 1.00 39.53 1.00 40.77 1.00 33.59 1.00 3.3.3 1.00 30.68 1.00 32.49 1.00 29.35 1.00 30.78 1.00 28.25 1.00 3 0.62 1.00 28.67 1.00 31.37 1.00 30.37 1.00 31.11 1.00 32.20 1.00 28.63 1.00 27.94 1.00 28.48 1.00 29.61 1.00 27.23 1.00 27.28 1.00 28.07 1.00 28.97 1.00 29.14 1.00 28.90 1.00 35.68 1.00 28.03 1.00 29.34 1.00 27.28 1.00 25.30 1.00 27.72 1.00 29.54 1.00 30.85 1.00 30.24 1.00 27.62 1.00 25.10 1.00 25.16 1.00 27.55 1.00 28.99 1.00 34.70 1.00 32.6 7 C J WO 99/50658 PCT/US99/06937

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1140 CE LYS 449 1141 NZ LYS 449 1142 C LYS 449 1143 0 LYS 449 1144 N SER 450 1145 CA SER 450 1146 CB SER 450 1147 OG SER 450 1148 C SER 450 1149 0 SER 450 1150 N ILE 451 1151 CA ILE 451 1152 CB ILE 451 1153 CG2 ILE 451 1154 CGI ILE 451 1155 CDI ILE 451 1156 C ILE 451 1157 0 ILE 451 1158 N ILE 452 1159 CA ILE 452 1160 CB ILE 452 1161 CG2 ILE 452 1162 CGI ILE 452 1163 CDI ILE 452 1164 C ILE 452 1165 0 ILE 452 1166 N LEU 453 1167 CA LEU 453 1168 CB LEU 453 1169 CG LEU 453 1170 CDI LEU 453 1171 CD2 LEU 453 1172 C LEU 453 1173 0 LEU 453 1174 N LEU 454 1175 CA LEU 454 1176 CB LEU 454 1177 CG LEU 454 1178 CDI LEU 454 1179 CD2 LEU. 454 1180 C LEU 454 1181 0 LEU 454 1182 N ASN 455 1183 CA ASN 455 1184 CB ASN 455 1185 CG ASN 455 1186 ODI ASN 455 1187 ND2 ASN 455 17.267 17.022 18.626 19.6 10 17.482 17.323 15.857 15.098 18. 176 18.763 18.231 19.032 18.950 20.0 19 17.553 17.377 20.489 21.161 20.977 22.359 22.660 23.982 22.718 22.768 22.656 23.650 2 1.779 2 1-984 20.843 20.712 21.815 19.328 22.092 22.962 2 1.220 21.234 19.852 18.737 17.405 19.037 22.292 22.778 22.638 23.604 23.284 24. 174 24.171 24.931 4.419 2.967 8.749 8.489 9.197 9.421 9.705 8.5 19 10.607 10.598 11.632 12.810 13.850 14.929 14.475 15.473 12.381 12.771 11.582 11.120 10. 155 9.435 10.949 10.060 10.419 10.708 9.497 8.768 7.764 7.189 6.165 6.535 9.687 9.50 1 10.687 11.599 12.242 11.222 11.926 10.478 12.703 13.148 13.146 14.236 14.998 16.2 17 17. 134 16.230 22.220 1.00 31.87 22.472 19.990 19.296 19.480 18.052 17.721 17.779 17.6 18 16.535 18.463 18.155 19.291 19.101 19.322 20.447 17.989 17.034 18.931 18.880 20.050 19.804 2 1.371 22.624 17.557 16.885 17.173 15.935 15.733 14.324 14. 107 14.156 14.7 17 13 .860 14.638 13.494 13.330 13.052 12.955 11.759 13.552 12.5 13 14.757 14.934 16.224 16.4 19 15.602 17.506 1.00 29.14 1.00 25.88 1.00 25.93 1.00 26.07 1.00 27.24 1.00 3 )2.24 1.00 3 )4.94 1.00 26.78 1 .00 25.85 1.00 26.94 1.00 26.13 1.00 27.72 1.00 20.53 1.00 29.49 1.00 3 6.2 4 1.00 24.88 1.00 26.96 1.00 22.72 1.00 21.95 1.00 23.57 1.00 221.10 1.00 21.70 1.00 25.30 1.00 23.02 1.00 21.25 1.00 22.83 1.00 22.05 1.00 22.06 1.00 22.03- 1.00 24.81 1.00 24.73 1.00 23.95 1.00 24.60 1.00 26.72 1.00 26.45 1.00 25.51- 1.00 30.16 1 .00 28.76 1.00 32.5 9 1.00 28.24 1.00 29.06 1.00 26.56 1.00 26.79- 1.00 26.20 1.00 27.26 1.00 30.83 1.00 27.16 WO 99/50658 PCTIUS99106937

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1188 C ASN 455 1189 0 ASN 455 1190 N SER 456 1191 CA SER 456 1192 CB SER 456 1193 OG SER 456 1194 C SER 456 1195 0 SER 456 1196 N GLY 457 1197 CA GLY 457 1198 C GLY 457 1199 0 GLY 457 1200 N VAL 458 1201 CA VAL 458 1202 CB VAL 458 1203 CGl VAL 458 1204 CG2 VAL 458 1205 C VAL 458 1206 0 VAL 458 1207 N TYR 459 1208 CA TYR 459 1209 CB TYR 459 1210 CG TYR 459 1211 CDI TYR 459 1212 CEI TYR 459 1213 CD2 TYR 459 1214 CE2 TYR 459 1215 CZ TYR 459 1216 OH TYR 459 1217 C TYR 459 1218 0 TYR 459 1219 N THR 460 1220 CA THR 460 1221 CB THR 460 1222 001I THR 460 1223 CG2 THR 460 1224 C THR 460 1225 0 THR 460 1226 N PHE 461 1227 CA PHE 461 1228 CB PHE 461 1229 CG PHE 461 1230 CD1 PI-E 461 1231 C D2 PHE 461 1232 CEI PHE 461 1233 CE2 PHE 461 1234 CZ PHE 461 1235 C PHE 461 25.062 25.965 25.268 26.5 72 26.393 25.87 1 27.627 28.599 27.437 28.393 27.876 28.3 10 26.967 26.438 25.231 24.209 24.638 27.472 27.39 1 28.432 29.456 29.647 28.375 28.094 26.900 27.430 26.234 25.976 24.790 30.79 1 3 1.793 30.800 32.018 .32.502 33.474 3 1.344 3 1.759 32.457 30.758 30.395 29.052 27.867 26.657 27.963 25.562 26.872 25.670 31.463 13 .782 14.517 12.569 11.928 10.393 9.953 12.344 13.041 11.886 12.189 13.0 17 12.805 13.956 14.802 15.648 15.713 15.098 15.801 16.265 16.144 17.114 18.129 18.870 19.229 19.867 19.175 19.8 12 20.154 20.764 16.489 17.189 15.173 14.474 13.531 12.6 13 12.759 13 .678 12.708 14.113 13.446 13 .975 13.147 13.754 11.760 12.996 10.994 11.616 13.604 14.954 1.00 30.63 14.525 1.00 27.69 15.461 1.00 30.48 15.579 1.00 35.26 15.505 1.00 39.69 14.243 1.00 30. 73" 14.562 1.00 35.56 14.884 1.00 33.00 13.334 1.00 33.88 12.292 1.00 36.77 11.136 1.00 37.02 10.013 1.00 38.6 6 11.392 1.00 39.12 10.317 1.00 43.81 10.755 1.00 44.25 9.631 1.00 44.51 12.013 1.00 50.53 9.817 1.00 46.72 8.681 1.00 47.08 10.670 1.00 50.74 10.301 1.00 55.43 11.433 1.00 56.62 11.781 1.00 59.34 13.095 1.00 60.73 13.429 1.00 62.14 10.795 1.00 62.16 11.118 1.00 63.83 12.437 1.00 62.88 12.767 1.00 62.56 9.928 1.00 57.21 9.798 1.00 56.86 9.750 1.00 59.22 9.366 1.00 62.25 10.499 1.00 63.07 9.983 1.00 67.80 11.084 1.00 60.23 8.086 1.00 63.54 7.782 1.00 63.91 7.326 1.00 65.06 6.080 1.00 67.00 5.563 1.00 66.48 5.991 1.00 66.30 6.3 12 1.00 65.58 6.085 1.00 66.41 6.723 1.00 65.45 6.494 1.00 66.83 6.814 1.00 65.12 5.004 1.00 68.38 WO 99/50658 ATOM 1236 0 PHE 461 ATOM 1237 N LEU 462 ATOM 1238 CA LEU 462 ATOM 1239 CB LEU 462 ATOM 1240 C LEU 462 ATOM 1241 0 LEU 462 ATOM 1242 N SER 463 ATOM 1243 CA SER 463 ATOM 1244 CB SER 463 ATOM 1245 C SER 463 ATOM 1246 0 SER 463 ATOM 1247 N SER 464 ATOM 1248 CA SER 464 ATOM 1249 CB SER 464 ATOM 1250 C SER 464 ATOM 1251 0 SER 464 ATOM 1252 N THR 465 ATOM 1253 CA THR 465 ATOM 1254 CB THR 465 ATOM 1255 OGI THR 465 ATOM 1256 CG2 THR 465 ATOM 1257 C THR 465 ATOM 1258 0 THR 465 ATOM 1259 N LEU 466 ATOM 1260 CA LEU 466 ATOM 1261 CB LEU 466 .ATOM 1262 CG LEU 466 ATOM 1263 CDI LEU 466 ATOM 1264 CD2 LEU 466 ATOM 1265 C LEU 466 ATOM 1266 0 LEU 466 ATOM 1267 N LYS 467 ATOM 1268 CA LYS 467 ATOM 1269 CB LYS 467 ATOM 1270 CG LYS 467 ATOM 1271 CD LYS 467 ATOM 1272 CE LYS 467 ATOM 1273 NZ LYS 467 ATOM 1274 C LYS 467 ATOM 1275 0 LYS 467 ATOM 1276 N SER 468 ATOM 1277 CA SER 468 ATOM 1278 CB SER 468 ATOM 1279 OG SER 468 ATOM 1280 C SER 468 ATOM 1281 0 SER 468 ATOM 1282 N LEU 469 ATOM 1283 CA LEU 469

G

PCT/US99/06937 32.181 31.542 32.511 32.080 32.810 33.725 32.043 32.262 32.544 31.126 30.455 30.932 29.892 30.514 29.108 28.657 28.954 28.205 28.185 27.525 29.606 26.767 26.349 26.013 24.625 24.013 22.953 22.156 22.033 23.817 22.961 24.093 23.399 23.802 22.829 23.561 23.105 24.150 23.738 22.884 24.989 25.457 26.976 27.407 24.778 24.473 24.547 23.890 14.606 12.601 12.545 11.475 13.856 14.590 14.141 15.343 14.942 16.362 16.528 17.049 18.063 19.457 17.887 18.862 16.638 16.343 14.824 14.135 14.287 '16.824 17.129 16.892 17.330 17.349 18.415 18.002 18.594 16.397 16.845 15.099 14.100 12.693 11.602 10.301 9.180 8.117 14.284 14.108 14.644 14.854 15.050 15.537 16.063 16.0621I 17. 100 18.301 4.962 1.00 68.98 4.132 1.00 69.57 3.039 1.00 71.68 2.030 1.00 71.00 2.304 1.00 72.40 2.680 1.00 73.45 1.253 1.00 73.22 0.449 1.00 72.61 -1.005 1.00 73.38 0.491 1.00 71.17 1.511 1.00 72.05 -0.633 1.00 68.86 -0.759 1.00 66.06 -0.704 1.00 66.26 -2.060 1.00 63.72 -2.662 1.00 62.88 -2.493 1.00 60.93 -3.709 1.00 57.47 -4.004 1.00 57.80 -2.934 1.00 54.75 -4.149 1.00 57.49 -3.523 1.00 54.93 -2.407 1.00 54.26 -4.614 1.00 51.85 -4.550 1.00 49.25 -5.956 1.00 48.74 -6.253 1.00 48.72 -7.482 1.00 48.32 -5.057 1.00 48.14 -3.650 1.00 48.16 -2.883 1.00 45.90 -3.750 1.00 46.47 -2.947 1.00 47.45 -3.395 1.00 49.38 -2.974 1.00 52.70 -2.682 1.00 56.48 -3.604 1.00 59.54 -3.732 1.00 61.22 -1.472 1.00 46.89 -0.604 1.00 46.06 -1.202 1.00 45.82 0.160 1.00 46.82 0.173 1.00 47.85 1.435 1.00 55.73 0.790 1.00 44.24 1.983 1.00 42.98 -0.011 1.00 42.33 0.486 1.00 40.42 WO 99/50658 PCT/US99/06937 ATOM 1284 CB LEU 469 ATOM 1285 CG LEU 469 ATOM 1286 CDI LEU 469 ATOM 1287 CD2 LEU 469 ATOM 1288 C LEU 469 ATOM 1289 0 LEU 469 ATOM 1290 N GLU 470 ATOM 1291 CA GLU 470 ATOM 1292 CB GLU 470 ATOM 1293 CG GLU 470 ATOM 1294 CD GLU 470 ATOM 1295 OEI GLU 470 ATOM 1296 OE2 GLU 470 ATOM 1297 C GLU 470 ATOM 1298 0 GLU 470 ATOM 1299 N GLU 471 ATOM 1300 CA GLU 471 ATOM 1301 CB GLU 471 ATOM 1302 CG GLU 471 ATOM 1303 CD GLU 471 ATOM 1304 OEI GLU 471 ATOM 1305 OE2 GLU 471 ATOM 1306 C GLU 471 ATOM 1307 0 GLU 471 ATOM 1308 N LYS 472 ATOM 1309 CA LYS 472 ATOM 1310 CB LYS 472 ATOM 1311 CG LYS 472 ATOM 1312 CD LYS 472 ATOM 1313 CE LYS 472 ATOM 1314 NZ LYS 472 ATOM 1315 C LYS 472 ATOM 1316 0- LYS 472 ATOM 1317 N ASP 473 ATOM 1318 CA ASP 473 ATOM 1319 CB ASP 473 ATOM 1320 CG ASP 473 ATOM 1321 ODI ASP 473 ATOM 1322 OD2 ASP 473 ATOM 1323 C ASP 473 ATOM 1324 0 ASP 473 ATOM 1325 N HIS 474 ATOM 1326 CA HIS 474 ATOM 1327 CB HIS 474 ATOM 1328 CG HIS 474 ATOM 1329 CD2 HIS 474 ATOM 1330 NDI HIS 474 ATOM 1331 CEI HIS 474 24.002 19.427 25.438 19.874 25.514 20.477 25.890 20.883 22.423 17.996 21.856 18.505 21.814 17.151 20.418 16.768 19.914 15.963 19.772 16.773 19.339 15.923 19.671 14.716 18.666 16.463 20.290 15.916 19.321 16.035 21.274 15.046 21.309 14.162 22.515 13.222 22.376 12.122 21.476 10.989 20.268 11.027 21.974 10.061 21.393 14.983 20.596 14.793 22.358 15.898 22.518 16.739 23.683 17.710 25.050 17.050 26.080 17.957 27.445 17.286 27.850 16.702 21.23 7 17.523 20.795 17.607 20.643 18.097 19.420 18.865 18.923 19.404 17.654 20.221 16.559 19.687 17.750 21.396 18.339 17.998 17.642 18.416 18.199 16.784 17.185 15.882 17.185 14.575 16.047 13.675 14.711 13.813 16.227 12.456 15.053 11.883 -0.545 1.00 44.47 -0.849 1.00 46.70 -2.246 1.00 46.70 0.199 1.00 47.32 0.786 1.00 39.06 1.760 1.00 34.97 -0.046 1.00 35.46 0.145 1.00 34.38 -1.052 1.00 38.02 -2.329 1.00 42.67 -3.509 1.00 48.30 -3.538 1.00 50.53 -4.412 1.00 51.06 1.403 1.00 34.37 2.157 1.00 32.60 1.606 1.00 34.66 2.766 1.00 35.68 2.671 1.00 34.57 1.614 1.00 37.98 2.063 1.00 39.79 1.743 1.00 41.12 2.737 1.00 32.11 4.052 1.00 34.79 4.969 1.00 32.80 4.112 1.00 33.93 5.291 1.00 35.58 5.097 1.00 39.11 5.138 1.00 41.47 5.794 1.00 46.97 5.862 1.00 48.40 4.547 1.00 51.55 5.582 1.00 34.78 6.724 1.00 33.95 4.545 1.00 3.347 4.720 1.00 34.63 3.380 1.00 37.21 3.522 1.00 43.24 3.230 1.00 45.20 3.932 1.00 45.59 5.338 1.00 32.93 6.264 1.00 32.87 4.827 1.00 32.74 5.343 1.00 32.21 4.568 1.00 32.79 4.924 1.00 36.22 4.750 1.00 38.33 5.542 1.00 38.97 5.732 1.00 37.99 C, c- 11 WO 99/50658 PCTIUS99/06937

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1332 NE2 HIS 474 1333 C HIS 474 1334 0 HIS 474 1335 N ILE 475 1336 CA ILE 475 1337 CB ILE 475 1338 CG2 ILE 475 1339 CG1 ILE 475 1340 CDI ILE 475 1341 C ILE 475 1342 0 ILE 475 1343 N HIS 476 1344 CA HIS 476 1345 CB HIS 476 1346 CG HIS 476 1347 CD2 HIS 476 1348 NDI HIS 476.

1349 CEl HIS 476 1350 NE2 HIS 476 1351 C HIS 476 1352 0 HIS 476 1353 N ARG 477 1354 CA ARG 477 1355 CB ARO 477 1356 CG ARG 477 1357 CD ARG 477 1358 NE ARG 477 1359 CZ ARG 477 1360 NHI ARG 477 1361 NH2 ARG 477 1362 C ARG 477 1363 0 ARG 477 1364 N VAL 478 1365 CA VAL 478 1366 CB VAL 478 1367 CGI VAL 478 1368 CG2 VAL 478 1369 C VAL 478 1370 0 VAL 478 1371 N LEU 479 1372 CA LEU 479 1373 CB LEU 479 1374 CG LEU 479 1375 CDI LEU 479 1376 CD2 LEU 479 1377 C LEU 479 1378 0 LEU 479 1379 N ASP 480 14.116 17.403 16.460 18.653 18.971 20.478 20.877 20.787 22.258 18.576 17.928 18.956 18.621 19.342 20.777 2 1.355 2 1.809 22.959 22.712 17. 120 16.636 16.374 14.929 14.343 14.425 13.698 14.107 13.647 12.756 14.084 14.3 10 13.360 14.863 14.35 1 14.937 14.461 14.506 14.696 13.860 15.929 16.360 17.799 18.9 10 20.231 19.028 15.411 14.997 15.076 12.686 5.261 1.00 317.43 15.5 73 6.815 1.00 29.74 15.543 7.596 1.00 29.90 15.326 7.185 1.00 27.80 15.014 8.571 1.00 25.61 14.708 8.720 1.00 25.59 14.713 10.193 1.00 27.17 13.341 8.092 1.00 26.17 13.071 7.849 1.00 27.07 16.201 9.460 1.00 27.91 16.038 10.485 1.00 29.16 17.404 9.054 1.00 29.41 18.575 9.846 1.00 29.73 19.796 9.281 1.00 3 2.27 19.867 9.699 1.00 3 9.44 19.707 10.915 1.00 3 9.81 20.067 8.808 1.00 39.79 20.027 9.456 1.00 39.98 19.809 10.735 1.00 40.26 18.81,0 9.948 1.00 31.40 19.336 10.951 1.00 29.79 18.396 8.929 1.00 31.82 18.570 8.956 1.00 31.53 18.376 7.557 1.00 34.95 19.627 6.700 1.00 40.46 19.445 5.370 1.00 45.22 20.456 4.399 1.00 53.05 21.705 4.376 1.00 55.89 22.106 5.274 1.00 .56.17 22.558 3.457 1.00 59.49 17.582 9.931 1.00 30.70 17.903 10.649 1.00 3 0.24 16.375 9.972 1.00 29.67 15.369 10.887 1.00 29.68 13.975 10.575 1.00 3 2.01 12.973 11.609 1.00 32.93 13.528 9.169 1.00 31.00 15.774 12.316 1.00 29.81 15.677 13.220 1.00 30.25 16.232 12.516 1.00 28.81 16.674 13.836 1.00 28.74 17.210 13.779 1.00 26.65 16.152 13.853 1.00 26.05 16.772 13.395 1.00 25.81 15.60'3 15.277 1.00 25.34 17.777 14.3 1 3 1.00 29.54 17.786 15.472 1.00 29.00 18.703 1 3 .415 1.00 3 1.52 WO 99/50658 PCT/US99/06937

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O 15 ATOM

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1380 CA ASP 480 1381 CB ASP 480 1382 CG ASP 480 1 383 ODI ASP 480 1384 0D2 ASP 480 1385 C ASP 480 1386 0 ASP 480 1387 N LYS 481 1388 CA LYS 481 1389 GB LYS 481 1390 C LYS 481 1391 0 LYS 481 1392 N ILE 482 13 9 3 CA ILE 482 1394 CB ILE 482 1395 CG2 ILE 482 1396 CGI ILE 482 1397 CD! ILE 482 1398 C ILE 482 1399 0 ILE 482 1400 N THR 483 1401 CA THR 483 1402 GB THR 483 1403 OGI THR 483 1404 GG2 THR 483 1405 C THR 483 1406 0 THR 483 1407 N ASP 484 1408 CA ASP 484 1409 GB ASP 484 1410 CG ASP '484 1411 ODI ASP 484 1412 0D2 ASP 484 14 1 3 C ASP 484 1414 0 ASP 484 1415 N TUR 485 1416 CA THR 485 1417 GB THR 485 1418 OGI THR 485 1419 CG2 THR 485 1420 C THR 485 1421 0 THR 485 1422 N LEU 486 14 23 GA LEU 486 1424 GB LEU 486 1425 CG LEU 486 1426 CDI LEU 486 1427 CD2 LEU 486 14. 162 13 .943 15 .055 15.119 15 .860 12.8 18 12.186 12.379 11.106 10.7 19 11.164 10.167 12.3 28 12.457 13.743 13 .877 13.697 14.978 12.456 11.946 13.027 13.022 13 .756 15.111 13.756 11.559 11.146 10.785 9.369 8.708 9.270 9.871 9.106 8.657 7.830 8.996 8.396 8.875 8.400 8.347 8.708 7.818 9.966 10.368 11.879 12.776 14.23 3 12. 635 19.800 20.712 2 1.743 22.354 21.951 19.222 19.724 18.16 1 17.536 16.489 16.895 16.869 16.377 15.764 14.9 13 14.338 13.785 12.969 16.853 16.649 18.012 19. 109 20.351 20.012 2 1.452 19.483 19.598 19.656 20 .003 20.013 21.080 22.045 20.952 18.985 19.339 17.7 15 16.635 15.268 15.094 14. 138 16.757 16.600 17.046 17.192 17.448 16.201 16.613 15.481 13.741 1.00 33.84 12.528 1.00 34. 37 12.345 1.00 36.26 11.257 1.00 36.56 13.274 1.00 34.19 14.174 1.00 33.4 8 15.105 1..00 33 .89 13.498 1.00 33 13.839 1.00 32.97 12.784 1.00 34.66 15.225 1.00 33.57 15.943 1.00 35.37 15.607 1.00 32.71 16.922 1.00 31.60 17.028 1.00 32.65 18.430 1.00 32.50 15.995 1.00 32.72 15.908 1.00 33.37 17.994 1.00 31.69 19.097 1.00 29.98 17.679 1.00 31.33 18.644 1.00 3 1.71 18.109 1.00 3 2.92 17.788 1.00 29.99 19.160 1.00 30.47 18.920 1.00 32.85 20.070 1.00 31.83 17.851 1.00 3 1.91 17.965 1.00 3 4.15 16.591 1.00 37.41 15.680 1.00 42.02 16.198 1.00 43.26 14.445 1.00 42.49 18.840 1.00 33. 16 19.676 1.00 3 4.86 18.646 1.00 3 3.91 19.414 1.00 34.41 18.885 1.00 -33.5 8 17.542 1.00 37.04 19.751 1.00 30.89 20.903 1.00 3)5.15 21.744 1.00 311.99 21.229 1.00 33.77 22.621 1.00 34.3 1 22.721 1.00 32.00 22.754 1.00 34.99 22.521 1.00 32.65 24.105 1.00 29.90 WO 99/50658 WO 9950658PCT/US99/06937

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4 5 ATOM

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1428 C LEU 486 1429 0 LEU 486 1430 N ILE 487 1431 CA ILE 487 1432 CB ILE 487 1433 CG2 ILE 487 1434 CGI 1435 CDI 1436 C 1437 0 1438 N 1439 CA 1440 CB 1441 CG 1442 CD2 1443 ND! 1444 CEI 1445 NE2 1446 C 1447 0 1448 N 1449 CA 1450 GB 1451 CG 1452 CDI 1453 CD2 1454 C 1455 0 1456 N 1457 CA 1458 GB 1459 CG 1460 SD 1461 CE 1462 C' 1463 0 1464 N 1465 CA 1466 GB 1467 C 1468 '0 1469 N 1470 CA 1471 GB 1472 CG 1473 CD 1474 CE 1475 NZ ILE 487 ILE 487 ILE 487 ILE 487 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 HIS 488 LEU 489 LEU 489 LEU 4'89 LEU 489 LEU 489 LEU 489 LEU 489 LEU 489 MET 490 MET 490 MET 490 MET 490 MET 490 MET 490 MET 490 MET 490 ALA 491 ALA 491 ALA 491 ALA 491 ALA 491 LYS 492 LYS 492 LYS 492 LYS 492 LYS 492 LYS 492 LYS 492 9.597 9.078 9.513 8.787 8.890 7.833 10.292 10.635 7.3 15 6.708 6.749 5.357 4.962 3.6 12 2.369 3.440 2.148 1.477 5.154 4.233 6.022 5.936 7.087 6.961 8.259 5.799 5.973 5.267 6.798 6.939 8.208 9.495 10.978 12.178 5.7 18 5.296 5.162 3.983 3.622 2.841 2.073 2.752 1.711 1.772 1.087 -0.002 -0.988 -1.351 18.348 18.225 19.469 20.625 21.826 22.884 22.443 23.041 20.257 20.628 19.521 19.096 18.282 17.647 18.175 16.298 16.023 17.144 18.254 18.498 17.266 16.399 15.396 14.242 13.456 13.345 17.203 16.888 18.246 19.102 19.953 19.169 20. 106 18.775 20.004 20.258 20.498 21.351 21.879 20.5 10 20.967 19.268 18.351 17.053 17.135 16.084 16.453 15.281 23.256 24.3 62 22.548 23.064 22.095 22.443 22.181 23.544 23 .276 24.282 22.326 22.427 21.197 21.305 2 1.2 14 21.534 211.577 21.385 23.685 24.467 23.879 25.048 25.048 24.056 24.027 24.459 26.339 2 7.29 8 26.353 17.522 27.394 27.608 27.161 27.056 27.7 17 28.848 26.6 16 26.693 25.311 27.251 28.095 26.783 27.222 26.411 25.062 24.930 23.827 22.976 1.00 34.87 1.00 35.85 1.00 35.59 1.00 36.79 1.00 37.32 1.00 40.19 1.00 36.00 1.00 33.58 1.00 38.56 1.00 38.52 1.00 40.33 1.00 42.29 1.00 44.26 1.00 47.75 1.00 47.46 1.00 51.09 1.00 51.15 1.00 50.22 1.00 42.55 1.00 43.02 1.00 39.91 1.00 3 9.93 1.00 38.83 1.00 39.31 1.00 39.01 1.00 41.98 1.00 40.24 1.00 3 8.72 1.00 39.94 1.00 41.50 1.00 39.15 1.00 41.69 1.00 35.76 1.00 39.22 1.00 42.33 1.00 41.09 1.00 43.15 1.00 43.79 1.00 43.93 1.00 46.16 1.00 44.69 1.00 46 29 1.00 49.90 1.00 50.03 1.00 53.81 1.00 59.00 1.00 61.85 1.00 62.89

C

WO 99/50658 PCT/US99/06937

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1476 C LYS 492 1477 0 LYS 492 1478 N ALA 493 1479 CA ALA 493 1480 CB ALA 493 1481 C ALA 493 1482 0 ALA 493 1483 N GLY 494 1484 CA GLY 494 1485 C GLY 494 1486 0 GLY 494 1487 N LEU 495 1488 CA LEU 495 1489 CB LEU 495 1490 CG LEU 495 1491 CDI LEU 495 1492 CD2 LEU 495 1493 C LEU 495 1494 0 LEU 495 1495 N THR 496 1496 CA THR 496 1497 CB THR 496 1498 OGI THR 496 1499 CG2 THR 496 1500 C THR 496 1501 0 THR 496 1502 N LEU 497 1503 CA LEU 497 1504 CB LEU 497 1505 CG LEU 497 1506 CDI LEU 497 1507 CD2 LEU 497 1508 C LEU 497 1509 0 LEU 497 1510 N GLN 498 1511 CA GLN 498 1512 CB GLN 498 1513 CG GLN 498 1514 CD GLN 498 1515 OEI GLN 498 1516 NE2 GLN 498 1517 C GLN 498 1518 0 GLN 498 1-519 N GLN 499 1520 CA GLN 499 1521 CB GLN 499 1522 CG GLN 499 1523 CD GLN 499 1.841 0.845 3.072 3.321 4.777 2.971 3.089 2.554 2.185 3.322 3.206 4.431 5.555 6.847 7.712 7.022 9.072 5.278 4.664 5.718 5.521 5.841 7.222 4.965 6.471 7.370 6.280 7.135 6.710 5.933 5.886 6.589 8.599 9.474 8.862 10.221 10.246 11.585 11.539 10.565 12.591 10.777 11.923 9.965 10.391 9.314 9.155 8.039 18.025 17.784 18.012 17.706 ,17.314 18.885 18.799 19.989 21.159 22.107 22.921 22.009 22.899 22.293 21.459 20.156 21.189 24.227 24.258 25.324 26.636 27.767 27.688 27.662 26.764 25.939 27.800, 28.020 29.286 29.080 30.397 27.990 28.135 27.516 28.927.

29.101 30.140 30.270 31.260 31.308 32.054 27.773 27.422 27.040 25.748 25.155 25.825 25.187 28.701 29.379 29.199 30.600 30.794 31.501 32.723 30.893 31.671 32.006 32.919 31.284 31.540 30.988 31.936 32.260 31.270 30.847 29.778 31.452 30.845 31.829 32.208 33.064 29.660 29.488 28.849 27.688 26.944 25.640 24.875 24.798 28.101 27.493 29.137 29.627 30.743 31.437 32.584 33.332 32.727 30.145 29.866 30.902 31.434 32.344 33.703 34.512 1.00 51.15 1.00 53.37 1.00 50.15 1.00 49.17 1.00 50.39 1.00 49.36 1.00 51.57 1.00 48.61 1.00 46.92 1.00 45.46 1.00 43.58 1.00 44.81 1.00 42.34 1.00 43.79 1.00 40.99 1.00 44.70 1.00 42.12 1.00 42.13 1.00 42.49 1.00 42.73 1.00 43.56 1.00 46.09 1.00 43.92 1.00 45.63 1.00 45.54 1.00 43.39 1.00 45.02 1.00 45.12 1.00 46.62 1.00 50.20 1.00 50.95 1.00 50.91 1.00 44.94 1.00 45.03 1.00 41.14 1.00 40.54 1.00 43.82 1.00 43.37 1.00 47.03 1.00 49.18 1.00 45.30 1.00 39.39 1.00 35.05 1.00 36.49 1.00 36.91 1.00 38.84 1.00 41.33 1.00 42.74

C-)

(I

WO 99/50658 PCTIUS99/06937 ATOM 1524 OEI GLN 499 ATOM 1525 NE2 GLN 499 ATOM 1526 C GLN 499 ATOM 1527 0 GLN 499 ATOM 1528 N GLN 500 ATOM 1529 CA GLN 500 ATOM 1530 CB GLN 500 ATOM 1531 CG GLN 500 ATOM 1532 CD GLN 500 ATOM 1533 OEI GLN 500 ATOM 1534 NE2 GLN 500 ATOM 1535 C GLN 500 ATOM 1536 0 GLN 500 ATOM 1537 N HIS 501 ATOM 1538 CA HIS 501 ATOM 1539 CB HIS 501 ATOM 1540 CG HIS 501 ATOM 1541 CD2 HIS 501 ATOM 1542 NDI HIS 501 ATOM 1543 CEI HIS 501 ATOM 1544 NE2 HIS 501 ATOM 1545 C HIS 501 ATOM 1546 0 HIS 501 ATOM 1547 N GLN 502 ATOM 1548 CA GLN 502 ATOM 1549 CB GLN 502 ATOM 1550 CG GLN 502 ATOM 1551 CD GLN 502 ATOM 1552 OEI GLN 502 ATOM 1553 NE2 GLN 502 ATOM 1554 C GLN 502 ATOM 1555 0 GLN 502 ATOM 1556 N ARG 503 ATOM 1557 CA ARG 503 ATOM 1558 CB ARG 503 ATOM 1559 CG ARG 503 ATOM 1560 CD ARG 503 ATOM 1561 NE ARG 503 ATOM 1562 CZ ARG 503 ATOM 1563 NHI ARG 503 ATOM 1564 NH2 ARG 503 ATOM 1565 C ARG 503 ATOM 1566 0 ARG 503 ATOM 1567 N LEU 504 ATOM 1568 CA LEU 504 ATOM 1569 CB LEU 504 ATOM 1570 CG LEU 504 ATOM 1571 CDI LEU 504 7.027 8.222 10.655 11.446 9.980 10.136 9.042 7.672 6.558 6.660 5.482 11.511 12.256 11.835 13.117 13.195 12.043 11.534 11.264 10.325 10.466 14.255 15.271 14.086 15.110 14.740 14.787 14.420 14.102 14.462 15.340 16.483 14.266 14.436 13.107 13.258 11.930 12.021 12.489 12.917 12.512 15.051 15.895 14.624 15.164 14.566 15.327 15.252 24.760 25.107 24.773 23.832 24.994 24.138 24.436 23.872 24.419 24.417 24.886 24.350 23.387 25.612 25.966 27.476 28.027 27.678 29.068 29.337 28.508 25.543 24.996 25.799 25.438 25.977 27.498, 28.028; 27.262 29.348 23.932 23.479 23. 146 21.704 21.011 19.541.

18.935 17.490 16.908 17.640 15.583 21.152 20.259 21.675 21.223 22.023 21.901 20.453 33.955 35.829 30.285 30.422 29.162 27.990 26.958 27.315 26.435 25.207 27.064 27.358 27.124 27.078 26.480 26.246 25.468 24.263 25.926 25.037 24.018 27.395 26.945 28.685 29.650 31.033 31.113 32.486 33.397 32.640 29.716 29.769 29.705 29.779 30.052 30.400 30.798 30.992 32.093 33.114 32.180 28.496 28.548 27.351 26.075 24.916 23.593 23.117 1.00 45.44 1.00 43.48 1.00 35.03 1.00 36.59 1.00 34.14 1.00 34.65 1.00 33.90 1.00 36.62 1.00 40.17 1.00 40.22 1.00 41.82 1.00 34.96 1.00 30.79 1.00 34.21 1.00 37.42 1.00 43.08 1.00 51.13 1.00 53.05 1.00 54.54 1.00 54.36 1.00 55.19 1.00 35.79 1.00 36.20 1.00 33.90 1.00 32.18 1.00 35.84 1.00 32.66 1.00 36.62 1.00 33.99 1.00 36.22 1.00 31.79 1.00 28.00 1.00 30.99 1.00 29.91 1.00 32.79 1.00 30.84 1.00 30.61 1.00 28.50 1.00 29.00 1.00 29.85 1.00 33.73 1.00 29.89 1.00 29.69 1.00 28.99 1.00 28.90 1.00 27.72 1.00 30.47 1.00 31.74 WO 99/50658 PCT/US99/06937 ATOM 1572 CD2 LEU 504 ATOM 1573 C LEU 504 ATOM 1574 0 LEU 504 ATOM 1575 N ALA 505 ATOM 1576 CA ALA 505 ATOM 1577 CB ALA 505 ATOM 1578 C ALA 505 ATOM 1579 0 ALA 505 ATOM 1580 N GLN 506 ATOM 1581 CA GLN 506 ATOM 1582 CB GLN 506 ATOM 1583 CG GLN 506 ATOM 1584 CD GLN 506 ATOM 1585 OEI GLN 506 ATOM 1586 NE2 GLN 506 ATOM 1587 C GLN 506 ATOM 1588 0 GLN 506 ATOM 1589 N LEU 507 ATOM 1590 CA LEU 507 ATOM 1591 CB LEU 507 ATOM 1592 CG LEU 507 ATOM 1593 CDI LEU 507 ATOM 1594 CD2 LEU 507 ATOM 1595 C LEU 507 ATOM 1596 0 LEU 507 ATOM 1597 N LEU 508 ATOM 1598 CA LEU 508 ATOM 1599 CB LEU 508 ATOM 1600 CG LEU 508 ATOM 1601 CDI LEU 508 ATOM 1602 CD2 LEU 508 ATOM 1603 C LEU 508 ATOM 1604 0 LEU 508 ATOM 1605 N LEU 509 ATOM 1606 CA LEU 509 ATOM 1607 CB LEU 509 ATOM 1608 CG LEU 509 ATOM 1609 CDI LEU 509 ATOM 1610 CD2 LEU 509 ATOM 1611 C LEU 509 ATOM 1612 0 LEU 509 ATOM 1613 N ILE 510 ATOM 1614 CA ILE 510 ATOM 1615 CB ILE 510 ATOM 1616 CG2 ILE 510 ATOM ,1617 CGI ILE 510 ATOM 1618 CDI ILE 510 ATOM 1619 C ILE 510 14.742 16.681 17.439 17.114 18.535 18.735 19.261 20.340 18.677 19.299 18.434 18.414 17.111 16.319 16.879 19.500 20.536 18.505 18.578 17.225 16.052 14.836 16.431 19.652 20.421 19.713 20.690 20.339 19.004 18.905 18.903 22.127 23.062 22.302 23.637 23.598 23.578 23.529 24.818 24.154 25.354 23.254 23.712 22.568 23.051 22.141 20.712 24.337 22.843 21.419 20.536 22.585 22.899 24.361 21.977 21.462 21.771 20.907 20.796 22.027 22.116 21.167 23.257 19.509 18.889 19.017 17.678 17.286 16.961 16.561 15.838 17.583 16.621 18.583 18.557 19.629 19.436 20.416 17.994 18.727 18.200 19.451 19.661 20.735 22.214 23.114 22.525 18.327 18.068 17.462 16.172 15.368 13.965 16.060 15.749 15.351 22.542 1.00 29.85 26.089 1.00 29.69 25.672 1.00 26.38 26.564 1.00 28.51 26.632 1.00 25.98 27.039 1.00 29.86 27.604 1.00 26.67 27.290 1.00 25.54 28.784 1.00 23.59 29.785 1.00 27.67 31.043 1.00 27.75 31.945 1.00 32.48 32.736 1.00 38.40 32.754 1.00 35.97 33.386 1.00 38.07 29.217 1.00 24.53 29.441 1.00 26.42 28.484 1.00 26.78 27.902 1.00 26.18 27.295 1.00 31.48 28.231 1.00 32.59 27.389 1.00 33.78 29.174 1.00 30.18 26.819 1.00 26.03 26.771 1.00 27.28 25.950 1.00 24.31 24.863 1.00 23.68 23.828 1.00 23.91 23.102 1.00 24.68 21.945 1.00 25.11 22.580 1.00 27.53 25.341 1.00 22.93 24.736 1.00 21.36 26.441 1.00 23.86 26.991 1.00 26.28 28.095 1.00 28.08 27.672 1.00 33.98 28.921 1.00 35.23 26.856 1.00 30.48 27.540 1.00 26.08 27.547 1.00 23.92 27.993 1.00 24.60 28.496 1.00 25.12 29.161 1.00 28:51 29.506 1.00 31.67 30.459 1.00 31.18 30.882 1.00 37.16 27.364 1.00 23.86 C

G

WO 99/50658 PCT/US99/06937

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1620 0 1621 N 1622 CA 1623 CB 1624 CG 1625 CD1 1626 CD2 1627 C 1628 0 1629 N 1630 CA 1631 CB 1632 OG 1633 C 1634 0 1635 N 1636 N 1637 CA 1638 CA 1639 CB 1640 CB 1641 CG 1642 CG ILE 510 LEU 511 LEU 511 LEU 511 LEU 511 LEU 511 LEU 511 LEU 511 LEU 511 SER 512 SER 512 SER 512 SER 512 SER 512 SER 512 AHIS 513 BHIS 513 AHIS 513 BHIS 513 AHIS 513 BHIS 513 AHIS 513 BHIS 513 1643 CD2AHIS 513 1644 CD2BHIS 513 1645 ND1AHIS 513 1646 NDIBHIS 513 1647 CEIAHIS 513 1648 CE1BHIS 513 1649 NE2AHIS 513 1650 NE2BHIS 513 1651 C AHIS 513 1652 C BHIS 513 1653 0 AHIS 513 1654 0 BHIS 513 1655 N ILE 514 1656 CA ILE 514 1657 CB ILE 514 1658 CG2 ILE 514 1659 CGI ILE 514 1660 CDI ILE 514 1661 C ILE 514 1662 0 ILE 514 1663 N ARG 515 1664 CA ARG 515 1665 CB ARG 515 1666 CG ARG 515 1667 CD ARG 515 25.225 23.889 24.420 23.628 22.152 21.648 21.990 25.912 26.641 26.372 27.787 28.023 29.271 28.594 29.742 27.993 28.008 28.645 28.696 27.920 27.991 28.145 28.800 29.223 30.095 27.204 28.285 27.693 29.225 28.916 30.334 28.666 28.720 29.601 29.707 27.633 27.572 26.154 26.169 25.185 23.752 28.641 29.298 28.825 29.861 29.861 31.003 30.664 14.534 15.586 14.862 15.225 14.801 14.920 13.363 15.152 14.332 16.319 16.637 18.129 18.327 15.765 15.383 15.456 15.453 14.624 14.607 14.776 14.636 16.109 14.032 16.616 14.211 17.117 13.105 18.185 12.740, 17.908 13.396 13.164 13.171 12.426" 12.457 12.753 11.396 11.086 9.800 10.965 10.649 11.256 10.226 12.294 12.243 13.535 13.611 12.818 27.600 26.133 24.977 23.714 23.659 22.224 24.146 24.771 24.214 25.213 25.076 25.358 25.986 26.050 25.769 27.192 27.202 28.196 28.174 29.536 29.536 30.179 30.642 30.824 31.001 30.160 31.523 30.763 32.376 31.176 32.081 27.738 27.652 28.026 27.809 27.015 26.492 25.953 25.123 27.139 26.753 25.398 25.285 24.589 23.554 22.726 21.737 20.491 1.00 24.14 1.00 25.10 1.00 25.63 1.00 23.89 1.00 25.78 1.00 26.55 1.00 26.29 1.00 27.10 1.00 24.98 1.00 24.75 1.00 23.68 1.00 26.12 1.00 37.17 1.00 23.15 1.00 22.15 0.50 21.53 0.50 20.99 0.50 21.79 0.50 20.94 0.50 23.59 0.50 21.59 0.50 27.34 0.50 23.94 0.50 27.56 0.50 24.22 0.50 30.62 0.50 27.00 0.50 26.32 0.50 24.40 0.50 28.30 0.50 25.54 0.50 19.81 0.50 19.42 0.50 22.45 0.50 22.62 1.00 20.76 1.00 20.94 1.00 27.76 1.00 28.26 1.00 27.91 1.00 34.31 1.00 20.66 1.00 22.21 1.00 20.48 1.00 21.98 1.00 23.11 1.00 25.76 1.00 28.55 WO 99/50658 PTU9/63 PCT/US99/06937

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1668 NE ARG 5 15 1669 CZ ARG 515 1670 NH1 ARO 515 1671 NH2 ARG 515 1672 C 1673 0 1674 N 1675 CA 1676 CB 1677 CG 1678 CD2 1679 ND1 1680 CEI 1681 NE2 1682 C 1683 0 1684 N 1685 CA 1686 CB 1687 CG 1688 SD 1689 CE 1690 C 1691 0 1692 N 1693 CA 1694 CB 1695 OG 1696 C 1697 0 1698 N 1699 CA 1700 CB 1701 CG 1702 ODI 1703 ND2 1704 C 1705 0 1706 N 1707 CA 1708 CB 1709 CG 1710 CD 1711 CE 1712 NZ 1713 C 1714' 0 1715 N- ARG 515 ARG 5 15 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 HIS 516 MET 517 MET 517 MET 517 MET 517 MET 517 MET 517 MET 517 MET 517 SER 518 SER 518 SER 518 SER 518 SER 518 SER 518 ASN 5 19 ASN 519 ASN 519.

ASN 519 ASN 519 ASN 519 ASN 519 ASN 519 LYS 520 LYS 520 LYS 520 LYS 520 LYS 520 LYS 520 LYS 520 LYS 520 LYS 520 GLY 5 21 29.580 29.6 15 30.689 28.579 .32.068 31.420 32.675 32.566 33.826 34. 138 34.938 35.882 35.422 32.965 34.059 3 1.969 32.109 30.837 30.607 29.435 27.914 32.399 33.213 31.736 3 1.977 30.976 31.283 33.432 34.111 33.923 35.295 35.605 34. 864 34.661 34.459 36.292 37.251 36.070 36.964 36.581 36.6 18 .37.962 39.047 .39.858 36.899 37.913 .35.704 13.482 13.827 13.566 14.459 12.087 11.305 12.844 12.8 12 13.794 13.948 13.587 14.586 14.613 14.0 13 11.390 10.852 10.786 9.436 9.038 9.903 9.222 9.390 8.448 7.547 8.612 7.7 17 8.027 7.336 7.862 6.866 9.097 9.309 10.807 11.469 10.864 12.7 15 8.643 8.0 15 8.782 8.171 8.592 10.101 10.7 10 10.307 11.480 6.644 5.957 6.117 19.788 18.508 17.776 17.971 24.225 23.795 25.293 26.034 27.206 27.990 29.257 27.489 28.4 11 29.495 26.537 26.J62 27.168 27.684 28.424 29.652 .30.790 29.807 26.564 26. 728 25.423 24.301 23.173 2 1.978 23 .8 10 23.532 23 .713 23.260 23.15 7 22.02 1 20.965 22.2-24 24.201 23.752 25.504 26.488 27.9 12 28.174 27.81 1 28.802 29.254 26.3 76 26.501 26.141 1.00 36.24 1.00 38.91 1.00 35.37 1.00 40.27 1.00 21.29 1.00 20.06 1.00 23.23 1.00 24.75 1.00 24.03 1.00 3 1.42 1.00 35.87 1.00 3 3.59 1.00 3 5.70 1.00 33.35 1.00 24.02 1.00 23.66 1.00 20.91 1.00 24.21 1.00 23.88 1.00 26.32 1.00 26.67 1.00 23.26 1.00 23.26 1.00 26.08 1.00 21.93 1.00 23.08 1.00 22.02 1.00 24.01 1.00 25.15 1.00 22.94 1.00 22.42 1.00 21.87 1.00 24.46 1.00 29.02 1.00 3 1.93 1.00 28.81 1.00 21.46 1.00 23.56 1.00 23.23 1.00 26.35 1.00 27.53 1.00 33.74 1.00 42.09 1.00 43.97 1.00 48.07 1.00 27.71 1.00 27.15 1.00 25.02 WO 99/50658 PCTIUS99/06937 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 27.06 ATOM 1718 0 GLY 521 36.924 3.128 24.775 1.00 26.84 ATOM 1719 N AMET 522 36.101 4.893 23.650 0.50 25.87 ATOM 1720 N BMET 522 36.095 4.908 23.658 0.50 27.62 ATOM 1721 CA AMET522 36.727 4.491 22.401 0.50 27.27 ATOM 1722 CA BMET 522 36.703 4.551 22.384 0.50 30.14 ATOM 1723 CB AMET522 36.267 5.396 21.260 0.50 26.50 ATOM 1724 CB BMET522 36.252 5.525 21.288 0.50 32.46 ATOM 1725 CG AMET 522 34.827 5.162 20.866 0.50 25.05 ATOM 1726 CG BMET522 35.681 4.854 20.045 0.50 35.70 ATOM 1727 SD AMET522 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 1729 CE AMET522 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 AMET522 38.242 4.532 22.512 0.50 28.99 ATOM 1732 C BMET522 38.224 4.567 22.483 0.50 30.76 ATOM 1733 0 AMET 522 38.939 3.743 21.870 0.50 31.65 ATOM 1734 0 BMET522 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 0 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 0 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 CDI 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 41.32 ATOM 1761 0 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 43.68 ATOM 1763 CA TYR 526 41.300 1.297 20.449 1.00 49.00 WO 99/50658 WO 9950658PCT/US99/06937 ATOM 1764 CB TYR 526 ATOM 1765 CG TYR 526 ATOM 1766 CDI TYR 526 ATOM .1767 CEI TYR 526 ATOM 1768 CD2 TYR 526 ATOM 1769 CE2 TYR 526 ATOM 1770 CZ TYR 526 ATOM 1771 OH TYR 526 ATOM 1772 C TYR 526 ATOM 1773 0 TYR 526 ATOM 1774 N SER 527 ATOM 1775 CA SER 527 ATOM 1776 CB SER 527 ATOM 1777 OG SER 527 ATOM 1778 C SER 527 ATOM 1779 0 SER 52 7 ATOM 1780 N MET 528 ATOM 1781 CA MET 528 ATOM 1782 CB MET 528 ATOM 1783 CG MET 528 ATOM 1784 SD MET 528 ATOM 1785 CE MET 528 ATOM 1786 C MET 528 ATOM 1787 0 MET 528 ATOM 1788 N LYS 529 ATOM 1789 CA LYS 529 ATOM 1790 CB LYS 529 ATOM 1791 C LYS 529 ATOM 1792 0 LYS 529 ATOM 1793 N CYS 530 ATOM. 1794 CA CYS 530 ATOM 1795 CB CYS 530 ATOM 1796 SG CYS 530 ATOM 1797 C CYS 530 ATOM 1798 0 CYS 530 ATOM 1799 N LYS 531 ATOM 1800 CA LYS 5,31 ATOM 1801 CB LYS 531 ATOM 1802 C LYS 531 ATOM 1803 0 LYS 531 ATOM 1804 N ASN 532 ATOM 1805 CA ASN 532 ATOM 1806 CB ASN 532 ATOM 1807 C ASN 532 ATOM 1808 0 ASN 532 ATOM 1809 N VAL 533 ATOM 1810 CA VAL 5331 ATOM 1811 CB VAL 533 4 1.376 42.305 4 1.835 42.681 43.653 44.510 44.016 44.851 42.671 43.471 42.930 44.205 44.351 43.752 44.365 45.398 43.335 43.347 42.534 4 1.237 39.895 39.23 1 42.726 42.170 42.834 42.274 42.508 42.813 43.990 4 1.932 42.279 41.004 40.447 43.098 43.241 43.637 44.424 45.600 43.508 42.549 43.784 42.984 43.550 4 1.485 40.904 40.859 .39.436 2.722 2.878 2.7 18 2.875 3.200 3.359 3..194 3343 0.871 0.303 1.139 0.790 1.516 0.788 -0.718 -1.185 -1.472 -2.929 -3.381 -2.606 -3.569 -4.412 -3.502 4.602 -2.739 -3.122, -2.004 -4.439 -4.762 -5.191 -6.474 -7.245 -8.491 -6.220 -5.076 -7.289 -7.187 -8.182 -7.467 -6.734 -8.539 -8.902 -10. 166 -9.082 10. 123 -8.055 -8.098 -7.7 15 19.890 1.00 51.86 18.704 1.00 57.70 17.400 1.00 5 8.93 16.305 1.00 61.21 18.883 1.00 58.58 17.790 1.00 61.15 16.505 1.00 61.09 15.417 1.00 63.79 20.964 1.00 50.14 20.223 1.00 50.73 22.240 1.00 52.72 22.85 7 1.00 55.88 24.199 1.00 55.00 25.257 1.00 52.46 23.054 1.00 60.39 23.534 1.00 60.43 22.678 1.00 63.86 22.788 1.00 67.95 24.008 1.00 67.85 2 4. 2 22 1.00 70.10 24.983 1.00 71.70 23.554 1.00 72.57 21.513 1.00 70.33 21.513 1.00 72.43 20.428 1.00 71.53 19.136 1.00 72.00 18.119 1.00 71.30 18.587 1.00 72.47 18.751 1.00 70.37 17.930 1.00 74.48 17.325 1.00 76.67 16.952 1.00 77.23 18.146 1.00 79.38 16.065 1.00 78.08 15.623 1.00 78.81 15.487 1.00 78.22 14.267 1.00 78.15 14.305 1.00 78.33 13.067 1.00 77.93 12.839 1.00 78.07 12.328 1.00 77.80 11.152 1.00 77.30 10.521 1.00 77.55 11.423 1.00 77.34 11.118 1.00 78. 13 11.988 1.00 76. 13 12.280 1.00 73.77 13.752 1.00 73.62

C

WO 99/50658 PCT/US99/06937 ATOM 1812 CG1- VAL 5 33 ATOM 1813 CG2 VAL 533 ATOM 1814 C VAL 53 3 ATOM 1815 0 VAL 5.33 ATOM 1816 N VAL 534 ATOM 1817 CA VAL 534 ATOM 1818 CB VAL 534 ATOM 1819 C VAL 534 ATOM 1820 0 VAL 534 ATOM 1821 N PRO 535 ATOM 1822 CD PRO 535 ATOM 1823 CA PRO 535 ATOM 1824 CB PRO 535 ATOM 1825 CG PRO 535 ATOM 1826 C PRO 535 ATOM 1827 0 PRO 535 ATOM 1828 N LEU 536 ATOM 1829 CA LEU 536 ATOM 1830 CB LEU 53 6 ATOM 1831 CG LEU 536 ATOM 1832 CD1 LEU 536 ATOM 1833 CD2 LEU 536 ATOM 1834 C LEU 536 ATOM 1835 0 LEU 536 ATOM 1836 N TYR 537 ATOM 1837 CA TYR 537 ATOM 1838 CB TYR 537 ATOM 1839 CG TYR 537 ATOM 1840 CDI TYR 537 ATOM 1841 CEI TYR 537 ATOM 1842 CD2 TYR 537 ATOM 1843 CE2 TYR 537 ATOM 1844 CZ TYR 537 ATOM 1845 OH TYR 537 ATOM 1846 C TYR 537 ATOM 1847 0 TYR 53 7 ATOM 1848 N ASP 538 ATOM 1849 CA ASP 538 ATOM 1850 CB ASP 538 ATOM 1851 CG ASP 538 ATOM 1852 ODI ASP 538 ATOM 1853 0D2 ASP 538 ATOM 1854 C ASP 538 ATOM 1855 0 ASP 538 ATOM 1856 N LEU 539 ATOM 1857 CA LEU 539 ATOM 1858 CB LEU 539 ATOM 1859 CG LEU 539 39.690 37.662 38.685 .39.024 37.671 36.866 35.6 19 36.463 35.895 36.756 -37.424 36.424 36.867 37.023 -34.944 34.067 34.672 33.301 -33.280 32.267 3 1.919 31.022 32.434 3 1.287 32.992 32.269 .33.200 32.483 32.190 3 1.504 32.073 3 1.383 31.100 30.401 31.683 30.500 32.521 32.097 -3 3 .322 3 4.361 35.436 34.097 31.071 30. 177 31.193 30.244 30.734 29.770 -6.327 -7.782 -7.143 -5.960 -7.666 -6.867 -7.646 -5.541 -5.5 19 -4.4 15 -4.354 -3.077 -2.13 5 -31.009 -2.902 -3.461 -2.120 -1.874 -0.796 -0.9 11 0.490 -1.654 -1.433 -1.862 -0.575 -0.066 0.786 1.558 0.964 1.660 2.975 3.584 2.967 3.648 -1.199 -1.191 -2.175 -3).309 -4.126 -3.284 -3.820 -2.079 -4.195 -4.738 34 5 -5.15 7 -5.351 -6.065 14.047 14.021 11.352 11.252 10.666 9.747 9.328 10. 3 9 3 11.486 9.719 8.408 10.229 9.107 7.893 10.571 9.908 11.610 12.042 13. 12 8 14.273 14.745 13.835 10.87 1 10.734 10.024 8.866 7.997 6.9 13 5.687 4.693 7.123 6.135 4.924 3.952 8.032 7.696 7.702 6.893 6.479 5.748 5.396 5.526 7.587 6.94 0 8.901 9.654 11.092 12.044 1.00 73.13 1.00 73. 14 1.00 72.97 1.00 73.91 1.00 70.02 1.00 66.70 1.00 67.32Q 1.00 63.87 1.00 63.55 1.00 60.92 1.00 61.01 1.00 56.83 1.00 58.70 1.00 61.55 1.00 52.90 1.00 52.01 1.00 48.60 1.00 45.08 1.00 44.35 1.00 43.48 1.00 43.41 1.00 39.55 1.00 43.58 1.00 42.14 1.00 43.02 1.00 43.34 1.00 44.76 1.00 48.28 1.00 48.46 1.00 52.48 1.00 49.99 1.00 53.73 1.00 54.01 1.00 55.90 1.00 43.15 1.00 41.54 1.00 44.67 1.00 45.49 1.00 51.32 1.00 56.17 1.00 57.29 1.00 59.24 1.00 43.48 1.00 43.95 1.00 41.57 1.00 39.11 1.00 41.88 1.00 46.11 WO 99/50658 PCT/US99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

270 ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

1860 CD1 LEU 539 1861 CD2 LEU 539 1862 C LEU 539 1863 0 LEU 539 1864 N LEU 540 1865 CA LEU 540 1866 CB LEU 540 1867 CG LEU 540 1868 CDI LEU 540 1869 CD2 LEU 540 1870 C LEU 540 1871 0 LEU 540 1872 N LEU 541 1873 CA LEU 541 1874 CB LEU 541 1875 CG LEU 541 1876 CDI LEU 541 1877 CD2 LEU 541 1878 C LEU 541 1879 0 LEU 541 1880 N GLU 542 1881 CA GLU 542 1882 CB GLU 542 1883 CG GLU 542 1884 CD GLU 542 1885 OEI GLU 542 1886 0E2 GLU 542 1887 C GLU 542 1888 0 GLU 542 1889 N MET 543 1890 CA MET 543 1891 CB MET 543 1892 CG MET 543 1893 SD MET 543 1894 CE MET 543 1895 C MET 543 1896 0 MET 543 1897 N LEU 544 1898 CA LEU 544 1899 CB LEU 544 1900 CG LEU 544 1901 CDI LEU 544 1902 CD2 LEU 544 1903 C LEU 544 1904 0 LEU 544 1905 N ASP 545 1906 CA ASP 545 1907 CB ASP 545 29.298 30.474 28.891 27.849 28.9 19 27.703 28.061 27.856 27.526 29.114 27.060 25.846 27.892 27.4 18 28.591 28.301 27.184 29.572 26.723 2-5.616 27.366 26.790 27.719 27.010 26.434 25.570 26.842 25.414 24.472 2-5.298 24.036 24.270 25.137 24.9 18 25.324 23.001 2 1.808 23.457 22.559 23.225 23.268 24.284 21.897 22.148 20.971 23.118 22.850 24.159 -7.379 11.423 -6.319 13.377 -4.451 -5.070 -3).146 -2.336 -0.877 0. 252 -1.299 0.506 -2.4 15 -2.585 -2.289 -2.340 -2.152 -2.112 -1.130 -1.716 3.676 -3.713 -4.770 -6.097 -7.170 -8.457 -9.245 -10.117 -8.996 -6.195 -6.720 -5.686 -5.731 -5.424 -6.459 -6.445 -4.749 -4.769 -5.073 -3.605 -2.603 -1.226 -0.562 0.564 -0.029 -2.941 -2.842 -3).338 -3).685 -3).780 9.651 9.436 9.894 9.903 10.2 19 11.605 12.645 11.985 8.5 10 8.371 7.483 6.101 5.145 3.643 3.348 2.908 5.833 5.297 6.230 6.037 6.620 7.052 5.887 6.130 4.72 8 6.691 6.102 7.915 8.634 10.11 1 10.808 12.604 12.964 8.072 8.048 7.629 7.074 7.111 8.490 8.478 8.846 5.640 5.294 4.8 17 3.4 18 2.620 1.00 46.99 1.00 45.76 1.00 36.38 1.00 35.74 1.00 35.50 1.00 35.59 1.00 37.63 1.00 40.28 1.00 38.5 1.00 41.04 1.00 35.50 1.00 33.21 1.00 37.01 1.00 38.51 1.00 39.6 7 1.00 40.92 1.00 42.44 1.00 44.18 1.00 39.75 1.00 3 6.48 1.00 40.88 1.00 41.89 1.00 44.11 1.00 50.60 1.00 55.80 1.00 58.81 1.00 57.19 1.00 41.58 1.00 42.82 1.00 40.09 1.00 36.43 1.00 39.95 1.00 41.95 1.00 47.17 1.00 40.88 1.00 3 5.02 1.00 35.31 1.00 32.90 1.00 36.88 1.00 3 4.51 1.00 3)1.94 1.00 32.27 1.00 29.02 1.00 38.94 1.00 39.52 1.00 41.05 1.00 40.78 1.00 37.75

C)

WO 99/50658 PCTIUS99/06937

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

ATOM

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25 ATOM

ATOM

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1908 CG ASP 545 1909 ODI ASP 545 1910 0D2 ASP 545 1911 C 1912 0 1913 N 1914 CA 1915 CB 1916 C 1917 0 1918 N 1919 CA 1920 CB 1921 CG 1922 CD2 1923 ND1 1924 CEI 1925 NE2 1926 C 1927 0 1928 N 1929 CA 1930 CB 1931 CG 1932 CD 1933 NE 1934 CZ.

1935 NHI 1936 NH-2 1937 C ASP 545 ASP 545 ALA 546 ALA 546 ALA 546 ALA 546 ALA 546 HIS 547 H-IS 547 HIS 547 HIS1 547 HIS 547 HIS 547 HIS 547 HIS 547 HIS 547 HIS 547 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 ARG 548 23.922 24.88 1 22.768 22.1 16 22.681 10.853 20.069 19.2 13 19.193 18.804 18.895 18.042 18.431 18.395 17.477 19.395 19.095 17.936 16.603 16.362 15.653 14.245 13.432 14.272 13.448 13.702 14.864 15. 89 1 15.00 1 13.695 12.500 14.576 14.188 15.43.3 16.461 17.699 15.823 13.43 1 12.759 13.541 12.858 13.753 14.977 15.539 15.793 16.805 .16.674 11.556 -3.937 -4.265 -3.734 -5.0 15 -6.030 -5.009 -6.229 -6.305 -6.362 -5.368 -7.606 -7.884 -9.223 -10.3 82 -10.752 -11.329 -12.232 -11.906 -7.936 -7.796 -8.139 -8.2 12 -7.171 -6.222 -5.061 -3.826 -3.178 -3.644 -2.063 -9.608 -9.781 10.603 -11.985 12.828 -12.19 1 -13.074 -11.972 12.574 -13.600 -11.920 -12.3 78 12. 190 -13.054 -13.821 -13.172 -13.972 -14.3 79 -11.603 1.120 0.380 0.691 3.349 2.929 3.755 3.746 5.006 2.508 1.88 3 2.152 1.006 0.369 1.317 2.242 1.371 2.286 2.830 1.5 18 2.72 0 0.612 0.987 0.208 -0.637 -1.171 0. 432 -0.429 -1.128 0.278 0.7 11 0.466 0.756- 0.507 0.195 -0.753 -0.878 -2.108 1.702 1.577 2.856 4.065 5.298 5.306 4.341 6.411 6.126 4.876 4.275 1.00 35.19 1.00 33. 4.8 1.00 31.33 1.00 42.87 1.00 44.32 1.00 43.49 1.00 46.96 1.00 47.82 1.00 49.55 1.00 48.75 1.00 50.98 1.00 53.77 1.00 52.69 1.00 '55.05 1.00 53.94 1.00 56.23 1.00 55.36 1.00 57.01 1.00 55.69 1.00 54.30 1.00 57.00 1.00 60.65 1.00 62.69 1.00 67.54 1.00 71.92 1.00 76.95 1.00 79.04 1.00 80.66 1.00 80.39 1.00 61.65 1.00 62.05 1.00 62.39 1.00 64.02 1.00 62.14 1.00 60.76 1.00 57.77 1.00 58.38 1.00 66.65 1.00 67.15 1.00 67.72 1.00 69.93 1.00 70.76 1.00 71.50 1.00 71.63 1.00 71.98 1.00 72.04 1.00 7 1.3")9 1.00 71.15 1938 0 ARG 548 1939 N LEU 549 1940 CA LEU 549 1941 CB .LEU. 549 1942 CG LEU 549 1943 CDI LEU 549 1944 CD2 LEU 549 1945 C LEU 549 1946 0 LEU 549 1947 N HIS 550 1948 CA HIS 550 1949 CB HIS 550 19 50 CG HIS 550 1951 CD2 HIS 550 1952 NDI HIS 550 1953 CEI HIS 550 1954 NE2 HIS 550 1955 C HIS 550 C0 WO 99/50658 PCT/US99/06937 ATOM 1956 0 ATOM 1957 N ATOM 1958 CA ATOM 1959 CB ATOM 1960 C ATOM 1961 0 ATOM 1962 OXT HETATM 1963 C10 HETATM 1964 C9 HETATM 1965 C8 HETATM 1966 CII HETATM 1967 C16 HETATM 1968 C15 HETATM 1969 C14 HETATM 1970 C13 HETATM 1971 C12 HETATM 1972 C7 HETATM 1973 Cl HETATM 1974 C2 HETATM 1975 C3 HETATM 1976 C4 HETATM 1977 04 HETATM 1978 C5 HETATM 1979 C6 HETATM 1980 C17 HETATM 1981 C18 HETATM 1982 C19 HETATM 1983 C20 HETATM 1984 020 HETATM 1985 C23 HETATM 1986 C24 HETATM 1987 N24 HETATM 1988 C25 HETATM 1989 C26 HETATM 1990 C21 HETATM 1991 C22 HETATM 1992 01 HETATM 1993 01 HETATM 1994 01 HETATM 1995 01 HETATM 1996 01 HETATM 1997 01 HETATM 1998 01 HETATM 1999 01 HETATM 2000 01 HETATM 2001 01 HETATM 2002 01 HETATM 2003 01 HIS 550 ALA 551 ALA 551 ALA 551 ALA 551 ALA 551 ALA 551 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 OHT 600 HOH 1 HOH 2 HOH 3 HOH 4 HOH 5 HOH 6 HOH 7 HOH 8 HOH 9 HOH 10 HOH 11 HOH 12 10.940 11.143 9.919 9.904 8.658 7.684 8.651 30.581 30.713 31.366 32.761 33.218 34.551 35.443 35.004 33.666 30.682 29.211 28.644 27.254 26.438 25.072 26.980 28.362 31.370 32.508 33.166 32.676 33.206 33.009 34.226 34.141 33.375 35.495 31.540 30.892 20.714 22.563 25.183 35.158 22.116 29.812 13.362 19.799 21.205 21.177 18.591 16.298 -11.684 -10.851 -10.057 -9.014 -10.920 -10.474 -12.025 1.481 -0.043 -0.385 0.05,1 0.797 1.237 0.923 0.185 -0.241 -1.089 -1.258 -2.526 -2.668 -1.553 -1.605 -0.286 -0.147 -1.692 -2.498 -3.052 -2.794 -3.566 -3.135 -3.490 -4.901 -5.040 -5.459 -2.005 -1.450 -12.010 -0.070 19.202 5.823 -9.922 6.536 4.463 -11.295 1.466 -4.961 1.863 21.566 5.340 3.258 3.338 2.221 3.266 2.621 3.852 29.471 29.358 28.037 27.916 26.797 26.747 27.792 28.890 28.955 27.077 27.052 26.706 26.580 26.813 26.716 27.130 27.231 25.942 26.151 25.072 23.786 22.795 21.448 20.575 20.203 18.933 20.004 23.558 24.645 23.057 25.819 23.149 37.390 18.914 19.652 20.376 20.187 23.794 29.066 20.518 15.992 1.00 70.66 1.00 72.22 1.00 73.58 1.00 73.21 1.00 74.69 1.00 76.12 1.00 73.79 1.00 26.84 1.00 22.85 1.00 25.56 1.00 27.51 1.00 28.35 1.00 30.39 1.00 30.23 1.00 31.45 1.00 27.93 1.00 24.41 1.00 24.26 1.00 25.92 1.00 26.32 1.00 29.02 1.00 28.42 1.00 26.98 1.00 25.23 1.00 26.61 1.00 26.77 1.00 27.50 1.00 27.50 1.00 31.35 1.00 40.09 1.00 44.80 1.00 49.00 1.00 51.64 1.00 52.06 1.00 27.19 1.00 27.92 1.00 27.20 1.00 25.77 1.00 42.52 1.00 33.92 1.00 30.18 1.00 26.11 1.00 29.40 1.00 28.70 1.00 22.47 1.00 33.00 1.00 32.59 1.00 33.42 WO 99/50658 PCT/US99/06937 HETATM 2004 01 HOH 13 18.611 1.976 24.494 1.00 29.70 HETATM 2005 01 HOH 14 38.009 8.91i0 21.156 1.00 39.92 HETATM 2006 01 HOH 15 26.549 11.664 18.080 1.00 30.25 HETATM 2007 01 HOH 16 20.282 -4.239 26.512 1.00 32.70 HETATM 2008 01 HOH 17 32.858 8.754 20.237 1.00 29.88 HETATM 2009 01 HOH 18 8.497 16.136 29.934 1.00 46.80 HETATM 2010 01 HOH 19 21.940 19.301 31.632 1.00 35.72 HETATM 2011 01 HOH 20 35.153 2.682 14.122 1.00 41.02 HETATM 2012 01 HOH 21 20.358 -2.268 21.013 1.00 29.43 HETATM 2013 01 HOH 22 35.562 10.036 36.334 1.00 41.37 HETATM 2014 01 HOH 23 17.248 18.187 17.571 1.00 33.96 HETATM 2015 01 HOH 24 18.445 20.973 12.346 1.00 43.44 HETATM 2016 01 HOH 25 12.152 23.054 33.132 1.00 36.04 HETATM 2017 01 HOH 26 13.181 22.222 9.699 1.00 37.03 HETATM 2018 01 HOH 27 19.399 -6.090 12.808 1.00 44.86 HETATM 2019 01 HOH 28 37.895 13.599 31.395 1.00 47.26 HETATM 2020 01 HOH 29 11.570 6.212 7.962 1.00 51.10 HETATM 2021 01 HOH 30 20.172 -2.568 23.445 1.00 51.70 HETATM 2022 01 HOH 31 36.402 -5.369 23.729 1.00 58.20 HETATM 2023 01 HOH 32 25.127 13.802 19.187 1.00 35.29 HETATM 2024 01 HOH 33 23.181 4.937 38.538 1.00 33.77 HETATM 2025 01 HOH 34 20.550 0.421 21.276 1.00 29.12 HETATM 2026 01 HOH 35 39.599 13.954 27.312 1.00 44.08 HETATM 2027 01 HOH 36 26.445 13.863 21.285 1.00 34.97 HETATM 2028 01 HOH 37 13.759 5.079 9.108 1.00 38.54 HETATM 2029 01 HOH 38 14.150 24.731 34.529 1.00 49.72 HETATM 2030 01 HOH 39 21.060 13.886 -6.319 1.00 59.79 HETATM 2031 01 HOH 40 32.215 6.217 8.726 1.00 60.22 HETATM 2032 01 HOH 41 35.105 15.704 9.069 1.00 45.15 HETATM 2033 01 HOH 42 11.427 19.451 9.903 1.00 38.56 HETATM 2034 01 HOH 43 19.662 23.472 10.333 1.00 47.71 HETATM 2035 01 HOH 44 9.231 3.690 12.337 1.00 45.98 HETATM 2036 01 HOH 45 15.313 -6.036 17.192 1.00 39.07 HETATM 2037 01 HOH 46 15.517 -3.266 17.907 1.00 37.67 HETATM 2038 01 HOH 47 28.784 -16.713 25.163 1.00 55.44 HETATM 2039 01 HOH 48 27.868 -10.898 28.271 1.00 31.27 HETATM 2040 01 HOH 49 6.955 13.568 28.233 1.00 48.83 HETATM 2041 01 HOH 50 22.051 -15.030 28.603 1.00 36.91 HETATM 2042 01 HOH 51 7.026 31.002 30.284 1.00 46.73 HETATM 2043 01 HOH 52 -1.489 12.385 15.164 1.00 51.17 HETATM 2044 01 HOH 53 3.499 6.444 14.452 1.00 50.38 HETATM 2045 01 HOH 54 18.655 -2.048 25.518 1.00 52.29 HETATM 2046 01 HOH 55 28.188 -15.195 38.996 1.00 55.22 HETATM 2047 01 HOH 56 35.275 -10.556 38.061 1.00 57.39 HETATM 2048 01 HOH 57 37.771 -9.103 34.605 1.00 54.17 HETATM 2049 01 HOH 58 31.403 -3.039 17.983 1.00 46.80 HETATM 2050 01 HOH 59 30.455 -6.352 17.005 1.00 47.05 HETATM 2051 01 HOH 60 25.985 8.255 0.416 1.00 43.32 WO 99/50658 PCT1US99/06937 HETATM 2052 01 HOH 61 35.679 0.749 .10.462 1.00 42.99 H-ETATM 2053 01 HOH 62 14.741 4.029 33.936 1.00 49.59 HETATM 2054 01 HOH 63 16.333 2.592 35.952 1.00 45.13 HETATM 2055 01 HOH 64 23.809 7.186 39.798 1.00 45.36 HETATM 2056 01 HOH 65 27.012 -1.948 46.995 1.00 63.39 H-ETATM 2057 01 HOT- 66 25.956 -6.422 42.144 1.00 44.94 HETATM 2058 01 HOH 67 23.510 -8.414 39.036 1.00 3 9.06 HETATM 2059 01 H0H 68 41.475 0.971 33. 110 1.00 55.50 HETATM 2060 01 HOH 69 36.519 8.863 38.836 1.00 41.56 HETATM 2061 01 HOH 70 30.111 14.823 12.793 1.00 44.58 HETATM 2062 01 HOH 71 26.850 -6.092 1.594 1.00 40.15 HETATM 2063 01 HOH 72 20.448 -3.169 1.055 1.00 42.50 HETATM 2064 01 HOH 7 3 33.896 3.047 16.172 1.00 '46.39 HETATM 2065 01 HOH 74 16.884 0.446 26.043 1.00 61.50 HETATM 2066 01 HOH 75 18.595 0.296 27.866 1.00 47.33 HETATM 2067 01 HOH 76 6..166 21.439 19.124 1.00 47.94 HETATM 2068 01 HOH 77 18.484 20.060 16.232 1.00 35.52 HETATM 2069 01 HOH 78 1.985 23.265 29.187. 1.00 46.42 HETATM'2070 01 HOH 79 12.729 3 0.461 27.530 1.00 62.79

END

Claims (122)

1. A method of identifying a compound that modulates nuclear receptor activity, the method comprising: modeling a test compound that fits spatially into a nuclear receptor ligand binding domain of interest using an atomic structural model of a portion of the estrogen receptor a ligand binding domain, wherein said atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and screening said test compound in an assay characterized by binding of a test compound to the ligand binding domain, thereby identifying a test compound that modulates nuclear receptor activity.

2. The method of Claim 1 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu 428, Gly 521, His524, Leu525, and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said test compound interacts with at least one of said amino acid residues.

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 a change in position of helix 12 so that helix 12 contacts the coactivator binding site thereby inhibiting coactivator binding. The method of Claim 1 wherein the test compound is an antagonist and nuclear receptor activity is measured by the blocking of coactivator binding to the coactivator binding site.

W:\dska\nki'pedes\34571d.doc 182

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.

The method of Claim 1 wherein the modeling comprises providing the atomic coordinates of the portion of the estrogen receptor a ligand binding domain to a computerized modeling system.

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 a.

14. A method of identifying a compound that modulates ligand binding to a nuclear receptor, the method comprising: modeling a test compound that fits spatially into a nuclear receptor ligand binding domain of interest using an atomic structural model of a portion of the estrogen receptor a ligand binding domain, wherein the atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and W:\dska\nkl\spldes\34571d.doc 183 screening said test compound in an assay characterized by binding of the test compound to the ligand binding domain, thereby identifying a test compound that modulates ligand binding to said nuclear receptor.

15. The method of Claim 14 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu 428, Gly 521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said test compound interacts with at least one of said amino acid residues.

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 a.

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

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 of ligand binding that facilitates binding of a coactivator to the coactivator binding site. W:diska\nkspedes\34571d.doc 184

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 of ligand binding to an estrogen receptor, the method comprising: modeling a test compound which fits spatially into an atomic structural model of the estrogen receptor a ligand binding domain, wherein the atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and screening in an assay for estrogen receptor activity a compound which increases the activity of the estrogen receptor by binding the ligand binding domain of the estrogen receptor, thereby identifying an agonist of ligand binding.

25. The method of Claim 24 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said test compound interacts with at least one of said amino acid residues.

26. 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 the nuclear receptor, wherein said compound is designed by a computational method that involves fitting an atomic model of the compound into an atomic structural model of the ligand binding domain of the estrogen receptor that comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator W:\ciska\nkRspedes34571d.doc 185 binding site, so that the molecule interacts with at least one amino acid residue corresponding to residues of human estrogen receptor a Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix 1).

27. The method of Claim 26 wherein the test compound is an antagonist that causes a change in position of helix 12 so that helix 12 contacts the coactivator binding site thereby inhibiting coactivator binding.

28. The method of Claim 26 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.

29. The method of Claim 28 wherein said nuclear receptor is an estrogen receptor.

The method of Claim 29 wherein said estrogen receptor is the estrogen receptor a.

31. A machine-readable data storage medium 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, wherein the data comprises coordinates of: a portion of an estrogen receptor ligand binding domain, including helix 12 of the ligand binding domain; a coactivator binding site; and a compound bound to the estrogen receptor coactivator binding site.

32. The machine-readable data storage medium of Claim 31 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387 Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix 1). W:\skaAnkl\species34571d.doc 186

33. The machine-readable data storage medium of Claim 31 wherein said molecular complex is defined by the set of structure coordinates depicted in Appendix 1, or a homologue of said molecular complex, said homologue having a root mean square deviation from the coordinates of the backbone atoms of said ligand binding domain of not more than 1.

34. 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.

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, mineralcorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

36. The machine-readable data storage medium of Claim 35 wherein said nuclear receptor is an estrogen receptor.

37. The machine-readable data storage medium of Claim 35 wherein said estrogen receptor is the estrogen receptor a.

38. A cocrystal comprising: a portion of an estrogen receptor ligand binding domain; an agonist bound to the ligand binding domain; and a molecule bound to a coactivator binding site of the estrogen receptor. W:CdskaVnkrpedes\3457 d.doc 187

39. The cocrystal of Claim 38 wherein said nuclear receptor is the estrogen receptor a.

The cocrystal of Claim 39 wherein said estrogen receptor a is human.

41. The cocrystal of Claim 40 wherein said molecule is a peptide.

42. The cocrystal of Claim 41 wherein said peptide comprises a NR-box amino acid sequence or derivative thereof.

43. A cocrystal comprising: a portion of an estrogen receptor ligand binding domain and an antagonist bound to the ligand binding domain, wherein said cocrystal diffracts with at least 1.9 A resolution.

44. The cocrystal of Claim 43 wherein said cocrystal diffracts with at least 2.03 A resolution.

The cocrystal of Claim 44 wherein said estrogen receptor is human.

46. A computational method of designing a nuclear receptor ligand comprising fitting an atomic model of the ligand into an atomic structural model of the ligand binding domain of the estrogen receptor, wherein the atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and carrying out a chemical modification of a first chemical moiety of said ligand that interacts with the ligand binding domain, to produce a second chemical moiety.

47. The method of Claim 46, wherein the atomic structural model additionally comprises coordinates of at least one amino acid residue that corresponds to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said first chemical moiety interacts with at least one of said amino acid residues. W:\iskankA\speles\34571d.doc 188

48. The method of Claim 46 further comprising determining a change in interaction between said interacting amino acid and said ligand after the chemical modification of said first chemical moiety.

49. The method of Claim 48 wherein said chemical modification enhances an interaction selected from the group consisting of: hydrogen bonding interaction, charge interaction, hydrophobic interaction, van der Waals interaction or dipole interaction between said second chemical moiety and one of said amino acid residues compared to said first chemical moiety.

The method of Claim 48 wherein said chemical modification reduces an interaction selected from the group consisting of: hydrogen bonding interaction, charge interaction, hydrophobic interaction, van der Waals interaction or dipole interaction between said second chemical moiety and one of said amino acid residues compared to said first chemical moiety.

51. The method of Claim 46 wherein said nuclear receptor is selected from the group consisting of estrogen receptors, thyroid receptors, retinoid receptors, glucocorticoid receptors, progestin receptors, mineralcorticoid receptors, androgen receptors, peroxisome receptors and vitamin D receptors.

52. The method of Claim 51 wherein said nuclear receptor is an estrogen receptor.

53. The method of Claim 51 wherein the estrogen receptor is the estrogen receptor a.

54. The method of Claim 53 wherein the ligand is an agonist. The method of Claim 54 wherein the ligand is selected from the group consisting of 17p-estradiol, diethylstilbestrol, moxestrol, mesohexestrol, coumestrol, A 9 -THC, o,p-DDT, zearalenone and kepone.

W:\dSkidnkspedeS3457td.doc 189

56. The method of Claim 55 wherein the ligand is 17p-estradiol, and the first chemical moiety is a free carbon of the A' ring located at a position selected from the group consisting of C6a, C7a, C12a, C16a and C17a.

57. The method of Claim 53 wherein the ligand is an antagonist.

58. The method of Claim 57 wherein the ligand is selected from the group consisting of ICI 164,368 and EM800.

59. The method of Claim 53 wherein the ligand is a selective estrogen receptor modulator.

The method of Claim 59 wherein the ligand is selected from the group consisting of tamoxifen, raloxifene and GW5638.

61. 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 fitting an atomic model of the ligand into an atomic structural model of the ligand binding domain of the estrogen receptor, wherein the atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and carrying out a chemical modification of a first chemical moiety of said ligand that interacts with the ligand binding domain, to produce a second chemical moiety.

62. The method of Claim 61 wherein the atomic structural model additionally comprises coordinates of at least one amino acid residue that corresponds to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said first chemical moiety interacts with at least one of said amino acid residues W:\dska\nkspecel34571d.doc 190

63. The method of Claim 61 wherein said ligand is an antagonist.

64. The method of Claim 61 wherein said ligand is an agonist.

The method of Claim 64 further comprising administering a coactivator mimic designed by a computational method that comprises: fitting an atomic model of the mimic into the atomic structural model where at least one amino acid residue of the 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 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, and selecting at least one chemical modification of said first chemical moiety to produce a second chemical moiety that has a structure to either decrease or increase an interaction between said coactivator binding site and said second chemical moiety compared to an interaction between said coactivator binding site and said first chemical moiety.

66. A method according to Claim 1, 14, 46 or 61, substantially as hereinbefore described.

67. A machine readable data storage medium according to claim 31, substantially as hereinbefore described.

68. The method of claim 1 wherein the test compound is an antagonist that permits helix 12 to bind to a static region of the coactivator binding site.

69. The method of claim 1 wherein the atomic structural model has coordinates presented in Appendix 1.

70. The method of Claim 1 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Ala350, Glu353, Leu387, Leu391, Arg394, and Phe404 (wherein the residues are numbered according to the W:\dska9nkIspedes34571d.doc 191 structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues.

71. The method of Claim 1 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Gly 521, His524, Leu525, and either residues Met421 and Met528, or residues Met388 and lle424 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues.

72. The method of Claim 1 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Thr347, Ala350, Trp383, Leu384, Leu387, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

73. The method of Claim 1 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Met421, lie 424, Gly 521, His524, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

74. The method of claim 1 wherein the atomic structural model is experimentally derived.

W:\dskaki\specdes34571d.doc 192 The method of claim 74 wherein the atomic structural model has a resolution of at least 2.03 A.

76. The method of claim 4 wherein the modeling further comprises comparing a second atomic structural model of a portion of the estrogen receptor a ligand binding domain with the atomic structural model, wherein the second atomic structural model comprises atomic coordinates of amino acid residues of helix 12 of the ligand binding domain and of a coactivator binding site, wherein the helix 12 contacts the coactivator binding site, and further comprises atomic coordinates of an antagonist molecule bound to the ligand binding domain.

77. The method of claim 76 wherein the second atomic structural model is experimentally derived.

78. The method of claim 77 wherein the second atomic structural model has a resolution of at least 1.90 A.

79. The method of Claim 14 wherein the test compound is an antagonist that causes a change in position of helix 12 so that helix 12 contacts the coactivator binding site thereby inhibiting coactivator binding.

The method of Claim 14 wherein the test compound is an antagonist that permits helix 12 to bind to a static region of the coactivator binding site.

81. The method of claim 14 wherein the atomic structural model has coordinates presented in Appendix 1.

82. The method of Claim 14 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Ala350, Glu353, Leu387, Leu391, Arg394, and Phe404 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues. W:Mlskasnksped es34571d.doc 193

83. The method of Claim 14 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Gly 521, His524, Leu525, and either residues Met421 and Met528, or residues Met388 and lle424 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues.

84. The method of Claim 14 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Thr347, Ala350, Trp383, Leu384, Leu387, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

The method of Claim 14 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Met421, lie 424, Gly 521, His524, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

86. The method of claim 14 wherein the atomic structural model is experimentally derived.

87. The method of claim 86 wherein the atomic structural model has a resolution of at least 2.03 A. W:\c1skankl\species%34571d.doc 194

88. The method of claim 79 wherein the modeling further comprises comparing a second atomic structural model of a portion of the estrogen receptor a ligand binding domain with the atomic structural model, wherein the second atomic structural model comprises atomic coordinates of amino acid residues of helix 12 of the ligand binding domain and of a coactivator binding site, wherein the helix 12 contacts the coactivator binding site, and further comprises atomic coordinates of an antagonist molecule bound to the ligand binding domain.

89. The method of claim 88 wherein the second atomic structural model is experimentally derived.

The method of claim 89 wherein the second atomic structural model has a resolution of at least 1.90 A.

91. The method of Claim 14 wherein the modeling comprises providing the atomic coordinates of the portion of the estrogen receptor a ligand binding domain to a computerized modeling system.

92. The method of Claim 24 wherein said screening is in vitro.

93. The method of Claim 92 wherein said screening is high throughput screening.

94. The method of Claim 24 wherein said test compound is from a library of compounds.

The method of Claim 24 wherein said test compound facilitates binding of a coactivator to the coactivator binding site.

96. The method of Claim 24 wherein said test compound is a small organic molecule, a peptide, or peptidomimetic.

97. The method of Claim 24 wherein the test compound is an agonist that permits the coactivator molecule to bind to a static region of the coactivator binding site. W:\clskanrl\species\34571d.doc 195

98. The method of Claim 24 wherein the modeling comprises providing the atomic coordinates of the portion of the estrogen receptor a ligand binding domain to a computerized modeling system.

99. The method of Claim 24 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Ala350, Glu353, Leu387, Leu391, Arg394, and Phe404 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues.

100. The method of Claim 24 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Gly 521, His524, Leu525, and either residues Met421 and Met528, or residues Met388 and Ile424 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an agonist that interacts with at least one of said amino acid residues. 20

101. The method of claim 24 wherein the atomic structural model is experimentally derived.

102. The method of claim 101 wherein the atomic structural model has a resolution of at least 2.03 A.

103. The method of claim 24 wherein the atomic structural model has coordinates presented in Appendix 1.

104. A method for identifying an antagonist of ligand binding to an estrogen receptor, the method comprising: W:clskfVid\species\34571d.doc 196 modeling a test compound which fits spatially into an atomic structural model of the estrogen receptor a ligand binding domain, wherein the atomic structural model comprises atomic coordinates of helix 12 of the ligand binding domain, and of a coactivator binding site, and further comprises atomic coordinates of a coactivator bound to the coactivator binding site; and screening in an assay for estrogen receptor activity a compound which decreases the activity of the estrogen receptor by binding the ligand binding domain of the estrogen receptor, thereby identifying an agonist of ligand binding.

105. The method of Claim 104 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Ala350, Glu353, Leu384, Leu387, Leu391, Arg394, Phe404, Met421, Leu428, Gly521, His524, Leu525 and Met528 (wherein the residues are numbered according to the structure of Appendix and wherein said test compound interacts with at least one of said amino acid residues.

106. The method of Claim 104 wherein said screening is in vitro.

107. The method of Claim 106 wherein said screening is high throughput screening.

108. The method of Claim 104 wherein said test compound is from a library of compounds.

109. The method of Claim 104 wherein the test compound is an antagonist that causes a change in position of helix 12 so that helix 12 contacts the coactivator binding site thereby inhibiting coactivator binding.

110. The method of Claim 104 wherein the test compound is an antagonist that permits helix 12 to bind to a static region of the coactivator binding site. W:\ciskabnkilspedes\34571d.doc 197

111. The method of claim 104 wherein the modeling further comprises comparing a second atomic structural model of a portion of the estrogen receptor a ligand binding domain with the atomic structural model, wherein the second atomic structural model comprises atomic coordinates of amino acid residues of helix 12 of the ligand binding domain and of a coactivator binding site, wherein the helix 12 contacts the coactivator binding site, and further comprises atomic coordinates of an antagonist molecule bound to the ligand binding domain.

112. The method of Claim 104 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Thr347, Ala350, Trp383, Leu384, Leu387, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

113. The method of Claim 104 wherein the atomic structural model additionally comprises coordinates of amino acid residues that correspond to human estrogen receptor a residues Met343, Leu346, Met421, lie 424, Gly 521, His524, and Leu525 (wherein the residues are numbered according to the structure of Appendix wherein said residues lie on a surface of a binding pocket in the ligand binding domain, and wherein said test compound is an antagonist that interacts with at least one of said amino acid residues.

114. The method of claim 104 wherein the atomic structural model is experimentally derived.

115. The method of claim 114 wherein the atomic structural model has a resolution of at least 2.03 A. W:\ciskank\species\34571d.doc 198

116. The method of claim 104 wherein the atomic structural model has coordinates presented in Appendix 1.

117. The method of claim 111 wherein the second atomic structural model is experimentally derived.

118. The method of claim 117 wherein the second atomic structural model has a resolution of at least 1.90 A.

119. The method of Claim 107 wherein the modeling comprises providing the atomic coordinates of the portion of the estrogen receptor a ligand binding domain to a computerized modeling system.

120. A method of modulating estrogen 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 an atomic structural model of a ligand binding domain of the estrogen receptor wherein said compound is designed so that binding of a coactivator to a coactivator binding site on the ligand binding domain is affected.

121. The method of claim 120 wherein said compound is an antagonist and binding of a coactivator is inhibited.

122. The method of claim 91 or 114 wherein the second atomic structure model has coordinates presented in Appendix 2. DATED: 29 October, 2003 PHILLIPS ORMONDE FITZPATRICK Attorneys for: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA and ARCH DEVELOPMENT CORPORATION W: dskadbnkAspees34571ddoc