AU733479B2 - Crystal structure and mutants of interleukin-1beta converting enzyme - Google Patents

Description

~A

1

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Actual Inventors:

VERTEX

INCORPORATED

PHARMACEUTICALS

Keith P WILSON, James P GRIFFITH, Eunice E KIM, David J LIVINGSTON 00 0 00 0000 0@ 00 0 *0 Address for Service: CULLEN CO., Patent Trade Mark Attorneys, 240 Queen Street, Brisbane, QId. 4000, Australia.

Invention Title: CRYSTAL STRUCTURE AND MUTANTS OF INTERLEUKIN-11 CONVERTING

ENZYME

Divisional Application of 27055/95 filed 16.6.95 The following, statement is a full description of this invention, including the best method of performing it known to us -la- CRYSTAL STRUCTURE AND MUTANTS OF INTERLEUKIN-1S CONVERTING ENZYME TECHNICAL FIELD OF INVENTION

S

The present invention relates to crystals of S 5 interleukin-1 converting enzyme and more particularly to the high resolution structure of ICE obtained by X-ray diffraction. This invention also relates to mutants of ICE. In addition, this invention relates to methods of using the structure coordinates of ICE and mutants thereof to screen and design compounds that bind to the active site and accessory binding site of ICE.

BACKGROUND ART Interleukin-1 is a major proinflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J.H. et al, Immunology Today, 7, pp. 45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes and exists in two distinct .agonist forms, IL-la and IL- 1. Mosely, B.S. et al., Proc. Nat. Acad. Sci., 84, 2 pp. 4572-4576 (1987); Lonnemann G. et al., Eur.J.

Immunol., 19, pp. 1531-1536 (1989).

IL-1 is synthesized as a biologically inactive precursor, pIL-19. pIL-1 is a 33kDa polypeptide that lacks a conventional leader sequence and is not processed by a signal peptidase. March, Nature, 315, pp. 641-647 (1985). Instead, pIL-1S is cleaved by interleukin-1i converting enzyme ("ICE") between Asp 116 and Ala 117 to produce the biologically 10 active C-terminal fragment of 17kDa molecular weight found in serum and synovial fluid. Sleath, P.R.

Set al., J. Biol. Chem., 265, pp. 14526-14528 (1992); Howard, A.D. et al., J. Immunol., 147, pp. 2964-2969 (1991). Processing by ICE is also necessary for the 15 transport of mature IL-1 through the cell membrane.

ICE is a cysteine protease localized primarily in monocytes. It converts precursor IL-1~ to the mature form. Black, R.A. et al., FEBS Lett., 247, pp. 386-390 (1989); Kostura, M.J. et al., Proc. Natl.

20 Acad. Sci. USA, 86, pp. 5227-5231 (1989). ICE, or its homologues, also appears to be involved in the regulation of cell death or apoptosis. Yuan, J.

et al., Cell, 75, pp. 641-652 (1993); Miura, M. et al., Cell, 75, pp. 653-660 (1993); Nett-Fiordalisi, M.A.

S 25 et al., J. Cell Biochem., 17B, p. 117 (1993). In particular, ICE or ICE homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer's and Parkinson's disease. Marx, J. and M. Baringa, Science, 259, pp. 760-762 (1993); Gagliardini, V. et al., Science, 263, pp. 826-828 (1994).

ICE has been previously described as a heterodimer composed of two subunits, p20 and and 10kDa molecular weight, respectively).

These subunits are derived from a 45kDa proenzyme 3 by way of a p30 form, through an activation mechanism that is autocatalytic. Thornberry, N.A. et al., Nature, 356, pp. 768-774 (1992). The ICE proenzyme has been divided into several functional domains: a prodomain (p14), a p22/ 2 0 subunit, a polypeptide linker and a pl0 subunit. Thornberrv et al., supra; Casano et al., Genomics, 20, pp. 474-481 (1994).

Full length p45 has been characterized by its cDNA and amino acid sequences. PCT patent applications 10 WO 91/15577 and WO 94/00154. The p20 and pl0 cDNA and amino acid sequences are also known. Thornberry 4 et al., supra. Murine and rat ICE have also been .sequenced and cloned. They have high amino acid and nucleic acid sequence homology to human ICE. Miller, 15 D.K. et al., Ann. N.Y. Acad. Sci., 696, pp. 133-148 (1993); Molineaux, S.M. et al., Proc. Nat. Acad. Sci., pp. 1809-1813 (1993). Knowledge of the primary structure of ICE, however, does not allow prediction of its tertiary structure. Nor does it afford an 20 understanding of the structural, conformational and chemical interactions of ICE and its substrate pIL-19 or other substrates or inhibitors.

ICE inhibitors represent a class of compounds useful for the control of inflammation or apoptosis or 25 both. Peptide and peptidyl inhibitors of ICE have been .described. PCT patent applications WO 91/15577; WO 93/05071; WO 93/09135; WO 93/14777 and WO 93/16710; and European patent application 0 547 699. However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J.J. and D.W. Norbeck, in Drug Discovery Technologies, C.R. Clark and W.H. Moos, Eds.

(Ellis Horwood, Chichester, England, 1990), pp. 92- 4 126. This has hampered their development into effective drugs.

SUMMARY OF THE INVENTION The present invention solves the above problems.

It is an object of this invention to solve the three-dimensional structure of interleukin-l8 converting enzyme and to determine its structure coordinates.

10 It is an object of this invention to use the structure coordinates of an ICE crystal to reveal the atomic details of the active site and one or more accessory binding sites of the enzyme.

It is also an object of this invention to use the structure coordinates of an ICE crystal to solve the structure of a different ICE crystal, or a crystal of a mutant, homologue or co-complex, of ICE.

It is a further object of this invention to provide interleukin-1i converting enzyme mutants characterized by one or more different properties as compared with wild-type ICE. These properties include altered surface charge, increased stability to subunit dissociation, altered substrate specificity or higher specific activity. ICE mutants are useful to identify those amino acids that are most important for the enzymatic activity of ICE. This information, in turn, allows the design of improved inhibitors of ICE as compared with peptidic ICE inhibitors.

It is also an object of this invention to use the structure coordinates and atomic details of ICE, or its mutants or homologues or co-complexes, to design, evaluate computationally, synthesize and use inhibitors of ICE that avoid the undesirable physical and pharmacologic properties of peptidic ICE inhibitors.

*1 I1 5 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents a ribbon drawing of the p20/pl0 interleukin-1S converting enzyme heterodimer.

The active site is at the top of the figure, roughly at the center of the cluster of displayed side chains.

Figure 2 represents a space-filling model of the (p20) 2 /(pl0) 2 tetramer of interleukin-1S converting enzyme. Two p20 subunits (dark shade) are in contact with two pl0 subunits (light shade). Black shading on 0 top left and bottom right represents a tetrapeptide aldehyde inhibitor bound in each of the two active S sites of the tetramer. The crystallographic two-fold s.,s axis is approximately perpendicular to the plane of *0r drawing, and runs through the small hole at the center of the interface between the two pl0 subunits. The Nand C-terminal ends qf each subunit are labeled.

Figure 3 is a graphic depiction of the activity of various interleukin-18 converting enzyme mutants in processing pIL-19 intracellularly, relative to wild-type interleukin-1i converting enzyme activity.

The particular mutants tested are designated on the x-axis using nomenclature listing the specific amino Sacid and its residue number. For example, "C285S" indicates replacement of amino acid Cys-285 with serine. Activity levels were measured at 16 hours (hatched.bar) and 24 hours (solid bars).

BRIEF DESCRIPTION OF THE TABLES Table A lists the amino acids of ICE that constitute the tetramer interface contacts between the ICE subunits and that constitute the accessory binding site moiety.

Table B lists the atomic structure coordinates for ICE as derived by X-ray diffraction 4.

I~ It.

-6from a crystal of ICE complexed to a tetrapeptide inhibitor.

ABBREVIATIONS AND DEFINITIONS

ABBREVIATIONS

S. Se 0@ S

S

S

0

*SSOO@

6 *5 0e 0

S.

5 0

S.

S S OS S 0S S 0 S 0@ *50S00

S

0@ 0

OS

0 Amino Acic A Ala V =Val L Leu I Ile 10 P Pro F Phe W Trp M Met G Gly S Ser T Thr C Cys Y Tyr= N Asn 20 Q Gin D Asp E Glu K Lys R Arg 25 H His Alanine Valine Leucime Isoleucine Prolime Phenylalanine Tryptophan Methionine Glycine Serine Threonine Cysteine Tyrosine Asparagine Glutamine Aspartic Acid Glutamic Acid Lysine Arginine Histidine

DEFINITIONS

The following terms are also used herein: The term "naturally occurring amino acids" means the L-isomers of the naturally occurring amino acids. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic 7 acid, asparagine, glutamic acid, glutamine, y-carboxyglutamic acid, arginine, ornithine and lysine.

Unless specifically indicated, all amino acids referred to in this application are in the L-form.

The term "unnatural amino acids" means amino acids that are not naturally found in proteins.

Examples of unnatural amino acids used herein, include racemic mixtures of selenocysteine and selenomethionine. In addition, unnatural amino acids include the D or L forms of nor-leucine, paranitrophenylalanine, homophenylalanine, parafluorophenylalanine, 3-amino-2-benzylpropionic acid, homoarginine, and D-phenylalanine.

The term "positively charged amino acid" 15 includes any naturally occurring or unnatural amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged naturally occurring amino acids are arginine, lysine and histidine.

20 The term "negatively charged amino acid" includes any naturally occurring or unnatural amino acid having a negatively charged side chain under normal physiological conditions. Examples of negatively charged naturally occurring amino acids are aspartic acid and glutamic acid.

The term "hydrophobic amino acid" means any amino acid having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine.

The term "hydrophilic amino acid" means any amino acid having an uncharged, polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids are serine, infra, 8 threonine, tyrosine, asparagine, glutamine, and cysteine.

The term "mutant" refers to an ICE polypeptide, a polypeptide displaying the biological activity of wild-type, human ICE, characterized by the replacement of at least one amino acid from the wild-type, human ICE sequence according to Thornberry, N.A. et al., Nature, 356, pp. 768-774 (1992). Such a mutant may be prepared, for example, by expression of ICE cDNA previously altered in its coding sequence by oligonucleotide-directed mutagenesis.

ICE mutants may also be generated by sitespecific incorporation of unnatural amino acids into ICE proteins using the general biosynthetic method of 15 Noren, et al., Science, 244, pp. 182-188 (1989).

In this method, the codon encoding the amino acid of interest in wild-type ICE is replaced by a "blank" nonsense codon, TAG, using oligonucleotide-directed mutagenesis (described in detail, infra). A suppressor 20 tRNA directed against this codon is then chemically aminoacylated in vitro with the desired unnatural amino acid. The aminoacylated tRNA is then added to an in I vitro translation system to yield a mutant ICE enzyme with the site-specific incorporated unnatural amino acid.

Selenocysteine or selenomethionine may be incorporated into wild-type or mutant ICE by expression of ICE-encoding cDNAs in auxotrophic E. coli strains.

Hendrickson, W.A. et al., EMBO pp. 1665-1672 (1990). In this method, the wild-type or mutagenized ICE cDNA may be expressed in a host organism on a growth medium depleted of either natural cysteine or methionine (or both) but enriched in selenocysteine or selenomethionine (or both).

9 The term "altered surface charge" means a change in one or more of the charge units of a mutant polypeptide, at physiological pH, as compared to wildtype ICE. This is preferably achieved by mutation of at least one amino acid of wild-type ICE to an amino acid comprising a side chain with a different charge at physiological pH than the original wild-type side chain.

The change in surface charge is determined by measuring the isoelectric point (pI) of the polypeptide molecule containing the substituted amino acid and comparing it to the isoelectric point of the wild-type ICE molecule.

SThe term "high specific activity" refers to a 15 specific activity of ICE where the second-order rate constant (kcat/Km) for hydrolysis of the substrate Ac- Tyr-Val-Ala-Asp-aminomethylcoumarin exceeds 7 x 104 M-1s-1 at 250C, using the assay described by Pennington, M.W. and N.A. Thornberry, Peptide Res., pp. 72- 20 76 (1994). Alternatively, the specific activity of ICE may be determined by monitoring hydrolysis of the substrate Ac-Tyr-Val-Ala-Asp-p-nitroaniline. Reiter, Intr. J. Peptide Protein Res., 43, pp. 8796 (1994).

The term "altered substrate specificity" refers to a change in the ability of a mutant ICE to cleave a substrate as compared to wild-type ICE.

Substrate specificity may be measured by hydrolysis of fluorogenic peptide substrates or of unmodified peptide substrates by ICE, as described in Thornberrv et al., supra. ICE mutants with altered substrate specificity demonstrate a second order rate constant (kcat/Km) for a substrate X 1 -Tyr-Val-Ala-X 2

-X

3 that exceeds the kcat/Km for the analogous peptide substrate X 1 -Tyr-Val-Ala- Asp-X 3 For both substrates, X 1 is an amino protecting 10 group, such as acetyl; X 2 is a natural or unnatural amino acid residue other than L-aspartate; and X 3 is a carboxyl protecting group, such as aminomethylcoumarin or p-nitroaniline.

The "kinetic form" of ICE refers to the condition of the enzyme in its free or unbound form or bound to a chemical entity at either its active site or accessory binding site.

A "competitive" inhibitor is one that 10 inhibits ICE activity by binding to the same kinetic 55 form, of ICE, as its substrate binds thus directly competing with the substrate for the active site of ICE. Competitive inhibition can be reversed completely by increasing the substrate concentration.

15 An "uncompetitive" inhibitor is one that inhibits ICE by binding to a different kinetic form of the enzyme than does the substrate. Such inhibitors bind to ICE already bound with the substrate and not to the free enzyme. Uncompetitive inhibition cannot be 20 reversed completely by increasing the substrate concentration.

A "non-competitive" inhibitor is one that can bind to either the free or substrate bound form of ICE.

Those of skill in the art may identify inhibitors as competitive, uncompetitive or noncompetitive, by computer fitting enzyme kinetic data using standard equations according to Segel, I.H., Enzyme Kinetics, J...Wiley Sons, (1975). It should also be understood that uncompetitive or noncompetitive inhibitors according to this invention may bind to the accessory binding site.

The term "homologue" means a protein having at least 30% amino acid sequence identity with ICE or any functional domain of ICE as defined by Thornberry et al., supra and Casano et al., supra.

11 The term "subunit dissociation" refers to the fact that at very high dilutions of wild-type ICE, or at concentrations of the enzyme below 10 nM, enzymatic activity shows a time dependent loss assayed in the presence of a tetrapeptide substrate. Reconcentration of the dilute, inactive mixture results in complete recovery of ICE activity. Wild-type ICE demonstrates a Kd for subunit dissociation between 1 and 10 nM.

Enzymatic activity is determined by measuring the 10 activity of ICE according to the assay of PenninQton 0* and Thornberrv, supra, at varying concentrations of the enzyme. The concentration of the enzyme is determined by active site titration.

The term "co-complex" means ICE or a mutant 15 or homologue of ICE in covalent or non-covalent association with a chemical entity or compound.

The term "associating with" refers to a condition of proximity between a chemical entity or compound, or portions thereof, and an ICE molecule or 20 portions thereof. The association may be noncovalent wherein the juxtaposition is energetically favored by hydrogen bonding or van der Waals or electrostatic interactions or it may be covalent.

The term "1-sheet" refers to the conformation of a polypeptide chain stretched into an extended zigzig conformation. Portions of polypeptide chains that run "parallel" all run in the same direction.

Polypeptide chains that are "antiparallel" run in the opposite direction from the parallel chains.

The term "active site" or "active site moiety" refers to any or all of the following sites in ICE: the substrate binding site; the site where the tetrapeptide inhibitor binds and the site where the cleavage of a substrate occurs. The active site is characterized by at least amino acid residues 173, 176, 12 177, 178, 179, 180, 236, 237, 238, 239, 244, 248, 283, 284, 285, 290, 338, 339, 340, 341, 342, 343, 344, 345, 348, 352, 381 and 383, using the sequence and numbering according to Thornberry et al., supra (SEQ ID NO:1).

The term "accessory binding site" or "accessory binding site moiety" refers to a binding site of ICE comprising amino acid residues adjacent to the two-fold axis of ICE but external to the active site, according to Table A. An accessory binding site may be a locus of ICE inhibition, although it is not S* the site of substrate cleavage.

The accessory binding site is characterized by at least amino acid residues 150, 151, 240, 259, 267, 268, 274, 291, 292, 293, 294, 295, 296, 297, 317, 15 318, 319, 320, 321, 322, 323, 324, 325, 327, 33.4, 335, 367, 371, 374, 375, 377, 378, 380, 382, 384, 386, 388, 389, 390, 391, 392, 393, 394, 395 and 396, using the sequence and numbering according to Thornberrv et al., supra (SEQ ID NO:1).

20 The term "P binding pocket" refers to a binding subsite, or portion of the binding site on the o.0 ICE molecule. The amino acid residues of an ICE substrate are given designations according to their position relative to the scissile bond, i.e. the bond that is broken by the protease. Residues are designated P1, P2, etc., for those extending toward the N-terminus from the scissile bond of the substrate.

The residues are designated P1', P2', etc., for those extending toward the C-terminus from the scissile bond of the substrate.

The portions of an ICE inhibitor that correspond to the P or P' residues of the substrate are also labeled P1, Pl', etc., by analogy with the substrate. The binding subsites of the ICE molecule that receive the residues labeled P1, Pl', etc., are 13 designated "the S1 site", "the PI' binding pocket", etc. Schechter, I. and A. Berger, "On the Size of the Active Site in Proteases", Biochem. Biophys. Res.

Commun., 27, pp. 157-162 (1967).

The "P1 binding pocket" of the ICE active site is defined as the space surrounded by amino acid residues Arg-179, His-237, Gln-283 and Arg-341.

The "P2 binding pocket" of the ICE active site is defined as the space surrounded by amino acid residues Pro-290, Val-338 and Trp-340.

The "P3 binding pocket" of the ICE active 0 site is defined as the space surrounded by amino acid residues Pro-177, Arg-178, Thr-180, Arg-341 and Pro-343.

*0 15 The "P4 binding pocket" of the ICE active site is defined as the space surrounded by amino acid residues Trp-340, His-342, Met-345, Val-348, Arg-352, Asp-381 and Arg-383.

The binding pocket" of the ICE active 20 site is defined as the space surrounded by amino acid residues Phe-173, Ile-176, His-237, Gly-238, Ile-239, Cys-244 and His-248.

The term "pl0 subunits interacting across the t: two-fold axis" means having at least 50% of the interface contacts according to Table A.

The term "structure coordinates" refers to mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of an ICE molecule in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.

14 The term "heavy atom derivatization" refers to the method of producing a chemically modified form of a crystal of ICE. In practice, a crystal is soaked in a solution containing heavy metal atom salts, or organometallic compounds, lead chloride, gold thiomalate, thimerosal or uranyl acetate, which can diffuse through the crystal and bind to the surface of the protein. The location(s) of the bound heavy metal atom(s) can be determined by X-ray diffraction analysis of the soaked crystal. This information, in turn, is a. 6a used to generate the phase information used to construct three-dimensional structure of the enzyme.

Blundel, T.L. and N.L. Johnson, Protein Crystallography, Academic Press (1976).

15 Those of skill in the art understand that a ID,. set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this invention, any set of structure coordinates for ICE or ICE homologues or ICE mutants 20 that have a root mean square deviation of protein backbone atoms Ca, C and 0) of less than 0.75A when .0 superimposed using backbone atoms on the 2 structure coordinates listed in Table B shall be .ee: considered identical.

0 The term "unit cell" refers to a basic parallelipiped shaped block. The entire volume of a crystal may be constructed by regular assembly of such blocks. Each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal.

The term "space group" refers to the arrangement of symmetry elements of a crystal.

The term "molecular replacement" refers to a method that involves generating a preliminary model of an ICE crystal whose structure coordinates are unknown, 15 by orienting and positioning a molecule whose structure coordinates are known ICE coordinates from Table B) within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal. Lattman, "Use of the Rotation and Translation Functions", in Methods in Enzvmology, 115, pp. 55-77 (1985); M.G. Rossmann, ed., "The Molecular Replacement Method", Int. Sci. Rev. Ser., 15 No. 13, Gordon Breach, New York, (1972). Using the structure coordinates of ICE provided by this invention, molecular replacement may be used to determine the structure coordinates of a crystalline mutant or homologue of ICE or of a different crystal 20 form of ICE.

0* OS 0 0 0@ S OS e

S

S*O

S.

0O 0 55 S DETAILED DESCRIPTION OF THE INVENTION 0

S

S

S* S In order that the invention described herein may be more fully understood, the following detailed description is set forth.

25 The present invention relates to crystalline interleukin-11 converting enzyme the structure of ICE as determined by X-ray crystallography, the use of that structure to solve the structure of ICE homologues and of other crystal forms of ICE, mutants and co-complexes of ICE, and the use of the ICE structure and that of its homologues, mutants and cocomplexes to design inhibitors of ICE.

16 A. The Structure of ICE The present invention provides, for the first time, crystals of human ICE grown in the presence of a tetrapeptide inhibitor from solutions of polyethylene glycol, as well as the structure of ICE as determined therefrom. The crystals have tetragonal space group symmetry P4 3 2 1 2. The unit cell of said crystals has a rectangular shape of dimensions a=b=65 5A, and c=162 5A. The structure coordinates of ICE, as determined by X-ray crystallography of crystalline ICE, are listed in Table B.

Crystal packing reveals that ICE is a (p20) 2 /(pl0) 2 tetramer. In the tetramer, two subunits contact two adjacent pl0 subunits which 15 interact across the crystallographic two-fold axis (Figure This axis corresponds to an oligomer interface in solution. Most of the dimer-dimer interface consists of p20 residues 291-297 and of residues 318-322 and 386-396.

20 Figure 1 represents a ribbon drawing of the p20/pl0 ICE heterodimer. As depicted in the figure, the p20 and pl0 subunits are intimately associated and the active site is at the top of the figure, roughly at "the center of the cluster of displayed side chains.

The enzyme core is a six-stranded 6-sheet with 5 parallel strands (numbered 1, 2, 3, 4 and 7) and one anti-parallel strand (numbered Six a-helices (lettered A, B, E and F) lie roughly parallel to the 9-strands. The last seven residues of p20 and the first seven of p10 protrude from this compact structure and form two anti-parallel g-strands [5 (residues 291- 297)] and 6 (residues 317-323)]. A few key residues are labelled according to their position in the amino acid sequence of ICE (Thornberrv et al., supra) 17 0@ OS

S

S

555.05 *5

SO

0 00

S

55 000@

S

5@ 0 *5 S 0

S.

*5@5e0 0 Our understanding of the structure of ICE has enabled, for the first time, identification of the active site and accessory binding site of the enzyme.

The p10 subunit from one ICE molecule contacts the subunit from a different molecule and together they create an active site. The active site spans both the and p10 subunits and comprises amino acid residues from both subunits. The active site moiety is characterized by at least amino acid residues 173, 176, 177, 178, 179, 180, 236, 237, 238, 239, 244, 248, 283, 284, 285, 290, 338, 339, 340, 341, 342, 343, 344, 345, 348, 352, 381 and 383 using the sequence numbering according to Thornberrv et al., supra (SEQ ID NO:1).

An accessory binding site is formed by amino 15 acid residues on the p10 subunits that interact across the two-fold axis. The accessory binding site moiety is characterized by at least amino acid residues 150, 151, 240, 259, 267, 268, 274, 291, 292, 293, 294, 295, 296, 297, 317, 318, 319, 320, 321, 322, 323, 324, 325, 20 327, 334, 335, 367, 371, 374, 375, 377, 378, 378, 380, 382, 384, 386, 388, 389, 390, 391, 392, 393, 394, 395 and 396 using the sequence numbering according to Thornberrv et al., supra (SEQ ID NO:1).

B. Uses of the Structure Coordinates of ICE 25 For the first time, the present invention permits the use of molecular design techniques to design, select and synthesize chemical entities and compounds, including inhibitory compounds, capable of binding to the active site or accessory binding site of ICE, in whole or in part.

On approach enabled by this invention, is to use the structure coordinates of ICE to design compounds that bind to the enzyme and alter the physical properties of the compounds in different ways, 18 solubility. For example, this invention enables the design of compounds that act as competitive inhibitors of the ICE enzyme by binding to, all or a portion of, the active site of ICE. This invention also enables the design of compounds that act as uncompetitive inhibitors of the ICE enzyme. These inhibitors may bind to, all or a portion of, the accessory binding site of an ICE already bound to its substrate and may be more potent and less non-specific than known competitive inhibitors that compete only for the ICE active site. Similarly, non-competitive inhibitors that bind to and inhibit ICE whether or not se ~it is bound to another chemical entity may be designed using the structure coordinates of ICE of this S15 invention.

*0*s A second design approach is to probe an ICE crystal with molecules composed of a variety of different chemical entities to determine optimal sites for interaction between candidate ICE inhibitors and 20 the enzyme. For example, high resolution X-ray diffraction data collected from crystals saturated with eo 5 solvent allows the determination of where each type of solvent molecule sticks. Small molecules that bind .tightly to those sites can then be designed and synthesized and tested for their ICE inhibitor activity. Travis, Science, 262, p. 1374 (1993).

This invention also enables the development of compounds that can isomerize to short-lived reaction intermediates in the chemical reaction of a substrate or other compound that binds to ICE, with ICE. Thus, the time-dependent analysis of structural changes in ICE during its interaction with other molecules is enabled. The reaction intermediates of ICE can also be deduced from the reaction product in co-complex with ICE. Such information is useful to design improved 19 analogues of known ICE inhibitors or to design novel classes of inhibitors based on the reaction intermediates of the ICE enzyme and ICE-inhibitor cocomplex. This provides a novel route for designing ICE inhibitors with both high specificity and stability.

Another approach made possible and enabled by this invention, is to screen computationally small molecule data bases for chemical entities or compounds that can bind in whole, or in part, to the ICE enzyme.

In this screening, the quality of fit of such entities :0 *.or compounds to the binding site may be judged either by shape complementarity or by estimated interaction energy. Meng, E.C. et al., J. Comp. Chem., 13, pp. 505-524 (1992) 15 Because ICE may crystallize in more than one oooo crystal form, the structure coordinates of ICE, or portions thereof, as provided by this invention are particularly useful to solve the structure of those other crystal forms of ICE. They may also be used to solve the structure of ICE mutants, ICE co-complexes, or of the crystalline form of any other protein with significant amino acid sequence homology to any functional domain of ICE.

One method that may be employed for this ooo purpose is molecular replacement. In this method, the unknown crystal structure, whether it is another crystal form of ICE, an ICE mutant, or an ICE cocomplex, or the crystal of-some other protein with significant amino acid sequence homology to any functional domain of ICE, may be determined using the ICE structure coordinates of this invention as provided in Table B. This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

I 20 In addition, in accordance with this invention, ICE mutants may be crystallized in cocomplex with known ICE inhibitors. The crystal structures of a series of such complexes may then be solved by molecular replacement and compared with that of wild-type ICE. Potential sites for modification within the various binding sites of the enzyme may thus be identified. This information provides an additional tool for determining the most efficient binding interactions, for example, increased hydrophobic interactions, between ICE and a chemical entity or compound.

All of the complexes referred to above may be Sstudied using well-known X-ray diffraction techniques 15 and may be refined versus 2-3A resolution X-ray data to an R value of about 0.20 or less using computer software, such as X-PLOR (Yale University, ©1992, distributed by Molecular Simulations, Inc.). See, Blundel Johnson, supra; Methods in Enzvmoloyv, 20 vol. 114 115, H.W. Wyckoff et al., eds., Academic Press (1985). This information may thus be used to optimize known classes of ICE inhibitors, and more importantly, to design and synthesize novel classes of ICE inhibitors.

The structure coordinates of ICE mutants provided in this invention also facilitate the identification of related proteins or enzymes analogous to ICE in function,. structure or both, thereby further leading to novel therapeutic modes for treating or preventing IL-I mediated diseases.

The design of compounds that bind to or inhibit ICE according to this invention generally involves consideration of two factors. First, the compound must be capable of physically and structurally associating with ICE. Non-covalent molecular 21 interactions important in the association of ICE with its substrate include hydrogen bonding, van der Waals and hydrophobic interactions.

Second, the compound must be able to assume a conformation that allows it to associate with ICE.

Although certain portions of the compound will not directly participate in this association with ICE, those portions may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on potency. Such conformational l ~requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the binding site, active site or accessory binding site of 4, e 15 ICE, or the spacing .between functional groups of a compound comprising several chemical entities that 49 e directly interact with ICE.

The potential inhibitory or binding effect of a chemical compound on ICE may be analyzed prior to its 20 actual synthesis and testing by the use of computer o modelling techniques. If the theoretical structure of the given compound suggests insufficient interaction and association between it and ICE, synthesis and SE 2 testing of the compound is obviated. However, if computer modelling indicates a strong interaction, the molecule may then be synthesized and tested for its Sability to bind to ICE and inhibit using the fluorescent substrate assay of Thornberrv et al., supra. In this manner, synthesis of inoperative compounds may be avoided.

An inhibitory or other binding compound of ICE may be computationally evaluated and designed by means of a series of steps in which chemical entities or fragments are screened and selected for their 22 ability to associate with the individual binding pockets or other areas of ICE.

One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with ICE and more particularly with the individual binding pockets of the ICE active site or accessory binding site. This process may begin by visual inspection of, for example, the active site on the computer screen based on the ICE coordinates in Table B. Selected fragments or chemical I* entities may then be positioned in a variety of orientations, or docked, within an individual binding pocket of ICE as defined supra. Docking may be S* accomplished using software such as Quanta and Sybyl, 15 followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARMM and AMBER.

Specialized computer programs may also assist in the process of selecting fragments or chemical 20 entities. These include: 1. GRID (Goodford, "A Computational Procedure S* for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules", J. Med. Chem., 28, pp. 849-857 (1985)). GRID is S 25 available from Oxford University, Oxford, UK.

2. MCSS (Miranker, A. and M. Karplus, "Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method. Proteins: Structure. Function and Genetics, 11, pp. 29-34 (1991)). MCSS is available from Molecular Simulations, Burlington, MA.

3. AUTODOCK (Goodsell, D.S. and A.J. Olsen, "Automated Docking of Substrates to Proteins by Simulated Annealing", Proteins: Structure, Function, and Genetics, 8, pp. 195-202 (1990)) AUTODOCK is available from Scripps Research Institute, La Jolla, CA.

4. DOCK (Kuntz, I.D. et al., "A Geometric Approach to Macromolecule-Ligand Interactions", J. Mol.

Biol., 161, pp. 269-288 (1982)) DOCK is 23 available from University of California, San Francisco, CA.

Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or inhibitor. Assembly may be proceed 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 ICE. This would 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: 1. CAVEAT (Bartlett, P.A. et al, "CAVEAT: A Program S 15 to Facilitate the Structure-Derived Design of Biologically Active Molecules". In Molecular to•* Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc., 78, pp. 182-196 (1989)). CAVEAT is available from the University of California, Berkeley, CA.

2. 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, CA). This area is reviewed in Martin, "3D Database Searching in Drug Design", J. Med. Chem., pp. 2145-2154 (1992)).

0 3. HOOK (available from Molecular Simulations, Burlington, MA).

Instead of proceeding to build an ICE inhibitor in a step-wise fashion one fragment or chemical entity at a time as described above, inhibitory or other ICE binding compounds may be designed as a whole or "de novo" using either an empty active site or optionally including some portion(s) of a known inhibitor(s). These methods include: 1. LUDI (Bohm, "The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors", J. Comp. Aid. Molec. Design, 6, pp. 61-78 (1992)). LUDI is available from Biosym Technologies, San Diego, CA.

24 2. LEGEND (Nishibata, Y. and A. Itai, Tetrahedron, 47, p. 8985 (1991)). LEGEND is available from Molecular Simulations, Burlington, MA.

3. LeapFrog (available from Tripos Associates, St. Louis, MO).

Other molecular modelling techniques may also be employed in accordance with this invention. See, Cohen, N.C. et al., "Molecular Modeling Software and Methods for Medicinal Chemistry, J. Med. Chem., 33, pp. 883-894 (1990). See also, Navia, M.A. and M.A.

*l Murcko, "The Use of Structural Information in Drug Design", Current Opinions in Structural Biolov, 2, pp. 202-210 (1992).

Once a compound has been designed or selected 15 by the above methods, the efficiency with which that compound may bind to ICE may be tested and optimized by computational evaluation. For example, a compound that has been designed or selected to function as an ICEinhibitor must also preferably traverse a volume not 20 overlapping that occupied by the active site when it is bound to the native substrate. An effective ICE inhibitor must preferably demonstrate a relatively small difference in energy between its bound and free states a small deformation energy of binding).

25 Thus, the most efficient ICE inhibitors should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole, preferably, not greater than 7 kcal/mole. ICE inhibitors may interact with the enzyme in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the inhibitor binds to the enzyme.

25 A compound designed or selected as binding to ICE may be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target enzyme. Such non-complementary electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the inhibitor and the enzyme when the inhibitor is bound to ICE, preferably make a neutral or favorable contribution to I* 'f the enthalpy of binding.

SSpecific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs 15 designed for such uses include: Gaussian 92, revision 6&C Frisch, Gaussian, Inc., Pittsburgh, PA 01992]; AMBER, version 4.0 Kollman, University of California at San Francisco, @1994]; QUANTA/CHARMM [Molecular Simulations, Inc., Burlington, MA 01994]; L A 20 and Insight II/Discover (Biosysm Technologies Inc., San Diego, CA @1994). These programs may be implemented, for instance, using a Silicon Graphics e workstation, IRIS 4D/35 or IBM RISC/6000 workstation model 550. Other hardware systems and software packages will be known to those skilled in the art.

Once an ICE-binding compound has been optimally selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted 26 chemical compounds may then be analyzed for efficiency of fit to ICE by the same computer methods described in detail, above.

C. Mutants Of ICE The present invention also enables mutants of ICE and the solving of their crystal structure. More particularly, by virtue of the present invention, the location of the active site, accessory binding site and interface of ICE based on its crystal structure permits 0 the identification of desirable sites for mutation.

For example, mutation may be directed to a particular site or combination of sites of wild-type e ICE, the accessory binding site or only the active site, or a location on the interface site may be 15 chosen for mutagenesis. Similarly, only a location on, at or near the enzyme surface may be replaced, resulting in an altered surface charge of one or more charge units, as compared to the wild-type enzyme.

0* Alternatively, an amino acid residue in ICE may be 20 chosen for replacement based on its hydrophilic or 0* hydrophobic characteristics.

Such mutants may be characterized by any one of several different properties as compared with wildtype ICE. For example, such mutants may have altered 25 surface charge of one or more charge units, or have an increased stability to subunit dissociation. Or such mutants may have an. altered substrate specificity in comparison with, or a higher specific activity than, wild-type ICE.

The mutants of ICE prepared by this invention may be prepared in a number of ways. For example, the wild-type sequence of ICE may be mutated in those sites identified using this invention as desirable for mutation, by means of oligonucleotide-directed 27 mutagenesis or other conventional methods, e.g.

deletion. Alternatively, mutants of ICE may be generated by the site specific replacement of a particular amino acid with an unnaturally occurring amino acid. In addition, ICE mutants may be generated through replacement of an amino acid residue, or a particular cysteine or methionine residue, with selenocysteine or selenomethionine. This may be achieved by growing a host organism capable of expressing either the wild-type or mutant polypeptide on a growth medium depleted of either natural cysteine or methionine (or both) but enriched in selenocysteine or selenomethionine (or both).

SMutations may be introduced into a DNA 15 sequence coding for ICE using synthetic oligonucleotides. These oligonucleotides contain nucleotide sequences flanking the desired mutation sites. Mutations may be generated in the full-length DNA sequence of ICE (p 4 5 or in any sequence coding for p30, or p20 or p10 polypeptides.

S. According to this invention, a mutated ICE DNA sequence produced by the methods described above, or any alternative methods known in the art, can be 0 expressed using an expression vector. An expression 25 vector, as is well known in the art, typically includes elements that permit autonomous replication in a host o* cell independent of the host genome, and one or more O phenotypic markers for selection purposes. Either prior to or after insertion of the DNA sequences surrounding the desired ICE mutant coding sequence, an expression vector also will include control sequences encoding a promoter, operator, ribosome binding site, translation initiation signal, and, optionally, a repressor gene or various activator genes and a signal for termination. In some embodiments, where secretion 28 of the produced mutant is desired, nucleotides encoding a "signal sequence" may be inserted prior to the ICE mutant coding sequence. For expression under the direction of the control sequences, a desired DNA sequence must be operatively linked to the control sequences they must have an appropriate start signal in front of the DNA sequence encoding the ICE mutant and maintaining the correct reading frame to permit expression of that sequence under the control of the control sequences and production of the desired product encoded by that ICE sequence.

Any of a wide variety of well known available expression vectors are useful to express the mutated ICE coding sequences of this invention.

15 These include, for example, vectors consisting of segments of chromosomal, non-chromosomal and synthetic DNA sequences, such as various known derivatives of SV40, known bacterial plasmids, e.g., plasmids from E. coli including col El, pCR1, pBR322, pMB9 and their derivatives, wider host range plasmids, RP4, phage DNAs, the numerous derivatives of phage X, NM 989, and other DNA phages, e.g., M13 and filamentous single stranded DNA phages, yeast plasmids such as the 2A plasmid or derivatives thereof, 25 and vectors derived from combinations of plasmids and phage DNAs, such as plasmids which have been modified to employ phage DNA or other expression control sequences. In the .preferred embodiments of this invention, we employ E. coli vectors.

In addition, any of a wide variety of expression control sequences sequences that control the expression of a DNA sequence when operatively linked to it may be used in these vectors to express the mutated DNA sequences according to this invention.

Such useful expression control sequences, include, for 29 example, the early and late promoters of SV40 for animal cells, the lac system, the trp system the TAC or TRC system, the major operator and promoter regions of phage X the control regions of fd coat protein, all for E. coli, the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase, Pho5, the promoters of the yeast a-mating factors for yeast, and other sequences known to control the expression of genes of prokaryotic or eukaryotic cells or their viruses, and various combinations thereof. In the preferred embodiments of this invention, we employ either E. coli or eukaryotic expression in COS-1 cells, a monkey kidney cell line.

A wide variety of hosts are also useful for *15 producing mutated ICE according to this invention.

These hosts include, for example, bacteria, such as .ooo. E. coli, Bacillus and Streptomyces, fungi, such as yeasts, and animal cells, such as CHO and COS-1 cells, plant cells and transgenic host cells. In preferred embodiments of this invention, the host cells are E. coli or COS-1 cells.

It should be understood that not all expression vectors and expression systems function in the same way to express mutated DNA sequences of this 25 invention and to produce modified ICE or ICE mutants.

Neither do all hosts function equally well with the same expression system. However, one of skill in the art may make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, an important consideration in selecting a vector, will be the ability of the vector to replicate in a given host.

The copy number of the vector, the ability to control that copy number, and the expression of any other 30 proteins encoded by the vector, such as antibiotic markers, should also be considered.

In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the system, its controllability, its compatibility with the DNA sequence encoding the modified ICE of this invention, particularly with regard to potential secondary structures.

Hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of the modified ICE to them, their ability to secrete mature products, their ability to fold proteins correctly, and to form tetramers, their fermentation 15 requirements, the ease of the purification of the modified ICE from them and safety. Within these oooo parameters, one of skill in the art may select various vector/expression control system/host combinations that will produce useful amounts of the mutant ICE.

The mutant ICE produced in these systems may o. be purified by a variety of conventional steps and strategies, including those used to purify wild-type

ICE.

Once the ICE mutants have been generated in the desired location, active site or accessory binding site, the mutants may be tested for any one of several.properties of interest.

For examp.le, mutants may be screened for an altered charge at physiological pH. This is determined by measuring the mutant ICE isoelectric point (pI) in comparison with that of the wild-type parent.

Isoelectric point may be measured by gelelectrophoresis according to the method of Wellner, D., Analyt. Chem., 43, p. 597 (1971). A mutant with an altered surface charge is an ICE polypeptide containing 31 0 0 *5

S

0.0

S..

S

0*

S

a replacement amino acid located at the surface of the enzyme, as provided by the structural information of this invention, and an altered pi.

Furthermore, mutants may be screened for high specific activity in relation to the wild-type ICE. A mutant would demonstrate high specific activity if its second order rate constant (Kcat/Km) for hydrolysis of the substrate Ac-Tyr-Val-Ala-Asp-amino methylcoumarin exceeds 7 x 104 M- 1 s 1 at 25°C, using the assay in Pennington Thornberrv, supra.

A mutant would be tested for altered ICE substrate specificity by measuring the hydrolysis of fluorgenic peptide substrates or unmodified ICE peptide substrates as described in Thornberrv et al., supra.

An enzyme with altered substrate specificity is an enzyme whose second order rate constant (kcat/Km) for a substrate X 1 -Tyr-Val-Ala-X 2

-X

3 that exceeds the kcat/Km for the analogous peptide substrate X 1 -Tyr-Val-Ala- Asp-X 3

X

1 is an amino protecting group, such as 20 acetyl; X 2 is a natural or unnatural amino acid residue other than L-aspartate; X 3 is a carboxyl protecting group such as aminomethylcoumarin or p-nitroaniline.

Further properties of interest also include mutants with increased stability to subunit dissociation. An ICE mutant with increased stability to subunit dissociation would demonstrate no loss of enzymic.activity at concentrations of the enzyme below nM in comparison with the wild-type ICE, which demonstrates a Kd between 1-10 nM.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

32 EXAMPLE 1 Crystal Structure of ICE The cDNA encoding the p30 precursor of active human ICE (residues Asn 120 to His 404 of (Thornberry et al., supra]) was cloned into a PL promoter expression vector (provided by Dr. J.

Mankovich) and expressed in E. coli by temperatureshift induction.

Pre-induction repression of the PL promoter was achieved by co-expression of the cI repressor gene on a co-resident, compatible plasmid (pACYC184cI) in the E. coli host, JM109. Yanish-Perron, et al., Gene, 33, pp. 103-199 (1985; ATCC #53323). The promoter was induced by increasing the temperature from 15 28 0 C to 42 0 C, at which point the temperature sensitive cI repressor gene product denatures and gene expression is initiated, directed by the PL promoter. Maintenance of the temperature at 42 0 C for a further 4 hours resulted in the accumulation of high levels of the 20 inactive ICE p30 precursor product within the host cell cytoplasm, in the form of inactive inclusion bodies.

After mechanical disruption of the cells, and S. harvesting of the insoluble fraction, the inclusion bodies were washed by suspension in 2M urea, 25mM tris, 0.5mM DTT, 0.1mM EDTA, 0.1mM PMSF, pH 7.5 at 4 0

C,

followed by centrifugation. The inclusion bodies were solubilized in the-above buffer containing 7M urea, centrifuged and subjected to size-exclusion chromatography in the same buffer. The p30 fractions, identified by SDS-PAGE and N-terminal sequence analysis, were pooled and diluted to 0.3 mg/ml using column buffer. This was followed by dialysis at 4 0

C

against 25mM tris, 1mM DTT, pH 7.5, until the urea 33 concentration was less than 20mM, thereby allowing the enzyme to refold.

The protein was concentrated to 3-5 mg/ml by ultrafiltration at 4°C, followed by incubation at room temperature. The disappearance of the p30 precursor, and the concomitant appearance of the p20 and subunits, was monitored by SDS-PAGE, evidence that autocatalytic processing of the enzyme had occurred.

ICE enzymatic activity was assayed by hydrolysis of a Succinyl-Tyr-Val-Ala-Asp-p-nitroanilide substrate at 37 0 C and correlated closely with conversion to subunits.

The autoprocessed ICE was inhibited fully by adding a 2x molar excess of a tetrapeptide aldehyde 15 inhibitor (acetyl-Tyr-Val-Ala-Asp-H). The protein-inhibitor complex sample was concentrated and fractionated by size-exclusion chromatography, in final preparation for crystallization experiments.

Crystals of ICE in complex with the inhibitor were grown by vapor diffusion. Davies, D.R. and D.M.

Segal, Meth. Enzvmol., 22, p. 266 (1971). Protein S" mg/ml in 50 mM citrate, 2.0 mM DTT, pH 6.5) was mixed with an equal volume of reservoir buffer (15% PEG 4K, 400 mM LiSO 4 200 mM sodium Hepes, 5mM sodium S" 25 cacodylate, 0.5% beta-octyl glucoside, pH 7.0) and allowed to stand over the reservoir solution at 4 0

C.

Crystals grew over a six week period to form tetragonal bipyramids and were equilibrated with 18% PEG 4K, 400 mM LiSO 4 200 mM sodium Hepes, 5mM sodium cacodylate, 0.5% beta-octyl glucoside, pH 7.0 prior to data collection or heavy atom derivatization.

Those of skill in the art will appreciate that the aforesaid crystallization conditions can be varied. Such variations may be used alone or in combination, and include final protein/inhibitor 34 complex concentrations between 5 mg/ml and 35 mg/ml; all combinations of ICE/inhibitor to precipitant ratios; citrate concentrations between 1mM and 200 mM; DTT concentrations between 0 mM and 10 mM; and any concentration of 8-mercaptoethanol; pH ranges between and 9.5; PEG concentrations between 10% and (gms/100ml); PEG weights between 2000 and 8000; LiSO 4 concentrations between 50 and 750 mM; HEPES concentrations between 5 and 395 mM; and any concentration or type of detergent; any temperature between -50C and 300C; and crystallization of ICE/inhibitor complexes by batch, liquid bridge, or dialysis method using these conditions or variations thereof.

All X-ray data sets were collected on a R-axis IIC image plate system except for the 2.2A Synchrotron data set that was used for refinement of the final model. This data was collected at Cornell High Energy Synchrotron Source ("CHESS") on a chargecouple device and was reduced to structure factor amplitudes using the Denzo Software Package (Denzo An Oscillation Data Processing Program For Macro Molecular Crystallography, 01993, Daniel Gewirth, Yale University). Oscillation photographs were integrated and reduced to structure factor amplitudes using software supplied by the manufacturer (Molecular Structures Corp., Dallas, Texas).

Refined heavy atom parameters were used to compute multiple isomorphous replacement phases.

Inclusion of the anomalous data for the Hg derivative in cross-phased difference Fourier maps showed the space group to be P4 3 2 1 2 rather than its enantiomorph.

The mean figure of merit, including anomalous data for the Hg derivative, was 0.65 to 3.5A resolution (Table 1).

35 Solvent flattening and phase extension (CCP4- Collaborative Computing Project No. 4, A Suite of Programs for Protein Crystallography; Daresbury Laboratory, Warrington, WA4 4AD, U.K. (1979)) improved the map and allowed identification of some of the residues in the protein core. Cycles of model building (Quanta, version 4.0b, Molecular Simulations Inc., Burlington MA), positional refinement, (Brunger, A.T., J. Acta Crvst., A46, pp. 46-57 (1990); Brunger, A.T.

et al., J. Acta Crvst., A46,.pp. 585-93 (1990)) and phase combination (CCP4-Collaborative Computing Project, supra) were carried out until the switch to phases calculated from the model could be made.

Refinement continued against the -16°C, 2.2A data S 15 (Table which allowed the more difficult loop regions of the protein to be constructed.

The following table summarizes the X-ray crystallography data sets of ICE derivatives that were used to determine the structure of ICE according to this invention.

Table 1 25 30 Complete- Unit cell Resolution ness of Rmerge dimensions, A No. of Rc Phasing Protein ModificationA data a.b c sites Power Tetrapeptide aldehyde* 20 2.2 87 7.1 64.9 164.1 Tetrapeptide aldehyde" 20- 2.6 90 8.3 64.4 163.3 Tetrapeptide aldehyde 20 2.8 78 8.3 64.7 162.9 lodinated tetrapeptide aldehyde 20-3.5 86 9.4 64.4 162.8 2 0.88 1.09 Thimerosal 20- 3.5 88 8.4 64.4 162.3 5 0.67 1.08 Gold Thiomalate 20- 3.5 74 9.5 64.7 162.7 3 0.72 1.22 Uranyl Acetate 20 4:0 80 10.8 64.7 162.9 2 0.79 1.32 Lead Chloride 20- 3.5 64 8.9 64.7 162.8 2 0.76 1.38 Data collected at -16 0 C at CHESS Data collected at -16 0

C

Definitions: Rmerge gives the agreement between repeated intensity measurements, with the number of crystals used in the data set given in parentheses.

The number of heavy-atom binding sites is given where 36 appropriate.

R

c is the Cullis R factor for centrosymmetric reflections, and the phasing power is the ratio of average heavy-atom scattering to the average lack of closure of the phase triangles.

Blundell, T.L. and Johnson, Protein Crystallography, Academic Press, New York (1976).

The ICE tetrameric model according to this invention has an R-factor of 19% against all observed data between 7A and 2.2A resolution, with root-mean-square deviation from ideal bond lengths and angles of 0.011A and 2.84A respectively.

EXAMPLE 2 Confirmation of the Active Site of ICE In order to confirm the location of the 15 active site in the tetrameric ICE molecule, as deduced from the structure coordinates of ICE, a series of ICE mutants was generated.

Oligonucleotide-directed mutagenesis was performed on pcDNA3 (Invitrogen) constructs using uracil-enrichment of single-strand DNA. Kunkel, T.A., Proc. Nat. Acad. Sci., 82, pp. 488-492 (1985); Kunkel, T.A. et al., Meth. Enzvmol., 154, pp. 367-382 (1987).

This is a modification of the method originally described for M13 mutagenesis. Zoller, M.J. and M. Smith, Nucleic Acids Res., 10, pp. 6487-6500 (1983); Zoller M.J. and M. Smith, Meth. Enzvmol., 100, pp. 468- 500 (1983).

Mutagenesis was performed using the reagents provided in the Muta-Gene Kit (BioRad). Mutagenesis primers were synthesized in the coding orientation.

The dut'ungq E. coli strain CJ326 was used for uracil enrichment of single-strand DNA, and the MV1190 strain was used for selection of heteroduplex DNA after extension-ligation reactions. All oligonucleotides 37 were synthesized on an applied Biosystems 380 DNA synthesizer and purified by electrophoreses in polyacrylamide-urea slab gels. Mutations made in the ICE-encoding cDNA were fully sequenced in the coding region by the dideoxy method. Sanger, F.

et al., Proc. Nat. Acad. Sci. 74, pp. 5463-5467 (1977).

Mutant DNA in preparation for COS-1 cell transfection, or alternatively E. coli transfection, was purified by alkaline lysis and cesium gradient centrifugation prior to transfection.

Each mutant cDNA was transfected into a COS- 1 cell line, then tested for its ability to process pIL-1i in vitro, to secrete mature IL-1l. The S COS-1 cell line used, had previously been transfected 15 with a pIL-1 encoding cDNA cloned into an MNC stuffer vector Seed, Harvard Medical School) which had subsequently integrated into the chromosome. pIL-1 production was maintained by the addition of 0.5 mg/ml G-418 Sulfate to culture media.

Approximately 3 x 106 COS-1 cells in 100mm tissue culture plates were transfected with 15 Ag of each plasmid. DNA was mixed with 200 L1 DEAE-Dextran, brought to 4 ml with phosphate-buffered saline, and added to the plates. Cells were incubated at 37 0 C for 25 30 min. 8 ml of an 80 M chloroquine/serum-free DMEM solution was added and the cells were incubated for 2.5 hr.. This solution was aspirated and cells were *treated for two minutes with 10% DMSO/serum-free DMEM.

After washing with serum-free media, 10 ml complete media was added. Conditioned media were sampled at 16 and 24 hr. Activity in this assay requires that transcription, translation and protein folding of mutants are not arrested. The amount of mutant ICE present in cell lysates was determined by Western blot using an anti-p20 rabbit antiserum that recognizes 38 amino acids 136-150 inclusive and which also recognizes the intact p30 precursor.

Mature IL-19 in the cell medium was detected by ELISA (R&D Systems). Samples were diluted to achieve concentrations in the linear range of the ELISA assay (8-60 pg/ml). Background IL-1 levels were determined in cells transfected with the expression vector lacking ICE cDNA, and this value was subtracted from all other concentrations. The activity values were calculated as the ratio of secreted IL-19 from cells transfected with mutant ICE divided by IL-1 secreted by cells transfected with wild-type ICE. The final ratio is the mean of at least two experiments.

These data are recorded in Figure 3.

15 Based on these data, it was determined that mutation of Cys-285 or His-237 eliminates pIL-19 processing activity, as well as autoprocessing.

Mutation of Arg-179, which contacts the P1 Asp to Glu, also abolishes activity. Mutation of Cys-244 to Ala, which may contact P' side chains of substrates, reduces enzymatic activity significantly. In contrast, mutation of other residues proximal to Cys-285 including Ser-332, -333 or -339, and His-249, does not eliminate activity. Accordingly, we confirmed the S 25 importance of various residues in the ICE active site.

f EXAMPLE 3 The Use of Molecular Replacement To Solve An Unknown ICE Crystal Structure The method of molecular replacement was used to determine the structure coordinates of crystals of ICE in complex with the tetrapeptide aldehyde inhibitor Ac-Tyr-Val-Pro-Asp-H in comparison with crystals of ICE in complex with the tetrapeptide aldehyde inhibitor Ac-Tyr-Val-Ala-Asp-H (as prepared in Example 1).

39 Crystals of ICE in complex with the tetrapeptide aldehyde inhibitor, Ac-Tyr-Val-Pro-Asp-H were grown under conditions identical to those for crystals of ICE in complex with the tetrapeptide aldehyde inhibitor, Ac-Tyr-Val-Ala-Asp-H X-ray diffraction data to 2.8A resolution was collected on the ICE/Pro co-complex. A difference electron density map that combined diffraction data of the form I Fro FAla I and phases calculated from the refined model of the Ala inhibited enzyme was used to locate structure changes that had occurred in the ICE/Pro co-complex.

Negative features were found in the map wherever localized atoms in the Ala complex were 15 removed or shifted by switching to the new ligand.

Positive features were found when localized atoms were introduced into the structure, and indicated the new positions of shifted atoms.

Replacement of the alanine that sits in the P2 binding pocket in Ala with proline in Pro introduced two methylene groups into the structure of the ICE cocomplex. The location of these new atoms was indicated by the presence of positive difference electron density adjacent to the beta-carbon of the alanine in the binding pocket P2. Another positive peak nearby S* indicated the binding of a new water molecule in the Pro complex relative to the Ala complex. There were -e also pairs of positive and negative peaks near the tyrosine moiety that sits in the P4 binding pocket of the inhibitor. These peaks indicated shifts in the position of these atoms in the Pro complex relative to their location in the Ala complex.

These shifts, plus the new atoms referred to above, were modeled, and the resulting structure was refined against the X-ray data to determine a final 40 picture of the co-complex of Pro with ICE. The space group (P4 3 2 1 2) and unit cell dimensions (a=b=65 c=162 5A) for the Pro complex were the same as those observed for the Ala complex.

The ICE structure coordinates known for the first time by virtue of this invention may be used to solve the unknown structure of any mutant, homologue or co-complex of ICE using the above-described method.

This method may also be used to determine the binding or orientation of a ligand or chemical entity in the active site or accessory binding site of ICE.

While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other 15 embodiments which utilize the products and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments which have been represented by way of example.

Tables A and B, following this page, list respectively, the tetramer interface contacts and the structure coordinates of the ICE molecule of this Sinvention.

S

41 TABLE A TETRAMER INTERFACE CONTACTS Residue Residue Plo i'io P10 Residue P20 240 259 267 293 268 293 274 295 *w 0 0 )@0090 0 0 000000 d 0 0e60 0*Oe 0e 00 0 *o 0 @0 4.0 0* 00 04 0 0g 00 0 @0040.

0 d 0 00 150 375 151 371 151 372 151 375 291 323 291 321 291 322 291 323 292 321 293 321 15 293 319 293 320 294 318 294 319 294 320 295 318 295 319 295 320 295 321 296 317 297 317 320 320 322 322 322 322 322 322 323 324 324 325 325 334 335 367 367 371 371 371 374 374 374 375 375 378 378 386 386 388 388 388 389 389 390 382 380 377 378 380 384 385 386 327 334 386 378 386 393 391 367 374 394 395 396 392 393 394 395 396 395 396 393 395 392 391 393 392 391 391 42 TABLE B STRUCTURE COORDINATES OF ICE Atom S ATOM I C ATOM 2 0 ATOM 3 HTI ATOM 4 HT2 ATOM 5 N ATOM 6 HT3 ATOM 7 CA ATOM 8 N ATOM 9 HI ATOM 10 CA ATOM 11 CB ATOM 12 CG 'ATOM 13 ODI *ATOM 14 ND2 ATOM 1S HD21 20 ATOM 16 HD22 ATOM 17 C ATOM 18 0 oATOM 19 N ATOM 20 H 25 ATOM 21 CA SATOM 22 CB ATOM 23 CG1 ATOM 24 CG2 ATOM 25 C ATOM 26 0 ATOM 27 N a *ATOM 28 NZ S.UATOM 29 CA ATOM 30 CB of 35 ATOM 31 CG ATOM 32 CD alATOM 33 CE *ATOM 34 NZ ATOM 35 HZI a 00g, 40 ATOM 36 HZ2 *ATOM 37 HZ3 ATOM 38 C d)ATOM 39 0 a' ATOM 40 N ATOM 41 H ATOM 42 CA ATOM 43 CB ATOM 44 CG ATOM 45 CDI ATOM 46 CD2 ATOM 47 C ATOM 48 0 ATOM 49 N ATOM 50 H ATOM 51 CA ATOM 52 C ATOM 53 0 ATOM 54 CB ATOM 55 SG

RESIDUE

GLY

GLY

GLY

GLY

GLY

GLY

GLY

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

CYS

CYS

CYS

CYS

CYS

CYS

CYS

13 131 131 131 131 131 131 131 132 132 132 132 132 132 132 132 132 132 132 133 133 133 133 133 133 133 133 134 134 134 134 134 134 134 134 134 134 134 134 134 135 135 135 135 135 135 135 135 135 136 136 136 136 136 136 x Y Z 0CC B 49.848 81.525 -9.909 l.00 66.26 50.205 82.686 -9.789 1.00 67.80 51.316 82.385 -11.694 1.00 0.00 49.746 82.510 -12.180 1.00 0.00 50.546 81.841 -12.148 1.00 71.76 50.783 81.456 -13.079 1.00 0.00 50.192 80.805 -11.207 1.00 65.90 49.175 80.916 -8.934 1.00 63.34 48.640 80.121 -9.141 1.00 0.00 49.178 81.466 -7.566 1.00 57.35 47.778 81.260 -6.979 1.00 63.76 47.550 82.132 -5.758 1.00 65.77 48.228 83.107 -5.487 1.00 65.21 46.506 81.860 -4.997 1.00 67.11 45.919 81.109 -5.228 1.00 0.00 46.382 82.450 -4.223 1.00 0.00 50.261 80.777 -6.706 1.00 51.45 50.487 80.946 -5.521 1.00 46.19 50.972 79.911 -7.425 1.00 47.07 50.765 79.856 -8.373 1.00 0.00 52.081 79.094 -6.973 1.00 42.45 52.214 77.891 -7.947 1.00 39.63 53.342 76.953 -7.538 1.00 39.92 50.868 77.172 -8.010 1.00 35.70 53.302 79.986 -7.029 1.00 42.39 53.511 80.670 -8.020 1.00 41.5 54.119 79.997 -5.986 1.00 43.94 53.921 79.394 -5.236 1.00 0.00 55.301 80.832 -5.918 1.00 43.48 55.942 80.694 -4.498 1.00 47.92 57.200 81 .347 -4.244 1.00 58.49 57.671 81.322 -2.773 1.00 68.37 56.793 82.161 -1.815 1.00 73.02 57.422 82.316 -0.513 1.00 74.14 58.339 82 .793 -0.625 1.00 0.00 57.568 81.376 -0.092 1.00 0.00 56.805 82.880 0.105 1.00 0.00 56.311 80.428 -6.979 1.00 43.98 56.604 79.261 -7.186 1.00 40.75 56.897 81.384 -7.698 1.00 45.99 56.807 82.326 -7.445 1.00 0.00 57.679 81.019 -8.861 1.00 47.05 57.569 82.064 -9.970 1.00 47.39 56.156 82.207 -10.535 1.00 45.83 56.210 83.182 -11.700 1.00 50.59 55.609 80.873 -11.014 1.00 48.32 59.140 80.819 -8.610 1.00 49.94 59.802 81.521 -7.860 1.00 47.32 59.601 79.787 -9.312 1.00 53.47 58.954 79.191 -9.740 1.00 0.00 61.014 79.522 -9.495 1.00 57.62 61 .688 80.552 -10.387 1.00 60.29 61.471 80.621 -11.594 1.00 62.12 61.208 78.144 -10.115 1.00 53.99 61 .894 76.980 -8.918 1.00 58.70 43 ATOM 56 N SER 137 62.538 81.402 -9.833 1.00 59.84 ATOM 57 H SER 137 62.572 81.519 -8.858 1.00 0.00 ATOM 58 CA SER 137 63.390 82.210 -10.667 1.00 62.00 ATOM 59 CB SER 137 64.149 83.158 -9.766 1.00 65.68 ATOM 60 OG SER 137 63.234 83.655 -8.792 1.00 75.16 ATOM 61 HG SER 137 62.492 84.111 -9.205 1.00 0.00 ATOM 62 C SER 137 64.313 81.329 -11.458 1.00 61.26 ATOM 63 0 SER 137 64.602 80.202 -11.086 1.00 62.99 ATOM 64 N LEU 138 64.823 81.792 -12.585 1.00 61.53 ATOM 65 H LEU 138 64.686 82.728 -12.829 1.00 0.00 ATOM 66 CA LEU 138 65.553 80.911 -13.478 1.00 64.28 ATOM 67 CB LEU 138 65.884 81.695 -14.748 1.00 63.19 ATOM 68 CG LEU 138 66.536 80.878 -15.866 1.00 61.50 ATOM 69 CDI LEU 138 65.823 79.540 -16.097 1.00 62.16 ATOM 70 CD2 LEU 138 66.528 81.749 -17.112 1.00 65.07 ATOM 71 C LEU 138 66.813 80.309 -12.877 1.00 67.11 ATOM 72 0 LEU 138 67.183 79.164 -13.115 1.00 66.56 ATOM 73 N GLU 139 67.503 81.099 -12.063 1.00 68.85 ATOM 74 H GLU 139 67.248 82.038 -11.982 1.00 0.00 ATOM 75 CA GLU 139 68.645 80.591 -11.330 1.00 71.48 ATOM 76 CB GLU 139 69.271 81.757 -10.558 1.00 78.29 ATOM 77 CG GLU 139 68.277 82.677 -9.821 1.00 89.52 ATOM 78 CD GLU 139 68.983 83.966 -9.426 1.00 98.5 ATOM 79 OEI GLU 139 68.705 85.009 -10.033 1.00 99.9 ATOM 80 OE2 GLU 139 69.811 83.927 -8.510 1.00 101.79 ATOM 81 C GLU 139 68.241 79.453 -10.411 1.00 69.73 ATOM 82 0 GLU 139 68.938 78.458 -10.328 1.00 70.27 t ago,* ATOM 83 N GLU 140 67.107 79.556 -9.711 1.00 67.40 ATOM 84 H GLU 140 66.567 80.364 -9.814 1.00 0.00 0 .h 30 ATOM 85 CA GLU 140 66.616 78.489 8.49 1.00 66.30 ATOM 86 CB GLU 140 65.290 78.874 -8.234 1.00. 69.93 ATOM 87 CG GLU 140 65.411 80.248 -7.577 1.00 79.22 ATOM 88 CD GLU 140 64.097 80.745 -7.015 1.00 83.51 ATOM 89 OEI GLU 140 63.207 79.947 -6.716 1.00 86.55 ATOM 90 OE2 GLU 140 63.971 81.956 -6.866 1.00 89.13 ATOM 91 C GLU 140 66.431 77.221 -9.621 1.00 64.12 ATOM 92 0 GLU 140 66.927 76.166 -9.273 1.00 61.28 ATOM 93 N ALA 141 65.703 77.298 -10.720 1.00 64.66 ATOM 94 H ALA 141 65.236 78.135 -10.921 1.00 0.00 40 ATOM 95 CA ALA 141 65.611 76.153 -11.604 1.00 68.98 ATOM 96 CB ALA 141 64.889 76.570 -12.884 1.00 70.25 ATOM 97 C ALA 141 66.979 75.596 -11.947 1.00 71.14 ATOM 98 0 ALA 141 67.313 74.428 -11.765 1.00 72.56 ATOM 99 N GLN 142 67.818 76.487 -12.459 1.00 72.92 a 45 ATOM 100 OH GLN 142 67.532 77.424 -12.537 1.00 0.00 ATOM 101 CA GLN 142 69.151 76.115 -12.892 1.00 73.96 ATOM 102 CB GLN 142 69.866 77.409 -13.316 1.00 77.97 ATOM 103 CG GLN 142 70.887 77.279 -14.452 1.00 87.44 a be ATOM 104' CD GLN 142 70.264 76.716 -15.714 1.00 92.53 ATOM 105 OE1 GLN 142 70.722 75.733 -16.286 1.00 95.95 ATOM 106 NE2 GLN 142 69.200 77.287 -16.242 1.00 93.80 ATOM 107 HE21 GLN 142 68.816 78.075 -15.810 1.00 0.00 ATOM 108 HE22 GLN 142 68.852 76.862 -17.056 1.00 0.00 ATOM 109 C GLN 142 69.900 75.373 -11.802 1.00 71.44 ATOM 110 0 GLN 142 70.472 74.312 -12.010 1.00 69.41 ATOM 11 N ARG 143 69.911 75.911 -10.590 1.00 70.71 ATOM 112 H ARG 143 69.467 76.774 -10.440 1.00 0.00 ATOM 113 CA ARG 143 70.560 75.235 -9.482 1.00 71.58 ATOM 114 CB ARG 143 70.398 76.011 -8.169 1.00 66.09 ATOM 115 CG ARG 143 71.452 77.103 -8.009 1.00 68.24 ATOM 116 CD ARG 143 71.260 77.893 -6.715 1.00 67.96 ATOM 117 NE ARG 143 70.068 78.720 -6.772 1.00 68.10 ATOM 118 HE ARG 143 69.189 78.300 -6.871 1.00 0.00 ATOM 119 CZ ARG 143 70.158 80.048 -6.694 1.00 68.46 44 ATOM 120 NHI ATOM 121 HHII ATOM 122 HH12 ATOM 123 NH2 ATOM 124 HH21 ATOM 125 11H22 ATOM 126 C ATOM 127 0 ATOM 128 N ATOM 129 H ATOM 130 CA ATOM 131 CB ATOM 132 CG2 ATOM 133 CGI ATOM 134 CDI ATOM 135 C ATOM 136 0 *ATOM 137 N .ATOM 138 H 20 ATOM 139 CA *ATOM 140 CB ATOM 141 CG *ATOM 142 CD2 'ATOM 143 CE2 S 25 ATOM 144 CE3 *ATOM 145 CD1 SATOM 146 NEI ATOM 147 HE! ATOM 148 CZ2 ATOM 149 CZ3 ATOM 150 CH2 ATOM 151 C *ATOM 152 0 *ATOM 153 N 35 ATOM 154 H *ATOM 155 CA ATOM 156 CB ATOM 157 C S.*ATOM 158 0 40 ATOM 159 N ATOM 160 H *ATOM 161 CA ATOM 162 CB sATOM 163 CG 45 ATOM 164 CD *ATOM 165 OEI ATOM 166 NE2 ATOM 167 HE21 ATOM 168 HE22 ATOM 169 C ATOM 170 0 ATOM 171 N ATOM 172 H ATOM 173 CA ATOM 174 CB ATOM 175 CG ATOM 176 CD ATOM 177 CE ATOM 178 NZ ATOM 179 HZI ATOM 180 HZ2 ATOM 181 HZ3 ATOM 182 C ATOM 183 0

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ILE

ILE

RLE

E

ILE

ILE

ILE

ILE

ILE

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

ALA

ALA

ALA

ALA

ALA

ALA

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

143 69.028 143 68.137 143 69.090 143 71.365 143 72.206 143 71.412 143 70.013 143 70.765 144 68.696 144 68.105 144 68.143 144 66.605 144 66.077 144 66.084 144 64.588 144 68.604 144 69.045 145 68.507 145 68.167 145 68.929 145 68.658 145 69.038 145 68.217 145 69.056 145 67.071 145 70.133 145 70.111 145 70.787 145 68.642 145 66.717 145 67.473 145 70.411 145 70.817 146 71.240 146 70.872 146 72.678 146 73.316 146 73.078 146 74.075 147 72.310 147 71.578 147 72.543 147 71.690 147 72.033 147 70.829 147 69.729 147 70.957 147 71.821 147 70.155 147 72.216 147 73.058 148 70.969 148 70.319 148 70.621 148 69.339 148 69.449 148 68.211 148 68.288 148 69.521 148 70.339 148 69.553 148 69.574 148 70.457 148 70.294 80.800 80.358 81.7917 80.664 80.125 81.661 73.850 72.907 73.662 74.411 72.352 72.394 70.990 73.3 14 73.5Q0 71.367 70.260 7 1.765 72.662 70.861 71.462 70.460 69.255 68.711 68.594 70.564 69.520 69.359 67.562 67.444 66.945 70.588 69.442 71.638 72.546 71 .479 72.866 70.678 69.975 70.767 71.421 69.925 70.379 69.642 69.585 70.018 68.991 68.602 68.987 68.479 67.595 68.171 68.869 66.770 66.539 66.861 66.386 66.715 66.190 66.615 65.158 66.411 66.096 64.882 754 -6.858 -6.697 -6.550 -6.498 -6.490 -9.263 -9.074 -9.285 -9.5 19 -8.995 -8.986 -8.729 -7.895 -8.061 -10.036 -9.743 -11.304 -11.5 14 -12.351 -13.746 -14.839 -15.098 -16.236 -14.711 -15.670 -16.475 -17. 166 -16.873 -15.394 -16.445 12. 184 -12.042 -12.196 -12.279 -12.055 -12.003 -10.827 -10.833 -9.739 -9.7 11 -8.583 -7.387 -6.090 -5.181 -5.491 -4.006 -3.760 -3.438 -8.875 -8.801 -9.211 -9.439 -9.239 -8.43 8 -6.954 -6.193 -4.706 -4.145 -4.627 -4.275 -3.131 -10.578 10.625 68.32 0.00 0.00 68.45 0.00 0.00 73.97 77.08 73.91 0.00 71.75 69.05 69.68 65.22 62.44 72.66 71.17 75.70 0.00 83.94 86.15 93.70 95.01 96.30 94.15 95.29 93.47 0.00 100.90 96.37 98.93 87.50 88.19 90.23 0.00 90.96 89.47 92.53 93.84 93.24 0.00 94.09 96.74 102.36 107.75 109.80 109.34 0.00 0.00 93.64 93.43 91.82 0.00 89.79 91.49 91.59 94.76 97.17 102.16 0.00 0.00 0.00 87.23 88.22 ATOM 184 N ATOM 185 H ATOM 186- CA ATOM 187 Ce ATOM 188 C ATOM 189 0 ATOM 190 N ATOM 191 H ATOM 192 CA ATOM 193 CB ATOM 194 C ATOM 195 0' ATOM 196 N ATOM 197 H ATOM 198 CA ATOM 199 CB :9c. 0 ATOM 200 CG 0 0ATOM 201 CD 0000 ATOM 202 OEI 20 ATOM 203 0E2 ATOM 204 C ATOM 205 0 .ATOM 206 N ATOM 207 H ATOM 208 CA s ATOM 209 CB 0ATOM 210 CG2 ATOM 211 CGl ATOM 212 CDI ATOM 213 C ATOM 214 0 ATOM 215 N 0 0 ATOM 216 H *ATOM 217 CA 35 ATOM 218

CB

cc*ATOM 219 CG ATOM 220 CD1 *.:ATOM 221 CEI ATOM 222 CD2 ATOM 223 CE2 0 00 0ATOM 224 CZ SATOM 225 OH ATOM 226 HH 00ATOM 227 C *0 45 ATOM 228 0 0 ATOM 229 N ATOM 230 CD ATOM 231 CA ATOM 232 CB ATOM 233 CG ATOM 234 C ATOM 235 0 ATOM 236 N ATOM 237 H ATOM 238 CA ATOM 239 CB ATOM 240 C02 ATOM 241 CGI ATOM 242 CDI ATOM 243 C ATOM 244 0 ATOM 245 N ATOM 246 H ATOM 247 CA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

ALA

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

TYR

TYR

TY

TYR

TYR

TYR

TY

TYR

TYR

TR

TR

TR

PRO

PRO

PRO

PRO

PRO

PRO

ILE

ILE

ILE

ILE

ILE

ILE

MET

MET

MET

149 149 149 149 149 149 150 150 150 150

ISO

1S0 151 151 151 151 151 151 151 151 151 151 152 152 152 152 152 152 152 152 152 153 153 153 153 153 153 153 153 153 153 153 153 153 153 154 154 154 154 154 154 154 155 155 155 155 155 155 155 155 155 156 156 156 70.496 70.728 70.27 1 71.4 16 70.092 69.034 71.079 7 1.903 70.928 72.254 69.786 69.332 69.298 69.693 68.153 68.612 69.5 10 69.733 68.753 70.887 66.966 66.237 66.751 67.390 65.578 66.006 64.846 66.456 67.026 64.838 65 .399 63.506 63. 125 62.606 61.131 60.815 60.889 60.661 60.496 60.266 60.352 60.116 59.896 62.734 62 .545 63.045 63.433 63.119 63.791 63.408 61.782 60.763 61 .791 62.636 60.623 60.8 10 59.893 60.584 59.370 60.648 61.71I5 59.5 10 58.677 59.471 66.825 -11.691 67.775 -11.599 66.316 .13.039 66.848 .13.906 64.807 -13.272 64.377 .13.709.

63.939 -13.002 64.290 -12.604 62.493 .13.224 61.803 .12.872 61.803 -12.458 60.728 -12.832 62.391 -11.366 63.225 -11.031 61 .823 -10.700 61.333 -9.316 60.091 -9.532 59.292 -8.259 58.778 -7.702 59.159 -7.846 62.759 -10.610 62.811 -9.632 63.538 -11.671 63.525 -12.419 64.379 -11.820 65.876 -11.979 66.776 -12.375 66.419 -10.633 67.826 -10.790 63.880 -13.063 63.521 -14.089 63.846 -12.966 64.015 -12.080 63.601 -14.098 63.521 -13.608 62. 157 -13.006 61.023 -13.795 59.769 -13.266 62.024 -11.663 60.774 -11.126 59.657 -11.934 58.405 -11.40-4 58.542 -10.481 64.754 -15.092 65.895 -14.708 64.585 -16.332 63 .298 -16.886 65.685 -17.300 65.078 -18.508 63.614 -18.383 66.309 -17.627 65.693 -17.860 67.620 -17.645 68.068 -17.453 68.417 -17.912 69.687 -17.067 70.851 -17.429 69.235 -15.624 68.340 -15.354 68.636 -19.414 68.804 -19.990 68.638 -20.116 68.455 -19.642 68.939 -21.542 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 83.64 0.00 81.28 80.46 80.23 81.20 77.26 0.00 72.54 71.93 67.17 64.24 58.90 0.00 55.46 60.03 67.91 72.08 75.94 70.44 49.03 40.75 46.24 0.00 41.23 41.97 37.44 39.50 45.38 39.41 38.70 37.18 0.00 34.02 30.99 28.2 1 27.24 25.65 24.92 20.91 24.92 22.74 0.00 31.41 30.52 29.09 26.14 26.59 21.73 26.66 27.17 30.28 27.49 0.00 27.05 27.13 28.62 27.98 30.26 33.41 34.72 33.95 0.00 31.70 46 ATOM 248 CB MET 156 58.252 68.339 -22.224 1.00 31.01 ATOM 249 CG MET 156 58.574 67.001 -22.838 1.00 30.35 ATOM 250 SD MET 156 57.118 66.252 -23.577 1.00 39.82 ATOM 251 CE MET 156 57.590 64.545 -23.528 1.00 34.89 ATOM 252 C MET 156 59.384 70.434 -21.735 1.00 34.78 ATOM 253 0 MET 156 59.035 71.208 -20.854 1.00 32.33 ATOM 254 N ASP 157 59.711 70.869 -22.942 1.00 37.95 ATOM 255 H ASP 157 59.923 70.224 -23.648 1.00 0.00 ATOM 256 CA ASP 157 59.715 72.281 -23.240 1.00 38.36 ATOM 257 CB ASP 157 60.385 72.438 -24.613 1.00 51.68 ATOM 258 CG ASP 157 60.369 73.848 -25.178 1.00 61.42 ATOM 259 ODI ASP 157 60.483 73.957 -26.401 1.00 68.30 ATOM 260 OD2 ASP 157 60.249 74.822 -24.421 1.00 67.14 ATOM 261 C ASP 157 58.315 72.829 -23.203 1.00 31.15 ATOM 262 0 ASP 157 57.360 72.284 -23.730 1.00 27.50 ATOM 263 N LYS 158 58.232 73.965 -22.543 1.00 30.63 *.ATOM 264 H LYS 158 59.032 74.318 -22.102 1.00 0.00 *ATOM 265 CA LYS 158 56.975 74.638 -22.320 1.00 33.69 *ATOM 266 CB LYS 158 57.265 75.906 -21.540 1.00 34.01 20 ATOM 267 CG LYS 158 56.037 76.664 -21.085 1.00 40.80 *ATOM 268 CD LYS 158 56.390 77.826 -20.154 1.00 48.58 ATOM 269 CE LYS 158 55.152 78.472 -19.524 1.00 52.61 *ATOM 270 NZ LYS 158 55.537 79.342 -18.431 1.00 59.47 ATOM 271 HZ! LYS 158 56.154 80.095 -18.794 1.00 0.00 ATOM 272 HZ2 LYS 158 56.050 78.792 -17.712 1.00 0.00 *ATOM 273 HZ3 LYS 158 54.691 79.763 -17.998 1.00 0.00 *ATOM 274 C LYS 158 56.275 74.942 -23.618 1.00 38.44 ATOM 275 0 LYS 158 55.076 74.803 -23.735 1.00 41.75 ATOM 276 N SER 159 56.962 75.367 -24.672 1.00 41.20 ATOM 277 H SER 159 57.938 75.470 -24.645 1.00 0.00 ATOM 278 CA SER 159 56.297 75.717 -25.916 1.00 39.99 ATOM 279 CB SER 159 57.30.4 76.202 -26.930 1.00 39.69 ,ATOM 280 00 SER 159 58.553 75.552 -26.729 1.00 40.47 ATOM 281 HG SER 159 58.453 74.606 -26.880 1.00 0.00 35 ATOM 282 C SER 159 55.543 74.590 26.548 1.00 40.83 *ATOM 283 0 SER 159 54.666 74.774 -27.370 1.00 43.09 ATOM 284 N SER 160 55.886 73.373 -26.184 1.00 43.73 ATOM 285 H SER 160 56.444 73.181 -25.399 1.00 0.00 SSATOM 286 CA SER 160 55.410 72.261 -26.959 1.00 45.71 40 ATOM 287 CB SER 160 56.592 71.756 -27.769 1.00 45.15 ATOM 288 00 SER 160 57.835 71.958 -27.083 1.00 53.30 *ATOM 289 HG SER 160 58.517 71.533 -27.614 1.00 0.00 ATOM 290 C SER 160 54.800 71.154 -26.121 1.00 45.78 ATOM 291 0 SER 160 54.262 70.217 -26.700 1.00 48.03 e 45 ATOM 292 N ARG 161 54.842 71.162 -24.782 1.00 38.45 *ATOM 293 H ARG 161 55.201 71.921 -24.278 1.00 0.00 ATOM 294 CA ARO 161 54.322 70.004 -24.097 1.00 32.89 ATOM 295 CB ARG 161 54.987 69.929 -22.727 1.00 31.71 ATOM 2%6 CG ARG 161 54.631 71.054 -21.769 1.00 29.23 ATOM 297 CD ARO 161 55.579 71.078 -20.571 1.00 26.52 ATOM 298 NE ARG 161 55.148 72.182 -19.760 1.00 23.86 ATOM 299 HE ARG 161 54.189 72.357 -19.663 1.00 0.00 ATOM 300 CZ ARG 161 56.001 72.971 -19.138 1.00 24.88 ATOM 301 NHI ARG 161 55.486 74.036 -18.477 1.00 23.22 ATOM 302 HHII ARG 161 54.499 74.198 -18.481 1.00 0.00 ATOM 303 HHI12 ARG 161 56.093 74.673 -18.006 1.00 0.00 ATOM 304 NH2 ARG 161 57.339 72.712 -19.115 1.00 26.60 ATOM 305 HH21 ARG 161 57.703 71.901 -19.572 1.00 0.00 ATOM 306 HH22 ARG 161 57.957 73.331 -18.630 1.00 0.00 ATOM 307 C ARG 161 52.816 70.077 -23.999 1.00 30.40 ATOM 308 0 ARG 161 52.219 71.144 -23.981 1.00 30.63 ATOM 309 N THR 162 52.134 68.955 -23.937 1.00 25.20 ATOM 310 H THR 162 52.595 68.099 -24.073 1.00 0.00 ATOM 311 CA THR 162 50.699 68.963 -23.791 1.00 23.14 47 ATOM 312 CB THR 162 50.068 68.276 -25.028 1.00 23.65 ATOM 313 001 THR 162 50.780 67.056 -25.252 1.00 26.56 ATOM 314 HGI THR 162 50.721 66.510 -24.445 1.00 0.0o ATOM 315 CG2 THR 162 50.148 69.114 -26.306 1.00 23.19 ATOM 316 C THR 162 50.373 68.219 -22.510 1.00 25.37 ATOM 317 0 THR 162 50.062 67.030 -22.548 1.00 27.75 ATOM 318 N ARG 163 50.423 68.826 -21.340 1.00 24.62 ATOM 319 H ARG 163 50.560 69.797 -21.312 1.00 0.00 ATOM 320 CA ARG 163 50.174 68.133 -20.077 1.00 24.12 ATOM 321 CB ARO 163 50.757 68.905 -18.918 1.00 15.48 ATOM 322 CG ARG 163 52.227 68.612 -18.793 1.00 17.34 ATOM 323 CDi ARG 163 52.721 69.593 -17.772 1.00 18.83 ATOM 324 NE ARG 163 54.136 69.427 -17.669 1.00 24.11 ATOM 325 HE ARG 163 54.592 68.736 -18.195 1.00 0.00 ATOM 326 CZ ARO 163 54.822 70.232 -16.883 1.00 25.67 ATOM 327 NHI ARO 163 56.160 70.051 -16.807 1.00 34.46 SATOM 328 HIil ARG 163 56.596 69.318 -17.328 1.00 0.00 ATOM 329 HH12 ARO 163 56.710 70.634 -16.209 1.00 0.00 ATOM 330 NH2 ARG 163 54.219 71.220 -16.167 1.00 27.39 ATOM 331 HH21 ARG 163 53.229 71.357 -16.223 1.00 0.00 0 86ATOM 332 HH22 ARG 163 54.772 71.806 -15.575 1.00 0.00 .ATOM 333 C ARO 163 48.738 67.876 -19.714 1.00 24.62 .ATOM 334 0 ARG 163 47.893 68.762 -19.750 1.00 29.04 S..ATOM 335 N LEU 164 48.357 66.667 -19.340 1.00 23.75 25 ATOM 336 H LEU 164 49.023 65.971 -19.147 1.00 0.00 0*ATOM 337 CA LEU 164 46.944 66.455 -19.043 1.00 24.57 *ATOM 338 CB LEU 164 46.366 65.336 -19.893 1.00 27.72 ATOM 339 CG LEU 164 45.556 65.607 -21.165 1.00 28.04 ATOM 340 CD1 LEU 164 46.108 66.789 -21.926 1.00 30.94 ATOM 341 CD2 LEU 164 45.573 64.331 -22.006 1.00 27.16 ATOM 342 C LEU 164 46.774 66.047 -17.612 1.00 23.76 ATOM 343 0 LEU 164 47.607 65.281 -17.142 1.00 22.71 0ATOM 344 N ALA 165 45.733 66.505 -16.907 1.00 21.51 ATOM 345 H AL.A 165 45.124 67.175 -17.292 1.00 0.00 35 ATOM 346 CA ALA 165 45.396 65.986 -15.589 1.00 24.14 ATOM 347 CB ALA 165 45.687 67.006 -14.488 1.00 21.16 ATOM 348 C ALA 165 43.924 65.668 -15.543 1.00 24.40 4* ATOM 349 0 ALA 165 43.162 66.279 -16.279 1.00 25.81 oATOM 350 N LEU 166 43.495 64.730 -14.699 1.00 24.86 ATOM 351 H LEU 166 44.143 64.282 -14.114 1.00 0.00 ATOM 352 CA LEU 166 42.091 64.361 -14.592 1.00 27.92 *ATOM 353 CB L.EU 166 41.914 62.948 -15.196 1.00 23.03 ATOM 354 CO LEU 166 40.571 62.280 -14.919 1.00 20.45 *ATOM 355 CDI LEU 166 39.446 62.990 -15.658 1.00 14.43 ATOM 356 CD2 LEU 166 40.691 60.807 -15.320 1.00 21.71 *ATOM 357 C LEU 166 41.580 64.404 -13.149 1.00 28.64 ATOM 358 0 LEU 166 42.207 63.838 -12.261 1.00 26.66 ATOM 359 N ILE 167 40.441 65.079 -12.901 1.00 27.07 ATOM 360 H ILE 167 39.991 65.549 -13.638 1.00 0.00 ATOM 361 CA ILE 167 39.802 65.137 -11.600 1.00 21.18 ATOM 362 CB ILE 167 39.494 66.602 -11.205 1.00 20.90 ATOM 363 CG2 ILE 167 38.719 66.663 -9.893 1.00 21.77 ATOM 364 CG1 ILE 167 40.793 67.354 -11.003 1.00 17.47 ATOM 365 CDI ILE 167 40.499 68.753 -10.522 1.00 17.98 ATOM 366 C ILE 167 38.513 64.358 -11.684 1.00 24.82 ATOM 367 0 ILE 167 37.634 64.653 -12.493 1.00 23.12 ATOM 368 N ILE 168 38.333 63.328 -10.865 1.00 25.26 ATOM 369 H ILE 168 39.066 63.004 -10.297 1.00 0.00 ATOM 370 CA IL.E 168 37.022 62.731 -10.757 1.00 23.44 ATOM 371 CB ILE 168 37.119 61.228 -11.076 1.00 23.97 ATOM 372 CG2 ILE 168 35.741 60.582 -10.863 1.00 28.80 ATOM 373 CGI ILE 168 37.581 61.030 -12.546 1.00 22.39 ATOM 374 CDI ILE 168 37.869 59.587 -12.959 1.00 22.21 ATOM 375 C ILE 168 36.506 62.981 -9.353 1.00 24.34 48 ATOM 376 0 ILE 168 37.126 62.633 -8.356 1.00 23.09 ATOM 377 N CYS 169 35.337 63.613 -9.260 1.00 26.60 ATOM 378 H CYS 169 34.821 63.777 -10.079 1.00 0.oo ATOM 379 CA CYS 169 34.765 64.030 -7.986 1.00 27.82 ATOM 380 CB CYS 169 34.847 65.544 -7.831 1.00 26.82 ATOM 381 SG CYS 169 34.147 66.177 -6.282 1.00 31.50 ATOM 382 C CYS 169 33.323 63.629 -7.866 1.00 28.36 ATOM 383 0 CYS 169 32.520 63.950 -8.735 1.00 25.83 ATOM 384 N ASN 170 32.948 62.918 -6.803 1.00 27.23 ATOM 385 H ASN 170 33.617 62.683 -6.124 1.00 0.00 ATOM 386 CA ASN 170 31.554 62.555 -6.619 1.00 29.76 ATOM 387 CBe ASN 170 31.372 61.071 -6.286 1.00 26.22 ATOM 388 CG ASN 170 31.674 60.138 -7.440 1.00 29.16 ATOM 389 ODI ASN 170 31.709 60.485 -8.614 1.00 32.47 ATOM 390 ND2 ASN 170 31.970 58.887 -7.151 1.00 25.45 ATOM 391 HD21 ASN 170 32.015 58.569 -6.216 1.00 0.00 ~*ATOM 392 HD22 ASN 170 32.132 58.288 -7.901 1.00 0.00 *ATOM 393 C ASN 170 30.957 63.328 -5.478 1.00 32.01 *ATOM 394 0 ASN 170 31.382 63.086 -4.361 1.00 34.71 20 ATOM 395 N GLU 171 30.000 64.247 -5.672 1.00 36.94 *ATOM 396 H GLU 371 29.711 64.420 -6.594 1.00 0.00 ATOM 397 CA GLU 173 29.301 64.905 -4.558 1.00 39.76 ATOM 398 CB GLU 171 29.119 66.413 -4.822 1.00 36.97 *ATOM 399 CG GLU 171 28.418 67.084 -3.634 1.00 43.98 ATOM 400 CD GLU 171 28.233 68.579 -3.777 1.00 47.95 ATOM 401 OEI GLU 173 28.302 69.095 -4.890 1.00 53.49 *ATOM 402 0E2 GLU 171 28.003 69.233 -2.761 1.00 48.17 ATOM 403 C GLU 171 27.914 64.338 -4.240 1.00 41.90 ATOM 404 0 GLU 171 27.509 64.214 -3.096 1.00 40.97 ATOM 405 N GLU 172 27.133 63.976 -5.251 1.00 48.24 ATOM 406 H GLU 172 27.505 63.929 -6.159 1.00 0.00 ATOM 407 CA GLU 172 25.760 63.534 -5.050 1.00 51.31 ATOM 408 CB GLU 172 24.802 64.170 -6.061 1.00 55.01 *ATOM 409 CG GLU 172 23.819 65.134 -5.408 1.00 66.24 35 ATOM 410 CD GLU 172 24.170 66.580 -5.699 1.00 74.35 eg *ATOM 411 OE1 GLU 172 23.249 67.402 -5.708 1.00 81.11 ATOM 412 0E2 GLU 172 25.342 66.893 -5.9 11 1.00 76.04 **ATOM 413 C GLU 172 25.676 62.035 -5.242 1.00 49.78 *ATOM 414 0 GLU 172 26.092 61.501 -6.266 1.00 46.42 ATOM 415 N PHE 173 25.125 61.338 -4.250 1.00 49.39 ATOM 416 H PHE 173 24.695 61.780 -3.485 1.00 0.00 *ATOM 417 CA PHE 173 25.085 59.888 -4.303 1.00 53.47 ATOM 418 CB PHE 173 25.878 59.313 -3.142 1.00 50.77 ATOM 419 CG PHE 173 27.371 59.547 -3.286 1.00 46.81 45 ATOM 420 CDI PHE 173 28.173 58.521 -3.768 1.00 40.36 *ATOM 421 CD2 PHE 373 27.927 60.747 -2.867 1.00 42.17 ATOM 422 CE! PHE 173 29.535 58.684 -3.778 1.00 37.00 ATOM 423 CE2 PHE 173 29.291 60.904 -2.902 1.00 38.90 ATOM 424 CZ PHE 173 30.089 59.870 -3.332 1.00 39.65 ATOM 425 C PHE 173 23.661 59.372 -4.221 1.00 56.43 ATOM 426 0 PHE 173 22.772 60.010 -3.675 1.00 60.38 ATOM 427 N ASP 174 23.394 58.194 -4.764 3.00 54.59 ATOM 428 H ASP 174 24.131 57.657 -5.134 3.00 0.00 ATOM 429 CA ASP 174 22.044 57.658 -4.745 1.00 53.81 ATOM 430 CB ASP 174 21.943 56.370 -5.557 1.00 51.10 ATOM 431 CG ASP 174 22.091 56.666 -7.030 1.00 53.87 ATOM 432 ODI ASP 174 22.150 55.698 -7.795 1.00 53.10 ATOM 433 0D2 ASP 174 22.148 57.850 -7.408 1.00 53.80 ATOM 434 C ASP 374 21.500 57.347 -3.370 3.00 56.79 ATOM 435 0 ASP 174 20.317 57.447 -3.086 3.00 60.64 ATOM 436 N SER 175 22.354 56.940 -2.457 1.00 57.04 ATOM 437 H SER 175 23.312 57.026 -2.628 1.00 0.00 ATOM 438 CA SER 175 21.856 56.461 -1.185 1.00 56.82 ATOM 439 CB SER 175 22.007 54.938 -1.152 1.00 53.73 49 ATOM 440 OG SER 175 21.821 54.307 -2.423 1.00 50.93 ATOM 441 HG SER 175 22.453 54.685 -3.041 1.00 0.00 ATOM 442 C SER 175 22.614 57.115 -0.038 1.00 59.19 ATOM 443 0 SER 175 22.050 57.584 0.945 1.00 63.80 ATOM 444 N ILE 176 23.949 57.172 -0.133 1.00 57.13 ATOM 445 H ILE 176 24.384 56.889 -0.963 1.00 0.00 ATOM 446 CA ILE 176 24.725 57.758 0.942 1.00 50.84 ATOM 447 CB ILE 176 26.167 57.155 0.920 1.00 52.16 ATOM 448 CG2 I.E 176 25.982 55.645 1.127 1.00 54.09 ATOM 449 CGI ILE 176 26.947 57.381 -0.375 1.00 51.82 ATOM 450 CDI I.E 176 28.205 56.486 -0.451 1.00 47.41 ATOM 451 C ILE 176 24.716 59.262 0.770 1.00 47.11 ATOM 452 0 ILE 176 24.516 59.755 -0.332 1.00 45.21 ATOM 453 N PRO 177 24.918 60.009 1.801 1.00 47.09 ATOM 454 CD PRO 177 25.067 59.502 3.162 1.00 46.36 ATOM 455 CA PRO 177 24.821 61.475 1.806 1.00 48.52 ATOM 456 CB PRO 177 24.733 61.862 3.280 1.00 45.72 *ATOM 457 CG PRO 177 25.513 60.744 3.937 1.00 45.89 ATOM 458 C PRO 177 25.870 62.308 1.096 1.00 51.58 20 ATOM 459 0 PRO 177 27.078 62.045 1.042 1.00 56.38 ATOM 4.60 N ARG 178 25.287 63.373 0.559 1.00 50.95 ATOM 461 H ARG 178 24.351 63.552 0.778 1.00 0.00 *ATOM 462 CA ARG 178 25.959 64.288 -0.328 1.00 52.24 ATOM 4.63 CB ARG 178 24.910 65.270 -0.842 1.00 54.80 25 ATOM 4.64 CG ARG 178 25.505 66.396 -1.661 1.00 62.55 *ATOM 465 CD ARG 178 24.484 67.300 -2.273 1.00 67.32 ATOM 466 NE ARG 178 25.167 68.507 -2.664 1.00 77.79 ATOM 467 HE ARG 178 26. 144 68.522 -2.727 1.00 0.00 ATOM 468 CZ ARG 178 24.473 69.607 -2.918 1.00 85.85 ATOM 469 NH1 ARG 178 23.102 69.585 -2.899 1.00 92.67 ATOM 470 HHI I ARG 178 22.609 68.736 -2.708 1.00 0.00 ATOM 471 HH12 ARG 178 22.586 70.415 -3.103 1.00 0.00 ATOM 472 NH2 ARG 178 25.133 70.773 -3.165 1.00 90.17 ATOM 473 HH21 ARG 178 26.133 70.802 -3.145 1.00 0.00 eee 35 ATOM 474 HH22 ARG 178 24.609 71.605 -3.354 1.00 0.00 ATOM 475 C ARG 178 27.133 65.020 0.280 1.00 49.82 ATOM 476 0 ARG 178 27.078 65.589 1.354 1.00 51.03 :ATOM 477 N ARG 179 28.243 65.007 -0.439 1.00 47.03 ATOM 478 H ARG 179 28.218 64.607 -1.336 1.00 0.00 ATOM 479 CA ARG 179 29.458 65.625 0.039 1.00 42.75 ATOM 480 CB ARG 179 30.625 64.919 -0.632 1.00 42.27 *ATOM 481 CG ARG 179 30.599 63.395 -0."47 1.00 39.14 ATOM 482 CD ARG 179 31.759 62.682 -1.159 1.00 40.61 00ATOM 483 NE ARG 179 33.057 63.164 -0.704 1.00 40.03 45 ATOM 484 HE ARG 179 33.387 62.869 0.169 1.00 0.00 ATOM 485 CZ ARG 179 33.827 63.996 -1.427 1.00 40.60 ATOM 486 NHI ARO 179 33.483 64.391 -2.691 1.00 35.23 ATOM 487 HHI I ARG 179 32.630 64.073 -3.103 1.00 0.00 ATOM 488 HHI12 ARO 179 34.077 65.023 -3.191 1.00 0.00 ATOM 489 NH-2 ARG 179 34.965 64.483 -0.859 1.00 35.40 ATOM 490 HH21 ARG 179 35.205 64.214 0.074 1.00 0.00 ATOM 491 HH22 ARG 179 35.562 65.100 -1.370 1.00 0.00 ATOM 492 C ARG 179 29.512 67.124 -0.198 1.00 44.55 ATOM 493 0 ARG 179 30.215 67.684 -1.034 1.00 44.42 ATOM 494 N THR 180 28.730 67.862 0.570 1.00 45.86 ATOM 495 H THR 180 28.063 67.420 1.138 1.00 0.00 ATOM 496 CA THR 180 28.816 69.308 0.548 1.00 46.36 ATOM 497 CB THR 180 27.770 69.840 1.532 1.00 50.60 ATOM 498 OGI THR 180 26.517 69.456 0.968 1.00 54.63 ATOM 499 HGI Th-R 180 25.800 69.689 1.568 1.00 0.00 ATOM 500 CG2 TH-R 180 27.792 71.351 1.735 1.00 53.13 ATOM 501 C THR 180 30.221 69.783 0.901 1.00 46.41 ATOM 502 0 THR 180 30.882 69.285 1.807 1.00 47.93 ATOM 503 N GLY 181 30.713 70.783 0.171 1.00 46.30 50 ATOM 504 H GLY 181 30.090 71.312 -0.350 1.00 0.oo ATOM 505 CA GLY 181 32.118 71.193 0.236 1.00 41.25 ATOM 506 C GLY 181 32.915 70.679 -0.948 1.00 40.64 ATOM 507 0 GLY 181 34.005 71.154 -1.278 1.00 37.29 ATOM 508 N ALA 182 32.381 69.688 -1.672 1.00 35.93 ATOM 509 H ALA 182 31.540 69.257 -1.418 1.00 0.00 ATOM 510 CA ALA 182 33.136 69.171 -2.785 1.00 39.67 ATOM 511 CB ALA 182 32.314 68.028 -3.377 1.00 35.68 ATOM 512 C AL.A 182 33.503 70.220 -3.824 1.00 39.67 ATOM 513 0 ALA 182 34.590 70.239 -4.378 1.00 40.75 ATOM 514 N GLU 183 32.599 71.153 -4.107 1.00 42.72 ATOM 515 H GLU 183 31.748 71.149 -3.627 1.00 0.00 ATOM 516 CA GLU 183 32.824 72.180 -5.108 1.00 40.12 ATOM 517 CB GLU 183 31.614 73.091 -5.246 1.00 47.30 ATOM 518 CG GLU 183 31.637 73.914 -6.544 1.00 63.74 **ATOM 519 CD GLU 183 30.918 73.216 -7.697 1.00 71.48 *ATOM 520 OEI GLU 183 30.272 73.920 -8.481 1.00 78.62 ATOM 521 OE2 GLU 183 30.994 71.988 -7.818 1.00 76.00 ATOM 522 C GLU 183 33.998 73.045 -4.776 1.00 35.44 20 ATOM 523 0 GLU 183 34.778 73.390 -5.639 1.00 37.02 ATOM 524 N VAL 184 34.197 73.424 -3.521 1.00 32.69 *ATOM 525 H VAL 184 33.502 73.236 -2.857 1.00 0.00 *ATOM 526 CA VAL 184 35.437 74.093 -3.114 1.00 32.56 ATOM 527 CB VAL 184 35.391 74.286 -1.598 1.00 30.19 25 ATOM 528 CGI VAL 184 36.568 75.090 -1.054 1.00 28.08 **ATOM 529 CG2 VAL 184 34.081 74.992 -1.308 1.00 34.05 ATOM 530 C VAL 184 36.707 73.335 -3.505 1.00 31.95 ATOM 531 0 VAL 184 37.716 73.836 -3.987 1.00 31.94 ATOM 532 N ASP 185 36.649 72.025 -3.278 1.00 36.44 ATOM 533 H ASP 185 35.811 71.642 -2.945 1.00 0.00 ATOM 534 CA ASP 185 37.768 71.151 -3.586 1.00 32.53 ATOM 535 CB ASP 185 37.470 69.728 -3.077 1.00 33.96 ATOM 536 CG ASP 185 37.375 69.592 -1.539 1.00 35.35 ATOM 537 ODI ASP 185 38.047 70.367 -0.833 1.00 28.61 35 ATOM 538 0D2 ASP 185 36.635 68.705 -1.082 1.00 32.20 aATOM 539 C ASP 185 38.020 71.139 -5.059 1.00 30.28 ATOM 54 0 ASP 185 39.161 71.233 -5.493 1.00 29.51 *ATOM 541 N ILE 186 36.956 71.032 -5.849 1.00 29.28 0ATOM 542 H ILE 186 36.070 70.902 -5.447 1.00 0.00 ATOM 543 CA ILE 186 37.096 71.078 -7.305 1.00 31.19 ATOM 544 CB ILE 186 35.728 70.861 -8.016 1.00 31.31 *ATOM 545 CG2 ILE 186 35.874 71.027 -9.5"4 1.00 29.98 ATOM 54 CGI RLE 186 35.212 69.446 -7.688 1.00 33.52 **ATOM 547 CDI ILE 186 33.829 69.127 -8.292 1.00 24.25 45 ATOM 548 C ILE 186 37.684 72.413 -7.748 1.00 30.16 *ATOM 549 0 ILE 186 38.691 72.466 -8.447 1.00 30.56 ATOM 550 N THR 187 37.132 73.560 -7.388 1.00 27.47 ATOM 551 H THR 187 36.310 73.583 -6.842 1.00 0.00 ATOM 552 CA THR 187 37.739 74.820 -7.788 1.00 27.93 ATOM 553 CB THR 187 36.943 75.985 -7.175 1.00 27.45 ATOM 554 OGI THR 187 35.600 75.803 -7.625 1.00 32.61 ATOM 555 HGI THR 187 35.578 75.839 -8.583 1.00 0.00 ATOM 556 CG2 THR 187 37.461 77.371 -7.566 1.00 24.19 ATOM 557 C THR 187 39.193 74.935 -7.395 1.00 28.16 ATOM 558 0 THiR 187 39.997 75.448 -8.163 1.00 28.74 ATOM 559 N GLY 188 39.561 74.456 -6.203 1.00 28.71 ATOM 560 H GLY 188 38.908 74.010 -5.619 1.00 0.00 ATOM 561 CA GLY 188 40.932 74.607 -5.753 1.00 25.69 ATOM 562 C GLY 188 41.872 73.681 -6.483 1.00 27.48 'ATOM 563 0 GLY 188 42.983 74.024 -6.871 1.00 28.61 ATOM 564 N MET 189 41.491 72.438 -6.720 2.00 27.34 ATOM 565 H MET 189 40.618 72.115 -6.415 1.00 0.00 ATOM 566 CA MET 189 42.405 71.582 -7.426 1.00 25.62 ATOM 567 CB MET 289 42.016 70.117 -7.218 1.00 31.58 51 ATOM 568 CG MET 189 42.445 69.542 -5.843 1.00 37.74 ATOM 569 SD MET 189 44.201 69.754 -5.409 1.00 37.50 ATOM 570 CE MET 189 44.983 68.533 -6.417 1.00 38.22 ATOM 571 C MET 189 42.477 71.893 -8.893 1.00 24.18 ATOM 572 0 MET 189 43.559 71.814 -9.460 1.00 27.99 ATOM 573 N THR 190 41.385 72.251 -9.570 1.00 24.30 ATOM 574 H THR 190 40.494 72.204 -9.158 1.00 0.00 ATOM 575 CA THR 190 41.446 72.677 -10.959 1.00 23.16 ATOM 576 CB THR 190 40.030 73.023 -11.453 1.00 23.46 ATOM 577 001 THR 190 39.259 71.861 -11.228 1.00 23.54 ATOM 578 HG! THR 190 38.355 72.025 -11.500 1.00 0.00 ATOM 579 CG2 ThR 190 39.922 73.321 -12.943 1.00 19.04 ATOM 580 C ThiR 190 42.363 73.878 -11.143 1.00 25.40 ATOM 581 0 THR 190 43.255 73.913 -11.989 1.00 25.28 ATOM 582 N MET 191 42.207 74.935 -10.353 1.00 25.85 ATOM 583 H MET 191 41.531 74.956 -9.640 1.00 0.00 ATOM 584 CA MET 191 43.092 76.058 -10.563 1.00 26.80 .ATOM 585 CB MET 191 42.618 77.263 -9.73! 1.00 31.82 ATOM 586 CG MET 191 41.203 77.811 -10.021 1.00 30.18 20 ATOM 587 SD MET 191 40.720 77.816 -11.767 1.00 42.05 ATOM 588 CE MET 191 42.005 78.898 -12.322 1.00 40.61 ATOM 589 C MET 191 44.534 75.727 -10.227 1.00 26.94 ATOM 590 0 MET 191 45.439 76.102 -10.949 1.00 28.00 ATOM 591 N LEU 192 44.841 75.015 -9.139 1.00 25.8! ATOM 592 H LEU 192 44.141 74.785 -8.487 1.00 0.00 *ATOM 593 CA LEU 192 46.207 74.599 -8.872 1.00 22.18 .ATOM 594 CB LEU 192 46.226 73.695 -7.637 1.00 19.29 ATOM 595 CG LEU 192 47.592 73.125 -7.246 1.00 25.33 ATOM 596 CD1 LEU 192 48.470 74.276 -6.797 1.00 25.29 ATOM 597 CD2 LEU 192 47.450 72.049 -6.153 1.00 25.35 ATOM 598 C LEU 192 46.798 73.872 -10.0-49 1.00 19.90 ATOM 599 0 LEU 192 47.87! 74.187 -10.546 1.00 19.35 ATOM 600 N LEU 193 46.115 72.857 -10.554 1.00 20.99 .ATOM 601 H LEU 193 45.208 72.654 -10.237 1.00 0.00 35 ATOM 602 CA LEU 193 46.743 72.049 -11.571 1.00 21.52 99ATOM 603 CB LEU 193 45.920 70.802 -11.849 1.00 21.31 ATOM 604 CG LEU 193 46.081 69.749 -10.749 1.00 23.69 ATOM 605 CDI LEU 193 45.125 68.587 -11.000 1.00 26.09 ATOM 606 CD2 LEU 193 47.509 69.236 -10.751 1.00 24.27 40 ATOM 607 C LEU 193 46.921 72.815 -12.844 1.00 25.18 ATOM 608 0 LEU 193 47.962 72.768 -13.484 1.00 25.97 .ATOM 609 N GLN 194 45.909 73.565 -13.262 1.00 27.74 ATOM 610 H GLN 194 45.038 73.515 -12.809 1.00 0.00 ATOM 611 CA GLN 194 46.07! 74.455 -14.391 1.00 29.82 45 ATOM 612 CB GLN 194 44.769 75.244 -14.530 1.00 28.29 ATOM 613 CG GLN 194 44.400 75.460 -15.983 1.00 33.28 ATOM 614 CD GLN 194 42.994 75.954 -16.10! 1.00 34.79 ATOM 615 OEI GLN 194 42.085 75.270 -16.546 1.00 33.62 ATOM 616 NE2 GLN 194 42.733 77.202 -15.779 1.00 36.58 ATOM 617 HE21 GLN 194 43.468 77.783 -15.495 1.00 0.00 ATOM 618 HE22 GLN 194 41.799 77.487 -15.861 1.00 0.00 ATOM 619 C GLN 194 47.28! 75.347 -14.146 1.00 31.33 ATOM 620 0 GLN 194 48.177 75.481 -14.964 1.00 31.54 ATOM 621 N ASN 195 47.356 75.986 .12.990 1.00 33.0! ATOM 622 H ASN 195 46.613 75.928 -12.354 1.00 0.00 ATOM 623 CA ASN 195 48.530 76.762 -12.606 1.00 30.77 ATOM 624 CB ASN 195 48.460 77.239 -11.151 1.00 34.88 ATOM 625 CG ASN 195 47.69! 78.525 -10.957 1.00 38.35 ATOM 626 ODI ASN 195 47.679 79.452 -11.753 1.00 43.57 ATOM 627 ND2 ASN 195 47.015 78.668 -9.836 1.00 36.28 ATOM 628 HD21 ASN 195 47.044 77.925 -9.206 1.00 0.00 ATOM 629 HD22 ASN 195 46.506 79.497 -9.715 1.00 0.00 ATOM 630 C ASN 195 49.860 76.066 .12.719 1.00 28.51 ATOM 63! 0 ASN 195 50.871 76.696 .12.949 1.00 26.10 52 ATOM 632 *N ATOM 633 H ATOM 634 CA ATOM 635 CB ATOM 636 CG ATOM 637 CDI ATOM 638 CD2 ATOM 639 C ATOM 640 0 ATOM 641 N ATOM 642 H ATOM 643 CA ATOM 644 C ATOM 645 0 ATOM 646 N ATOM 647 H ATOM 648 CA *ATOM 649 CB ATOM 650 CG 20 ATOM 651 CDI *ATOM 652 CEl ATOM 633 CD2 ATOM 654 CE2 .ATOM 655 CZ ATOM 656 OH *ATOM 657 HH *ATOM 658 C ATOM 659 0 ATOM 660 N ATOM 661 H ATOM 662 CA ATOM 663 CB *ATOM 664 OG ATOM 665 HG 35 ATOM 666 C ATOM 667 0 ATOM 668 N ATOM 669 H :ATOM 670 CA 40 ATOM 671 CB ATOM 672 CGI *ATOM 673 CG2 ATOM 674 C ATOM 675 0 45 ATOM 676 N ATOM 677 H ATOM 678 CA ATOM 679 CB ATOM 680 CG ATOM 681 ODi ATOM 682 0D2 ATOM 683 C ATOM 684 0 ATOM 685 N ATOM 686 H ATOM 687 CA ATOM 688 CB ATOM 689 CGI ATOM 690 CG2 ATOM 691 C ATOM 692 0 ATOM 693 N ATOM 694 H ATOM 695 CA

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLY

GLY

GLY

GLY

GLY

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

SYR

SER

SER

SER

SER

SER

SER

SER

VAL

VAL

VAL

VAL

VAL.

VAL

VAL.

VAL

VAP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

VASP

VAL

VA!.

VAL

VAL.

VAL

VAL.

VAL.

LYS

LYS

LYS

196 196 196 196 196 196 196 1%6 196 197 197 197 197 197 198 198 198 198 198 198 198 198 198 198 198 198 198 198 199 199 199 199 199 199 199 199 200 200 200 200 200 200 200 200 201 201 201 201 201 201 201 201 201 202 202 202 202 202 202 202 202 203 203 203 49.928 49.112 51. 193 51.179 51. 188 50.972 52 .519 5 1.433 52.442 50.478 49.631 50.704 49.860 50.142 48.830 48.531 48. 125 47.870 49.145 49.919 51.123 49.572 50.771 5 1.567 52.806 53. 179 46.794 46. 136 46.353 46.951 44.953 44.776 45 .617 45.356 44.163 44.489 43.095 42.823 42.321 42.090 4 1.528 43.399 40.978 40.073 40.787 4 1.548 39.459 39.501 39,387 38.413 40.251I 38 .786 39.402 37.561 37 .092 36. 820 36 .274 35.461 37 .434 35.669 34. 893 35 .496 36. 163 34. 334 74.758 -12.542 74.264 -12.313 74.051 -12.683 72.795 -11.806 73.150 -10.326 71.914 -9.481 73.794 -9.985 73.661 -14.123 73.078 -14.503 73.970 -14.993 74.363 -14.695 73.779 -16.401 72.707 -17.015 72.320 -18.140 72.188 -16.360 72.597 -15.518 71.016 -16.872 69.968 -15.744 69.319 -15.195 69.969 -14.251 69.433 -13.835 67.572 -15.298 68.265 -14.399 67.774 -14.022 68.383 -13.376 71.385 -17.465 72.288 -16.959 70.714 -18.533 70.163 -19.m9 70.775 -18.924 70.400 -20.402 71.216 -21.197 72.131 -21.040 69.810 -18.077 68.636 -17.967 70.325 -17.471 71.240 -17.708 69.612 -16.481 70.526 -15.284 69.691 -14.142 71.222 -14.885 69.116 -16.979 69.889 -17.248 67.815 -17.115 67.209 -17.020 67.259 -17.292 65.852 -17.808 65.818 -19.271 65.246 -19.737 66.358 -19.949 67.159 -15.940 66.593 -15.030 67.665 -15.755 68.158 -16.463 67.390 -14.543 68.690 -13.955 68.387 -12.696 69.634 -13.649 66.447 -14.865 66.731 -15.763 65.309 -14.183 65.050 -13.508 64.448 -14.372 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 27.38 0.00 25.33 24.19 23.30 24.60 31.63 26.23 24.03 27.17 0.00 25.75 26.04 27.75 24.74 0.00 24.17 24.44 17.56 17.53 19.28 16.54 17.99 22.77 26.91 0. 00 25.30 28.39 27.93 0.00 29.13 31.52 44.44 0.00 25.88 28.99 22.17 0.00 21.46 17.18 19.27 17.36 25.60 26.95 25.10 0.00 26.46 32.29 40.02 53.36 48.96 28.68 25.09 26.15 0.00 29.60 29.43 26.97 26.15 33.37 36.29 33.12 0.00 28.52 53 ATOM 696 CB ATOM 697 CG ATOM 698 CD ATOM 699 CE ATOM 700 NZ ATOM 701 HZI ATOM 702 HZ2 ATOM 703 HZ3 ATOM 704 C ATOM 705 0 ATOM 706 N ATOM 707 H ATOM 708 CA ATOM 709 CB ATOM 710 CG ATOM 711 CD *ATOM 712 CE ATOM 713 NZ 6ATOM 714 HZI 20 ATOM 715 HZ2 *ATOM 716 HZ3 ATOM 717 C *ATOM 718 0 ATOM 719 N ATOM 720 H *.aATOM 721 CA S6ATOM 722 CB ATOM 723 CG ATOM 724 ODI ATOM 725 ND2 ATOM 726 HD21 ATOM 727 HD22 699ATOM 728 C 6ATOM 729 0 ATOM 730 N 96ATOM 731 H ATOM 732 CA *6*ATOM 733 CB ATOM 734 CO ATOM 735 CDI ATOM 736 CD2 6ATOM 737 C ATOM 738 0 66ATOM 739 N 45 ATOM 740 H *ATOM 741 CA ATOM 742 CB ATOM 743 001 ATOM 744 HGl ATOM 745 CG2 ATOM 746 C ATOM 747 0 ATOM 748 N ATOM 749 H ATOM 750 CA ATOM 751 CB ATOM 752 C ATOM 753 0 ATOM 754 N ATOM 755 H1 ATOM 756 CA ATOM 757 CB ATOM 758 00 ATOM 759 HG

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

THR

THR

THR

THR

THR

THR

THR

THR

THR

ALA

ALA

ALA

ALA

ALA

ALA

SER

SER

SER

SER

SER

SER

203 203 203 203 203 203 203 203 203 203 204 204 204 204 204 204 204 204 204 204 204 204 204 205 205 205 205 205 205 205 205 205 205 205 206 206 206 206 206 206 206 206 206 207 207 207 207 207 207 207 207 207 208 208 208 208 208 208 209 209 209 209 209 209 34.749 35.590 34.746 35 .53 1 34.651 34.274 33.854 35. 168 33.596 34.220 32.268 31.711 31.6 10 30.827 31.646 30.858 31.660 30.997 30.884 30.058 31.568 30.603 30.073 30.378 30.983 29.340 27 .956 27.915 28 .416 27.363 27.014 27 .318 29.323 28.356 30.354 31I.09 30.352 3 1.657 32.070 33.375 31.010 30. 196 30.211 30.043 29.939 30.012 28.851 27.728 26.926 28.942 31.381 32.157 3 1.747 31.129 33 .047 33 .042 33 .402 34 .525 32.4 19 31.5 16 .32.623 3 1.471 30.259 29.534 63.050 -14.826 62.990 -16.088 63.437 -17.266 63.532 -18.574 64.012 -19.625 64.946 -19.364 63.352 -19.738 64.088 -20.524 64.313 -13.046 64.117 -12.016 64.402 -12.954 64.391 .13.762 64.417 -11.655 65.701 -11.363 66.950 -11.553 68.196 -11.188 69.462 -11.544 70.674 -11.086 70.631 -10.052 70.742 -11.528 71.505 -11.339 63.311 -11.602 62.894 -12.625 62.866 -10.365 63.186 -9.659 61 .902 -10.003 62.531 -10.122 63.623 -9.103 63.536 -7.988 64.768 -9.456 64.830 -10.369 65.493 -8.798 60.626 -10.792 60.317 -11.453 59.799 -10.793 59.947 -10. 163 58.667 -11.698 58.587 -12.498 59.852 -13.281 59.557 -14.009 60.255 -14.297 57.402 -10.933 57.314 -9.715 56.331 -11.664 56.423 -12.631 55.027 -11.058 54.344 -11.773 54.701 -10.986 54.355 -11.394 52.841 -11.905 54.358 -11.219 54.742 -12.079 53.344 -10.429 53.028 -9.745 52.699 -10.537 51.453 -9.643 52.325 -11.959 52.467 -12.425 51.840 -12.707 51.718 -12.349 51.470 -14.096 50.593 -14.573 51.040 -13.965 50.500 -14.307 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 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 28.62 32.11 40.39 50.57 59.39 0.00 0.00 0.00 29.68 30.93 32.55 0.00 34.17 32.07 37.18 44.8 54.50 60.66 0.00 0.00 0.00 32.66 33.79 31.17 0.00 29.81 25.29 26.48 29.97 29.11 0.00 0.00 30.34 32.35 31.19 0.00 28.61 29.20 29.46 30.38 33.07 30.76 35.60 32.87 0.00 36.34 36.91 42.24 0.00 42.72 36.64 39.32 36.10 0.00 34.66 32.92 36.07 38.58 38.40 0.00 38.81 45.07 56.06 0.00 54 ATOM 760 C ATOM 761 0 ATOM 762 N ATOM 763 H ATOM 764 CA ATOM 765 CB ATOM 766 CG ATOM 767 ODI ATOM 768 OD2 ATOM 769 C ATOM 770 0 ATOM 771 N ATOM 772 H ATOM 773 CA ATOM 774 CB ATOM 775 CG ATOM 776 SD 0 ATOM 777 CE ATOM 778 C ATOM 779 0 0 ATOM 780 N ATOM 781 H ATOM 782 CA ATOM 783 CB ATOM 784 O01 ATOM 785 HG "s 5 ATOM 786 CG2 ATOM 787 C ATOM 788 0 ATOM 789 N ATOM 790 H ATOM 791 CA ATOM 792 CB ATOM 793 O01 ATOM 794 HGI ATOM 795 CG2 ATOM 796 C ATOM 797 0 ATOM 798 N 40 ATOM 799 H ATOM 800 CA ATOM 801 CB ATOM 802 CG O -ATOM 803 CD 45 ATOM 804 OEI ATOM 805 OE2 ATOM 806 C ATOM 807 0 ATOM 808 N ATOM 809 H ATOM 810 CA ATOM 811 CB ATOM 812 CG ATOM 813 CDI ATOM 814 CD2 ATOM 815 C ATOM 816 0 ATOM 817 N ATOM 818 H ATOM 819 CA ATOM 820 CB ATOM 821 CG ATOM 822 CD ATOM 823 OEI

SER

SER

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

MET

MET

MET

MET

MET

MET

MET

MET

MET

THR

ThR

THR

THR

THR

THR

THR

THR

THR

THR

THR

ThR

THR

THR

THR

THR

THR

THR

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

209 32.724 209 33.571 210 31.877 210 31.138 210 32.061 210 31.103 210 29.602 210 ,29.209 210 28.830 210 33.469 210 34.155 211 33.944 211 33.371 211 35.310 211 35.574 211 34.914 211 35.182 211 34.219 211 36.310 211 37.247 212 36.140 212 35.445 212 36.997 212 36.443 212 36.580 212 37.491 212 37.128 212 37.122 212 38.195 213 35.973 213 35.126 213 35.869 213 34.354 213 33.818 213 34.273 213 34.086 213 36.571 213 37.304 214 36.356 214 35.706 214 37.082 214 36.673 214 35.275 214 34.998 214 35.754 214 34.015 214 38.561 214 39.348 215 38.976 215 38.327 215 40.392 215 40.670 215 40.608 215 40.822 215 41.648 215 40.966 215 41.998 216 40.334 216 39.555 216 40.802 216 39.922 216 39.940 216 39.089 216 39.535 52.676 52.733 53.687 53.563 54.930 56.049 55.780 54.945 56.441 55.432 55.935 55.299 54.919 55.693 55.528 56.611 56.360 57.715 54.866 55.382 53.551 53.118 52.704 51.289 50.901 50.999 50.325 53.142 53.275 53.375 53.245 53.796 53.892 52.581 51.966 54.420 55.122 55.298 56.097 55.963 57.351 58.355 58.972 59.508 60.353 59.057 57.147 57.759 56.276 55.881 55.922 54.929 55.547 54.470 56.656 55.300 55.738 54.261 53.884 53,695 52.537 51.319 50.173 49.546 -14.978 -15.857 -14.779 -14.150 -15.516 -15.088 -15.228 -16.060 14.507 -15.219 -16.096 -13.965 -13.268 -13.629 -12.130 -11.271 -9.493 -8.954 -14.404 -14.999 -14.436 -13.893 -15.242 -15.170 -13.805 -13.515 -16.127 -16.681 -17.241 -17.297 -16.813 -18.681 -19.044 -18.856 -19.436 -20.467 -18.900 -19.865 -18.006 -17.279 -18.103 -17.025 -17.161 -18.559 -19.052 -19.154 -17.960 -18.665 -17.045 -16.422 -16.942 -15.786 -14.386 -13.329 14.292 -18.190 -18.686 -18.740 -18.282 -19.991 -20.463 -19.517 -20.064 -21.027 35.05 36.86 33.45 0.00 36.67 43.07 51.26 52.07 50.26 36.66 34.14 36.25 0.00 36.30 32.55 31.33 38.31 38.56 33.55 35.45 30.54 0.00 31.66 30.49 36.43 0.00 30.70 30.78 30.06 34.48 0.00 33.70 38.71 42.49 0.00 40.74 31.43 30.44 29.82 0.00 29.65 33.21 39.44 44.47 46.83 48.55 26.00 23.58 26.22 0.00 30.25 28.64 31.22 30.89 24.41 29.50 32.89 27.46 0.00 30.27 38.22 54.67 60.29 63.24 ATOM 824 0E2 ATOM 825 C ATOM 826 0 ATOM 827 N ATOM 828 H ATOM 829 CA ATOM 830 CB ATOM 831 C ATOM 832 0 ATOM 833 N ATOM 834 H ATOM 835 CA ATOM 836 CB ATOM 837 CG ATOM 838 CDI ATOM 839 CD2 00ATOM 840 CEI *ATOM 841 CE2 ATOM 842 CZ 20 ATOM 843 C ATOM 844 0 ATOM 845 N *ATOM 846 H *SATOM 847 CA ATOM 848 CB ATOM 849 C 'S*ATOM 850 0 ATOM 851 N ATOM 852 H ATOM 853 CA ATOM 854 CB ATOM 855 CG aATOM 856 CD2 *ATOM 857 ND1 ATOM 858 HDI *ATOM 859 CEI ATOM 860 NE2 ATOM 861 HE2 *ATOM 862 C b 40 ATOM 863 0 *ATOM 86 N *ATOM 865 H ATOM 866 CA 0oATOM 867 CB ATOM 868 CG ATOM 869 CD ATOM 870 NE ATOM 871 HE ATOM 872 CZ ATOM 873 KH I ATOM 874 HH 11 ATOM 875 HHI12 ATOM 876 NH-2 ATOM 877 HH21 ATOM 878 HH22 ATOM 879 C ATOM 880 0 ATOM 88! N ATOM 882 CD ATOM 883 CA ATOM 884 CB ATOM 885 CG ATOM 886 C ATOM 887 0

GLU

GLU

GLU

ALA

ALA

ALA

ALA

ALA

ALA

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

ALA

ALA

ALA

ALA

ALA

ALA

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

PRO

PRO

PRO

PRO

PRO

PRO

PRO

216 216 216 217 217 217 217 217 217 218 218 218 218 218 218 218 218 218 218 218 218 219 219 219 219 219 219 220 220 220 220 220 220 220 220 220 220 220 220 220 221 221 221 221 221 221 221 221 221 221 221 221 221 221 221 221 221 222 222 222 222 222 222 222 38.003 40.823 4 1.722 39.836 39.086 39.851 38 .530 41.008 41.79! 41. 179 40.554 42.258 42. 185 43.236 44 .361 43.036 45.234 43.920 45.005 43.603 4.495 43.772 43 .083 44.971 44.884 45.224 46.335 44.155 43.276 44.260 43.030 43. 153 43 .712 42.884 42.460 43 .283 43.788 44. 189 44.431 44.482 44.5 19 4.453 44.684 44.496 43.089 42.164 42.527 43. 163 42.025 4 1.323 4 1.185 40.981 42. 162 42.631 41.797 46.030 47.097 46.0 15 ".795 47.204 46.670 45.279 48. 125 49.329 49.907 -19.525 54.724 -21.094 54.757 -21.926 55.617 -21.144 55.550 -20.516 56.698 -22.121 57.477 -22.045 57.620 -21.855 57.934 -22.740 58.083 -20.624 57.809 -19.917 58.999 -20.319 59.322 -18.828 60.340 -18.445 59.929 -17.742 61.686 -18.721 60.889 -17.262 62.634 -18.228 62.234 -17.484 58.427 -20.701 59.110 -21.209 57.138 -20.456 56.655 -19.953 56.429 -20.858 54.979 -20.375 56.436 -22.351 56.29! -22.834 56.608 -23.131 56.759 -22.722 56.691 -24.578 56.108 -25.287 54.627 -25.144 53.790 -26.069 53.894, -24.069 54.202 -23.244 52.673 -24.28 1 52.624 -25.483 51.815 -25.855 58.066 -25.139 58.222 -26.346 59.129 -24.354 59.018 -23.381 60.441 -24.935 61.4.60 -23.847 61.433 -23.298 62.262 -24.150 63.666 -24.117 64.003 -24.780 64.537 -23.214 64.137 -22.120 63.163 -21.950 64.814 -21.467 65.884 -23.412 66.223 -24.228 66.529 -22.740 60.643 -25.605 60.475 -25.015 61 .030 -26.842 61 .277 -27.621 61 .317 -27.635 61.799 -28.976 62.298 -28.634 62.326 -26.990 62.305 -27.184 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 60.46 29.88 27.84 27.72 0.00 27.12 27.01 26.62 26.18 25.15 0.00 23.19 20.84 25.38 24.12 23.15 23.97 23.08 21.26 25.14 29.00 23.61 0.00 24.15 24.62 30.25 30.75 31.80 0.00 32.54 33.65 38.22 40.87 2.77 0.00 41.06 39.69 0.00 31.27 34.54 31.23 0.00 25.20 23.87 24.28 24.77 30.34 0.00 36.39 37.62 0.00 0.00 36.36 0.00 0.00 27.94 27.32 30.14 28.66 26.80 27.03 26.07 28.33 34.07 56 ATOM 888 N ATOM 889 H ATOM 890 CA ATOM 891 CB ATOM 892 CG ATOM 893 CD ATOM 894 OEI ATOM 895 0E2 ATOM 896 C ATOM 897 0 ATOM 898 N ATOM 899 H ATOM 900 CA ATOM 901 CB ATOM 902 CG ATOM 903 CD2 ATOM 904 NDI 'ATOM 905 HDI ATOM 906 CEI ATOM 907 NE2 ATOM 908 HE2 ATOM 909 C ATOM 910 0 *'ATOM 911 N ATOM 912 H cATOM 913 CA 914 CB ATOM 915 CG ATOM 916 CD ATOM 917 CE ATOM 918 NZ ATOM 919 HZI e, 4b ATOM 920 HZ2 a ATOM 921 HZ3 ATOM 922 C ATOM 923 0 ATOM 924 N a a*ATOM 925 H :ATOM 926 CA ATOM 927 CB ATOM 928 OGi aATOM 929 HGI ATOM 930 CG2 ATOM 931 C 45 ATOM 932 0 ATOM 933 N ATOM 934 H ATOM 935 CA ATOM 936 CB ATOM 937 00 ATOM 938 HG ATOM 939 C ATOM 940 0 ATOM 941 N ATOM 942 H ATOM 943 CA ATOM 944 CB ATOM 945 CG ATOM 946 ODI ATOM 947 0D2 ATOM 948 C ATOM 949 0 ATOM 950 N ATOM 951 H

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

THR

THR

THR

THR

THR

THR

THR

THR

THR

SER

SER

SER

SER

SER

SER

SER

SER

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

SER

SER

47.627 46.669 48.500 47.671 46.658 45.293 44.328 45. 177 49.569 50.606 49.343 48.522 50.346 49.960 48.774 47.721I 48.546 49.236 47.382 46.889 46.004 51.646 52.700 5 1.608 50.750 52.826 52.503 52.645 52.548 52.57 1 5 1.337 50.529 51.211 51.387 53 .638 54.854 53.015 52.045 53 .803 53 .293 51.944 5 1.452 ,54.127 53.770 53.809 53.685 53 .657 53 .733 52 .412 52 .319 51.584 54.872 55.409 55 .246 54 .753 56.270 57 .305 56.663 57 .311 55 .524 55 .732 56.509 54 .425 53 .756 63.254 -26.189 63.259 -26.005 64.265 -25.620 65.306 -24.887 66.030 -25 .769 65.38 1 -25.726 66.114 -25.534 64.168 -25.880 63.758 -24.663 64.371 -24.461 62.599 -24.034 62. 108 -24.230 62.037 -23.139 60.670 -22.601 60.779 -21.676 59.901 -21.673 61 .704 -20.722 62.337 -20.408 61.423 -20.177 60.352 -20.773 59.939 -20.625 61.845 -23.859 62.029 -23.281 61.474 -25.138 61.290 -25.594 61.359 -25.937 60.985 -27.373 59.492 -27.564 59.057 -29.024 57.524 -29.181 56.917 -28.699 57.292 -29.236 57.140 -27.691 55.887 -28.827 62.627 -25.985 62.599 -26.05 1 63.792 -25.975 63.869 -26.061 64.992 -25.854 66.018 -26.896 65.709 -27.203 66.009 -26.422 65.983 -28.180 65.546 -24.441 66.756 -24.226 64.702 -23.408 63.727 -23.528 65.1% -22.055 64.917 -21.322 65.533 -20.021 65.178 -19.486 64.535 -21.301 63.498 -21.661 65.201 -20.199 66.020 -19.977 64.715 -19.270 65.848 -18.973 67.095 -18.438 68.115 -18.499 67.071 -17.976 64.156 -17.923 63.644 -17.121 64.213 -17.599 64.595 -18.213 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 25.34 0.00 28.40 27.51 32.04 34.72 35.25 38.35 28.17 28.18 26.29 0.00 25.11 21.67 28.93 29.23 26.59 0.00 31.44 33.43 0.00 26.89 30.62 30.81 0.00 32.77 39.91 55.31 67.66 75.00 78.51 0.00 0.00 0.00 30.17 32.06 29.27 0.00 29.35 28.73 27.05 0.00 31.09 30.98 34.36 27.84 0.00 25.31 23.69 29.36 0.00 27.92 22.67 28.65 0.00 28.62 21.37 23.40 25.53 24.44 29.79 33.42 30.06 0.00 57 ATOM 952 CA SER 229 53.905 63.708 -16.336 1.00 24.85 ATOM 953 CB SER 229 54.314 64.599 -15.182 1.00 21.77 ATOM 954 OG SER 229 54.171 6S.969 -15.547 1.00 21.06 ATOM 955 HG SER 229 54.272 66.564 -14.792 1.00 0.00 ATOM 956 C SER 229 52.413 63.747 -16.437 1.00 23.31 ATOM 957 0 SER 229 51.900 64.273 -17.423 1.00 23.18 ATOM 958 N THR 230 51.720 63.201 -15.435 1.00 24.93 ATOM 959 H THR 230 52.164 62.618 -14.780 1.00 0.00 ATOM 960 CA THR 230 50.303 63.473 -15.239 1.00 22.17 ATOM 961 CB THR 230 49.501 62.410 -16.052 1.00 18.90 ATOM 962 OGI THR 230 48.158 62.903 -16.198 1.00 23.08 ATOM 963 HGI THR 230 48.158 63.784 -16.611 1.00 0.00 ATOM 964 CG2 THR 230 49.485 61.030 -15.391 1.00 17.19 ATOM 965 C THR 230 49.933 63.471 -13.739 1.00 22.19 ATOM 966 0 THR 230 50.683 63.015 -12.887 1.00 19.95 .ATOM 967 N PHE 231 48.751 63.999 -13.412 1.00 23.01 *ATOM 968 H PHE 231 48.196 64.345 -14.142 1.00 0.00 0ATOM 969 CA PHE 231 48.168 64.022 -12.081 1.00 22.98 a ATOM 970 .CB PHE 231 47.955 65.441 -11.549 1.00 22.01 ATOM 971 CG PHE 231 49.190 65.978 -10.873 1.00 23.66 *ATOM 972 'CDI PHE 231 49.220 66.071 -9.486 1.00 22.17 *ATOM 973 CD2 PHE 231 50.273 66.392 -11.635 1.00 21.19 @0ATOM 974 CEI PHE 231 50.361 66.561 -8.861 1.00 23.83 ATOM 975 CE2 PHE 231 51.391 66.900 -11.010 1.00 18.70 25 ATOM 976 CZ PHE 231 51.442 66.965 -9.620 1.00 22.93 0ATOM 977 C PHE 231 46.792 63.409 -12.160 1.00 21.75 ATOM 978 0 PHE 231 46.067 63.809 -13.062 1.00 21.91 ATOM 979 N LEU 232 46.343 62.479 -11.312 1.00 20.85 ATOM 980 H LEU 232 46.949 62.069 -10.654 1.00 0.00 ATOM 981 CA LEU 232 44.915 62.139 -11.293 1.00 19.87 ATOM 982 CB LEU 232 44.627 60.672 -11.588 1.00 23.90 ATOM 983 CG LEU 232 45.050 60.289 -12.995 1.00 30.22 ~*ATOM 984 CDI LEU 232 46.486 59.760 12.956 1.00 32.80 ATOM 985 CD2 LEU 232 44.089 59.240 -13.555 1.00 32.58 35 ATOM 986 C LEU 232 44.338 62.387 -9.941 1.00 18.92 @0 dATOM 987 0 LEU 232 44.980 62.002 -8.979 1.00 22.64 ATOM 988 N VAL 233 43.174 62.998 -9.754 1.00 20.69 *ATOM 989 H VAL 233 42.629 63.238 -10.535 1.00 0.00 .ATOM 990 CA VAL 233 42.664 63.290 -8.423 1.00 22.20 40 ATOM 991 CB VAL 233 42.519 64.812 -8.180 1.00 21.39 ATOM 992 CGI VAL 233 42.185 65.090 -6.706 1.00 20.83 ATOM 993 CG2 VAL 233 43.826 65.525 -8.539 1.00 27.2! 0ATOM 994 C VAL 233 41.291 62.645 -8.264 1.00 27.10 ATOM 995 0 VAL 233 40.429 62.803 -9.122 1.00 24.87 45 ATOM 996 N PHE 234 41.049 61.906 -7.176 1.00 24.72 ATOM 997 H PHE 234 41.749 61.801 -6.495 1.00 0.00 ATOM 998 CA PHE 234 39.764 61.286 -6.938 1.00 23.25 ATOM 999 CB PHE 234 39.870 59.773 -6.767 1.00 20.01 ATOM 1000 CG PHE 234 40.400 59.110 -8.005 1.00 21.08 ATOM 1001 CDI PHE 234 39.525 58.555 -8.904 1.00 26.42 ATOM 1002 CD2 PHE 234 41.768 59.045 -8.222 1.00 25.79 ATOM 1003 CE! PHE 234 40.019 57.951 -10.046 1.00 29.30 ATOM 1004 CE2 PHE 234 42.262 58.445 -9.353 1.00 23.33 ATOM 1005 CZ PHE 234 41.379 57.910 -10.266 1.00 31.52 ATOM 1006 C PHE 234 39.259 61.858 -5.650 1.00 25.38 ATOM 1007 0 PHE 234 39.990 61.926 -4.664 1.00 27.17 ATOM 1008 N MET 235 38.006 62.298 -5.583 1.00 26.22 ATOM 1009 H MET 235 37.441 62.301 -6.384 1.00 0.00 ATOM 1010 CA MET 235 37.451 62.780 -4.326 1.00 25.64 ATOM 1011 CB MET 235 37.276 64.294 -4.345 1.00 24.45 ATOM 1012 CG MET 235 38.619 64.946 -4.681 1.00 30.66 ATOM 1013 SD MET 235 38.60 66.742 -4.848 1.00 37.65 ATOM 1014 CE MET 235 38.003 66.982 -6.481 1.00 33.32 ATOM 1015 C MET 235 36.120 62.112 -4.236 1.00 29.15 58 ATOM 1016 0 MET 235 35.339 62.186 -5.175 1.00 29.75 ATOM 1017 N SER 236 35.808 61.432 -3.138 1.00 31.99 ATOM 1018 H SER 236 36.441 61.364 -2.382 1.00 0.00 ATOM 1019 CA SER 236 34.531 60.769 -2.995 1.00 32.91 ATOM 1020 Ce SER 236 34.412 59.596 -3.971 1.00 31.29 ATOM 1021 OC SER 236 33.125 58.996 -3.885 1.00 32.86 ATOM 1022 HG SER 236 32.463 59.641 -4.143 1.00 0.00 ATOM 1023 C SER 236 34.462 60.246 -1.573 1.00 32.69 ATOM 1024 0 SER 236 35.389 60.340 -0.778 1.00 33.35 ATOM 1025 N HIS 237 33.329 59.661 -1.203 1.00 33.10 ATOM 1026 H HIS 237 32.551 59.730 -1.783 1.00 0.00 ATOM 1027 CA HIS 237 33.332 58.809 -0.016 1.00 34.12 ATOM 1028 CB HIS 237 31.882 58.331 0.377 1.00 37.00 ATOM 1029 CC HIS 237 31.079 59.375. 1.141 1.00 42.87 15 ATOM 1030 CD2 HIS 237 29.798 59.740 0.816 1.00 40.88 *ATOM 1031 NDI HIS 237 31.457 60.128 2.188 1.00 41.19 ATOM 1032 HDI HIS 237 32.325 60.120 2.661 1.00 0.00 ATOM 1033 CEI HIS 237 30.460 60.934 2.446 1.00 43.14.

*ATOM 1034 NE2 HIS 237 29.466 60.721 1.609 1.00 42.94 2.0 ATOM 1035 HE2 HIS 237 28.639 61.252 1.540 1.00 0.00 *ATOM 1036 C HIS 237 34.194 57.577 -0.321 1.00 33.55 0. ATOM 1037 0 HIS 237 34.520 57.234 -1.462 1.00 32.97 ATOM 1038 N GLY 238 34.606 56.852 0.702 1.00 32.27 ATOM 1039 H GLY 238 34.429 57.073 1.646 1.00 0.00 25 ATOM 1040 CA CLY 238 35.369 55.668 0.428 1.00 31.94 ATOM 1041 C GLY 238 35.217 54.774 1.609 1.00 31.47 ATOM 1042 0 CLY 238 34.874 55.189 2.707 1.00 29.62 ATOM 1043 N ILE 239 35.475 53.512 1.370 1.00 30.61 ATOM 1044 H ILE 239 35.767 53.236 0.474 1.00 0.00 ATOM 1045 CA ILE 239 35.461 52.548 2.439 1.00 36.45 ATOM 1046 CB ILE 239 34.416 51.450 2.210 1.00 38.77 ATOM 1047 CG2 ILE 239 33.067 52.124 2.180 1.00 42.42 ATOM 1048 CCI IL-E 239 34.645 50.683 0.928 1.00 42.77 0 0 ATOM 1049 CDI ILE 239 33.745 49.470 0.810 1.00 45.44 0. 35 ATOM 1050 C ILE 239 36.822 51.930 2.435 1.00 37.10 ATOM 1051 0 ]ILE 239 37.640 52.175. 1.572 1.00 37.25 *ATOM 1052 N ARC 240 37.118 51.076 3.398 1.00 39.29 *ATOM 1053 H ARC 240 36.434 50.847 4.063 1.00 0.00 ATOM 1054 CA ARC 240 .38.428 50.462 3.465 1.00 42.79 :000 40 ATOM 1055 CB ARC 240 38.400 49.475 4.647 1.00 45.84 ATOM 1056 CG ARC 240 39.680 48.660 4.892 1.00 52.68 ATOM 1057 CD ARG 240 40.939 49.489 5.139 1.00 57.36 00 0ATOM 1058 NE ARC 240 42.114 48.829 4.594 1.00 60.04 0 0ATOM 1059 HE ARC 240 42.319 48.953 3.645 1.00 0.00 ATOM 1060 CZ ARC 240 42.922 48.052 5.327 1.00 66.92 ATOM 1061 NH1 ARC 240 44.059 47.576 4.740 1.00 71.12 ATOM 1062 HHI I ARC 240 44.259 47.811 3.789 1.00 0.00 ATOM 1063 HH 12 ARC 240 44.688 46.986 5.247 1.00 0.00 ATOM 1064 NH-2 ARC 240 42.657 47.711 6.622 1.00 65.55 ATOM 1065 HH21 ARC 240 41.828 48.040 7.073 1.00 0.00 ATOM 1066 HH22 ARC 240 43.298 47.122 7.115 1.00 0.00 ATOM 1067 C ARC 240 38.863 49.791 2.164 1.00 41.91 ATOM 1068 0 ARC 240 40.040 49.875 1.864 1.00 39.72 ATOM 1069 N CLU 241 37.969 49.138 1.389 1.00 46.63 ATOM 1070 H CLU 241 37.022 49.233 1.606 1.00 0.00 ATOM 1071 CA CLU 241 38.318 48.416 0.151 1.00 49.66 ATOM 1072 CB CLU 241 37.185 47.460 -0.280 1.00 58.65 ATOM 1073 CC CLU 241 37.559 46.447 -1.379 1.00 76.02 ATOM 1074 CD CLU 241 36.387 45.686 -2.058 1.00 84.57 ATOM 1075 OEI CLU 241 35.539 46.310 -2.712 1.00 86.53 ATOM 1076 0E2 CLU 241 36.350 44.449 -1.970 1.00 90.34 ATOM 1077 C CLU 241 38.559 49.403 -1.0019 1.00 45.34 ATOM 1078 0 CLU 241 39.236 49.102 -1.985 1.00 45.76 ATOM 1079 N CLY 242 38.015 50.628 -0.966 1.00 40.75 59 ATOM 1080 H GLY 242 37.428 50.949 -0.241 1.00 0.oo ATOM 1081 CA GLY 242 38.362 51.556 -2.014 1.00 35.23 ATOM 1082 C GLY 242 37.375 52.679 -2.047 1.00 33.55 ATOM 1083 0 GLY 242 36.694 52.955 -1.071 1.00 32.49 ATOM 1084 N ILE 243 37.290 53.311 -3.213 1.00 31.51 ATOM 1085 H ILE 243 37.707 52.888 '-3.992 1.00 0.00 ATOM 1086 CA ILE 243 36.590 54.576 -3.407 1.00 30.20 ATOM 1087 CB ILE 243 37.364 55.376 -4.511 1.00 31.68 ATOM 1088 CG2 ILE 243 36.739 56.740 -4.856 1.00 28.31 ATOM 1089 CGI ILE 243 38.749 55.674 -3.963 1.00 31.33 ATOM 1090 CDI ILE 243 39.643 56.077 -5.135 1.00 35.46 ATOM 1091 C ILE 243 35.148 54.304 -3.806 1.00 30.26 ATOM 1092 0 IL.E 243 34.920 53.418 -4.618 1.00 30.91 ATOM 1093 N CYS 244 34.151 55.017 -3.276 1.00 29.95 ATOM 1094 H CYS 244 34.337 55.767 -2.666 1.00 0.00 .ATOM 1095 CA CYS 244 32.774 54.760 -3.652 1.00 31.93 ATOM 1096 CB CYS 244 31.855 55.223 -2.553 1.00 29.44 ATOM 1097 SG CYS 244 32.093 54.318 -1.030 1.00 36.45 *ATOM 1098 C CYS 244 32.291 55.415 -4.945 1.00 35.60 ATOM 1099 0 CYS 244 32.427 56.619 -5.169 1.00 34.97 *ATOM 1100 N GLY 245 31.695 54.653 -5.863 1.00 34.56 .ATOM 1101 H GLY 245 31.752 53.680 -5.763 1.00 0.00 ATOM 1102 *CA GLY 245 30.973 55.279 -6.%62 1.00 37.28 ATOM 1103 C GLY 245 29.574 55.745 -6.552 1.00 42.13 25 ATOM 110o4 0 GLY 245 29.085 55.433 -5.470 1.00 41.53 ATOM 1105 N LYS 246 28.868 56.501 -7.415 1.00 44.81 ATOM 1106 H LYS 246 29.231 56.669 -8.312 1.00 0.00 ATOM 1107 CA LYS 24.6 27.604 57.140 -7.033 1.00 47.47 ATOM 1108 CB LYS 246 27.040 57.989 4.186 1.00 4.6.88 ATOM 1109g CG LYS 246 26.636 57.098 -9.348 1.00 51.88 ATOM 1110 CD LYS 246 25.882 57.806 -10.459 1.00 62.88 *ATOM 1111 CE LYS 246 24.560 58.422 -10.000 1.00 69.93 ATOM 1112 NZ LYS 246 24.007 59.246 -11.063 1.00 76.93 ATOM 1113 HZ1 LYS 246 23.833 58.663 -11.905 1.00 0.00 35 ATOM 1114 HZ2 LYS 246 24.678 60.006 -11.295 1.00 0.00 ATOM 1115 HZ3 LYS 246 23.112 59.670 -10.742 1.00 0.00 soATOM 1116 C LYS 246 26.477 56.209 -6.574 1.00 48.40 *ATOM 1117 0 LYS 246 25.597 56.538 -5.778 1.00 42.25 ATOM 1118 N LYS 247 26.479. 54.982 -7.079 1.00 45.29 40 ATOM 1119 H LYS 247 27.176 54.727 -7.713 1.00 0.00 ATOM 1120 CA LYS 247 25.465 54.045 -6.685 1.00 49.00 ATOM 1121 CB LYS 247 25.209 53.130 -7.875 1.00 54.11 ATOM 1122 CG LYS 247 24.508 53.886 -9.004 1.00 62.74 ATOM 1123 CD LYS 247 24.243 53.001 -10.220 1.00 72.81 ATOM 1124 CE LYS 247 23.531 53.721 -11.379 1.00 81.38 ATOM 1125 NZ LYS 247 23.373 52.835 -12.526 1.00 86.55 ATOM 1126 HZI LYS 247 22.808 52.005 -12.261 1.00 0.00 ATOM 1127 HZ2 LYS 247 24.310 52.525 -12.854 1.00 0.00 ATOM 1128' HZ3 LYS 247 22.899 53.347 13.297 1.00 0.00 ATOM 1129 C LYS 247 25.856 53.257 -5.450 1.00 49.50 ATOM 1130 0 LYS 247 25.319 52.203 -5.182 1.00 51.73 ATOM 1131 N HIS 248 26.793 53.661 -4.603 1.00 50.46 ATOM 1132 H HIS 248 27.235 54.526 -4.728 1.00 0.00 ATOM 1133 CA HIS 248 27.155 52.799 -3.498 1.00 45.73 ATOM 1134 CB HIS 248 28.438 53.305 -2.813 1.00 40.60 ATOM 1135 CG HIS 248 28.924 52.330 -1.737 1.00 36.78 ATOM 1136 CD2 HIS 248 29.411 51.071 -1.973 1.00 33.70 ATOM 1137 NDI HIS 248 28.983 52.505 -0.416 1.00 38.30 ATOM 1138 HDI HIS 248 28.728 53.315 0.070 1.00 0.00 ATOM 1139 CEI HIS 248 29.467 51.412 0.129 1.00 34.58 ATOM 1140 NE2 HIS 248 29.720 50.547 -0.817 1.00 33.39 ATOM 1141 HE2 HIS 248 30.051 49.640 -0.658 1.00 0.00 ATOM 1142 C HIS 248 26.055 52.703 -2.473 1.00 48.32 ATOM 1143 0 HIS 248 25.591 53.685 -1.918 1.00 44.66 60 ATOM 1144 N SER 249 25.626 51.478 -2.198 1.00 53.23 ATOM 1145 H SER 249 25.852 50.711 -2.770 1.00 0.00 ATOM 1146 CA SER 249 24.798 51.233 -1.040 1.00 57.14 ATOM 1147 CB SER 249 23.445 50.596 -1.432 1.00 56.80 ATOM 1148 00G SER 249 23.488 49.267 -1.938 1.00 58.69 ATOM 1149 HG SER 249 23.996 49.345 -2.757 1.00 0.00 ATOM 1150 C SER 249 25.626 50.270 -0.262 1.00 59.00 ATOM 1151 0 SER 249 26.610 49.741 -0.760 1.00 55.94 ATOM 1152 N GLU 250 25.285 50.003 0.982 1.00 68.05 ATOM 1153 H GLU 250 24.519 50.460 1.391 1.00 0.00 ATOM 1154 CA GLU 250 25.982 48.958 1.710 1.00 77.66 ATOM 1155 CB* GLU 250 25.518 48.929 3.169 1.00 85.81 ATOM 1156 CG GLU 250 25.746 50.253 3.922 1.00 96.97 ATOM 1157 CD GLU 250 25.505 50.056 5.411 1.00 103.17 ATOM 1158 OEI GLU 250 25.196 51.045 6.085 1.00 108.23 *ATOM 1159 0E2 GLU 250 25.633 48.922 5.895 1.00 105.30 ATOM 1160 C GLU 250 25.778 47.573 1.115 1.00 77.89 ATOM 1161 0 GLU 250 26.649 46.720 1.119 1.00 78.08 *ATOM 1162 .N GLN 251 24.574 47.369 0.595 1.00 77.62 2 0 ATOM 1163 H GLN 251 23.971 48.135 0.546 1.00 0.00 *ATOM 1164 CA GLN 251 24.155 46.078 0.085 1.00 77.63 **ATOM 1165 CB GLN 251 22.616 45.902 0.224 1.00 86.21 ATOM 1166 CG GLN 251 21.677 47.096 0.015 1.00 97.44 000ATOM 1167 CD GLN 251 21.754 48.076 1.182 1.00 106.14 25 ATOM 1168 OEI GLN 251 22.556 49.005 1.219 1.00 112.85 ATOM 1169 NE2 GLN 251 20.940 47.965 2.214 1.00 108.86 ATOM 1170 HE21 GLN 251 20.288 47.236 2.234 1.00 0.00 ATOM 1171 HE22 GLN 251 21.031 48.635 2.926 1.00 0.00 ATOM 1172 C GLN 251 24.544 45.830 -1.356 1.00 74.59 ATOM 1173 0 GLN 251 24.771 44.704 -1.778 1.00 73.25 ATOM 1174 N VAL 252 24.636 46.863 -2.185 1.00 70.06 *ATOM 1175 H VAL 252 24.241 47.718 -1.911 1.00 0.00 ATOM 1176 CA VAL 252 25.375 46.711 -3.425 1.00 66.24 ATOM 1177 CB VAL 252 24.482 46.902 -4.657 1.00 68.01 ATOM 1178 CGI VAL 252 25.271 47.177 -5.941 1.00 67.58 ATOM 1179 CG2 VAL .252 23.711 45.600 -4.832 1.00 71.77 *ATOM 1180 C VAL 252 26.466 47.745 -3.424 1.00 60.42 *ATOM 1181 0 VAL 252 26.282 48.961 -3.409 1.00 57.54 ATOM 1182 N PRO 253 27.648 47.275 -3.427 1.00 57.04 40 ATOM 1183 CD PRO 253 28.022 45.875 -3.278 1.00 57.51 ATOM 1184 CA PRO 253 28.812 48.113 -3.455 1.00 53.11 ATOM 1185 CB PRO 253 29.905 47.251 -2.798 1.00 57.01 *ATOM 1186 CO PRO 253 29.165 46.035 -2.272 1.00 57.83 oATOM 1187 C PRO 253 29.113 48.551 -4.866 1.00 47.52 ATOM 1188 0 PRO 253 28.988 47.837 -5.853 1.00 45.85 ATOM 1189 N ASP 254 29.533 49.808 -4.931 1.00 42.76 ATOM 1190 H ASP 254 29.509 50.376 -4.143 1.00 0.00 ATOM 1191 CA ASP 254 30.038 50.374 -6.156 1.00 38.48 ATOM 1192' CB ASP 254 29.051 51.4461 -6.580 1.00 36.32 ATOM 1193 CG ASP 254 29.341 51.949 -7.979 1.00 36.27 ATOM 1194 ODI ASP 254 28.990 53.090 -8.264 1.00 39.87 ATOM 1195 0D2 ASP 254 29.903 51.204 -8.786 1.00 36.65 ATOM 1196 C ASP 254 31.400 50.909 -5.739 1.00 35.50 ATOM 1197 0 ASP 254 31.506 52.050 -5.321 1.00 34.98 ATOM 1198 N ILE 255 32.448 50.092 -5.837 1.00 33.54 ATOM 1199 H ILE 255 32.350 49.250 -6.329 1.00 0.00 ATOM 1200 CA ILE 255 33.761 50.400 -5.307 1.00 35.65 ATOM 1201 CB ILE 255 34.181 49.317 -4.295 1.00 39.66 ATOM 1202 CG2 ILE 255 35.615 49.605 -3.797 1.00 4.0.81 ATOM 1203 CGI ILE 255 33.157 49.254 -3.144 1.00 39.28 ATOM 1204 CDI ILE 255 32.955 50.590 -2.435 1.00 40.52 ATOM 1205 C ILE 255 34.790 50.453 -6.428 1.00 39.99 ATOM 1206 0 ILE 255 34.826 49.556 -7.258 1.00 40.26 ATOM 1207 N LEU 256 35.642 51.480 -6.503 1.00 39.89 61 ATOM 1208 H LEU 256 35.471 52.284 -5.964 1.00 0.00 ATOM 1209 CA LEU 256 36.831 51.410 -7.340 1.00 39.66 ATOM 1210 CB LEU 256 37.066 52.755 -8.074 1.00 38.42 ATOM 1211 CG LEU 256 38.298 52.842 -8.988 1.00 37.25 ATOM 1212 CDI LEiU 256 38.214 51.825 -10.115 1.00 36.68 ATOM 1213 CD2 LEU 256 38.377 54.245 -9.571 1.00 39.39 ATOM 1214 C LEU 256 38.022 51.095 -6.407 1.00 38.52 ATOM 1215 0 LEU 256 38.368 51.793 -5.455 1.00 40.24 ATOM 1216 N GLN 257 38.658 49.977 -6.715 1.00 39.82 ATOM 1217 H GLN 257 38.308 49.468 -7.488 1.00 0.00 ATOM 1218 CA GLN 257 39.795 49.436 -5.992 1.00 42.81 ATOM 1219 CB GLN 257 40.050 48.020 -6.455 1.00 49.86 ATOM 1220 CG GLN 257 40.720 47.077 -5.487 1.00 62.03 ATOM 1221 CD GLN 257 39.707 46.054 -5.046 1.00 66.77 ATOM 1222 0E1 GLN 257 38.568 46.361 -4.726 1.00 70.03 *S SATOM 1223 NE2 GLN 257 40.013 44.767 -5.063 1.00 67.84 *ATOM 1224 HE21 GLN 257 40.897 44.483 -5.369 1.00 0.00 *ATOM 1225 HE22 GLN 257 39.295 44.174 -4.752 1.00 0.00 ATOM 1226 C GLN 257 40.991 50.253 -6.300 1.00 43.83 2 0 ATOM 1227 0 GLN 257 41.296 50.526 -7.457 1.00 44.09 *ATOM 1228 N LEU 258 41.747 50.678 -5.315 1.00 45.79 .ATOM 1229 H LEU 258 41.461 50.433 -4.414 1.00 0.00 *ATOM 1230 CA LEU 258 42.951 51.468 -5.556 1.00 48.19 ATOM 1231 CB LEU 258 43.638 51.714 -4.187 1.00 62.23 ATOM 1232 CO LEU 258 45.178 51.726 -4.015 1.00 71.72 ATOM 1233 CD1 LEU 258 45.742 53.135 -3.795 1.00 65.86 ATOM 1234 CD2 LEU 258 45.495 50.830 -2.809 1.00 80.83 ATOM 1235 C LEU 258 43.958 50.864 -6.564 1.00 46.26 ATOM 1236 0 LEU 258 44.583 51.564 -7.368 1.00 43.62 ATOM 1237 N ASN 259 44.214 49.561 -6.654 1.00 41.70 ATOM 1238 H ASN 259 43.687 48.856 -6.205 1.00 0.00 ***ATOM 1239 CA ASN 259 45.197 49.203 -7.648 1.00 41.88 *ATOM 1240 CB ASN 259 46.029 48.071 -7.151 1.00 46.19 S **ATOM 1241 CG ASN 259 45.376 46.750 -7.280 1.00 49.87 ATOM 1242 ODI ASN 259 44.187 46.674 -7.008 1.00 56.41 ATOM 1243 ND2 ASN 259 46.115 45.710 -7.644 1.00 50.33 ATOM 1244 HD21 ASN 259 47.075 45.857 -7.810 1.00 0.00 *.*ATOM 1245 HD22 ASN 259 45.682 44.830 -7.714 1.00 0.00 ATOM 1246 C ASN 259 44.636 48.900 -9.007 1.00 38.03 40 ATOM 1247 0 ASN 259 45.417 48.585 -9.896 1.00 35.47 *ATOM 1248 N ALA 260 43.309 48.952 -9.180 1.00 33.64 ATOM 1249 H ALA 260 42.708 49.000 -8.409 1.00 0.00 ATOM 1250 CA ALA 260 42.732 48.991 -10.512 1.00 29.46 *ATOM 1251 CB ALA 260 41.224 49.011 -10.356 1.00 25.72 ATOM 1252 C ALA 260 43.243 50.221 -11.230 1.00 28.23 ATOM 1253 0 ALA 260 43.637 50.176 -12.385 1.00 31.28 ATOM 1254 N ILE 261 43.255 51.359 -10.532 1.00 28.30 ATOM 1255 H ILE 261 42.856 51.344 -9.640 1.00 0.00 ATOM 1256- CA ILE 261 43.812 52.619 -11.027 1.00 25.68 ATOM 1257 CB ILE 261 43.758 53.698 -9.884 1.00 27.06 ATOM 1258 CG2 ILE 261 44.364 55.014 -10.371 1.00 22.81 ATOM 1259 CGt ILE 261 42.300 53.941 -9.444 1.00 23.10 ATOM 1260 CDI ILE 261 42.175 54.847 -8.215 1.00 15.19 ATOM 1261 C ILE 261 45.246 52.443 -11.516 1.00 27.03 ATOM 1262 0 ILE 261 45.594 52.815 -12.626 1.00 30.14 ATOM 1263 N PHE 262 46.130 51.861 -10.699 1.00 25.11 ATOM 1264 H PHE 262 45.832 51.647 -9.79 1 1.00 0.00 ATOM 1265 C A PHE 262 47.511 51.582 -11.075 1.00 23.29 ATOM 1266 CB PHE 262 48.275 50.853 -9.941 1.00 23.94 ATOM 1267 CG PHE 262 48.795 51.855 -8.914 1.00 22.84 ATOM 1268 CDI PHE 262 47.919 52.571 -8.110 1.00 26.50 ATOM 1269 CD2 PHE 262 50.147 52.112 -8.831 1.00 22.06 ATOM 1270 CEI PHE 262 48.402 53.570 -7.279 1.00 29.99 ATOM 1271 CE2 PHE 262 50.619 53.093 -7.974 1.00 24.85 62 ATOM 1272 CZ ATOM 1273 C ATOM 1274 0 ATOM 1275 N ATOM 1276 H ATOM 1277 CA ATOM 1278 CB ATOM 1279 CG ATOM 1280 ODI ATOM 1281 ND2 ATOM 1282 HD21 ATOM 1283 HD22 ATOM 1284 C ATOM 1285 0 ATOM 1286 N ATOM 1287 H ATOM 1288 CA ATOM 1289 CB ATOM 1290 CG ATOM 1291 SD ATOM 1292 CE ATOM 1293 C 0o** ATOM 1294 0 ATOM 1295 N 25 ATOM 1296 H ATOM 1297 CA ATOM 1298 CB ATOM 1299 CG ATOM 1300 CDI ATOM 1301 CD2 ATOM 1302 C ATOM 1303 0 ATOM 1304 N ATOM 1305 H 35 3 ATOM 1306 CA ATOM 1307 CB d ATOM 1308 CG S ATOM 1309 ODI ATOM 1310 ND2 40 ATOM 1311 HD21 ATOM 1312 HD22 ATOM 1313 C ATOM 1314 0 ATOM 1315 N 45 ATOM 1316 H ATOM 1317 CA ATOM 1318 CB ATOM 1319 OGI ATOM 1320 HGI ATOM 1321 CG2 ATOM 1322 C ATOM 1323 0 ATOM 1324 N ATOM 1325 H ATOM 1326 CA ATOM 1327 CB ATOM 1328 CG ATOM 1329 CD ATOM 1330 CE ATOM 1331 NZ ATOM 1332 HZI ATOM 1333 HZ2 ATOM 1334 HZ3 ATOM 1335 C

PHE

PHE

PHE

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

MET

MET

MET

MET

MET

MET

MET

MET

MET

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

THR

THR

THR

THR

THR

THR

THR

THR

THR

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

262 262 262 263 263 263 263 263 263 263 263 263 263 263 264 264 264 264 264 264 264 264 264 265 265 265 265 265 265 265 265 265 266 266 266 266 266 266 266 266 266 266 266 267 267 267 267 267 267 267 267 267 268 268 268 268 268 268 268 268 268 268 268 268 49.756 47.573 48.285 46.796 46.219 46.827 45.872 46.483 47.677 45.694 44.728 46.129 46.450 47.043 45.443 44.940 45.054 43.742 42.552.

40.953 40.447 46.036 45.903 47.044 47.167 47.941 47.844 46.508 45.942 46.722 49.365 50.309 49.583 48.832 50.918 50.905 50.208 50.004 49.889 50.148 49.389 51.463 50.834 52.671 53.155 53.325 54.807 55.330 54.960 55.686 52.618 52.606 51.988 52.010 51.228 50.800 49.912 49.406 48.410 47.936 48.737 47.453 47.263 50.013 53.842 -7.209 50.725 -12.288 50.994 -13.247 49.640 -12.270 49.470 -11.496 48.683 -13.372 47.495 -13.119 46.467 -12.141 46.416 -11.842 45.600 -11.517 45.639 -11.681 44.947 -10.928 49.332 -14.673 49.081 -15.715 50.203 -14.640 50.348 -13.807 50.956 -15.817 51.698 -15.565 50.779 -15.835 51.627 -15.768 51.015 -14.191 51.979 -16.362 52.396 -17.500 52.435 -15.617 52.116 -14.695 53.456 -16.133 54.709 -15.272 55.432 -15.452 55.833 -14.099 56.641 -16.339 52.980 -16.157 53.724 -16.327 51.696 -15.972 51.117 -15.737 51.154 -16.072 49.810 -15.355 48.692 -16.103 48.725 -17.302 47.599 -15.435 47.527 -14.492 46.885 -15.880 51.028 -17.496 51.391 -18.480 50.496 -17.668 50.095 -16.911 50.491 -18.965 50.073 -18.787 51.030 -17.858 50.998 -16.964 50.139 -20.052 49.591 -19.933 49.803 -21.128 48.543 -19.427 48.391 -18.464 47.643 -20.275 46.427 -19.458 45.417 -20.194 44.239 -19.341 44.674 -18.258 43.541 -17.483 43.066 -17.022 42.877 -18.122 43.878 -16.766 48.367 -20.803 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 -20.46 27.29 29.20 29.26 0.00 32.07 36.54 48.06 52.97 50.97 0.00 0.00 31.78 30.44 30.71 0.00 31.45 36.38 44.27 51.17 51.48 30.63 25.16 27.60 0.00 23.27 24.95 30.77 35.13 30.86 21.55 21.21 20.49 0.00 21.68 20.66 26.15 30.13 26.18 0.00 0.00 27.52 25.25 29.62 0.00 31.01 31.03 36.10 0.00 28.06 31.70 31.87 34.40 0.00 34.41 38.03 46.78 51.28 59.23 63.39 0.00 0.00 0.00 34.09 63 ATOM 1336 0 ATOM 1337 N ATOM 1338 H ATOM 1339 CA ATOM 1340 Ce ATOM 1341 CG ATOM 1342 ODI ATOM 1343 ND2 ATOM 1344 HD21 ATOM 1345 HD22 ATOM 1346 C ATOM 1347 0' ATOM 1348 N ATOM 1349 H ATOM 1350 CA 9ATOM 1351 CB ATOM 1352 SG ATOM 1353 C *ATOM 1354. 0 20 ATOM 1355 N .ATOM 1356 CD *ATOM 1357 CA *ATOM 1358 CB ATOM 1359 CG 25 ATOM 1360 C ATOM 1361 0 ATOM 1362 N ATOM 1363 H ATOM 1364 CA ATOM 1365 CB ATOM 1366 00 ATOM 1367 HG ATOM 1368 C .9.ATOM 1369 0 ATOM 1370 N ATOM 1371 H 9..*ATOM 1372 CA *ATOM 1373 CB ATOM 1374 CG 40 ATOM 1375 CD1 ATO 1369 ATOM 1376 CD :*ATOM 1378 0 ATOM 1379 N ATOM 1380 H ATOM 1381 CA ATOM 1382 CB ATOM 1383 CG ATOM 1384 CD ATOM 1385 CE ATOM 1386 NZ ATOM 1387 HZI ATOM 1388 HZ2 ATOM 1389 HZ3 ATOM 1390 C ATOM 1391 0 ATOM 1392 N ATOM 1393 H ATOM 1394 CA ATOM 1395 CB ATOM 1396 CG ATOM 1397 ODI ATOM 1398 0D2 ATOM 1399 C

LYS

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

ASN

CYS

CYS

CYS

CYS

CYS

CYS

CYS

PRO

PRO

PRO

PRO

PRO

PRO

PRO

SER

SER

SER

SER

SER

SER

SER

SER

LEU

LEU

LEU

LEU

LELJ

LEU

LEU

LEU

LEU

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

268 269 269 269 269 269 269 269 269 269 269 269 270 270 270 270 270 270 270 271 271 271 271 271 271 271 272 272 272 272 272 272 272 272 273 273 273 273 273 273 273 273 273 274 274 274 274 274 274 274 274 274 274 274 274 274 275 275 275 275 275 275 275 275 49.735 49.267 49.577 48 .012 46.995 46.685 46.295 46.896 47.263 46.674 48. 130 47.253 49.228 49.948 49.351 49.028 48.971 50.770 51.5 15 51.237 50.428 52.628 52.694 51.292 53.104 54.259 52.220 51.287 52.617 51.440 50.225 50.053 53.068 53.666 52.826 52.343 53.350 52.250 5 1.343 50.112 52. 168 54.5 19 54.948 55. 108 54.753 56.3 14 56.853 58.111 58.619 59.960 61.040 60 .925 61.021 6 1.949 57.348 57 .594 57.942 57 .514 59.007 60 .222 60.849 61 .282 60.919 58.618 48.325 -21.979 49.054 -19.948 49.149 -19.020 49.651 -20.366 49.607 -19.263 48.179 -19.067 47.488 -19.988 47.620 -17.892 48.175 .17.168 46.672 -17.821 51.078 .20.767 51.677 -21.370 51.744 -20.458 51.324 -19.931 53.133 -20.848 54.048 -19.676 55.800 -20.133 53.374 -21.287 54.159 -20.711 52.761 -22.313 52.006 -23.263 52.860 -22.730 51.997 -23.974 52.036 -24.514 54.281 -22.955 54.644 -22.776 55.180 -23.365 54.942 -23.574 56.555 -23.545 57.305 -24.135 56.635 -23.790 56.659 -22.8Q0 57.208 -22.269 58.259 -22.345 56.687 -21.064 55.839 -20.921 57.384 -19.910 57.567 -18.851 58.788 -19.139 58.798 -18.225 60.056 -18.965 56.632 -19.336 56.803 -18.205 55.731 -20.112 55.544 -21.008 55.053 -19.684 54.212 -20.819 53.417 -20.485 52.783 -21.777 52.073 -21.658 53.035 -21.669 53.685 -20.867 53.571 -22.560 52.537 -21.580 56.087 -19.285 57.057 -19.983 55.858 -18.123 55.152 -17.599 56.689 -17.546 56.827 -18.507 55.482 -18.831 55.358 .19.970 54.577 -17.980 58.090 -17.114 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 34.97 29.59 0.00 24.54 26.50 32.19 35.32 35.76 0.00 0.00 27.02 27.85 26.07 0.00 23.70 22.29 27.75 26.34 24.34 26.04 26.80 26.32 25.30 24.28 29.26 31.29 30.94 0.00 31.44 37.05 53.17 0.00 30.10 30.70 29.16 0.00 26.90 23.25 24.56 20.80 20.75 28.09 24.97 28.29 0.00 27.08 28.08 32.44 40.58 45.30 47.25 0.00 0.00 0.00 27.81 27.52 26.78 0.00 24.40 24.70 28.62 35.31 31.3.4 21.07 64 ATOM 1400 0 ASP 275 59.450 58.931 -16.787 1.00 22.30 ATOM 1401 N LYS 276 57.332 58.409 .17.087 1.00 20.11 ATOM 1402 H LYS 276 56.635 57.754 -17.318 1.00 0.00 ATM 143 C LYS 276 56.918 59.738 -16.690 1.00 20.03 ATOM 1404 CA Y 276 55.977 60.268 -17.772 1.00 15.62 AO 145 CG LYS 276 56.700 60.352 -19.129 1.00 20.79 ATOM 14065 D Y 276 55.762 60.74.1 -20.275 1.00 25.10 ATOM 1407 CE LYS 27 631 60.584 -21.682 1.00 24.43 ATOM 1408 NZ LYS 276 55.317 60.858 -22.677 1.00 26.93 AO 10 ZI LS 276 54.962 61.828 -22.562 1.00 0.00 ATOM 1410 HZ2 LYS 276 54.528 60.192 -22.550 1.00 0.0 ATOM 1411 HZ3 LYS 276 55.716 60.744 -23.630 1.00 0.00 AO 142 C LS 276 56.238 59.664 -15.339 1.00 21.33 ATOM 1413 0 LYS 27 559 58.696 -15.080 10 37 ATOM 1414 N PRO 277 56.342 60.565 -14.432 1.00 18.25 *0 0 AOM 115 C PRO 277 57.125 61.779 -14.555 1.00 20.11 ATOM 1416 CAD R 277 55.658 60.491 -13.158 1.00 19.61 oAO 147 CB PRO 27 5.78 61.665 -12.348 1.00 19.47 *0**ATOM 14187 G PR 7 57.365 62.160 -13.113 1.00 17.30 ATOM 1419. CG PRO 277 54.146 60.506 -13.252 1.00 21.46 a:*:ATOM 1420 0 PRO 277 53.522 61.268 -13.988 1.00 24.07 *ATOM 1421 N LYS 278 53.531 59.642 -12.473 1.00 19.22 *0 *ATOM 1422 H LYS 278 54.049 58.986 -11.955 1.00 0.00 ::oATOM 1423 CA LYS 278 52.093 59.598 -12.436 1.00 18.47 25 ATOM 1424 CB LYS 278 51.654 58.233 -12.953 1.00 16.94 goATOM 1425 CG LYS 278 52.074 58.090 -14.435 1.00 15.20 ATOM 1426 CD LYS 278 51.919 56.673 -14.945 1.00 16.03 ATOM 1427 CE LYS 278 53.057 55.723 -14.550 1.00 18.36 ATOM 1428 NZ LYS 278 54.258 55.975 -15.318 1.00 19.84 ATOM 1429 HZI LYS 278 54.573 56.952 -15.158 1.00 0.00 ATOM 1430 HZ2 LYS 278 54.052 55.841 -16.328 1.00 0.00 ATOM 1431 HD3 LYS 278 55.008 55.317 -15.025 1.00 0.00 ATOM 1432 C LYS 278 51.698 59.807 -11.016 1.00 21.76 *ATOM 1433 0 LYS 278 51.903 58.916 -10.202 1.00 23.16 35 ATOM 1434 N VAL- 279 51.133 60.956 -10.655 1.00 18.92 ATOM 1435 H VAL- 279 50.893 61.619 -11.338 1.00 0.00 ATOM 1436 CA VAL- 279 50.830 61.249 -9.270 1.00 16.68 ATOM 1437 CB VAL 279 51.262 62.707 -8.960 1.00 15.16 aATOM 1438 CG1 VAL- 279 51.042 63.041 -7.494 1.00 12.89 0:0, 40 ATOM 1439 CG2 VAL 279 52.737 62.882 -9.318 1.00 13.20 0ATOM 1440 C VAL- 279 49.340 61.054 -9.066 1.00 20.13 ATOM 1441 0 VA]- 279 48.520 61.647 -9.770 1.00 20.96 0 0 ATOM 1442 N ILE 280 48.946 60.212 -8.099 1.00 20.07 ATOM 1443 H IL-E 280 49.628 59.772 -7.543 1.00 0.00 ATOM 1444 CA IL-E 280 47.535 59.939 -7.830 1.00 20.53 ATOM 1445 CB IL-E 280 47.306 58.401 -7.914 1.00 25.21 ATOM 1446 CG2 ILE 280 45.900 58.000 -7.454 1.00 17.77 ATOM 1447 CGI IL-E 280 47.519 57.977 -9.377 1.00 24.13 ATOM 1448' CIA1 ILE 280 48.045 56.562 -9.513 1.00 30.13 ATOM 1449 C ILE 280 47.150 60.496 -6.467 1.00 21.62 ATOM 1450 0 ILE 280 47.789 60.204 -5.464 1.00 22.51 ATOM 1451 N ILE 281 46.108 61.318 -6.363 1.00 20.14 ATOM 1452 H ILE 281 45.542 61 .495 -7.148 1.00 0.00 ATOM 1453 CA ILE 281 45.770 61.940 -5.109 1.00 19.43 ATOM 1454 CB ILE 281 45.858 63.465 -5.300 1.00 19.82 ATOM 1455 CG2 ILE 281 45.338 64.229 -4.081 1.00 16.34 ATOM 1456 CGI ILE 281 47.333 63.810 -5.516 1.00 24.03 ATOM 1457 CDI ILE 281 47.627 65.269 -5.781 1.00 26.46 ATOM 1458 C ILE 281 44.389 61.476 -4.737 1.00 22.29 ATOM 1459 0 ILE 281 43.495 61.498 -5.568 1.00 21.67 ATOM 1460 N ILE 282 44.128 61.032 -3.509 1.00 23.39 ATOM 1461 H ILE 282 44.833 61.012 -2.823 1.00 0.00 ATOM 1462 CA ILE 282 42.781 60.593 -3.163 1.00 24.32 ATOM 1463. CB ILE 282 42.761 59.050 -3.045 1.00 21.45 65 ATOM 1464 CG2 ILE 282 41.368 58.517 -2.706 1.00 22.39 ATOM 1465 CG1 ILE 282 43.224 58.492 .4.387 1.00 17.29 ATOM 1466 CDI ILE 282 43.645 57.044 -4.387 1.00 18.62 ATOM 1467 C ILE 282 42.275 61.214 -1.878 1.00 24.17 ATOM 1468 0 ILE 282 42.837 61.022 -0.802 1.00 23.02 ATOM 1469 N GLN 283 41.195 61.985 -1.981 1.00 24.17 ATOM 1470 H GLN -283 40.880 62.229 -2.879 1.00 0.00 ATOM 1471 CA GLN 283 40.417 62.361 -0.807 1.00 26.94 ATOM 1472 Ce GLN 283 39.916 63.809 -0.951 1.00 29.78 ATOM 1473 CG GLN 283 38.790 64.295 -0.003 1.00 30.76 ATOM 1474 CD GLN 283 39.213 64.338 1.454 1.00 31.96 ATOM 1475 OEI GLN 283 40.263 64.820 1.835 1.00 26.84 ATOM 1476 NE2 GLN 283 38.367 63.923 2.370 1.00 32.78 ATOM 1477 HE21 GLN 283 37.468 63.628 2.058 1.00 0.00 ATOM 1478 HE22 GLN 283 38.632 63.911 3.299 1.00 0.00 ATOM 1479 C GLN 283 39.227 61.397 -0.673 1.00 27.75 *ATOM 1480 0 GLN 283 38.396 61.282 -1.580 1.00 27.45 ATOM 1481 N ALA 284 39.127 60.692 0.460 1.00 24.57 ATOM 1482 H AL.A 284 39.827 60.742 1.148 1.00 0.00 ATOM 1483 CA ALA 284 38.115 59.682 0.688 1.00 22.92 ATOM 1484 CB ALA 284 38.196 58.595 -0.383 1.00 15.36 CATOM 1485 C ALA 284 38.438 59.060 2.029 1.00 25.81 5ATOM 1486 0 AL.A 284 39.598 58.871 2.387 1.00 29.97 *ATOM 1487 N ALD 285 37.396 58.754 2.795 1.00 27.43 25 ATOM 1488 CA ALD 285 37.538 58.081 4.104 1.00 26.59 .ATOM 1489 C ALD 285 38.038 56.689 3.860 1.00 26.61 ATOM 1490 0 ALD 285 37.779 56.155 2.790 1.00 30.02 ATOM 1491. CB ALD 285 36.215 57.908 4.846 1.00 26.43 ATOM 1492 SG ALD 285 35.603 59.475 5.487 1.00 34.69 ATOM 1493 Ni ALD 285 32.516 69.905 10.851 1.00 58.66 ATOM 1494 CI ALD 285 33.306 68.911 10.160 1.00 48.23 ATOM 1495 CS ALD 285 32.529 67.649 10.069 1.00 45.89 ATOM 14% 02 ALD 285 31.833 67.247 10.983 1.00 47.20 ATOM 1497 C9 ALD 285 34.623 68.691 10.902 1.00 46.18 35 ATOM 1498 CG ALD 285 35.549 69.731 10.350 1.00 50.40 *ATOM 1499 CDI ALD 285 35.586 71.002 10.923 1.00 53.28 ATOM 1500 CD2 ALI) 285 36.268 69.456 9.185 1.00 53.34 *ATOM 1,501 CEl ALD 285 36.376 71.984 10.326 1.00 55.15 cATOM 1502 CE2 ALD 285 37.056 70.446 8.595 1.00 52.67 40 ATOM 1503 CZ ALD 285 37.109 71.725 9.163 1.00 57.31 ATOM 1504 OH ALD 285 37.756 72.792 8.546 1.00 63.58 ATOM 1505 N2 ALD 285 32.657 67.034 8.925 1.00 38.70 ATOM 1506 C2 ALD 285 31.932 65.809 8.702 1.00 34.11 S. *ATOM 1507 C6 AiD 285 33.033 64.915 8.206 1.00 33.25 ATOM 1 508 03 AiD 285 34.021 65.383 7.657 1.00 27.84 ATOM 1509 CIO AiD 285 30.819 66.116 7.661 1.00 39.67 ATOM 1510 CGI AiD 285 30.399 64.915 6.822 1.00 44.49 ATOM 1511 CG2 ALD 285 29.588 66.547 8.453 1.00 40.46 ATOM 1512 N3 AiD 285 32.851 63.630 8.422 1.00 31.01 ATOM 1513 C3 AiD 285 33.824 62.646 7.997 1.00 33.50 ATOM 1514 C7 ALD 285 33.316 62.147 6.681 1.00 37.64 ATOM 1515 04 ALD 285 32.114 62.219 6.432 1.00 44.05 ATOM 1516 CII AiD 285 33.899 61.464 8.952 1.00 31.45 ATOM 1517 N4 ALD 285 34.265 61 .650 5.908 1.00 35.48 ATOM 1518 C4 ALD 285 34.210 61.553 4.464 1.00 33.98 ATOM 1519 C 8 AiD 285 34.763 60.203 4.008 1.00 36.52 ATOM 1520 C12 ALD 285 35.030 62.710 3.971 1.00 35.04 ATOM 1521 C13 ALD 285 34.835 62.936 2.510 1.00 37.05 ATOM 1522 ODI ALD 285 35.766 63.453 1.898 1.00 37.30 ATOM 1523 0D2 ALD 285 33.772 62.594 1.993 1.00 34.87 ATOM 1524 05 ALD 285 33.751 59.337 3.478 1.00 42.82 ATOM 1525 H I ALD 285 36.497 58.977 2.418 1.00 0.00 ATOM 1526 C14 ALD 285 3 1.983 70.803 10.042 1.00 65.26 ATOM 1527 H 5 ALD 285 32.384 69.885 11.844 1.00 0.00 66 ATOM 1528 H6 ATOM 1529 H7 ATOM 1530 H8 ATOM 1531 H9 ATOM 1532 C15 ATOM 1533 01 ATOM 1534 H2 ATOM 1535 N ATOM 1536 H ATOM 1537 CA ATOM 1538 CB ATOM 1539 CG ATOM 1540 CD ATOM 1541 NE ATOM 1542 HE .ATOM 1543 CZ *ATOM 1544 NHI ATOM 1545 HHII ATOM 15465 HH12 ATOM 1547 NH2 ATOM 1548 HH21 *ATOM 1549 HH22 ***ATOM 1550 C ATOM 1551 0 ATOM 1552 N ATOM 1553 H ATOM 1554 CA ATOM 1555 C ATOM 1556 0 ATOM 1557 N ATOM 1558 H *ATOM 1559 CA *ATOM 1560 CB ATOM 1561 CG 35 ATOM 1562 ODI *ATOM 1563 0D2 ATOM 1564 C *ATOM 1565 0 .ATOM 1566 N 40 ATOM 1567 H a ATOM 1568 CA ATOM 1569 CB 0 00ATOM 1570 00 *..ATOM 1571 HG ATOM 1572 C ATOM 1573 0 ATOM 1574 N ATOM 1575. CD ATOM 1576 CA ATOM 1577 CB ATOM 1578 CG ATOM 1579 C ATOM 1580 0 ATOM 1581 N ATOM 1582 H ATOM 1583 CA ATOM 1584 C ATOM 1585 0 ATOM 1586 N ATOM 1587 H ATOM 1588 CA ATOM 1589 CB ATOM 1590 CGI ATOM 1591 CG2

ALD

ALD

ALD

ALD

ALD

ALD

ALD

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

GLY

.GLY

GLY

GLY

GLY

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

SER

SER

SER

SER

SER

SER

SER

SER

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLY

GLY

GLY

GLY

GLY

VAL

VAL

VAL

VAL

VAL

VAL

285 37.739 72.711 285 33.249 67.364 285 32.004 63.3 10 285 35.098 61.322 285 30.476 70.799 285 32.684 71.569 285 35.481 60.411 286 38.740 56.061 286 38.960 56.493 286 39.231 54.719 286 40.747 54.692 286 41.387 55.701 286 42.430 54.961 286 43.768 55.251 286 43.926 55.944 286 44.798 54.588 286 46.050 55.018 286 46.181 55.814 286 46.845 54.538 286 44.621 53.491 286 43.700 53.161 286 45.416 53.010 286 38.629 53.755 286 39. 160 52.683 287 37.495 54.113 287 37.021 54.925 287 36.905 53.350 287 36.162 54.330 287 35.932 55.475 288 35.804 53.848 288 36.263 53.019 288 34.941 54.525 288 33.839 53.609 288 33.043 52.985 288 33.051 51.752 288 32.413 53.731 288 35.710 55.003 288 35.283 55.884 289 36.884 54.437 289 37.321 53.757 289 37.596 54.805 289 38.704 53.801 289 38 .083 52.535 289 38.773 51.861 289 38.069 56.239 289 38.394 56.809 290 38.143 56.885 290 37.408 56.497 290 38.631 58.270 290 38.051 58.769 290 37.920 57.494 290 40.138 58.521 290 40.637 59.638 291 40.904 57.441 291 40.473 56.576 291 42.342 57.513 291 43.153 57.845 291 44.292 58.236 292 42.646 57.715 292 41.794 57.243 292 43.348 58.171 292 42.800 59.510 292 43.027 60.664 292 41.311 59.404 7.587 8.179 8.842 6.347 10.002 9.386 3.215 4.793 5.65 1 4.550 4.682 3.739 2.926 3.356 4.031I 2.845 3.144 3.735 2.774 2.058 1.851 1.689 5.538 5.803 6.133 5.943 7.208 8.100 7.728 9.292 9.545 10.273 10.820 9.706 9.6 12 8.944 11.500 12.250 11.775 11.200 12 .969 13.071 13.042 13.003' 12.940 11.907 14.041 15 .249 14. 136 15 .454 16.266 14.026 13 .939 14.034 14. 160 13 .835 15.056 14.877 16.287 16.4 14 17.491 18. 102 17. 151 18.371 0.00 0.00 0.00 0.00 65.03 73.24 0.00 26.38 0.00 25.85 24.02 23.75 27.07 29.64 0.00 26.29 25.89 0.00 0.00 19.53 0.00 0.00 26.43 27.12 26.73 0.00 27.46 30.03 32.06 33.55 0.00 32.84 40.57 48.86 53.99 51.26 31.98 32.42 28.78 0.00 24.44 22.45 33.26 0.00 24.99 26.10 27.20 22.52 25.66 27.04 21.06 28.40 26.84 24.70 0.00 27.48 26.97 24.56 24.36 0.00 26.77 24.74 28.54 25.92 67 ATOM 1592 C ATOM 1593 0 ATOM 1594 N ATOM 1595 H ATOM 1596 CA ATOM 1597 CB ATOM 1598 CGI ATOM 1599 CG2 ATOM 1600 C ATOM 1601 0 ATOM 1602 N ATOM 1603 H ATOM 1604 CA ATOM 1605 CB ATOM 1606 CG ATOM 1607 CD2 .ATOM 1608 CE2 *ATOM 1609 CE3 ATOM 1610 CDI 20 ATOM 1611 NEI *4SATOM 1612 HEI ATO 1634 ATOM 1613 CZ2 ATOM 1615 CH2 25 ATOM 1616 C ***ATOM 1617 0 ATOM 1618 N ATOM 1619 H ATOM 1620 CA ATOM 1621 CB ATOM 1622 CO ATOM 1623 CDI ATOM 1624 CD2 ATOM 1625 CEI 4: 35 ATOM 1626 CE2 ATOM 1627 CZ ATOM 1628 C 0*ATOM 1629 0 *ATOM 1630 N ATOM 1631 H .ATOM 1632 CA ATOM 1633 CB *ATOM 1634 CG *ATOM 1635 CD ATOM 1636 CE ATOM 1637 NZ ATOM 1638 HZ ATOM 1639 HZ2 ATOM 1640 HD3 ATOM 1641 C ATOM 1642 0 ATOM 1643 N ATOM 1644 H ATOM 1645 CA ATOM 1646 CB ATOM 1647 CG ATOM 1648 ODI ATOM 1649 0D2 ATOM 1650 C ATOM 1651 0 ATOM 1652 OT ATOM 1653 CB ATOM 1654 C ATOM 1655 0

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL.

VAL

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

TRP

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ALA

ALA

ALA

292 43.273 57.168 292 42.441 56.276 293 44.199 57.326 293 44.833 58.079 293 44.287 56.466 293 45.426 55.456 293 46.801 55.914 293 45.069 54.152 293 44.564 57.485 293 45.149 58.538 294 44.153 57.245 294 43.657 56.424 294 44.490 58.156 294 43 .553 58.075 294 42.160 58.474 294 41.796 59.897 294 40.345 59.680 294 42.2%6 61.171 294 41.128 57.603 294 40.077 58.356 294 39.189 57.990 294 39.526 60.761 294 41.421 62.218 294 40.084 62.017 294 45.823 57.790 294 46.217 56.632 295 46.574 58.751 295 46.375 59.702 295 47.704 58.370 295 49.007 58.377 295 49.439 59.770 295 50.325 60.433 295 48.853 60.419 295 50.559 61.777 295 49.086 61.764 295 49.928 62.44 1 295 47.765 59.359 295 47.343 60.503 296 48.314 58.905 2% 48.708 58.012 296 48.421 59.737 2% 48.497 58.862 296 48.194 59.668 2% 47.966 58.760 2% 49.201 57.947 296 50.320 58.836 296 50.088 59.472 2% 50.511 59.398 296 51.159 58.270 296 49.684 60.547 296 50.729 59.951I 297 49.591 61.860 297 49.170 62.489 297 50.160 62.460 297 51.698 62.430 297 52.196 61.867 297 51.766 62.345 297 53.019 60.945 297 49.705 63.893 297 49.463 64.419 297 49.571 64.477 317 65.517 45.642 317 63.053 45.718 317 62.644 46.858 18.641 18 .749 19.569 19.525 20.719 20.369 20.80 1 2 1.025 21.845 21.595 23.098 23.290 24.193 25.389 25.030 24 .914 24.556 25.019 24.792 24.518 24.324 24.347 24.795 24.478 24.766 24.801 25.25 1 25.116 26.063 25.207 24.852 25.679 23.779 25.480 23.583 24.444 27.208 27.145 28.3 16 28.341 29.496 30.739 31.988 33. 189 33 .534 33.780 34.569 32.925 34.015 29.397 29. 161 29.569 28.934 30.750 30.748 32.082 33. 140 32.067 30.706 29.608 3 1.777 -31.211I -30.743 -30.593 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 26.43 28.53 27.36 0.00 28.84 27.36 23.55 28.81 30.19 30.10 27.38 0.00 26.27 24.27 26.12 27.34 25.56 28.09 25.19 28.67 0.00 21.74 27.80 25.43 27.42 26.36 32.18 0.00 41.42 40.27 44.54 45.58 48.03 49.71 47.03 52.74 46.22 42.87 57.30 0.00 64.18 65.20 68.41 72.60 75.23 81.49 0.00 0.00 0.00 68.26 72.09 72.66 0.00 82.26 88.06 92.95 94.73 96.27 84.91 87.39 84.32 60.98 55.95 55.33 68 ATOM 1656 HTI ATOM 1657 HTr2 ATOM 1658 N ATOM 1659 HT3 ATOM 1660 CA ATOM 1661 N ATOM 1662 H- ATOM 1663 CA ATOM 1664 CB ATOM 1665 CG2 ATOM 1666 CGI ATOM 1667 CD1i ATOM 1668 C ATOM 1669 0 ATOM 1670 N oATOM 1671 H 0ATOM 1672 CA *ATOM 1673 CB &:to:ATOM 1674 CG ATOM 1675 CD ATOM 1676 CE *ATOM 1677 NZ ***ATOM 1678 HZI ATOM 1679 HZ2 S0:06 25 ATOM 1680 HZ3 go 0ATOM 1681 C ATOM 1682 0 ATOM 1683 N ATOM 1684 H ATOM 1685 CA ATOM 1686 CB .ATOM 1687 CG ATOM 1688 CD o:ATOM 1689 CE 35 ATOM 1690 NZ so ATOM 1691 HZ! ATOM 1692 HZ2 so a0 ATOM 1693 HZ3 .ATOM 1694 C ATOM 1695 0 a ATOM 1696 N ATOM 1697 H *ATOM 1698 CA oe ATOM 1699 CB 45 ATOM 1700 C ATOM 1701 0 ATOM 1702 N ATOM 1703 H ATOM 1704 CA ATOM 1705 CB ATOM 1706 CG ATOM 1707 CD2 ATOM 1708 NDI ATOM 2709 HDI ATOM 1710 CEI ATOM 1711 NE2 ATOM 1712 HE2 ATOM 2713 C ATOM 1714 0 ATOM 1715 N ATOM 1716 H ATOM 2717 CA ATOM 1718 CB ATOM 1719 CG2

ALA

ALA

ALA

ALA

ALA

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

ALA

ALA

ALA

ALA

ALA

ALA

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

ILE

ILE

ILE

ILE

ILE

317 317 317 317 317 318 318 318 318 318 318 318 318 318 319 319 319 319 319 329 319 319 319 319 319 319 319 320 320 320 320 320 320 320 320 320 320 320 320 320 321 321 321 321 321 321 322 322 322 322 322 322 322 322 322 322 322 322 322 323 323 323 323 323 63.898 47.390 -32.203 62.879 46.419 -33.062 63.865 46.499 -32.753 64.541 46.464 -33.540 64.124 45.449 -31.790 62.584 44.702 -30.035 62.850 43.777 -30.235 61.755 44.926 -28.863 60.789 43.749 -28.729 59.718 43.915 -29.796 61 .523 42.407 -28.849 60.596 41.194 -28.946 62.702 45.020 -27.656 63.754 44.390 -27.651 62.3512 45.808 -26.630 61.527 46.341 -26.691 63.102 45.893 -25.383 63.641 47.280 -25.184 65.100 47.492 -25.528 65.488 48.878 -24.982 66.995 49.115 -24.757 67.263 50.131 -23.739 66.878 49.820 -22.825 66.840 51.037 -24.022 68.294 50.246 -23.654 62.157 45.597 -24.229 60.960 45.806 -24.324 62.635 45.096 -23.105 63.577 44.830 -23.064 61.823 44.993 -21.894 62.389 43.928 -20.978 62.391 42.526 -21.549 63.120 41.594 -20.583 63.108 40.150 -21.065 64.002 39.368 -20.235 63.689 39.403 -19.245 64.966 39.751 -20.319 63.995 38.382 -20.571 61.701 46.280 -21.053 62.635 47.066 -20.917 60.521 46.503 -20.461 59.777 45.870 -20.580 60.307 47.641 -19.592 59.387 48.636 -20.288 59.653 47.109 -18.320 58.914 46.143 -18.310 59.889 47.690 -17.150 60.599 48.347 -17.216 59.185 47.349 -15.904 59.573 48.206 -14.672 61.001 48.032 -14.197 61.504 46.919 -13.586 62.036 48.845 -14.409 61.980 49.784 -14.696 63.132 48.250 -14.001 62.800 47.082 -13.515 63.431 46.421 -13.150 57.741 47.676 -16.169 57.445 48.725 -16.715 56.837 46.786 .15.797 57.138 45.908 .15.473 55.418 47.059 -15.946 54.711 45.724 -15.720 54.531 45.378 -14.233 1.00 1.00 1.00 1.00 1.00 2.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 2.00 1.00 1.00 2.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.00 0.00 63.55 0.00 59.35 52.67 0.00 48.35 43.28 39.84 35.21 36.89 48.70 46.83 47.06 0.00 42.30 46.07 59.38 73.60 83.83 85.82 0.00 0.00 0.00 36.54 36.02 34.11 0.00 35.41 36.15 40.56 40.42 43.28 52.04 0.00 0.00 0.00 33.67 31.28 28.86 0.00 26.84 26.05- 25.85 29.25 25.43 0.00 20.62 18.17 16.95 13.40 20.74 0.00 17.22 19.50 0.00 23.43 21.27 27.07 0.00 25.91 23.73 19.80 69 ATOM 1720 CGI ATOM 1722 CDI ATOM 1722 C ATOM 1723 0 ATOM 1724 N ATOM 1725 H ATOM 1726 CA ATOM 1727 CB ATOM 1728 CG ATOM 1729 CD ATOM 1730 OEI ATOM 1731 .0E2 ATOM 1732 C ATOM 1733 0 ATOM 1734 N :~.00ATOM 1735 H .ATOM 1736 CA *ATOM 1737 CB ATOM 1738 CG 20 ATOM 1739 CD ATOM 1740 CE 0ATOM 2742 NZ O**ATOM 1742 HZI '0ATOM 1743 HZ2 25 ATOM 1744 HZ3 *0*ATOM 1745 C ATOM 1746 0 ATOM 1747 N ATOM 1748 H ATOM 1749 CA ATOM 1750 CB 0ATOM 1752 CG .ATOM 1752 ODI 004ATOM 1733 0D2 ATOM 1754 C ATOM 1755 0 ATOM 1756 N *ATOM 1757 H 0ATOM 1758 CA 40 ATOM 1759 CB ATOM 1760 CG ATOM 1761 CDI ATOM 1762 dD2 0 0ATOM 1763 CEl ATOM 1764 CE2 ATOM 1765 CZ ATOM 1766 C ATOM 1767 0 ATOM 1768 N ATOM 1769 H ATOM 1770 CA ATOM 1771 CB ATOM 1772 CG2 ATOM 1773 CGI ATOM 1774 CDI ATOM 1775 C ATOM 1776 0 ATOM 2777 N' ATOM 1778 H ATOM 2779 CA ATOM 1780 CB ATOM 1781 C ATOM 1782 0 ATOM 1783 N

ILE

ILE

ILE

GLE

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLY

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

AS

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

AP

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PLE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ILE

ALA

ALA

ALA

ALA

ALA

ALA

PHE

53.411 45.795 52.688 44.478 54.891 48.183 53.998 48.930 55.418 48.357 56.140 47.768 54.973 49.441 54.186 48.824 53.692 49.837 52.88 1 49.122 52.275 48.099 52.858 49.586 56.191 50.205 57.106 49.587 56.245 51.531 55.526 52.005 57.37 1 52.335 58.571 52.036 59.855 52.715 61.087 52.259 61.101 52.703 61.146 54.143 62.010 54.507 60.311 54.557 61.145 54.397 56.861 53.774 55.928 .54.033 57.480 54.700 58.191 54.415 57.214 56.136 57.422 56.737 58.721 56.273 59.806 56.575 58.646 55.579 55.835 56.529 55.284 57.559 55.222 55.721 55.626 54.862 53.972 56. 107 53.008 54.938 52.290 54.444 51.070 55.004 52.772 53.338 50.334 .54.424 52.022 52.752 50.801 53.298 54.219 56.643 55.237 56.323 53.302 57.460 52.602 57.853 53.255 57.771 54.123 59.032 53.663 60.311 54 .026 59.244 55.177 60.055 51.802 58.030 51.153 58.692 51.225 57.543 51.716 56.924 49.867 57.908 48.985 56.671 49.854 58.614 50.648 58.289 48 .969 59.584 .16 .4612 .16.349 .15.046 -15.420 -13.843 -13 .556 .12.974 -11.82 1 -10.8 16 -9.775 -10.071 -8.649 -12.459 -11.922 -12.604 .13.083 -12.203 -13.135 -12 .663 -13.405 -14.851 -14.983 -14.531 -14.522 .15.993 .12.340 -13.094 -11.589 -10.974 -11.6 10 -13.034 -13 .707 -13.224 .14.7 11 -11. 122 -11.488 10.264 -10.024 -9.608 -9.4 10 -10.658 -11.016 -11.3612 -12 .043 12 .380 -12 .718 -8.201 -7.588 -7.673 -8.243 -6.266 -5.9214 -6.612 -4.395 -3.780 -5.976 -6.769 -4.873 -4.289 -4.507 -4.395 -3.168 -2.296 -2.%67 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 2.00 2.00 1.00 2.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 2.00 1.00 1.00 17.37 24.35 27.83 26.39 27.46 0.00 26.27 25.82 23.38 24.43 25.59 25.24 29.36 26.17 26.30 0.00 24.24 19.60 14.81 11.93 20.28 21.10 0.00 0.00 0.00 26.70 25.97 26.25 0.00 23.30 23.42 24.74 24.42 21.44 20.53 24.45 19.21 0.00 18.83 16.54 20.45 17.51 21.65 20.17 18.97 20.53 18.93 17.66 18.15 0.00 16.96 17.42 19.49 15.51 15.10 18.38 18.62 20.05 0.00 20.56 17.55 24.24 22.82 22.84 ATOM 1784 H ATOM 1785 CA ATOM 1786 CB ATOM 1787 CG ATOM 1788 CD1 ATOM 1789 CD2 ATOM 1790 CEI ATOM 1791 CE2 ATOM 1792 CZ ATOM 1793 C ATOM 1794 0 ATOM 1795 N ATOM 1796 H ATOM 1797 CA ATOM 1798 CB ATOM 1799 SG ATOMI1800 C ATOM 1801 0 ATOM 1802. N ATOM 1803 H ATOM 1804 CA ATOM 1805 CB a.*ATOM 1806 00 ATOM 1807 HG 25 ATOM 1808 C **'ATOM 1809 0 ATOM 1810 N ATOM 1811 H ATOM 1812 CA ATOM 1813 CB ATOM 1814 00 .ATOM 1815 HG *ATOM 1816 C ATOM 1817 0 35 ATOM 181 N ATOM 1819 H ATOM 1820 CA 4**ATOM 1821 CB ATOM 1822 001 40 ATOM 1823 HOI 4 .ATOM 1824 CG2 ATOM 1825 C I ~ATOM 1826 0 44ATOM 1827 N 45 AO 88 C ATOM 1828 CA ATOM 1829 CA ATOM 1830 CG ATOM 1831 CO ATOM 1833 0 ATOM 1834 N ATOM 1835 H ATOM 1836 CA ATOM 1837 CB ATOM 1838 CO ATOM 1839 ODI ATOM 1840 0D2 ATOM 1841 C ATOM 1842 0 ATOM 1843 N ATOM 1844 H ATOM 1845 CA ATOM 1846 CB ATOM 1847 CO

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

CYS

CYS

CYS

CYS

CYS

CYS

CYS

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

SER

THR

THR

THR

THR

THR

THR

THR

THR

THR

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASP

ASN

ASN

ASN

ASN

ASN

330 48.352 59.823 330 48.869 60.291 330 49.268 61.745 330 49.659 62.459 330 49.771 63.841 330 49.931 61.760 330 50.147 64.514 330 50.309 62.438 330 50.409 63.815 330 47.425 60.183 330 46.536 60.673 331 47. 169 59.539 331 47.914 59.170 331 45.831 59.362 331 45.584 57.950 331 45.613 56.747 331 45.649 60.235 331 46.586 60.508 332 44.421 60.692 332 43.659 60.414 332 44.084 61 .598 332 42.690 62.162 332 41.835 61.127 332 40.977 61.499 332 44.120 61.144 332 44.290 61.947 333 43.945 59.844 333 43.779 59.215 333 43.971 59.274 333 42.580 58.895 333 41.566 58.641 333 40.748 58.468 333 44.745 57.979 333 45.104 57.510 334 45.003 57.359 334 44.646 57.711 334 45.720 56.099 334 46.501 56.407 334 47.797 55.855 334 48.191 56.183 334 45.753 55.956 334 44.639 54.990 334 43.459 55.273 335 44.853 53.756 335 46.175 53.207 335 43.804 52.736 335 44.565 51.473 335 45.823 52.030 335 42.850 52.545 335 43.309 52.608 336 41.545 52.314 336 41.220 52.278 336 40.529 52.137 336 40.940 51.344 336 41.344 49.933 336 42.285 49.465 336 40.725 49.302 336 40.046 53.423 336 39.121 53.427 337 40.623 54.569 337 41.271 54.602 337 40.284 55.789 337 41.565 56.352 337 42.065 55.421 -3.694 -1.709 -1.937 -0.647 -0.652 0.521I 0.490 1.665 1.653 -1.260 -1.956 -0.117 0.402 0.402 0.841 -0.490 1.609 2.342 1.836 1.268 2.928 2.616 2.164 2.030 4.389 5.302 4.657 3.918 5.984 6.523 5.556 6.021 5.819 4.736 6.951 7.788 6.997 8.296 8.169 7.351 9.5 19 6.904 7.098 6.619 6.4 14 6.469 6.155 5.529 7.636 8.769 7.406 6.479 8.449 9.7 10 9.397 10.040 8.531 9.046 9.849 8.686 7.951I 9.372 9.973 11.068 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.00 18.35 18.09 22.46 21.17 20.68 22.56 20.88 23.44 20.07 16.75 20.04 0.00 17.86 16.56 23.49 21.19 20.65 22.22 0.00 21.44 19.68 24.42 0.00 21.99 20.58 23.27 0.00 20.50 21.15 23.77 0.00 23.49 19.23 23.40 0.00 24.09 28.30 34.11 0.00 14.09 22.20 23.69 20.97 15.82 19.65 20.20 20.66 25.5 3 29.15 24.20 0.00 28.39 32.12 43.11 52.99 51.49 29.38 34.19 25.69 0.00 23.68 22.73 22.82 71 ATOM 1848 ODI ASN 337 41.379 54.991 11.987 1.00 25.91 ATOM 1849 ND2 ASN 337 43.293 54.940 10.989 1.00 18.06 ATOM 1850 HD21 ASN 337 43.822 55.204 10.218 1.00 0.00 ATOM 1851 HD22 ASN 337 43.604 54.320 11.691 1.00 0.00 ATOM 1852 C ASN 337 39.600 56.812 .8.496 1.00 258 ATOM 1853 0 ASN 337 39.737 56.860 7.283 1.00 29.96 ATOM 1854 N VAL 338 38.815 57.691 9.095 1.00 27.31 ATOM 1855 H VAL 338 38.760 57.662 10.072 1.00 0.00 ATOM 1856 CA VAL 338 38.117 58.722 8.361 1.00 24.45 ATOM 1857 CB VAL 338 36.902 59.297 9.168 1.00 24.69 ATOM 1858 CGl VAL 338 35.901 58.187 9.486 1.00 25.15 ATOM 1859 CG2 VAL 338 37.369 59.946 10.467 1.00 25.43 ATOM 1860 C VAL 338 39.045 59.870 8.024 1.00 25.97 ATOM 1861 0 VAL 338 40.124 60.040 8.588 1.00 26.18 ATOM 1862 N SER 339 38.588 60.680 7.067 1.00 27.49 .ATOM 1863 H SER 339 37.756 60.450 6.596 1.00 0.00 *ATOM 1864 CA SER 339 39.231 61.948 6.743 1.00 32.77 ATOM 1865 CB SER 339 39.666 62.030 5.285 1.00 30.77 ATOM 1866 00 SER 339 39.874 60.771 4.672 1.00 38.35 ATOM 1867 HG SER 339 39.097 60.209 4.677 1.00 0.00 ATOM 1868 C SER 339 38.181 63.015 6.948 1.00 32.35 qATOM 1869 0 SER 339 37.008 62.669 6.924 1.00 29.99 ATOM 1870 N TRP 340 38.549 64.280 7.130 1.00 31.11 ATOM 1871 H TRP 340 39.494 64.546 7.074 1.00 0.00 25 ATOM 1872 CA TRP 340 37.580 65.306 7.447 1.00 32.42 ATOM 1873 CB TRP 3.40 38.110 66.071 8.665 1.00 28.07 ATOM 1874 CO TRP 340 38.069 65.153 9.851 1.00 31.22 ATOM 1875 CD2 TRP 340 36.790 64.901 10.522 1.00 33.69 ATOM 1876 CE2 TRP 340 37.281 63.820 11.450 1.00 38.45 ATOM 1877 CE3 TRP 340 35.473 65.302 10.526 1.00 37.14 ATOM 1878 CD1 TRP 340 39.112 64.394 10.320 1.00 32.03 3.ATOM 1879 NEI TRP 340 38.611 63.616 11.256 1.00 35.26 **ATOM 1880 HEI TRP 340 39.143 62.912 11.687 1.00 0.00 ATOM 1881 CZ2 TRP 3.40 36.364 63.217 12.277 1.00 43.31 35 ATOM 1882 CZ3 TRP 340 34.612 64.660 11.389 1.00 42.02 ATOM 1883 CH2 TRP 340 35.043 63.639 12.227 1.00 45.40 ATOM 1884 C TRP 340 37.260 66.265 6.311 1.00 35.22 0.0 **ATOM 1885 0 TRP 340 38.137 66.652 5.544 1.00 .36.37 ATOM 1886 N ARG 341 35.989 66.670 6.210 1.00 37.03 ATOM 1887 H ARG 341 35.321 66.289 6.821 1.00 0.00 41ATOM 1888 CA ARG 341 35.487 67.607 5.211 1.00 36.96 ATOM 1889 CB ARG 341 34.687 66.815 4.170 1.00 34.84 ATOM 1890 CO ARG 341 34.391 67.533 2.861 1.00 37.33 ATOM 1891 CD ARG 341 33.517 66.655 1.972 1.00 39.02 ATOM 1892 NE ARG 341 32.151 66.768 2.441 1.00 48.98 ATOM 1893 HE ARO 341 31.684 67.621 2.324 1.00 0.00 ATOM 1894 CZ ARG 341 31.501 65.767 3.031 1.00 51.01 ATOM 1895 NHI ARG 341 32.089 64.556 3.232 1.00 56.13 ATOM 1896 HH1I ARO 341 33.030 64.400 2.934 1.00 0.00 ATOM 1897 HH12 ARG 341 31.577 63.821 3.676 1.00 0.00 ATOM 1898 NH2 ARG 341 30.219 65.962 3.440 1.00 58.28 ATOM 1899 HH21 ARO 341 29.777 66.848 3.294 1.00 0.00 ATOM 1900 HH22 ARG 341 29.720 65.218 3.884 1.00 0.00 ATOM 1901 C ARG 341 34.616 68.684 5.864 1.00 37.23 ATOM 1902 0 ARG 341 33.969 68.486 6.883 1.00 38.61 ATOM 1903 N HIS 342 34.550 69.880 5.324 1.00 39.36 ATOM 1904 H HIS 342 35.002 70.055 4.471 1.00 0.00 ATOM 1905 CA HIS 342 33.820 70.966 5.934 1.00 43.08 ATOM 1906 CB HIS 342 34.885 71.921 6.463 1.00 41.90 ATOM 1907 CO HIS 342 34.284 73.095 7.199 1.00 45.95 ATOM 1908 CD2 HIS 342 33.508 74.035 6.600 1.00 46.70 ATOM 1909 NDI HIS 342 34.247 73.368 8.511 1.00 48.38 ATOM 1910 HDI HIS 342 34.661 72.884 9.248 1.00 0.00 ATOM 1911 CEI HIS 342 33.458 74.387 8.703 1.00 48.44 72 ATOM 1912 NE2 ATOM 1913 HE2 ATOM 1914 C ATOM 1915 0 ATOM 1916 N ATOM 1917 CD ATOM 1918 CA ATOM 1919 CB ATOM 1920 CG ATOM 1921 C ATOM 1922 0 ATOM 1923 N ATOM 1924 H ATOM 1925 CA ATOM 1926 CB SATOM 1927 001 *ATOM 1928 HGI *ATOM 1929 CG2 ATOM 1930 C ATOM 1931 0 ATOM 1932 N ATOM 1933 H *ATOM 1934 CA ATOM 1935 CB 25 ATOM 1936 CG eS )ATOM 1937 SD ATOM 1938 CE ATOM 1939 C ATOM 1940 0 ATOM 1941 N ATOM 1942 H *ATOM 1943 CA ATOM 1944 C ***ATOM 1945 0 35 ATOM 1946 N ATOM 1947 H ATOM 1948 CA 1949 CB oATOM 1950 OG 40 ATOM 1951 HG ATOM 1952 C *ATOM 1953 0 *ATOM 1954 N **ATOM 1955 H 45 ATOM 1956 CA ATOM 1957 CB ATOM 1958 CGI ATOM 1959. CG2 ATOM 1960 C ATOM 1961 0 ATOM 1962 N ATOM 1963 H ATOM 1964 CA ATOM 1965 CB ATOM 1966 CG ATOM 1967 CDI ATOM 1968 CD2 ATOM 1969 CEI ATOM 1970 CE2 ATOM 1971 CZ ATOM 1972 C ATOM 1973 0 ATOM 1974 N ATOM 1975 H

HIS

HIS

HIS

HIS

PRO

PRO

PRO

PRO

PRO

PRO

PRO

THR

THR

THR

THR

THR

THR

THR

THR

THR

MET

MET

MET

MET

MET

MET

MET

MET

MET

GLY

GLY

GLY

GLY

GLY

SER

SER

SER

SER

SER

SER

SER

SER

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

PHE

PHE

PHE

PHE

PHE

PHE

PHE-

PHE

PHE

PHE

PHE

PHE

ILE

ILE

33.020 74.776 32.497 75.591 32.894 71.612 33.367 71.960 31.637 71.844 30.984 71.752 30.678 72.297 29.387 72.590 29.512 71.689 31.068 73.489 30.905 73.585 31.615 74.459 3 1.830 74.264 31.911 75.771 31.577 76.802 31.901 76.175 31.164 75.W6 30.088 77.164 33.367 75.826 33.802 76.516 34.192 75.055 33.844 74.348 35.604 75.172 36.357 75.229 36. 128 76.474 36.752 76. 178 38.405 76.807 36.133 74.006 37.288 74.042 35.383 72.947 34.439 72.892 35.981 71.822 36.764 70.915 36.680 70.988 37.567 70.012 37.693 70.023 38 .274 68.999 38.454 67.768 37.262 67.491 36.547 67.238 39.631 69.491 40.397 70.136 39.920 69.144 39.306 68.543 41.127 69.588 41.215 68.976 42.237 69.746 39.895 69.060 42.345 69.177 43.247 69.968 42.425 67.917 41.695 67.278 43.621 67.455 43.443 65.960 44.459 65.361 44.029 64.916 45.790 65.223 44.918 64.278 46.677 64.590 46.232 64.101 43.848 68.243 44.966 68.632 42.799 68 .499 41.912 68.220 7.542 7.407 4.899 3.826 5.101 6.398 4.073 4.824 6.0 15 3.199 1.988 3.909 4.837 3.354 4.429 5.672 5.752 4.490 2.944 2.046 3.632 4 '202 3.363 4.662 5.498 7.176 7.073 2.553 2.179 2.236 2.503 1.544 2.495 3.718 1.949 0.980 2.698 1.820 1.098 1.697 3.157 2.438 4.411 4.887 5.086 6.494 7.309 7.2 19 4.305 4.071 3.862 4.0 13 3.181 2.908 1.941 0.702 2.311 -0.127 1.459 0.252 1.898 1.609 1.097 1.396 49.68 0.00 46.18 43.57 48.28 46.23 49.91 44.40 41.79 53.27 55.64 54.13 0.00 53.54 56.09 63.15 0.00 57.44 53.06 53.90 51.25 0.00 52.69 60.31 71.30 86.57 81.62 47.27 48.63 40.77 0.00 36.57 35.51 40.26 32.41 0.00 28.45 24.81 30.64 0.00 3 1.86 33.18 29.14 0.00 25.67 27.65 29.29 29.60 25.79 31.26 23.67 0.00 22.69 18.76 20.55 14.77 15.53 16.44 13.87 12.07 23.64 23.92 23.51 0.00 73 ATOM 1976 CA ILE 350 42.969 69.170 -0.185 1.00 23.11 ATOM 1977 CB ILE 350 41.617 69.131 -0.939 1.00 23.98 ATOM 1978 CG2 ILE 350 41.741 69.922 -2.229 1.00 24.02 ATOM 1979 CG1 ILE 350 41.200 67.689 -1.267 L.00 20.37 ATOM 1980 CDI ME 350 42.089 66.972 -2.272 1.00 14.33 ATOM 1981 C ILE 350 43.451 70.600 0.073 1.00 23.87 ATOM 1982 0 ILE 350 44.428 71.058 -0.510 1.00 25.61 ATOM 1983 N GLY 351 42.813 71.359 0.962 1.00 21.19 ATOM 1984 H GLY 351 42.057 70.988 1.467 1.00 0.00 ATOM 1985 CA GLY 351 43.248 72.720 1.212 1.00 19.54 ATOM 1986 C GLY 351 44.702 72.800 1.640 1.00 26.25 ATOM 1987 0 GLY 351 45.524 73.568 1.138 1.00 28.41 ATOM 1988 N ARG 352 45.064 71.963 2.614 1.00 28.53 ATOM 1989 H ARG 352 44.388 71.391 3.045 1.00 0.00 ATOM 1990 CA ARG 352 46.49 71.872 3.042 1.00 26.92 *ATOM 1991 CB ARG 352 46.589 70.842 4.167 -1.00 31.79 ATOM 1992 CG ARG 352 47.697 71.286 5.104 1.00 35.13 ATOM 1993 CD ARG 352 47.091 71.997 6.310 1.00 38.95 *ATOM 1994. NE ARG 352 47.179 71.107 7.452 1.00 44.61 2.0 ATOM 1995 HE ARG 352 47.920 70.468 7.491 1.00 0.00 .ATOM 1996 CZ ARG 352 46.307 71.116 8.449 1.00 41.51 ATOM 1997 NHI ARG 352 46.502 70.272 9.494 1.00 48.56 ATOM 1998 HHI I ARG 352 47.294 69.660 9.507 1.00 0.00 ATOM 1999 HH12 ARG 352 45.849 70.267 10.251 1.00 0.00 two. 25 ATOM 2000 N112 ARG 352 45.227 71.943 8.435 1.00 44.65 ATOM 2001 HH21 ARG 352 45.080 72.554 7.657 1.00 0.00 ATOM 2002 H{H22 ARG 352 44.570 71.936 9.187 1.00 0.00 ATOM 2003 C ARG 352 47.419 71.483 1.931 1.00 26.87 ATOM 2004 0 ARG 352 48.535 71.995 1.866 1.00 26.27 ATOM 2005 N LEU 353 47.033 70.567 1.037 1.00 25.01 00ATOM 2006 H LEU 353 46.156 70.135 1.143 1.00 0.00 ATOM 2007 CA LEU 353 47.866 70.154 -0.070 1.00 23.26 ATOM 2008 CB LEU 353 47.222 68.947 -0.778 1.00 25.55 ATOM 2009 CG LEU 353 47.975 68.452 -2.020 1.00 23.59 0. 35 ATOM 2010 CDI L.EU 353 49.420 68.121 -1.696 1.00 25.86 ATOM 2011 CD? LEU 353 47.258 67.230 -2.552 1.00 29.54 so *ATOM 2012 C LEU 353 48.034 71.303 -1.031 1.00 27.31 *ATOM 2013 0 LEU 353 49.142 71.600 -1.485 1.00 24.83 ATOM 2014 N ILE 354 46.923 71.977 -1.350 1.00 22.68 :t 40 ATOM 2015 H ILE 354 46.049 71.660 -1.035 1.00 0.00 ATOM 2016 CA RE 354 47.019 73.174 -2.168 1.00 24.25 ATOM 2017 CB ME 354 45.595 73.782 -2.327 1.00 21.11 *ATOM 2018 CG2 RLE 354 45.652 75.176 .2.940 1.00 21.96 so ATOM 2019 CGI RLE 354 44.769 72.893 -3.248 1.00 17.07 ATOM 2020 CDI RLE 354 43.279 73.267 -3.187 1.00 18.04 ATOM 2021 C RLE 354 48.000 74.172 -1.540 1.00 25.12 ATOM 2022 0 RLE 354 48.967 74.616 -2.165 1.00 27.26 ATOM 2023. N GLU 355 47.806 74.559 -0.276 1.00 27.20 ATOM 2024 H GLU 355 47.040 74.212 0.235 1.00 0.00 ATOM 2025 CA GLU 355 48.719 75.507 0.341 1.00 25.06 ATOM 2026 CB GLU 355 48.501 75.685 1.803 1.00 32.73 ATOM 2027 CG GLU 355 47.165 76.212 2.282 1.00 45.70 ATOM 2028 CD GLU 355 47.053 75.777 3.746 1.00 58.26 ATOM 2029 QEI GLU 355 45.921 75.683 4.245 1.00 61.90 ATOM 2030 0E2 OLU 355 48.092 75.513 4.385 1.00 61.89 ATOM 2031 C GLU 355 50.150 75.114 0.242 1.00 23.42 ATOM 2032 0 GLU 355 51.029 75.893 -0.054 1.00 25.26 ATOM 2033 N HIS 356 50.461 73.862 0.489 1.00 26.55 ATOM 2034 H HIS 356 49.739 73.225 0.663 1.00 0.00 ATOM 2035 CA HIS 356 51.855 73.438 0.432 1.00 26.58 ATOM 2036 CB HIS 356 51.997 72.019 1.041 1.00 27.11 ATOM 2037 CG HIS 356 51.846 72.065 2.551 1.00 23.74 ATOM 2038 CD2 HIS 356 52.890 72.264 3.421 1.00 22.80 ATOM 2039 NDI HIS 356 50.728 72.044 3.288 1.00 25.98 74 ATOM 2040 HDI ATOM 2041 CEI ATOM 2042 NE2 ATOM 2043 HE2 ATOM 2044 C ATOM 2045 0 ATOM 2046 N ATOM 2047 H ATOM 2048 CA ATOM 2049 CB ATOM 2050 CG ATOM 2051 SD ATOM 2032 CE ATOM 2053 C 15 ATOM 2054 0 *ATOM 2055 N ATOM 2056 H go 0go:ATOM 2057 CA ATOM 2038 CB 20 ATOM 2059 CG 0ATOM 2060 CD *ATOM 2061 OEI ATOM 2062 NE2 eo:,,ATOM 2063 HE21 25 ATOM 2064 HE22 ATOM 2065 C ATOM 2066 0 ATOM 2067 N ATOM 2068 H ATOM 2069 CA ATOM 2070 CB 0 ATOM 2071 CG 0ATOM 2072 CD *ATOM 2073 OEI 35 ATOM 2074 0E2 ATOM 2075 C *ATOM 2076 0 0 ATOM 2077 N ATOM 2078 H 0.:000 40 ATOM 2079 CA ATOM 2080 CB ATOM 2081 CC so* *S*ATOM 2082 CD1 ATOM 2083 CEI ATOM 2084 CD2 ATOM 2085 CE2 ATOM 2086 CZ ATOM 2087. O" ATOM 2088 HH ATOM 2089 C ATOM 2090 0 ATOM 2091 N ATOM 2092 H ATOM 2093 CA ATOM 2094 CB ATOM 2095 C ATOM 2096 0 ATOM 2097 N ATOM 2098 H ATOM 2099 CA ATOM 2100 C ATOM 2101 0 ATOM 2102 CB ATOM 2103 SG

HIS

HIS

HIS

HIS

HIS

HIS

MET

MET

MET

MET

MET

MET

MET

MET

MET

CLN

GLN

CLN

GLN

CLN

CLN

GLN

CLN

GLN

GLN

GLN

GLN

CLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

OLU

GLU

TYR

TY

TYR

TYR

TYR

TYR

TY

TYR

AYA

ALA

ALA

ALA

ALA

CLA

CYS

CYS

CYS

CYS

CYS

49.819 71.907 51.036 72.231 52.333 72.360 52.814 72.450 52.411 73.447 53.560 73.809 51.586 73.039 50.672 72.732 52.037 73.060 50.995 72.413 50.860 70.870 52.182 69.919 51.449 69.433 52.249 74.503 53.237 74.846 51.365 75.428 50.539 75. 168 51.650 76.808 50.505 77.693 49.262 77 .438 48.063 78.234 47.170 78.570 47.919 78.558 48.611 78.285 47.124 79.077 52.982 77.344 53.783 77.971 53.234 77.083 52.581I 76.563 54.425 77.558 54.178 77.382 55.215 77.874 55.241I 79.379 54.197 79.992 56.320 79.940 55.638 76.809 56.664 77.422 55.584 75.475 54.723 75.002 56.814 74.710 56.902 73.528 56.910 74.022 55 .765 73.873 55.711 74.433 58.022 74.677 57.974 75.239 56.813 75.114 56.737 75 .692 55.852 75.603 57.148 74.120 58.243 73.583 56.288 74.169 55.459 74.682 56.544 73.494 55.328 73.717 57.818 73.954 58.461 73.249 58.273 75.178 57.694 75.795 59.576 75.578 60.768 74.919 61.761 74.529 59.746 77 .086 61.400 77.655 2.953 4.550 4.608 5.460 -0.983 -1.239 -1.948 -1.747 -3.316 -4.239 -4.254 -5.054 -6.584 704 -4.338 -3.360 -2.897 -3.709 -3.2 14 -4.067 -4.362 -2.329 -1.693 -2.095 182 -3.869 -1.906 -1.386 -1.243 0.251 1.245 1.308 1.550 1.132 -1.721 -1.974 -1.867 -1.843 -2.053 -1.079 0.333 1.087 2.342 0.824 2.080 2.823 4.073 4.430 -3.389 -3.525 -4.4 11 -4.320 -5.678 -6.600 -6.355 -7.116 -6.133 -5.620 -6.659 -5.987 -6.575 -6.546 -7.050 0.00 19.00 22.63 0.00 26.45 20.78 17.38 0.00 28.28 30.75 34.53 43.28 37.66 29.20 31.64 25.95 0.00 27.58 24.97 26.18 28.54 30.13 31.54 0.00 0.00 30.98 31.45 32.65 0.00 32.96 37.33 51.69 63.61 70.65 69.55 33.19 36.20 33.15 0.00 28.52 30.16 28.83 30.92 33.76 30.38 32.36 35.09 41.75 0.00 27.85 27.93 27.66 0.00 28.82 26.34 32.26 35.01 38.50 0.00 42.41 41.51 41.46 47.61 (A.18 75 ATOM 2104 N SER 363 60.741 74.757 -4.681 1.00 40.95 ATOM 2105 H SER 363 59.909 74.803 -4.165 1.00 0.00 ATOM 2106 CA SER 363 61.955 74.338 -4.026 1.00 43.35 ATOM 2107 CB SER 363 62.122 75.236 -2.900 1.00 44.65 ATOM 2108 OG SER 363 60.899 75.837 -2.362 1.00 53.93 ATOM 2109 HG SER 363 60.553 76.414 -3.046 1.00 0.00 ATOM 2110 C SER 363 61.985 72.866 -3.661 1.00 40.77 ATOM 2111 0 SER 363 63.036 72.255 -3.593 1.00 43.37 ATOM 2112 N CYS 364 60.857 72.220 -3.399 1.00 38.31 ATOM 2113 H CYS 364 59.976 72.633 -3.542 1.00 0.00 ATOM 2114 CA. CYS 364 60.937 70.839 -2.979 1.00 33.39 ATOM 2115' CB CYS 364 60.056 70.623 -1.755 1.00 32.55 ATOM 2116 SG CYS 364 60.308 71.767 -0.422 1.00 40.02 ATOM 2117 C CYS 364 60.478 69.967 -4.121 1.00 29.84 1S ATOM 2118 0 CYS 364 59.610 70.346 -4.887 1.00 30.07 ATOM 2119 N ASP 365 61.025 68.770 -4.300 1.00 28.01 ATOM 2120 H ASP 365 61.859 68.579 -3.828 1.00 0.00 ATOM 2121 CA ASP 365 60.406 67.794 -5.164 1.00 27.07 ATOM 2122 CB ASP 365 61.379 66.619 -5.419 1.00 27.73 ATOM 2123 CG ASP 365 61.757 65.825 -4.171 1.00 31.83 ATOM 2124 ODI ASP 365 61.026 64.918 -3.783 1.00 34.71 ATOM 2125 OD2 ASP 365 62.805 66.094 -3.599 1.00 42.02 ATOM 2126 C ASP 365 59.111 67.254 -4.538 1.00 28.95 ATOM 2127 0 ASP 365 58.838 67.420 -3.343 1.00 27.98 ATOM 2128 N VAL 366 58.277 66.590 -5.336 1.00 27.55 ATOM 2129 H VAL 366 58.5" 66.434 -6.268 1.00 0.00 ATOM 2130 CA VAL 366 56.968 66.183 -4.857 1.00 27.84 ATOM 2131 CB VAL 366 56.251 65.513 -6.051 1.00 24.13 ATOM 2132 CGI VAL 366 55.102 64.601 -5.672 1.00 23.78 ATOM 2133 CG2 VAL 366 55.629 66.654 -6.848 1.00 23.21 ATOM 2134 C VAL 366 57.007 65.309 -3.611 1.00 28.22 ATOM 2135 0 VAL 366 56.256 65.536 -2.674 1.00 30.81 ATOM 2136 N GLU 367 57.856 64.298 -3.489 1.00 28.49 ATOM 2137 H GLU 367 58.450 64.111 -4.237 1,00 0.00 ATOM 2138 CA GLU 367 57.867 63.516 -2.259 1.00 27.85 ATOM 2139 CB GLU 367 58.939 62.428 -2.289 1.00 26.64 ATOM 2140 CG GLU 367 58.553 61.219 -3.144 1.00 28.69 ATOM 2141 CD GLU 367 59.442 60.019 -2.820 1.00 37.41 ATOM 2142 OEI GLU 367 59.643 59.736 -1.632 1.00 42.87 ATOM 2143 OE2 GLU 367 59.937 59.388 -3.767 1.00 37.88 ATOM 2144 C GLU 367 58.106 64.352 -1.012 1.00 28.61 ATOM 2145 0 GLU 367 57.604 64.052 0.059 1.00 31.13 ATOM 2146 N GLU 368 58.972 65.437 -1.099 1.00 28.39 ATOM 2147 H GLU 368 59.242 65.725 -1.959 1.00 0.00 ATOM 2148 CA GLU 368 59.094 66.231 0.076 1.00 26.65 ATOM 2149 CB GLU 368 60.278 67.145 -0.069 1.00 34.26 ATOM 2150 CG GLU 368 61.017 66.888 1.244 1.00 53.59 ATOM 2151. CD GLU 368 61.471 68.195 1.941 1.00 63.52 ATOM 2152 OEI GLU 368 61.948 69.099 1.078 1.00 71.58 ATOM 2153 OE2 GLU 368 61.444 68.298 3.071 1.00 64.40 ATOM 2154 C GLU 368 57.923 67.082 0.3% 1.00 23.42 ATOM 2155 0 GLU 368 57.561 67.224 1.555 1.00 27.18 ATOM 2156 N ILE 369 57.268 67.677 -0.591 1.00 22.22 ATOM 2157 H ILE 369 57.595 67.596 -1.513 1.00 0.00 ATOM 2158 CA ILE 369 56.027 68.395 -0.295 1.00 19.89 ATOM 2159 CB ILE 369 55.403 68.931 -1.624 1.00 22.54 ATOM 2160 CG2 ILE 369 54.089 69.671 -1.355 1.00 20.28 ATOM 2161 CGI ILE 369 56.360 69.917 -2.281 1.00 17.77 ATOM 2162 CDI ILE 369 55.911 70.256 -3.701 1.00 15.38 ATOM 2163 C ILE 369 55.024 67.497 0.435 1.00 20.18 ATOM 2164 0 ILE 369 54.331 67.885 1.371 1.00 20.19 ATOM 2165 N PHE 370 54.923 66.241 0.020 1.00 21.39 ATOM 2166 H PHE 370 55.470 65.932 -0.733 1.00 0.00 ATOM 2167 CA PHE 370 53.962 65.359 0.654 1.00 23.30 76 ATOM 2168 CB ATOM 2169 CG ATOM 2170 CDI ATOM 2171 CD2 ATOM 2172 CEl ATOM 2173 CE2 ATOM 2174 CZ ATOM 2175 C ATOM 2176 0 ATOM 2177 N ATOM 2178 H ATOM 2179 CA ATOM 2180 CB ATOM 2181 CG 15 ATOM 2182 CD *ATOM 2183 NE ATOM 2184 HE ATOM 2185 CZ *ATOM 2186 NHI .09: 20 ATOM 2187 HHI1 *ATOM 2188 HH12 0ATOM 2189 NH2 ATOM 2190 HH21 go :96ATOM 2191 HH22 25 ATOM 2192 C ATOM 2193 0 ATOM 2194 N ATOM 2195 H ATOM 2196 CA ATOM 2197 CB ATOM 2198 CG 00ATOM 2199 CD ATOM 2200 CE :.ATOM 2201 NZ 35 ATOM 2202 HZI ATOM 2203 HZ2 ATOM 2204 HD3 ATOM 2205 C ATOM 2206 0 *:see* 40 ATOM 2207 N ATOM 2208 H ATOM 2209 CA 0~*ATOM 2210 CB goATOM 2211 CGI ATOM 2212 CG2 ATOM 2213 C ATOM 2214 0 ATOM 2215 N ATOM 2236 H ATOM 2217 CA ATOM 2238 CB ATOM 2219 CG ATOM 2220 CD ATOM 2221 NE ATOM 2222 HE ATOM 2223 CZ ATOM 2224 NHI ATOM 2225 HHII ATOM 2226 HHI12 ATOM 2227 NH2 ATOM 2228 HH21 ATOM 2229 HH22 ATOM 2230 C ATOM 2231 0

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

ARO

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

LYS

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

53.842 64.029 53.140 64.222 53.037 63.153 52.624 65.444 52.427 63.311 52.013 65.595 51.906 64.521 54.360 65 .076 53.543 65.031 55.654. 64.883 56.291 64.804 56. 103 64.783 57.611 64.627 57.954 64.338 59.453 64.358 60.022 65.650 60.521 65.766 59.899 66.694 59.207 66.648 58.750 65.805 59.163 67.463 60.525 67.849 61.067 67.884 60.471 68.649 55.704 65.999 55.105 65.907 56.020 67.200 56.525 67.28 1 55.576 68.377 56.008 69.609 57.506 69.718 57.933 70.852 59.042 71.666 58.499 72.323 58.138 71.612 57.7 17 72.944 59.239 72.893 54.085 68.434 53.617 68.867 53.240 68.015 53.577 67.723 51.813 67.977 50.927 67.520 49.442 67.520 51.108 68.476 51.588 67.006 50.792 67.332 52.251 65.839 52.897 65.603 52.025 64.926 52.827 63.601 52.332 62.777 52.822 61.333 54.262 61.249 54.727 61.264 54.973 61.142 54.335 61.136 53.340 61.217 54.864 61.061 56.344 61.046 56.811 61.053 56.874 60.966 52.423 65.570 51.724 65.539 -0.121 -1.451 -2.304 -1.941 -3.533 -3.069 919 2.069 2.978 2.3134 1.573 3.683 3.722 5.180 5.411 5.122 4.286 5.969 7.152 7.435 7.729 5.632 4.795 6.231 4.505 5.576 4.020 3.182 4.733 3.976 4.053 3.136 3.789 4.969 5.636 4.674 5.426 4.960 6.008 4.026 3.154 4.333 3.121 3.541 1.933 5.471 6.336 5.540 4.838 6.660 6.5 11 5.307 5.253 5.278 6.141 4.161 2.971 2.923 2.126 4.208 5.094 3.362 7.958 8.§55 1.00 1.00 1.00 3.00 3.00 1.00 1.00 3.00 3.00 3.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 3.00 1.00 3.00 1.00 1.00 1.00 23.30 23.92 27.01 29.88 26.34 27.67 27.89 23.38 24.64 24.62 0.00 26.21 25.42 26.24 27.46 34.213 0.00 40.22 39.64 0.00 0.00 39.43 0.00 0.00 29.69 32.42 26.46 0.00 23.67 25.18 21.18 33.26 42.84 50.90 0.00 0.00 0.00 22.44 25.03 24.85 0.00 26.14 29.33 23.06 20.17 26.25 25.40 22.91 0.00 24.92 24.92 26.50 23.69 21.59 0.00 19.13 22.36 0.00 0.00 22.93 0.00 0.00 23.27 20.79 77 ATOM 2232 N ATOM 2233 H ATOM 2234 CA ATOM 2235 CB ATOM 2236 CG ATOM 2237 CDI ATOM 2238 CD2 ATOM 2239 CEI ATOM 2240 CE2 ATOM 2241 CZ ATOM 2242 C~ ATOM 2243 0 ATOM 2244 N ATOM 2245 H ATOM 2246 CA *..ATOM 2247 CB ATOM 2248 00 ATOM 2249 HG *ATOM 2250, C 20 ATOM 2251 0 ATOM 2252 N ATOM 2253 H *e9ATOM 2254 CA ATOM 2255 CB 25 ATOM 2256 CG ATOM 2257 CDI ATOM 2258 CD2 ATOM 2259 CEI ATOM 2260 CE2 ATOM 2261 CZ ATOM 2262 C *ATOM 2263 0 ATOM 2264 N ATOM 2265 H 35 ATOM 2266 CA ATOM 2267 CB ***ATOM 2268 CG ATOM 2269 CD ATOM 2270 OEI 40 ATOM 2271 0E2 ATOM 2272 C ATOM 2273 0 *ATOM 2274 N ATOM 2275 H ATOM 2276 CA ATOM 2277 CB ATOM 2278 CG ATOM 2279. CD) ATOM 2280 0OE1 ATOM 2281 NE2 ATOM 2282 HE21 ATOM 2283 HE22 ATOM 2284 C ATOM 2285 0 ATOM 2286 N ATOM 2287 CD ATOM 2288 CA ATOM 2289 CB ATOM 2290 CG ATOM 2291 C ATOM 2292 0 ATOM 2293 N ATOM 2294 H ATOM 2295 CA

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

SER

SER

SER

SER

SER

SER

SER

SER

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

PRO

PRO

PRO

PRO

PRO

PRO

PRO

ASP

ASP

ASP

53.58 1 66.204 54.147 66.181 54.025 66.896 55.388 67.523 56.010 68.272 56.926 67.655 55.684 69.589 57.518 68.348 56.281 70.277 57.202 69.659 52.982 67.917 52.775 68.135 52.260 68.589 52.414 68.468 51.281 69.562 50.7 15 70.398 49.984 69.740 50.480 68.972 50.124 68.979 49.395 69.683 49.927 67.671 50.511 67.127 48.882. 66.990 48.276 65.883 47.359 66.445 47.815 66.654 46.040 66.714 46.933 67.097 45.173 67.155 45.613 67.337 49.407 66.381 48.713 65.615 50.634 66.675 51.151 67.389 51.169 65.910 52.649 66.182 53.146 64.886 54.632 64.790 55.130 63.668 55.292 65.826 50.502 66.092 50.366 65.153 50.053 67.255 50.149 68.039 49.268 67.367 49.380 68.788 50.771 69.437 51.711 68.603 51.480 68.345 52.809 68.101 52.996 68.281 53.371 67.564 47.797 67.066 47.241 67.723 47.098 66.157 47 .634 65.095 45.670 65.984 45.261 64.815 46.548 64.024 44.890 67.242 44.736 67.733 44.366 67.794 44.538 67.356 43.596 69.021 7.996 7.193 9.187 8.829 9.989 10.803 10.221 11.838 11.255 12.064 9.664 10.857 8.742 7.783 9.208 8.047 7.034 6.709 9.960 10.647 9.838 9.265 10.570 9.691 8.647 7.363 8.961 6.390 7.981 6.688 11.860 12.528 12.279 11.850 13 .374 13.534 14.168 14.234 14.3 15 14.2 10 14.7 19 15.483 15.116 14.543 16.328 16.896 16.941 17 .767 18 .938 17 .225 16.281I 17 .826 16.009 15.130 16.602 17,.439 16. 367 17 .243 17 .310 16.664 17.776 15 .586 14.721 15 .617 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 24.10 0.00 23.34 29.16 35.30 36.99 3:3.65 36.47 38.44 37.61 28.21 28.91 28.48 0.00 28.11 24.30 26.36 0.00 30.03 27.69 33.33 0.00 30.24 21.45 21.79 23.05 22.87 23.70 21.35 16.45 30.42 29.72 30.87 0.00 35.50 33.01 38.65 42.24 45.42 51.72 36.27 39.55 39.19 0.00 48.22 56.51 63.32 69.92 74.88 72.82 0.00 0.00 50.39 51.95 51.98 50.16 58.10 53.72 49.03 67.86 70.34 77.19 0.00 83.19 78 ATOM 2296 CB ATOM 2297 CG ATOM 2298 ODI ATOM 2299 0D2 ATOM 2300 C ATOM 2301 0 ATOM 2302 N ATOM 2303 H ATOM 2304 CA ATOM 2305 C ATOM 2306 0 ATOM 2307 N ATOM 2308 H ATOM 2309 CA ATOM 2310 CB .ATOM 2311 CG 9ATOM 2312 CD ATOM 2313 NE *ATOM 2314 HE 2.0 ATOM 2315 CZ ATOM 2316 NHI ATOM 2317 HH11 **ATOM 2318 HH12 ATOM 2319 NH2 25 ATOM 2320 H-H21 *ATOM 2321 HH22 ATOM 2322 C ATOM 2323 0 ATOM 2324 N ATOM 2325 H ATOM 2326 CA ATO 232.C ATOM 2327 CB ATOM 2329 0 35 ATOM 2330 N ATOM 2331 H ATOM 2332 CA **.ATOM 2333 CB *ATOM 2334 CG 40 ATOM 2335 CD *ATOM 2336 OEI ATOM 2337 NE2 .ATOM 2338 HE21 .ATOM 2339 HE22 ATOM 2340 C ATOM 2341 0 ATOM 2342 N ATOM 2343. H ATOM 2344 CA ATOM 2345 CB ATOM 2346 CG ATOM 2347 SD ATOM 2348 CE ATOM 2349 C ATOM 2350 0 ATOM 2351 N ATOM 2352 CD ATOM 2353 CA ATOM 2354 CB ATOM 2355 CG ATOM 2356 C ATOM 2357 0 ATOM 2358 N ATOM 2359 H

ASP

ASP

ASP

ASP

ASP

ASP

GLY

GLY

GLY

GLY

GLY

ARG

ARG

ARG

ARG

ARO

ARG

ARG

ARG

ARG

ARG

ARG

ARO

ARG

ARG

ARG

ARG

ARO

ALA

AL.A

ALA

ALA

ALA

ALA

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

GLN

MET

MET

MET

MET

MET

MET

MET

MET

MET

PRO

PRO

PRO

PRO

PRO

PRO

PRO

THR

THR

43.541 69.494 43.014 70.910 43.143 71.746 42.481 71.167 42.223 68.750 41.197 69.227 42.096 67.981 42.906 67.764 40.780 67.478 40.321 66.448 40.458 65.247 39.759 66.873 39.519 67.824 39.629 66.003 39.071 66.738 37.832 67.576 36.696 66.741 35.525 67.573 35.556 68.516 34.408 67.087 33.341 67.925 33.413 68.873 32.487 67.594 34.322 65.793 35.108 65.180 33.469 65.461 41.041 65.557 41.896 66.385 41.392 64.279 40.809 63.578 42.711 63.902 43.392 63.101 42.614 63.088 41.666 62.329 43.604 63.245 44.264 63.968 43.794 62.325 42.964 62.733 43.318 64.098 42.355 64.422 41.375 65.120 42.598 63.875 43.370 63.272 42.007 64.105 45.276 62.394 45.955 63.312 45.844 61.457 45.253 60.770 47.281 61.417 47.980 60.448 49.459 60.203 50.369 61.710 50.297 62.580 47.376 60.904 47.187 59.706 47.623 61.710 47.479 63.144 47.706 61.309 47.813 62.609 48.153 63.635 48.825 60.365 49.849 60.377 48.671 59.504 47.904 59.580 14. 153 13 .938 14.843 12.84 16.235 15 .766 17.3 16 17.831 17 .697 16.669 16.841 15.545 15.480 14.381 13. 173 13.4 14 13 .993 14. 194 13.929 14.732 14.847 14.534 15.250 15. 173 15.101 15.576 14.005 13.7 10 13.985 14.357 13 .518 14.618 12.237 12 .029 12.349 11.422 10.258 9.034 8.48 1 7.399 7.586 6.223 6.110 5.478 9.937 10.363 9.197 8.827 8.921 9.881 9.609 9.227 10.768 7.503 7.306 6.539 6.670 5.134 4.355 5.396 4.853 5.523 3.859 3.255 90.96 908.27 12.43 102.13 83.61 86.07 80.88 0.00 78.25 75.15 79.53 69.56 0.00 64.31 67.34 69.84 75.22 78.64 0.00 79.29 80.15 0.00 0.00 76.12 0.00 0.00 59.27 63.51 51.06 0.00 43.97 39.32 41.10 42.25 30.93 0.00 26.81 23.54 27.75 29.52 30.67 29.71 0.00 0.00 26.43 26.69 25.50 0.00 25.53 22.77 22.60 24.47 22.26 25.56 24.42 24.46 25.50 22.74 21.24 25.14 24.30 23.73 22.51 0.00 79 ATOM 2360 CA ATOM 2361 CB ATOM 2362 O01 ATOM 2363 HGI ATOM 2364 CG2 ATOM 2365 C ATOM 2366 0 ATOM 2367 N ATOM 2368 H ATOM 2369 CA ATOM 2370 CB ATOM 2371 O01 ATOM 2372 HGI ATOM 2373 CG2 ATOM 2374 C ATOM 2375 0 9 ATOM 2376 N ATOM 2377 H ATOM 2378 CA ATOM 2379 CB ATOM 2380 CG ATOM 2381 CD ATOM 2382 OEI ATOM 2383 OE2 25 ATOM 2384 C ATOM 2385 0 ATOM 2386 N ATOM 2387 H ATOM 2388 CA ATOM 2389 CB ATOM 2390 CG ATOM 2391 CD ATOM 2392 NE ATOM 2303 HE ATOM 2394 CZ ATOM 2395 NHI ATOM 2396 HHII ATOM 2397 HH12 ATOM 2398 NH2 ATOM 2399 HH21 ATOM 2400 HH22 ATOM 2401 C ATOM 2402 0 ATOM 2403 N ATOM 2404 H ATOM 2405 CA ATOM 2406 CB ATOM 2407 CGI ATOM 2408 CG2 ATOM 2409 C ATOM 2410 0 ATOM 2411 N ATOM 2412 H ATOM 2413 CA ATOM 2414 CB ATOM 2415 OGI ATOM 2416 HGI ATOM 2417 CG2 ATOM 2418 C ATOM 2419 0 ATOM 2420 N ATOM 2421 H ATOM 2422 CA ATOM 2423 CB

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

THR

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

GLU

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

VAL

VAL

VAL

VAL

VAL

VAL

VAL

VAL

THR

THR

THR

THR

THR

THR

THR

THR

THR

LEU

LEU

LEU

LEU

49.646 58.448 49.037 57.083 48.399 57.238 49.021 57.669 50.105 56.009 50.062 58.416 49.262 58.508 51.357 58.279 51.974 58.285 51.933 58.099 53.304 58.762 53.043 60.143 52.584 60.204 54.305 58.266 51.981 56.611 52.421 55.845 51.532 56.183 51.265 56.821 51.461 54.770 49.993 54.334 49.716 54.258 48.453 53.567 47.644 53.290 48.274 53.314 52.032 54.416 52.148 55.236 52.406 53.145 52.314 52.613 52.871 52.472 51.677 52.087 51.351 50.594 51.041 50.062 49.890 49.159 49.248 49.211 49.642 48.255 50.302 48.156 51.042 48.794 50.046 47.45.

48.749 47.269 48.279 47.209 48.561 46.597 53.842 53.303 53.590 53.655 54.998 53.634 55.287 53.159 55.880 54.629 56.630 55.422 57.408 56.628 55.579 55.918 56.865 53.948 57.628 53.121 56.890 54.255 56.183 54.810 57.958 53.731 57.450 52.681 56.238 53.135 56.027 52.485 57.220 51.333 58.633 54.850 59.201 54.661 58.605 56.072 58.080 56.246 59.379 57.138 59.097 58.483 3.685 4.100 5.359 5.956 4.257 2.233 1.316 2.016 2.771 0.709 0.775 0.521 -0.321 -0.223 0.446 1.307 -0.742 -1.440 -1.017 -0.902 0.612 1.001 0.129 2.192 -2.351 -3.244 -2.449 -1.634 -3.655 -4.548 -4.650 -6.066 -6.094 -5.356 -7.068 -8.246 -8.455 -8.910 -6.849 -5.968 -7.567 -4.477 -5.630 -3.892 -3.085 -4.494 -3.404 -3.936 -2.436 -5.392 -4.915 -6.691 -7.081 -7.506 -8.535 -9.148 -9.822 -7.855 -8.235 -9.303 -7.719 -6.913 -8.338 -7.647 1.00 1.00 3.00 1.00 1.00 3.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 23.26 26.15 34.81 0.00 24.27 19.72 20.10 20.14 0.00 22.14 22.05 32.86 0.00 26.26 27.05 23.21 23.67 0.00 21.51 27.17 35.02 38.42 50.83 47.46 22.05 25.04 20.72 0.00 20.99 24.04 27.32 27.94 36.16 0.00 38.21 39.70 0.00 0.00 47.46 0.00 0.00 24.89 24.46 25.48 0.00 21.84 19.22 11.40 18.72 24.62 20.00 23.61 0.00 20.89 21.30 22.68 0.00 17.80 22.52 22.98 19.99 0.00 20.68 18.77 80 ATOM 2424 CG ATOM 2425 CDI ATOM 2426 CD2 ATOM 2427 C ATOM 2428 0 ATOM 2429 N ATOM 2430 H ATOM 2431 CA ATOM 2432 CB ATOM 2433 OGI ATOM 2434 HG I ATOM 2435 CG2 ATOM 2436 C ATOM 2437 0 ATOM 2438 N ***ATOM 2439 H ATOM 2440 CA ATOM 2441 CB ATOM 2442 CG ATOM 2443 CD ATOM 2444 NE ATOM 2445 HE ATOM 2446 CZ ocC ATOM 2447 NHI 25 ATOM 2448 HH1I ATOM 2449 HHI2 ATOM 2450 NH2 ATOM 2451 HH21 ATOM 2452 HH22 ATOM 2453 C ATOM 2454 0 ATOM 2455 N ATOM 2456 H ATOM 2457 CA ATOM 2458 CB ATOM 2459 SG ATOM 2460 C ATOM 2461 0 ATOM 2462 N ATOM 2463 H ATOM 2464 CA ATOM 2465 CB 0 ATOM 2466 CG ATOM 2467 CDI ATOM 2468 CD2 ATOM 2469 CEI ATOM 2470 CE2 ATOM 2471 CZ ATOM 2472 C ATOM 2473 0 ATOM 2474 N ATOM 2475 H ATOM 2476 CA ATOM 2477 CB ATOM 2478 CG ATOM 2479 CDI ATOM 2480 CEI ATOM 2481 CD2 ATOM 2482 CE2 ATOM 2483 CZ ATOM 2484 OH ATOM 2485 HH ATOM 2486 C ATOM 2487 0

LEU

LEU

LEU

LEU

LEU

THR

THR

THR

THR

THR

THR

THR

THR

THR

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

ARG

CYS

CYS

CYS

CYS

CYS

CYS

CYS

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

TYR

394 57.683 59.073 394 57.642 60.395 394 57.320 59.347 394 60.851 56.789 394 61.273 56.518 395 61.659 56.769 395 61.325 56.899 395 63.090 56.503 395 63.474 55.581 395 63.062 56.260 395 63.298 55.742 395 62.748 54.238 395 63.957 57.778 395 65.167 57.754 396 63.362 58.947 396 62.385 58.998 396 64.097 60.187 396 64.189 60.695 396 64.986 59.799 396 64.666 60.158 396 65.266 59.145 396 64.830 58.27! 396 66.403 59.385 396 66.982 58.338 396 66.539 57.441 396 67.836 58.466 396 66.961 60.635 396 66.516 61.394 396 67.815 60.786 396 63.286 61.210 396 62.133 60.990 397 63.840 62.377 397 64.766 62.545 397 63.114 63.404 397 64.086 64.447 397 65.267 63.936 397 62.170 64.045 397 62.531 64.263 398 60.945 64.386 398 60.638 64.172 398 60.072 65.094 398 58.677 64.374 398 57.644 65.009 398 58.011 65.812 398 56.306 64.770 398 57.052 66.367 398 55.358 65.320 398 55.716 66.121 398 59.960 66.512 398 59.258 66.853 399 60.703 67.377 399 61.396 67.062 399 60.538 68.809 399 61.878 69.467 399 62.706 69.308 399 63.584 68.255 399 64.366 68.168 399 62.601 70.258 399 63.376 70.173 399 64.262 69.125 399 65.009 68.999 399 65.683 68.322 399 59.536 69.292 399 59.668 69.103 -7.778 -7.031 -9.243 -8.181 -7.073 -9.243 -10.160 -9.136 -10.303 -11.471 -12.244 -10.343 -9.146 -8.943 -9.392 -9.428 -9.519 -10.936 -11.825 -13.248 -14.075 -14.157 -14.715 -15.382 -15.369 -15.885 -14.722 -14.247 -15.219 -8.805 -8.488 -8.546 -8.830 -7.849 -7.306 -6.027 -8.834 -9.977 -8.464 -7.560 -9.380 -9.454 -10.409 -11.494 -10.186 -12.329 -11.028 -12.095 -8.872 -7.926 -9.537 -10.144 -9.395 -9.624 -8.397 -8.293 -7.155 -7.395 -6.258 -6.156 -5.005 -5.130 -10.432 -11.630 17.38 16.87 17.98 21.53 21.60 24.17 0.00 22.29 19.28 22.57 0.00 15.70 23.98 25.97 23.31 0.00 26.02 28.35 32.64 43.18 51.29 0.00 57.25 62.75 0.00 0.00 55.06 0.00 0.00 25.66 25.00 27.52 0.00 25.75 33.69 39.19 24.55 23.49 21.44 0.00 20.44 22.28 21.70 26.69 18.84 27.09 24.85 25.47 22.33 22.03 24.80 0.00 25.89 25.90 27.28 25.30 33.32 30.60 31.42 31.10 35.89 0.00 27.64 23.69 81 ATOM 2488 N ATOM 2489 H ATOM 2490 CA ATOM 2491 CB ATOM 2492 CG ATOM 2493 CDI ATOM 2494 CD2 ATOM 2495 C ATOM 2496 0 ATOM 2497 N ATOM 2498 H ATOM 2499 CA ATOM 2500 CB ATOM 2501 CG ATOM 2502 CDI -ATOM 2503 CD2 ATOM 2504 CEI ATOM 2505 CE2 'ATOM 2506 CZ ATOM 2507 C ATOM 2508 0 ATOM 2509 N ATOM 2510 CD ATOM 2511 CA S* 25 ATOM 2512 CB ATOM 2513 CO ATOM 2514 C ATOM 2515 0 ATOM 2516 N ATOM 2517 H ATOM 2518 CA ATOM 2519 C ATOM 2520 0 ATOM 2521 N ATOM 2522 H ATOM 2523 CA 99 ATOM 2524 CB •ATOM 2525 CG ATOM 2526 CD2 ATOM 2527 NDI ATOM 2528 HDI ATOM 2529 CEI oATOM 2530 NE2 ATOM 2531 HE2 ATOM 2532 C ATOM 2533 0 ATOM 2534 OT ATOM 2535 OH2 ATOM 2536 HI ATOM 2537 H2 ATOM 2538 OH2 ATOM 2539 HI ATOM 2540 H2 ATOM 2541 OH2 ATOM 2542 HI ATOM 2543 H2 ATOM 2544 OH2 ATOM 2545 HI ATOM 2546 H2 ATOM 2547 OH2 ATOM 2548 HI ATOM 2549 H2 ATOM 2550 OH2 ATOM 2551 HI

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

LEU

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PHE

PRO

PRO

PRO

PRO

PRO

PRO

PRO

GLY

GLY

GLY

GLY

GLY

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

HIS

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

WAT

58.468 69.931 -10.000 58.337 70.072 -9.041 57.598 70.629 -10.934 56.310 71.032 -10.186 55.445 69.821 -9.832 54.671 70.119 -8.568 54.550 69.476 -11.022 58.422 71.858 -11.293 59.402 72.088 -10.612 58.287 72.708 -12.295 57.660 72.565 -13.041 59.210 73.839 -12.269 60.245 73.706 -13.407 61.399 72.857 -12.928 61.474 71.519 -13.260 62.416 73.423 -12.173 62.582 70.764 -12.892 63.512 72.653 -11.790 63.611 71.326 -12.167 58.367 75.031 -12.475 58.334 75.584 -13.558 57.638 75.512 -11.527 57.751 75.159 -10.125 56.710 76.609 -11.755 56.137 76.946 -10.380 57.161 76.376 -9.428 57.461 77.757 -12.427 58.588 78.123 -12.070 56.770 78.302 -13.431 55.816 78.096 -13.558 57.339 79.300 -14.327 58.024 78.691 -15.553 58.363 79.436 -16.458 58.258 77.372 -15.646 57.856 76.702 -15.043 59.038 76.818 -16.735 60.391 76.313 -16.275 61.057 77.377 -15.470 62.077 78.167 -15.913 60.694 77.798 -14.262 59.973 77.436 -13.710 61.438 78.828 -13.970 62.266 79.045 -14.963 62.923 79.771 -14.979 58.318 75.633 -17.302 58.804 75.085 -18.288 57.304 75.238 -16.718 57.131 53.937 -16.157 57.956 53.989 -16.611 56.715 53.157 -16.559 59.288 45.222 -12.720 59.678 44.463 -12.289 59.326 45.020 -13.638 61.365 66.988 -12.454 61.282 66.754 -11.566 61.920 66.336 -12.878 54.401 52.311 -15.488 53.455 52.320 -15.423 54.685 52.959 -14.831 52.948 45.165 -10.748 53.471 44.927 -9.991 52.622 46.039 -10.552 39.932 72.422 -0.681 40.131 72.039 0.168 24.40 0.00 31.95 27.67 25.95 26.52 24.92 36.21 44.83 36.07 0.00 33.57 32.22 33.80 32.31 39.98 33.77 40.60 36.46 32.19 29.45 29.88 27.11 31.83 27.59 24.71 37.62 38.17 37.83 0.00 40.55 39.74 40.77 40.90 0.00 41.51 43.86 47.48 46.94 50.29 0.00 47.33 49.11 0.00 41.65 44.03 41.54 21.86 0.00 0.00 24.45 0.00 0.00 18.38 0.00 0.00 26.12 0.00 0.00 22.53 0.00 0.00 41.66 0.00 82 ATOM 2552 H2 WAT ATOM 2553 OH2 WAT ATOM 2554 HI WAT ATOM 2555 H2 WAT ATOM 2556 OH2 WAT ATOM 2557 HI WAT ATOM 2558 H2 WAT ATOM 2559 OH2 WAT ATOM 2560 HI WAT ATOM 2561 H2 WAT ATOM 2562 OH2 WAT ATOM 2563 Hi WAT ATOM 2564 H2 WAT ATOM 2565 OH2 WAT 0 15 ATOM 2566 HI WAT 0 ATOM 2567 H2 WAT 0 0 ATOM 2568 OH2 WAT ATOM 2569 HI WAT 0 ATOM 2570 H2 WAT 2.0 ATOM 2571 OH2 WAT ATOM 2572 HI WAT ATOM 2573 H2 WAT ATOM 2574 OH2 WAT ATOM 2575 HI WAT 2 5 ATOM 2576 H2 WAT ATOM 2577 OH2 WAT ATOM 2578 HI WAT ATOM 2579 H2 WAT ATOM 2580 OH2 WAT ATOM 2581 Hi WAT ATOM 2582 H2 WAT ATOM 2583 OH2 WAT ATOM 2584 HI WAT ATOM 2585 H2 WAT 35 ATOM 2586 OH2 WAT ATOM 2587 HI WAT ATOM 2588 H2 WAT ATOM 2589 OH2 WAT ATOM 2590 HI WAT 40 ATOM 2591 H2 WAT ATOM 2592 OH2 WAT ATOM 2593 HI WAT ATOM 2594 H2 WAT ATOM 2595 OH2 WAT 45 ATOM 2596 HI WAT ATOM 2597 H2 WAT ATOM 2598 OH2 WAT ATOM 2599 HI WAT ATOM 2600 H2 WAT ATOM 2601 OH2 WAT ATOM 2602 HI WAT ATOM 2603 H2 WAT ATOM 2604 OH2 WAT ATOM 2605 HI WAT ATOM 2606 H2 WAT ATOM 2607 OH2 WAT ATOM 2608 HI WAT ATOM 2609 H2 WAT ATOM 2610 OH2 WAT ATOM 2611 HI WAT ATOM 2612 H2 WAT ATOM 2613 OH2 WAT ATOM 2614 HI WAT ATOM 2615 H2 WAT 261 39.184 71.954 262 40.595 65.620 262 40.213 65.976 262 39.866 65.614 263 59.703 63.723 263 59.734 63.118 263 59.203 63.239 264 57.975 70.486 264 57.886 69.546 264 58.580 70.685 265 49.889 74.051 265 49.381 73.658 265 49.717 74.986 266 55.224 73.467 266 56.050 73.568 266 55.324 73.889 267 57.220 72.666 267 57.189 73.255 267 56.964 71.837 268 35.858 66.670 268 36.152 66.629 268 35.860 67.587 269 48.789 71.281 269 47.897 71.644 269 49.355 71.928 270 59.440 63.444 270 59.959 62.711 270 58.513 63.193 271 48.923 44.941 271 48.905 44.016 271 49.386 44.932 272 44.435 59.093 272 44.989 59.185 272 44.990 58.678 273 53.920 52.043 273 54.603 52.710 273 54.232 51.362 274 62.871 68.183 274 62.632 67.292 274 63.467 68.466 275 46.942 70.044 275 47.058 69.784 275 47.406 69.414 276 50.771 63.408 276 50.872 64.350 276 50.541 63.304 277 45.555 65.749 277 46.291 65.423 277 44.772 65.498 278 57.066 46.788 278 56.509 46.154 278 56.806 47.667 279 50.499 65.012 279 50.711 64.860 279 51.009 65.791 280 42.398 64.363 280 41.614 64.685 280 42.691 65.121 281 47.580 50.658 281 47.146 51.280 281 48.027 50.065 282 40.354 58.806 282 39.834 59.191 282 41.237 58.816 -1.011 4.462 5.270 3.842 -5.839 -5.108 -6.512 -7.257 -7.232 -6.537 7.407 6.713 7.331 -12.629 -12.183 -13.488 -15.238 -16.021 -15.606 -2.607 -1.699 -2.844 -21.710 -21.837 -22.109 -17.067 -16.814 -17.097 -15.001 -14.762 -15.826 9.639 8.877 10.300 -8.038 -8.021 -8.608 -1.698 -1.909 -2.393 -23.874 -24.775 -23.326 17.889 17.946 16.967 12.972 12.436 12.518 -11.771 -12.204 -12.005 -29.411 -28.494 -29.571 -27.639 -28.072 -27.145 -26.241 -26.806 -26.836 -25.242 -25.936 -25.588 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 0.00 27.37 0.00 0.00 23.97 0.00 0.00 26.26 0.00 0.00 51.01 0.00 0.00 54.87 0.00 0.00 33.22 0.00 0.00 29.58 0.00 0.00 49.48 0.00 0.00 23.58 0.00 0.00 59.67 0.00 0.00 24.08 0.00 0.00 23.85 0.00 0.00 38.92 0.00 0.00 49.11 0.00 0.00 54.39 0.00 0.00 27.42 0.00 0.00 27.22 0.00 0.00 47.42 0.00 0.00 73.43 0.00 0.00 45.60 0.00 0.00 51.46 0.00 0.00 83 ATOM 2616 OH2 WAT 283 59.582 57.507 -22.297 1.00 50.06 ATOM 2617 HI WAT 283 59.205 58.060 -22.973 1.00 0.0 ATOM 2618 H2 WAT 283 60.461 57.302 -22.574 1.00 0.00 ATOM 2619 OH2 WAT 284 62.787 66.431 -21.929 1.00 64.67 ATOM 2620 HI WAT 284 62.786 67.378 -21.776 1.00 0.00 ATOM 2621 H2 WAT 284 63.310 66.298 -22.709 1.00 0.00 ATOM 2622 OH2 WAT 285 42.178 68.676 -21.635 1.00 47.92 ATOM 2623 HI WAT 285 42.226 68.152 -20.834 1.00 0.00 ATOM 2624 H2 WAT 285 41.528 68.220 -22.154 1.00 0.00 ATOM 2625 OH2 WAT 286 59.860 64.459 -20.626 1.00 45.90 ATOM 2626 HI WAT 286 59.529 63.613 -20.882 1.00 0.00 ATOM 2627 H2 WAT 286 60.034 64.935 -21.429 1.00 0.00 ATOM 2628 OH2 WAT 287 38.592 60.429 -19.380 1.00 45.23 ATOM 2629 HI WAT 287 37.765 59.995 -19.240 1.00 0.00 ATOM 2630 H2 WAT 287 38.339 61.266 -19.751 1.00 0.00 ATOM 2631 OH2 WAT 288 49.737 64.079 -19.712 1.00 31.09 ATOM 2632 HI WAT 288 49.889 64.551 -20.540 1.00 0.00 ATOM 2633 H2 WAT 288 48.791 63.991 -19.646 1.00 0.00 ATOM 2634 OH2 WAT 289 45.077 74.284 -19.985 1.00 58.31 ATOM 2635 HI WAT 289 44.803 75.186 -19.856 1.00 0.00 ATOM 2636 H2 WAT 289 45.225 73.984 -19.086 1.00 0.00 6 ATOM 2637 OH2 WAT 290 36.463 68.596 -18.372 1.00 41.38 ATOM 2638 HI WAT 290 36.206 68.878 -19.244 1.00 0.00 ATOM 2639 H2 WAT 290 37.302 69.021 -18.240 1.00 0.00 25 ATOM 2640 OH2 WAT 291 42.509 73.175 -18.360 1.00 30.40 ATOM 2641 HI WAT 291 42.018 73.868 -17.902 1.00 0.00 ATOM 2642 H2 WAT 291 41.926 72.928 -19.071 1.00 0.00 ATOM 2643 OH2 WAT 292 52.772 54.057 -17.864 1.00 34.00 ATOM 2644 HI WAT 292 52.675 54.050 -16.919 1.00 0.00 ATOM 2645 "2 WAT 292 53.709 54.139 -17.997 1.00 0.00 ATOM 2646 OH2 WAT 293 58.499 51.544 -17.264 1.00 39.19 ATOM 2647 HI WAT 293 58.896 50.712 -17.042 1.00 0.00 ATOM 2648 H2 WAT 293 59.231 52.121 -17.413 1.00 0.00 ATOM 2649 OH2 WAT 294 55.293 76.832 -15.365 1.00 77.96 o 35 ATOM 2650 HI WAT 294 55.586 76.689 -14.489 1.00 0.00 ATOM 2651 H2 WAT 294 55.894 76.271 -15.896 1.00 0.00 ATOM 2652 OH2 WAT 295 50.254 47.990 -11.950 1.00 34.08 ATOM 2653 HI WAT 295 49.709 48.063 -12.721 1.00 0.00 00 ATOM 2654 H2 WAT 295 49.755 47.316 -11.486 1.00 0.00 40 ATOM 2655 OH2 WAT 296 37.749 48.038 -8.897 1.00 50.16 ATOM 2656 HI WAT 296 36.805 48.072 -8.734 1.00 0.00 ATOM 2657 H2 WAT 296 37.815 47.302 -9.501 1.00 0.00 ATOM 2658 OH2 WAT 297 61.144 72.978 -8.832 1.00 30.80 ATOM 2659 Hi WAT 297 62.021 72.636 -8.821 1.00 0.00 ATOM 2660 H2 WAT 297 61.120 73.515 -8.053 1.00 .0.00 ATOM 2661 OH2 WAT 298 46.716 77.808 -7.102 1.00 36.58 ATOM 2662 HI WAT 298 47.000 78.075 -6.217 1.00 0.00 ATOM 2663 H2 WAT 298 47.380 78.176 -7.649 1.00 0.00 ATOM 2664 OH2 WAT 299 43.918 76.808 -6.081 1.00 35.53 ATOM 2665 HI WAT 299 43.850 77.750 -6.052 1.00 0.00 ATOM 2666 H2 WAT 299 44.809 76.650 -5.782 .00 0.00 ATOM 2667 OH2 WAT 300 60.882 61.010 -5.837 1.00 32.21 ATOM 2668 HI WAT 300 60.547 60.543 -5.092 1.00 0.00 ATOM 2669 H2 WAT 300 60.943 61.933 -5.683 1.00 0.00 ATOM 2670 OH2 WAT 301 56.234 77.147 -5.325 1.00 45.88 ATOM 2671 HI WAT 301 55.449 77.454 -4.859 1.00 0.00 ATOM 2672 H2 WAT 301 56.348 77.843 -5.971 1.00 0.00 ATOM 2673 OH2 WAT 302 43.603 47.976 -4.116 1.00 46.63 ATOM 2674 HI WAT 302 43.969 48.651 -4.654 1.00 0.00 ATOM 2675 H2 WAT 302 43.745 47.160 -4.601 1.00 0.00 ATOM 2676 OH2 WAT 303 41.712 55.660 -0.536 1.00 36.50 ATOM 2677 HI WAT 303 41.333 54.851 -0.150 1.00 0.00 ATOM 2678 H2 WAT 303 42.325 55.359 -2.193 1.00 0.00 ATOM 2679 OH2 WAT 304 51.729 51.156 -0.590 1.00 72.02 84 ATOM 2680 HI WAT 304 52.459 50.567 -0.423 1.00 0.00 ATOM 2681 H2 WAT 304 51.363 51.290 0.284 1.00 0.00 ATOM 2682 OH2 WAT 305 44.576 76.180 0.284 1.00 70.30 ATOM 2683 HI WAT 305 44.696 75.258 0.070 1.00 0.00 ATOM 2684 H2 WAT 305 44.178 76.553 -0.493 1.00 0.00 ATOM 2685 OH2 WAT 306 38.913 54.669 0.203 1.00 39.19 ATOM 2686 HI WAT 306 39.203 55.452 -0.255 1.00 0.00 ATOM 2687 H2 WAT 306 38.207 54.284 -0.306 1.00 0.00 ATOM 2688 OH2 WAT 307 42.134 58.338 1.150 1.00 29.79 ATOM 2689 HI WAT 307 41.312 57.982 1.511 1.00 0.00 ATOM 2690 H2 WAT 307 42.564 57.551 0.838 1.00 0.00 ATOM 2691 OH2 WAT 308 56.648 60.941 0.737 1.00 38.97 ATOM 2692 HI WAT 308 55.700 60.977 0.666 1.00 0.00 ATOM 2693 H2 WAT 308 56.928 61.839 0.583 1.00 0.00 15 ATOM 2694 OH2 WAT 309 45.030 48.554 9.192 1.00 48.96 ATOM 2695 HI WAT 309 44.943 47.651 9.474 1.00 0.00 ATOM 2696 H2 WAT 309 45.909 48.606 8.834 1.00 0.00 ATOM 2697 OH2 WAT 310 41.590 59.650 10.888 1.00 32.65 ATOM 2698 HI WAT 310 41.965 59.981 11.702 1.00 0.00 ATOM 2699 H2 WAT 310 41.171 60.430 10.534 1.00 0.00 ATOM 2700 OH2 WAT 311 30.678 62.812 10.599 1.00 48.30 ATOM 2701 HI WAT 311 31.519 63.059 10.280 1.00 0.00 ATOM 2702 H2 WAT 311 30.787 61.904 10.876 1.00 0.00 ATOM 2703 OH2 WAT 312 44.035 51.425 12.296 1.00 49.62 25 ATOM 2704 HI WAT 312 43.759 51.313 11.383 1.00 0.00 ATOM 2705 H2 WAT 312 43.889 50.557 12.653 1.00 0.00 ATOM 2706 OH2 WAT 313 53.084 69.483 13.408 1.00 45.11 ATOM 2707 HI WAT 313 53.666 68.732 13.409 1.00 0.00 ATOM 2708 H2 WAT 313 52.885 69.526 12.474 1.00 0.00 ATOM 2709 oH2 WAT 314 33.280 54.578 14.147 1.00 71.20 ATOM 2710 HI WAT 314 32.487 54.073 14.271 1.00 0.00 *4 ATOM 2711 H2 WAT 314 33.372 54.689 13.208 1.00 0.00 v 0. ATOM 2712 OH2 WAT 315 60.509 60.787 -18.332 1.00 30.28 .0:0 ATOM 2713 HI WAT 315 60.849 61.538 -18.810 1.00 0.00 35 ATOM 2714 H2 WAT 315 60.079 61.112 -17.565 1.00 0.00 ATOM 2715 OH2 WAT 316 36.436 51.291 10.254 1.00 49.82 ATOM 2716 HI WAT 316 36.114 50.786 9.515 1.00 0.00 S* ATOM 2717 H2 WAT 316 35.650 51.562 10.727 1.00 0.00 ATOM 2718 OH2 WAT 317 47.543 66.402 -29.189 1.00 49.95 40 ATOM 2719 HI WAT 317 46.808 66.985 -29.300 1.00 0.00 ATOM 2720 H2 WAT 317 48.149 66.611 -29.900 1.00 0.00 ATOM 2721 OH2 WAT 318 39.908 61.653 -21.569 1.00 55.32 4 ATOM 2722 HI WAT 318 39.811 62.356 -20.946 1.00 0.00 ATOM 2723 H2 WAT 318 40.435 61.009 -21.097 1.00 0.00 ATOM 2724 OH2 WAT 319 43.648 51.317 -20.053 1.00 55.22 ATOM 2725 HI WAT 319 44.217 51.632 -19.345 1.00 0.00 ATOM 2726 H2 WAT 319 42.798 51.245 -19.643 1.00 0.00 ATOM 2727 OH2 WAT 320 42.904 66.185 -19.404 1.00 43.44 ATOM 2728 HI WAT 320 43.844 66.182 -19.470 1.00 0.00 ATOM 2729 H2 WAT 320 42.797 66.244 -18.456 1.00 0.00 ATOM 2730 OH2 WAT 321 52.576 73.792 -19.312 I.00 47.88 ATOM 2731 HI WAT 321 52.248 73.438 -18.497 1.00 0.00 ATOM 2732 H2 WAT 321 51.924 73.486 -19.932 1.00 0.00 ATOM 2733 OH2 WAT 322 61.556 50.185 -16.806 1.00 60.71 ATOM 2734 HI WAT 322 60.747 49.697 -16.824 1.00 0.00 ATOM 2735 H2 WAT 322 62.307 49.596 -16.932 1.00 0.00 ATOM 2736 OH2 WAT 323 24.851 56.075 -3.153 1.00 38.05 ATOM 2737 HI WAT 323 25.114 55.419 -2.507 1.00 0.00 ATOM 2738 H2 WAT 323 25.365 55.812 -3.916 1.00 0.00 ATOM 2739 OH2 WAT 324 30.036 71.409 -2.744 1.00 45.31 ATOM 2740 HI WAT 324 29.383 70.770 -3.022 1.00 0.00 ATOM 2741 H2 WAT 324 29.785 71.599 -1.852 1.00 0.00 ATOM 2742 OH2 WAT 325 33.127 79.276 0.558 1.00 57.23 ATOM 2743 HI WAT 325 33.528 79.402 -0.294 1.00 0.00 ATOM 2744 H2 WAT 325 32.600 80.047 0.708 1.00 0.00 ATOM 2745 OH2 WAT 326 35.907 47.459 2.721 1.00 52.14 ATOM 2746 HI WAT 326 35.224 48.120 2.665 1.00 0.00 ATOM 2747 H2 WAT 326 36.753 47.864 2.620 1.00 0.00 ATOM 2748 OH2 WAT 327 54.215 72.016 6.546 1.00 52.02 ATOM 2749 Hi WAT 327 55.027 71.530 6.405 1.00 0.00 ATOM 2750 H2 WAT 327 54.516 72.859 6.883 1.00 0.00 ATOM 2751 OH2 WAT 328 41.269 52.487 1.122 1.00 51.87 ATOM 2752 HI WAT 328 40.694 51.781 1.440 1.00 0.00 ATOM 2753 H2 WAT 328 42.127 52.127 1.259 1.00 0.00 ATOM 2754 OH2 WAT 329 34.066 58.806 13.164 1.00 55.71 ATOM 2755 Hi WAT 329 34.724 59.474 13.292 1.00 0.00 ATOM 2756 H2 WAT 329 34.564 58.010 12.945 1.00 0.00 ATOM 2757 OH2 WAT 330 41.816 52.756 13.918 1.00 44.03 ATOM 2758 HI WAT 330 42.281 53.408 13.395 1.00 0.00 ATOM 2759 HZ WAT 330 42.525 52.335 14.395 1.00 0.00 ATOM 2760 OH2 WAT 331 39.370 62.098 14.302 1.00 54.70 ATOM 2761 HI WAT 331 38.736 62.661 14.727 1.00 0.00 ATOM 2762 H2 WAT 331 39.761 62.569 13.574 1.00 0.00 ATOM 2763 OH2 WAT 332 50.309 69.365 13.364 1.00 54.23 ATOM 2764 HI WAT 332 50.055 69.719 12.508 1.00 0.00 ATOM 2765 H2 WAT 332 51.043 69.910 13.645 1.00 0.00 ATOM 2766 OH2 WAT 333 40.562 55.451 15.773 1.00 61.39 ATOM 2767 HI WAT 333 39.723 55.080 16.041 1.00 0.00 ATOM 2768 H2 WAT 333 40.748 55.017 14.937 1.00 0.00 The following abbreviations are used in Table B.

"Atom type" refers to the element whose coordinates are measured. The first letter in the column defines the element.

30 Y, Z" crystallographically define the atomic position of the element measured.

S"B" is a thermal factor that measures movement of the atom around its atomic center.

Atoms numbered 153-158 (Lys-146) and 184-189

SQ

35 (Ser-149) were modeled as Ala residues.

Atoms numbered 1487-1534 and designated "Ald" in the column titled "Residue" are Cys-285 bound to the tetrapeptide aldehyde inhibitor.

Structure coordinates for ICE according to Table B may be modified from this original set by mathematical manipulation. Such manipulations include, but are not limited to, crystallographic permutations of the raw structure coordinates, fractionalization of the raw structure coordinates, integer additions or subtractions to sets of the raw structure coordinates, 86 inversion of the raw structure coordinates, and any combination of the above.

.9 4e *0 0 *600*9* 4, 0 *a 40 87 SEQUENCE LISTING GENERAL INFORMATION:

APPLICANT:

NAME: Vertex Pharmaceuticals, Inc.

STREET: 40 Allston Street CITY: Cambridge STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02139 TELEPHONE: 617-576-3111 TELEFAX: 617-576-2109 o (ii) TITLE OF INVENTION: CRYSTAL STRUCTURE AND MUTANTS OF S INTERLEUKIN-1 BETA CONVERTING ENZYME (iii) NUMBER OF SEQUENCES: 1 (iv) COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: PatentIn Release Version #1.30 (EPO) (vi) PRIOR APPLICATION DATA: APPLICATION NUMBER: US 08/261,582 FILING DATE: 17-JUN-1994 INFORMATION FOR SEQ ID NO: 1: SEQUENCE CHARACTERISTICS: LENGTH: 404 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: protein (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Met Ala Asp Lys Val Leu Lys Glu Lys Arg Lys Leu Phe Ile Arg Ser 1 5 10 Met Gly Glu Gly Thr Ile Asn Gly Leu Leu Asp Glu Leu Leu Gln Thr 25 88 Arg Val Leu Asn Lys Glu Giu ~O 50 a a

I

I

*0060a 0 a 0 90 a 0 9.

0* 0 0 0i Sa S a. a .0 0 a a I a a a.

Thr Gly Ser Asn Ala Ser Trp, 145 Arg Pro Leu Ser Lys 225 Giu Gin Leu Ser Val 50 Ala Tyr Tyr Pro Glu 130 Lys Thr Arg Gin Asp 210 Thr Gly Leu Lys Pro 290 Met Gin Leu Leu Gin 115 Gly Gin Arg Arg Asn 195 Met Ser le Asn Asp 275 Gly Asp Ala Ala Asn 100 Ala Asn Lys Leu Thr 180 Leu Thr Asp Cys Ala 260 Lys Val1 Lys Cys Gly Met Val Val Ser Ala 165 Gly Gly Thr Ser Gly 245 Ile Pro Val Thr Gin 70 Thr Gin Gin Lys Ala 150 Leu Ala .Tyr Giu Thr 230 Lys Phe Lys Trp Arg 55 Ile Leu Asp Asp Leu 135 Giu Ile Giu Ser Leu 215 Phe Lys Asn Val Phe 295 Met Giu 40 Ala Leu Cys Ile Gly Leu Ser Gin 105 Asn Pro 120 Cys Ser Ile Tyr Ile Cys Val Asp 185 Val Asp 200 Giu Ala Leu Val His Ser Met Leu 265 Ile Ile 280 Lys Asp Lys Ile Thr Ser 90 Gly Ala Leu Pro Asn 170 Ile Val Phe Phe Giu 250 Asn Ile Ser Val Asp Tyr 75 Al a Val1 Met Glu Ile 155 Giu Thr Lys Ala Met 235 Gin Thr Gin Val Lys Ser Ile Asp Leu Pro Giu 140 Met Giu Gly L~ys His 220 Ser Val Lys Ala Gly 300 Arg Val Cys Gin Ser Thr 125 Ala Asp Phe Met Asn 205 Arg His Pro Asn Cys 285 Val1 Giu Ile GlU Thr Ser 110 Ser Gin Lys Asp Thr 190 Leu Pro Gly Asp Cys 270 Arg Ser Asn Ala Pro Lys Glu Asp Ser Gly Phe Pro Ser Gly Arg Ile Ser Ser 160 Ser Ile 175 Met Leu Thr Ala Giu His Ile Arg 240 Ile Leu 255 Pro Ser Gly Asp Gly Asn Leu Ser Leu Pro Thr Thr Giu Glu Phe Giu Asp Asp Ala Ile Lys Lys 305 310 315 320 89 00 0 0 a 6 *0 0 a 00P o bea of~ His Val Ile Phe 370 Met Pro Lys 325 Arg Met Val Thr Asp His Gin Arg Giu 390 Phe Pro Giu Phe 375 Arg Aila Met 345 Aila Phe Thr Phe 330 Gly Cys Giu Leu Cys Ser Ser Gin Thr 395 Pro 335 Gly Giu Arg Tyr Asp Arg Giu Aia Leu 400

Claims (9)

1. An isolated interleukin-1 converting enzyme, wherein one or more of the amino acids in the active site or in the accessory binding site are replaced by one or more amino acids selected from the group consisting of naturally occurring amino acids, unnatural amino acids, selenocysteine and selenomethionine

2. The interleukin-lp converting enzyme according to claim 1, wherein a hydrophilic or hydrophobic amino acid residue in said active site or said accessory binding site is replaced.

3. The interleukin-lp converting enzyme 20 according to claim 1, wherein said active site amino acid is selected from the group consisting of amino acids 173, 176, 177, 178, 179, 180, 236, 237, 238, 239, 244, 248, 283, 284, 285, 290, 338, 339, 340, 341, 342, 343, 345, 348, 352, 381, and 383 of SEQ ID NO:. o: o

4. The interleukin-lP converting enzyme according to claim 1, wherein said accessory binding site amino acid is selected from the group consisting of amino acids 150, 151, 240, 259, 267, 268,. 274, 291, 292, 293, 294, 295, 296, 297, 317, 318, 319, 320, 321, 322, 323, 324, 325, 327, 334, 335, 367, 371, 374, 375, 9] 377, 378, 380, 382, 384, 386, 388, 389, 390, 391, 392, 393, 394, 395 and 396 of SEQ ID NO:1. The interleukin-l converting enzyme according to claim 1, wherein at least one cysteine amino acid is replaced by an amino acid selected from the group consisting of selenocysteine or selenomethionine.

6. The interleukin-1l converting enzyme according to claim 1, wherein at least one methionine amino acid is replaced by an amino acid selected from the group consisting of selenocysteine or selenomethionine.

7. The interleukin-l converting enzyme S.according to any one of claims 1 to 6, wherein said enzyme is in crystalline form. 20

8. The interleukin-lp converting enzyme according to claim 1, wherein said enzyme is characterized by increased stability to subunit dissociation. 25 9. The interleukin-10 converting enzyme according to claim 1, said enzyme having higher specific activity than the wild-type enzyme. The interleukin-13 converting enzyme according to claim 1, said enzyme having altered substrate specificity. 92

11- The use of an interleukin-l converting enzyme according to claim 1 to determine binding interactions between a chemical compound and the enzyme.

12. An isolated interleukin-l converting enzyme, wherein at least one amino acid residue on, at or near the surface of said enzyme is replaced, resulting in an altered surface charge of one or more charge units. DATED this 5 t h day of March 2001 Vertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN CO. S S S