EP1297175A2 - Methods and compounds for modulating nuclear receptor coactivator binding - Google Patents

Abstract

The present invention relates to methods and agonist/antagonist compounds for modulating nuclear receptor coactivator binding. The invention includes a method for identifying residues comprising a coactivator binding site for a nuclear receptor of interest. Also included is a method of identifying agonists and/or antagonists that bind to a coactivator binding site of a nuclear receptor of interest. Agonists and antagonists of coactivator binding to nuclear receptors also are provided. The invention is exemplified by identification and manipulation of the coactivator binding site of the thyroid receptor (TR), and compounds that bind to this sites. The methods can be applied to other nuclear receptors including RAR, RXR, PPAR, VDR, ER, GR, PR, MR, and AR.

Description

METHODS AND COMPOUNDS FOR MODULATING NUCLEAR RECEPTOR

COACTIVATOR BINDING

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and benefit of U.S. Application Number 09/609,361, filed on June 30, 2000, which is incorporated herein by reference in its entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This invention was supported in part by grants from the National Institutes of Health: Grant Nos. DK 51083, DK 51281, and P41-RR01081, the Sidney Kimmel Cancer Research Foundation, The Sandier Program in Basic Sciences, the UCSF Academic Senate, and from the Army of the United States: Grant No. AD3S#562. The Government of the United States of America may have certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to methods and compounds for modulating nuclear receptor coactivator binding.

BACKGROUND OF THE INVENTION

Cells contain receptors that can elicit a biological response by binding various molecules including proteins, hormones and/or drugs. Nuclear receptors represent a super family of proteins that are hormone/ligand-activated transcription factors that enhance or repress transcription in a cell type-, ligand- and promoter-dependent manner. The nuclear receptor family includes receptors for glucocorticoids (GRs), androgens (ARs), mineralocorticoids (MRs), progestins (PRs), estrogens (ERs), thyroid hormones (TRs), vitamin D (VDRs), retinoids (RARs and RXRs), peroxisomes (XPARs and PPARs) and icosanoids (IRs). The so-called "orphan receptors" for which ligands have not been identified are also part of the nuclear receptor superfamily, as they are structurally homologous to the classic nuclear receptors, such as steroid and thyroid receptors.

Although overall sequence conservation between nuclear receptors varies between different families of receptors, sequence conservation between functional regions, or modules, of the receptors is high. For example, nuclear receptors can be organized into functional modules comprising an N-terminal transcriptional activation domain, a central DNA binding domain (DBD), and a C-terminal ligand binding domain (LBD). The LBD of nuclear receptors represents a hormone/ligand-dependent molecular switch. Binding of hormone to a nuclear receptor's LBD changes its ability to modulate transcription of DNA, although they may have transcription-independent actions. Nuclear receptors also bind proteins, such as chaperone complexes, corepressors, or coactivators, that are involved in receptor function. Hormone binding by a nuclear receptor can increase or decrease binding affinity to these proteins, and can influence or mediate the multiple actions of the nuclear receptors on transcription. For example, nuclear receptors can stimulate transcription in response to hormone binding by recruiting coactivator proteins to promoters of responsive genes (Glass et al., Curr. Opin. Cell Biol. (1997) 9:222-32); and Horwitz et al, Mol. Endocrinol. (1996) 10:1167-77).

Coactivators of the pi 60 family mediate activity of a transcriptional activation domain, called AF2, that is part of the nuclear receptor's LBD. A few receptor mutants deficient in coactivator-dependent activation have been isolated (TR: CoUingwood et al. Proc. Natl. Acad. Sci. (1997) 94:248-253; VDR: Jurutka et al., J. Biol. Chem. (1997) 227:14592-14599, Masayama et al., Mol. Endocrinol. (1997) 11: 1507-1517; ER and RAR: Henttu et al, Mol. Cell Biol. (1997) 7:1832-1839). While these studies support the physiological relevance of the observed interaction, the structural and functional nature of the site to which coactivators bind has not been defined.

The medical importance of nuclear receptors is significant. They have been implicated in breast cancer, prostate cancer, cardiac arrhythmia, infertility, osteoporosis, hyperthyroidism, hypercholesterolemia, obesity and other conditions. However, limited treatments are available and current agonist/antagonist drugs used to target nuclear receptors are ligands that bind to the receptor's LBD buried deep within the receptor. Although additional targets on nuclear receptors are desired for drug development, the structural and functional basis of such sites, including the coactivator binding site, have not been fully described.

Accordingly, a need exists for identification and characterization of the coactivator binding sites of nuclear receptors, and molecules that affect their interaction with cellular coactivator proteins. This would provide a major new target for iterative drug design, synthesis, and selection. It also would be advantageous to devise methods and compositions for reducing the time required to discover compounds that target the coactivator binding site of nuclear receptors and administer them to organisms to modulate physiological processes regulated by nuclear receptors.

Relevant Literature

Wagner et al., (Nature (1995) 575:690-697) disclose the crystal structure of rat TR-alpha LBD. Various references disclose mutations in carboxyl-terminal helices of nuclear receptors (Henttu et al., supra; O'Donnell et al., Mol. Endocrinol. (1991) 5:94-99; Whitfield et al., Mol. Endocrinol. (1995) 9:1166-79; Saatcioglu et al., Mol. Cell Biol. (1997) i7:4687-95; CoUingwood et al, supra; Kamei et al., Cell (1996) 55:403-14). Hong et al. (Proc. Natl. Acad. Sci. USA (1996) 93(10):498-49452) and Hong et al. (Mol. Cell. Biol. (1997) 77:2735-2744) disclose cloning and expression of GRJP1 coactivator. Torchia et al, (Nature (1997) 357:677-84), Le Douarin et al., (EMBO J (1996) 75:6701-6715) and Heery et al. (Nature (1997) 357:733-736) disclose sequence alignment of various coactivator proteins showing a (SEQ ID NO: 1) LxxLL motif.

SUMMARY OF THE INVENTION

The present invention relates to identification and manipulation of the coactivator binding site of nuclear receptors. Identification of this site permits design and obtention of compounds that bind to the coactivator binding site of nuclear receptors and modulate coactivator binding to the receptor. The compounds include agonists and antagonists that modulate nuclear receptor activity by promoting (agonists) or blocking (antagonists) hormone-dependent coactivator binding to the receptor, particularly antagonists. The compounds of the invention can be receptor-, cell- and/or tissue-specific.

The present invention also includes protein cocrystals of nuclear receptors with a molecule bound to the coactivator binding site and methods for making them. The cocrystals provide means to obtain atomic modeling information of the specific amino acids and their atoms forming the coactivator binding site and that interact with molecules that bind to the site, such as coactivator. The cocrystals also provide modeling information regarding the coactivatoπnuclear receptor interaction, as well as the structure of coactivators bound thereto. The present invention further provides methods for identifying and designing small molecules that bind to the coactivator binding site using atomic models of nuclear receptors. The method involves modeling test compounds that fit spacially into a nuclear receptor coactivator binding site of interest using an atomic structural model comprising a nuclear receptor coactivator binding site or portion thereof, coactivator structure or portion thereof, screening the test compounds in a biological assay characterized by binding of a test compound to a nuclear receptor coactivator binding site, and identifying a test compound that modulates coactivator binding to the nuclear receptor.

The invention also includes compositions and methods for identifying coactivator binding sites of nuclear receptors. The methods involve examining the surface of a nuclear receptor of interest to identify residues that modulate coactivator binding. The residues can be identified by homology to the coactivator binding site of human TR described herein. Overlays and superpositioning with a three dimensional model of a nuclear receptor LBD, or a portion thereof that contains a coactivator binding site, also can be used for this purpose. Additionally, alignment and/or modeling can be used as a guide for the placement of mutations on the LBD surface to characterize the nature of the site in the context of a cell.

Also provided is a method of modulating the activity of a nuclear receptor. The method can be in vitro or in vivo. The method comprises administering, in vitro or in vivo, a sufficient amount of a compound that binds to the coactivator binding site. Preferred compounds bind to the site with greater affinity than coactivator proteins found in a cell of interest. Binding at this site, the compound can compete for binding of coactivator proteins, thereby inhibiting gene transcription, or in some cases promoting it, even when hormone is or is not bound. The structures of the bound coactivator NR box helices from GRIPl and SRC1 bound to various nuclear receptors, such as ER, TR, and PPAR, have been analyzed and have been shown to have similar backbone conformations. It is therefore believed that organic scaffolds that mimic this helix geometry could serve as a general basis for combinatorial libraries targeted to all NR:GRIP-1 complexes. These scaffolds and libraries would serve to affect the interactions of nuclear receptors and their coactivators.

The invention further includes a method for identifying an agonist or antagonist of coactivator binding to a nuclear receptor. The method comprises providing the atomic coordinates comprising a nuclear receptor coactivator binding site or portion thereof to a computerized or mechanical modeling system; and/or providing the atomic coordinates comprising a molecule or molecules bound to the nuclear receptor coactivator binding site or portion thereof to a computerized or mechanical modeling system; modeling compounds or libraries of compounds which fit spatially into the nuclear receptor coactivator binding site; and identifying in an assay for nuclear receptor activity a compound or compounds that increases or decreases activity of the nuclear receptor through binding the coactivator binding site.

Also provided is a machine-readable data storage medium with information for constructing and manipulating an atomic model comprising a coactivator binding site or portion thereof. The medium comprises a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex for a nuclear receptor coactivator binding site.

Also provided is a method of identifying a compound that selectively modulates the activity of one type of nuclear receptor compared to other nuclear receptors. The method is exemplified by modeling test compounds, combinatorial libraries, and probe molecules that have a spatial and/or electrostatic preference for a nuclear receptor coactivator binding site of interest using an atomic structural model of a nuclear receptor coactivator binding site, selecting a compound that interacts with one or more aspects of the coactivator binding site unique in the context of that site, and identifying in an assay for coactivator binding activity a compound that selectively binds to the coactivator binding site compared to other nuclear receptors. The unique features involved in receptor-selective coactivator binding can be identified by comparing atomic models of different receptors or isoforms of the same type of receptor, and by comparing features of molecules that show preferential complementarity for different receptors or isoforms of the same type of receptor.

The invention further provides a set of scaffolds and virtual libraries derived from those scaffolds. These scaffolds have been designed to fit the coactivator binding site and are potential modulators of the interaction between the interaction of a coactivator and the coactivator binding site of any nuclear receptor. Also provided are covalently conformationally constrained peptides that function as modulators of the interaction between a coactivator and a coactivator binding site of any nuclear receptor.

The invention further includes an assay suitable for screening large numbers of compounds to determine which compounds modulate the binding of coactivators to nuclear receptors.

The invention finds use in the selection and characterization of peptide, peptidomimetic, as well as other small molecule compounds, such as small organic molecules, identified by the methods of the invention, particularly new lead compounds, scaffolds and combinatorial libraries useful in treating nuclear receptor-based disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the specific effects of mutations on hTRβl transcriptional activation in HeLa cells and correlation with effects on binding to GST-GRIP 1. T₃ dependent activation of transcription of a reporter gene, expressed as the percentage of WT is plotted for each mutant. GST-GRIPl binding, analyzed by autoradiography after separation using 10% SDS-PAGE, was also expressed as the percentage of WT and plotted for each mutant. The GST-GRIPl used included GRIPl amino acids 721-1121; the same results were obtained using a GST-GRDPl construct including GRIPl amino acids 563-1121 (data not shown).

Figure 2 shows that overexpression of full-length GRIPl rescues loss of transcriptional activation by hTRβl mutants. Indicated amounts of the expression vector for full-length GRIPl, pSG5-GRD?l, is included in the cotransfections, which otherwise are performed as in Figure 1. The WT or different representative hTRβl mutants are indicated.

Figure 3 shows specific hERα surface mutants cause loss of transcriptional activation in HeLa cells in parallel with their loss of in vitro GRIPl binding. The fold E activation, expressed as the percentage of WT, and the phosphorimager quantitation of in vitro binding of [³⁵S]-labeled hERα WT and mutants to GST-GRIPl (GRIPl amino acids 721-1121) also expressed as the percentage of WT is plotted for each mutant.

Figure 4 shows a plot of the fold E₂ activation observed when the indicated amounts of the full-length GRIPl expression vector, pSG5-GRIPl, are added to the co- transfection experiment, which otherwise is performed as for Figure 3. The WT or different hERα mutants are indicated. The data represent the averages of three independent experiments, with standard deviations less than 10%.

Figure 5 shows a CPK model of the TRα-LBD, indicating the LBD surface locations of mutations made in the full-length hTRβl. Mutated residues having no effect on GRIPl binding or effect on activation in HeLa cells are shaded gray. Mutated residues with diminished GRIPl and SRC-la binding and diminished activation in HeLa cells are colored to reflect chemical properties of the residues: red, blue (purple), and green indicate acidic, basic, and hydrophobic residues, respectively. The main chain structures of the TRα- and TRβ-LBDs are the same (data not shown).

Figure 6 shows sequence alignment of amino acid residues of members of the pi 60 coactivator family. Single amino acid designations are used. Members of the pi 60 coactivator family interact with the nuclear receptors through conserved (SEQ ID NO: 1) LxxLL motifs.

Figure 7 shows binding affinity assays of GST-GRIPl constructs with NR- boxes 1, 2, and/or 3 and their interaction with TR LBD. GRIP-1 NR boxes 1,2 and 3 interact differently with TRβ LBD. Single letter designations are used for the amino acids.

Figure 8 shows binding affinity assays of GST-GRIPl constructs with NR- boxes 1, 2, and/or 3 and their interaction with TR and GR LBDs. TR and GR differ in their interactions with GRIP-1.

Figure 9 shows binding affinity assays for NR-box 2- and 3-peptides and GRIPl and their interaction with TR LBD. NR box 2- and 3 -containing peptides reproduce the affinity and specificity of the NR interaction domain.

Figure 10 shows binding affinity assays for NR-box 2- and 3-peptides and their interaction with TR LBD. Sequence adjacent to the (SEQ ID NO: 1) LxxLL motif modulate the affinity of NR-box-TRβ LBD interactions.

Figure 11 shows binding affinity assays for mutant GRIPl and NR-box 2- and 3-peptides and their interaction with TR LBD. The individual leucine residues of the (SEQ ID NO: 1) LxxLL motif are crucial for binding of the GRIP-1 NR interaction domain to TRβ LBD. Figure 12 shows the contents of the asymmetric unit of the crystallized hTRβ LBD:GRIP1 NR-box 2 peptide complex. The crystal lattice consists of a repeating unit containing a 2:2 complex of hTR LBD and GRIPl site 2 peptide. Positions of the two GRIPl site 2 peptides are boxed, in green (sitel), and red (site 2), with the peptides drawn as a C-alpha trace. The two NCS related monomers of the hTR LBD are shown as a secondary structure ribbon drawing, with monomer 1 in light grey, and monomer 2 in dark grey. The side chains of the hydrophobic residues 1689, L690, L693, L694 of the GRIPl NR-box 2 peptides are drawn to emphasize those interactions observed in both bound peptides.

Figure 13 shows a ribbon diagram depicting the interaction of the GRIPl NR-box 2 peptide with the hTRβ LBD. The GRIPl NR-box 2 peptide (dark grey) forms three turns of α-helix, and binds the hTR LBD (light gray) in a hydrophobic cleft defined by helices H3, H4, H5, and H12. Portions of the hTRβ LBD, and the neighboring monomer, are omitted for clarity.

Figure 14 shows interface between the GRIPl NR-box 2 peptide and the hTRβ LBD. Side chains of residues of the hTRβ LBD within 4.5A of the GRIP-1 NR-box 2 peptide are labeled. The color of the individual side chains reflects the chemical nature of the residue: acidic residues are red, basic residue are blue, aliphatic residues are green, aromatic residues are brown, and polar residues are orange. The peptide is depicted as a C- alpha trace with the side chains of (SEQ ID NO: 2) ILxxLL motif shown explicitly.

Figure 15 shows residues in the hTRβ LBD that are necessary for transactivation. The transactivation mutations are mapped onto the interface between the GRIPl NR-box 2 peptide and the hTRβ LBD.

Figure 16 shows molecular surface of the hTR LBD. The side chains of the leucines resides fit within a hydrophobic groove formed from helices H3, H5, and H12, while the side chain of the non-conserved isoleucine residue packs against the outside edge of the groove. The remainder of the peptide is shown as main chain.

Figure 17 shows complementarity between the (SEQ ID NO: 1) LxxLL motif and the surface of the hTR LBD. The side chains of the (SEQ ID NO: 2) ILxxLL motif are shown in a CPK representation, with the main chain of the peptide drawn as a C- alpha trace. The three leucince residues fit into pockets of the coactivator binding site of the hTRβ LBD, depicted as mesh, while the isoleucine residue rests on the edge of the site's cleft.

Figure 18 shows the coactivator binding site cleft, one side of which is formed by conformationally hormone-responsive residues. On the left is a view of the TR- LBD molecular surface showing the concave surfaces in gray. The cavity is shown at the center of the figure. On the right is shown a CPK model of the TR-LBD, overlaid with a molecular surface view, which is restricted to a 12A radius of the hydrophobic cavity. Mutated residues of the coactivator binding site that are hormone-insensitive (V284, K288, 1302 and K306) are located on one side of the cleft and are colored yellow. Mutated CBS residues likely undergo a conformational change upon hormone binding (L454 and E457) are located on the opposite side of the cleft and are colored red.

Figure 19 shows alignment of amino acid sequences (single letter amino acid designations) containing residues that form the coactivator binding sites of several nuclear receptors. The boxes represent residues of alpha-helix (H3, H4, H5, H6 and H12); lower case letters "h" and "q" represent hydrophobic and polar residues, respectively.

Figure 20 shows a table of sequences and circular dichroism data for 9 peptides designed to fit tightly to the coactivator binding site. These data reveal that TG17 is highly helical relative to the others.

Figure 21 shows the relative competitive abilities of the 9 peptides in blocking the binding of a GRIPl NR box 2 peptide to the binding site of hTRbeta.

Figure 22 shows the ability of TG17 to block the binding of GRIPl to the LBD of hTRbeta.

Figure 23 shows structural families of scaffolds from database searches. Substituent attachment points are indicated with R groups.

Figure 24 shows the manual optimization of an exemplary docked scaffold to improve fit, atom economy, and alignment of substituents into sub-pockets within the coactivator binding site.

Figure 25 shows the amino acid sequence and chemical structure of native GRIPl. In addition, an IC 50 value is shown, reflecting the ability of native GRIP 1 to competitively inhibit the interaction of hTR and GRIPl. Figure 26 shows the amino acid sequence and chemical structure of TG 17. In addition, an IC 50 value is shown, reflecting the ability of TG17 to competitively inhibit the interaction of hTR and GRIPl.

Figure 27 shows the amino acid sequence and chemical structure of TG 14. In addition, an IC 50 value is shown, reflecting the ability of TG14 to competitively inhibit the interaction of hTR and GRIPl.

Figure 28 shows the amino acid sequence and chemical structure of TG 15. In addition, an IC 50 value is shown, reflecting the ability of TGI 5 to competitively inhibit the interaction of hTR and GRIPl.

Figure 29 shows the amino acid sequence and chemical structure of TG 13. In addition, an IC 50 value is shown, reflecting the ability of TG13 to competitively inhibit the interaction of hTR and GRIPl.

Figure 30 shows the amino acid sequence and chemical structure of TG 16. In addition, an IC 50 value is shown, reflecting the ability of TG16 to competitively inhibit the interaction of hTR and GRIPl.

Figure 31 shows the amino acid sequence and chemical structure of TG 8. In addition, an IC 50 value is shown, reflecting the ability of TG8 to competitively inhibit the interaction of hTR and GRIPl.

Figure 32 shows the amino acid sequence and chemical structure of TG3FL. In addition, an IC 50 value is shown, reflecting the ability of TG3FL to competitively inhibit the interaction of hTR and GRIPl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods and compositions for identifying compounds that modulate nuclear receptor activity. The compounds can be nuclear receptor agonists or antagonists that bind to the coactivator binding site (and that act as mimetics to the coactivator in this regard), and promote (agonists) or block (antagonists) binding of the coactivator to the target nuclear receptor. Compounds that bind to the coactivator binding site also are provided. The compounds can be natural or synthetic. Preferred compounds are small organic molecules, peptides and peptidomimetics (e.g., cyclic peptides, peptide analogs, or constrained peptides). As described in the Examples, mutagenesis and coactivator binding studies, coupled with analysis of atomic models derived from cocrystals, reveals for the first time a previously unknown structure for nuclear receptors, the coactivator binding site. By "coactivator binding site" is intended a structural segment or segments of nuclear receptor polypeptide chain folded in such a way so as to give the proper geometry and amino acid residue conformation for binding a coactivator. This is the physical arrangement of protein atoms in three-dimensional space forming a coactivator binding site pocket or cavity. Residues forming the site are amino acids corresponding to (i.e., the same as or equivalent to) human TR residues of C-terminal helix 3 (Ile280, Thr281, Val283, Val284, Ala287, and Lys288), helix 4 (Phe293), helix 5 (Gln301, He302, Leu305, Lys306), helix 6 (Cys309), and helix 12 (Leu454, Glu457, Val458 and Phe459). The coactivator binding site is highly conserved among the nuclear receptor super family (Figure 19). Thus, this site corresponds to a surprisingly small cluster of residues on the surface of the LBD that form a prominent hydrophobic cleft. The hydrophobic cleft is formed by hydrophobic residues corresponding to human TR residues of C-terminal helix 3 (He280, Val283, Val284, and Ala287), helix 4 (Phe293), helix 5 (He302 and Leu305), helix 6 (Cys309), and helix 12 (Leu454, Val458 and Phe459). The hydrophobic cleft of the coactivator binding site also is highly conserved among the nuclear receptor super family (Figure 19).

The invention also includes compositions and methods for identifying coactivator binding sites of nuclear receptors. The methods involve examining the surface of a nuclear receptor of interest to identify residues and contiguous peptide sequences that modulate coactivator binding. The residues and contiguous peptide sequences can be identified by homology to the coactivator binding site or by alignment of consensus sequences found in human TR described herein. A preferred method is alignment with the residues or conserved peptide sequences of any nuclear receptor corresponding to (i.e., equivalent to) human TR residues of the C-terminal helix 3 (Ue280, Thr281, Val283, Val284, Ala287, and Lys288), helix 4 (Phe293), helix 5 (Gln301, He302, Leu305, Lys306), helix 6 (Cys309), and helix 12 (Pro453, Leu454, Glu457, Val458 and Phe459). Overlays and superpositioning with a three-dimensional model of a'nuclear receptor LBD, or a portion thereof that contains a coactivator binding site, also can be used for this purpose. For example, three-dimensional structures of TR, RAR, RXR and ER LBDs can be used for this purpose. For example, nuclear receptors identifiable by homology alignment include normal nuclear receptors or proteins structurally related to nuclear receptors found in humans, natural mutants of nuclear receptors found in humans, normal or mutant receptors found in animals, as well as non-mammalian organisms such as pests or infectious organisms, or viruses.

Alignment and/or modeling also can be used as a guide for the placement of mutations on the LBD surface to characterize the nature of the site in the context of a cell. Selected residues are mutated to preserve global receptor structure and solubility. To destroy the coactivator binding interaction, preferred mutations are of hydrophobic residues to charged residues (e.g., Arg, Lys, or Glu) on the basis that bulky, surface charged residues might disrupt coactivator binding, yet preserve global receptor structure and solubility, and of hydrogen bonding residues to alanine on the basis that such a mutation will preserve the global fold and local binding site shape, but alter the electrostatic components of coactivator binding. Mutants can be tested for coactivator binding as well as the relative change in strength of the binding interaction. Ligand-dependent coactivator interaction assays also can be tested for this purpose, such as those described herein.

Compounds that bind to the coactivator binding site of nuclear receptors can be identified by computational modeling and design and/or screening. For example, coactivator agonists or antagonists can be identified by providing atomic coordinates comprising a nuclear receptor coactivator binding site or portion thereof to a computerized or mechanical modeling system, modeling them, and identifying compounds that fit spatially into the coactivator binding site. By a "portion thereof is intended the atomic coordinates corresponding to a sufficient number of residues or their atoms of the coactivator binding site that interact with a compound capable of binding to the site. This includes receptor residues having an atom within 4.5A of a bound compound or fragment thereof. For instance, human TR residues V284, Phe293, He302, Leu305 and Leu454 contain side chain atoms that are within 4.5A, and interact with, hydrophobic residues of a (SEQ ID NO: 1) LxxLL motif of an NR-box 2 coactivator peptide. As another example, an atomic structural model utilized for modeling and/or screening of compounds that bind to the coactivator binding site may include a portion of atomic coordinates of amino acid residues corresponding to the site composed of residues of human thyroid receptor selected from Val284, Lys288, Ile302, Lys306, Leu454 and Glu457, or their structural and functional equivalents found in other receptors. Thus, for example, the atomic coordinates provided to the modeling system can contain atoms of the nuclear receptor LBD, part of the LBD such as atoms corresponding to the coactivator binding site or a subset of atoms useful in the modeling and design of compounds that bind to a coactivator binding site. It is also possible to identify components of the coactivator that are important for binding to nuclear receptors and to design molecules that will match those criteria. Programs that users skilled in the art would employ to perform such de novo design include programs such as LUDI, Leapfrog, Invention, and Hook.

The atomic coordinates of a compound that fits into the coactivator binding site also can be used for modeling to identify compounds or fragments that bind the site. By "modeling" is intended quantitative and qualitative analysis of molecular structure/function based on atomic structural information and receptor-coactivator agonists/antagonists interaction models. This includes conventional numeric-based molecular dynamic and energy minimization models, interactive computer graphic models, modified molecular mechanics models, distance geometry and other structure-based constraint models, as well as mechanical modeling. Modeling is preferably performed using a computer and may be further optimized using known methods. By "fits spatially" is intended that the three- dimensional structure of a compound is accommodated geometrically by a cavity or pocket of a nuclear receptor coactivator binding site

Compounds of particular interest fit spatially, preferentially, and/or electrostatically into the coactivator binding site. By "fits spatially and preferentially" it is intended that a compound possesses a three-dimensional structure and conformation for selectively interacting with a nuclear receptor coactivator binding site. By "fits electrostatically" it is intended that a compound possesses a three-dimensional structure and conformation that matches the electrostatics of the binding site. Compounds that fit spatially and preferentially into the coactivator binding site interact with amino acid residues forming the primarily hydrophobic cleft of this site. In particular, the primarily hydrophobic cleft of the coactivator binding site comprises a small cluster of hydrophobic residues. Compounds that fit electrostatically into the coactivator binding site interact with polar or hydrogen bonding groups within the site. The site also contains polar or charged residues at its periphery. The present invention also includes a method for identifying a compound capable of selectively modulating coactivator binding to different nuclear receptors. The method comprises the steps of modeling test compounds that fit spatially and/or electrostatically and preferentially into the coactivator binding site of a particular nuclear receptor of interest using atomic structural models of the nuclear receptors, choosing compounds that exhibit preferential modeling scores to the receptor of interest, screening the test compounds in a biological assay for nuclear receptor activity characterized by preferential binding of a test compound to the coactivator binding site of a nuclear receptor, and identifying a test compound that selectively modulates the activity of a nuclear receptor. Such receptor-specific compounds are selected that exploit differences between the coactivator binding sites of one type of receptor versus a second type of receptor, such as the differences depicted in Figure 19.

Sequence and structural comparisons, as well as evidence of differential specificity for coactivator binding to different nuclear receptors such as TR, GR, and ER, reveal that minor differences between the receptors, such as found in helix 12, are likely to influence the specificity of a coactivator for different types of nuclear receptors.

Coactivators bound to different nuclear receptors have been shown to have similar alpha-helical conformations in the bound and unbound states. The recognition that the helical geometry of the coactivator NR box remains constant during binding even though each coactivator binding site of the nuclear receptors is different allows for the targeting of all nuclear receptors with the same scaffolds and libraries rather than designing a separate scaffold or library for each nuclear receptor. The design of the compounds, including peptides, peptidomimetics and small molecules is based on this helical coactivator structure. The individual compounds that will bind each nuclear receptor will vary, but the general structure (i.e., the scaffold) will remain the same.

Stabilized α-helical peptides, often utilizing macrolactams formed by the side chains of lysine and glutamic acid or aspartic acid in an i to i+3, i to i+4, or i to i+1 relationship, have been applied with some success to dissect the function of peptide hormone receptors. A series of macrolactam GRIP 1 NR box compounds were synthesized by solid phase peptide synthesis using the Fmoc synthesis strategy with orthogonal protection of the relevant lactam precursor side chains.

Thus this invention also is applicable to generating new compounds that distinguish nuclear receptor isoforms. This can facilitate generation of either tissue-specific or function-specific compounds. For instance, GR subfamily members have usually one receptor encoded by a single gene, although there are exceptions. For example, there are two PR isoforms, A and B, translated from the same mRNA by alternate initiation from different AUG codons. There are two GR forms, one of which does not bind ligand. This method is especially applicable to the TR subfamily which usually has several receptors that are encoded by at least two (TR: α, β) or three (RAR, RXR, and PPAR: α, β, γ) genes or have alternate RNA splicing.

The receptor-specific compounds of the invention preferably interact differently with conformationally constrained residues of the coactivator binding site that are conserved among one type of receptor compared to a second type of receptor. "Conformationally constrained" is intended to refer to the three-dimensional structure of a chemical or moiety thereof having certain rotations about its bonds fixed by various local geometric and physical-chemical constraints. Conformationally constrained structural features of a coactivator binding site include residues that have their natural flexible conformations fixed by various geometric and physical-chemical constraints, such as local backbone, local side chain, and topological constraints. These types of constraints are exploited to restrict positioning of atoms involved in receptor-coactivator recognition and binding.

For instance, comparison of sequences of the GR and TR coactivator interaction surface shows a highly negatively charged sequence at the C-terminal end of TR helix 12 (E460 and D461) that is neutral in the equivalent positions in GR helix 12 (GR residues T788 and N759, corresponding to TR residue positions 460 and 461, as depicted in Figure 19). As described in the Examples, the cocrystal of the hTR§ LBD complexed with the GRIPl NR-box 2 peptide shows that TR residues E460 and D461 interact with positively charged residues of the NR-box 2 peptide. Also, when comparing the RAR LBD structure to that of the TR LBD, conformation of helix 12 differs slightly, whereas helices 3, 4, 5 and 6 are substantially the same. Thus, differences in helix 12, particularly charge differences at the C-terminal end of the helix, may modulate preferential interaction of TR for NR-box 2 containing coactivators. As further demonstrated in the Examples, TR and GR differ in their specificity for different NR-boxes containing the conserved (SEQ ID NO: 1) LxxLL motif found in members of the pl60 family of coactivator proteins. As also demonstrated in the Examples, GR but not TR is able to interact with peptides containing the hydrophobic interaction motifs of ρ53 (SEQ ID NO: 3; FxxLW) and VP16 (SEQ ID NO: 4; FxxAL). Thus, TR exhibits preferential interaction with NR-box peptides comprising the (SEQ ID NO: 1) LxxLL motif, but GR does not discriminate and can bind peptides containing a generic amphipathic helix motif. Accordingly, these real differences among the various nuclear receptors can be exploited in the identification and design of compounds that modulate coactivator binding to one nuclear receptor compared to another.

For modeling, docking algorithms and computer programs that employ them can be used to identify compounds that fit into the coactivator binding site. For example, docking programs can be used to predict how a small molecule of interest can interact with the nuclear receptor coactivator binding site and to rank these existing compounds by estimated binding interactions. Molecules or scaffolds for combinatorial libraries that are potentially new chemical entities can also be built de novo to fit inside the coactivator binding site, by arranging chemical fragments that complement the coactivator binding site to optimize intermolecular interactions. By scaffolds is meant the portion of the compounds in a library that remains constant in all the compounds. It is the molecule that is used to build a library. A substituent is a variable, pendant group that is attached to the scaffold to form a compound in the library. By combinatorial library is meant a collection of compounds built by variation of substituents on a common scaffold. The combinatorial libraries are useful in both the discovery phase (for identifying lead compounds) and in the development phase (for optimizing certain properties).

Scaffolds for combinatorial libraries can be designed to deliver substitutents to subpockets in the coactivator binding site. Substituents at positions in a combinatorial library built from these scaffolds can be selected to optimize interaction with a binding site structure. This design approach has been made possible by identification of the coactivator binding site structure. Thus, the principles of molecular recognition can now be used to design a compound which is complementary to the structure of this site. Compounds fitting the coactivator binding site serve as a starting point for an iterative design, synthesis and test cycle in which new compounds are selected and optimized for desired properties including affinity, efficacy, and selectivity. For example, the compounds can be subjected to additional modification, such as replacement and/or addition of R-group substituents of a core structure identified for a particular class of binding compounds, modeling and/or activity screening if desired, and then subjected to additional rounds of testing. Computationally small molecule databases can be screened for chemical entities or compounds that can bind in whole, or in part, to a nuclear receptor coactivator binding site of interest. In this screening, the quality of fit of such entities or compounds to the binding site may be judged by shape complementarity (DesJalais et al., J. Med. Chem. (1988) 37:722-729) or by estimated interaction energy (Meng et al., J. Comp. Chem. (1992) 73:505-524), or by combinations of such scoring schemes. The molecule databases include any virtual or physical database, such as electronic and physical compound library databases, and are preferably used in developing compounds and virtual combinatorial libraries that modulate coactivator binding. Libraries can consist of, for example, information regarding small organic molecules, peptides or peptidomimetics.

Compounds can be rationally designed by exploiting available structural and functional information by gaining an understanding of the quantitative structure-activity relationship (QSAR) from known ligands such as the bound GRIPl structure, or from data gained from assaying libraries. For example, a library of conformationally restricted peptides or other compounds could be utilized. The basis of such a peptide library is described below. One can use this understanding to design new compound libraries, particularly, focused libraries having chemical diversity of one or more particular groups of a core structure, and incorporating any structural data into that iterative design process. For example, one skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with the coactivator binding site of a nuclear receptor of interest. This process may begin by visual inspection of, for example, the coactivator binding site on the computer screen. Selected fragments or chemical entities may then be positioned manually or by using programs into all or part of the site. Docking may be accomplished using software such as Quanta and Sybyl, followed by energy minimization and molecular dynamics with standard molecular mechanics force-fields, such as CHARMM and AMBER.

For example, compounds and/or fragments can be designed to fill up the hydrophobic cleft, the pocket deep within the cleft, the upper end of the site, and/or the lower end of the site. Residues comprising a coactivator binding site, when defined by the user as those residues having an atom within 4.5 A of an atom of a bound chemical entity, can be modeled to look for energetic contributions and interaction with the bound chemical entity. For example, a compound or fragment can be designed to contain hydrophobic groups that interact with hydrophobic residues of the coactivator binding site. As described in the examples, human TR residues V284, Phe293, Ile302, Leu305 and Leu454 contain side chain atoms that are within 4.5A, and interact with, hydrophobic residues of a (SEQ ID NO: 1) LxxLL motif of an NR-box 2 coactivator peptide. Thus, for example, peptides and/or peptide mimetics having a hxxhh motif, where "h" is a hydrophobic residue and x is any residue, can be constructed. Small organic molecules that mimic one or more of these particular interactions also can be designed, for example, by including one or more R- groups that are hydrophobic and fit into the site.

Specialized computer programs may also assist in the process of selecting chemical entity fragments or whole compounds. These include: GRID (Goodford, J. Med. Chem. (1985) 25:849-857; available from Oxford University, Oxford, UK); MCSS (Miranker et al., Proteins: Structure, Function and Genetics, (1991) 77:29-34; available from Molecular Simulations, Burlington, MA); AUTODOCK (Goodsell et al, Proteins: Structure, Function and Genetics (1990) 5:195-202; available from Scripps Research Institute, La Jolla, CA); and DOCK (Kuntz et al, J. Mol. Biol (1982) 767:269-288; available from University of California, San Francisco, CA).

Additional commercially available computer databases for small molecular compounds include Cambridge Structural Database and Fine Chemical Database (Rusinko, Chem. Des. Auto. News (1993) 5:44-47), CMC (Comprehensive Medicinal Chemistry), ACD (Available Chemicals Directory), and MDDR (Molecular Design Drug Registry).

Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound. Assembly may be preceded by visual inspection of the relationship of the fragments' to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of a nuclear receptor. This can be followed by manual model building using software such as Quanta or Sybyl.

Useful programs to aid one of skill in the art in connecting and/or further developing the individual chemical entities, fragments or scaffolds include: CAVEAT (Bartlett et al., "CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules", In: Molecular Recognition in Chemical and Biological Problems", Special Pub., Royal Chem. Soc. (1989) 75:182-196; CAVEAT is available from the University of California, Berkeley, CA); COMBBUTLD (Roe, D. C. and I. D. Kuntz (1995) 9(3): 269-82.). 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, CA; reviewed in Martin, J. Med. Chem. (1992) 35:2145-2154); and HOOK (available from Molecular Simulations, Burlington, MA).

In addition to building a compound in a step-wise fashion, one fragment or chemical entity at a time as described above, compounds that bind to a coactivator binding site of interest also may be designed as a whole or de novo using either an empty coactivator binding site or optionally including some portion(s) of a molecule known to binds to the site, such as an NR-box type peptide. These methods include: LUDI (Bohm, J. Comp. Aid. Molec. Design (1992) 6:61-78; LUDI is available from Biosym Technologies, San Diego, CA); LEGEND (Nishibata et al., Tetrahedron (1991) 47:8985; LEGEND is available from Molecular Simulations, Burlington, MA); and LeapFrog (available from Tripos Associates, St. Louis, MO).

Alternatively, entities may be designed by selecting a core chemical entity, or scaffold, that possess the correct geometry to present pendent groups, or substituents, to subpockets within the coactivator binding site. Scaffolds can be designed to match vectors, geometrical descriptors of the arrangement of chemical fragments in space within the coactivator binding site, drawn from central areas of the binding site into pockets. These vectors can be derived from atoms in a bound ligand such as the GRTPl peptide or from the position of the pockets. Databases can be searched for molecules matching these vectors using programs such as CAVEAT. Virtual libraries built from those scaffolds, by adding sets of substituents can be evaluated by the computational methods described to test for expected fit to the coactivator binding site.

For example, this method was applied to generate the virtual combinatorial libraries represented by the structures in Figure 23. Two molecules were designed as scaffolds by carrying out a CAVEAT search of available databases. One of these molecules, was manually redesigned after visual inspection of its best docked configuration (shown in the left panel of Figure 24). The substituent attachment points of the molecule were modified to achieve better delivery of R groups to the target pockets. A six-membered ring was removed to improve the shape complementarity of the molecule to the TR binding site and reduce the average molecular weight of the compounds in the libraries designed from this scaffold. A five-membered ring was changed to a six-membered ring to facilitate synthesis. A quaternary methyl group was added to block aromatization of the indole system. Virtual combinatorial libraries were created by adding all combinations of substituents from Figure X to the Rl, R2, and R3 positions of scaffolds 1 and 2 in Figure 23. Libraries were created by adding the substituents to the R positions through linking groups. The groups at R4 are exposed to solvent in the predicted binding conformation of the scaffolds. The R4 positions of scaffolds with the highest scoring linking groups were later varied to alter the calculated logP of the compounds to improve their predicted pharmacological properties.

The examination of the differences between the coactivator binding sites of the nuclear receptors revealed that there were significant areas of unutilized space within the subpockets of the binding sites. This finding implies that variation of the chemical character of the side chains of the coactivator peptide could result in more favorable interactions with the binding site and thus provide a peptide that binds with higher affinity to the coactivator binding site. This increased affinity would most likely be additive with that realized by covalent conformational constraint of the coactivator peptide. Therefore, a combinatorial library of covalently constrained coactivator peptides that varied the chemical structure of the side chains of the amino acids of the coactivator would be likely to yield modulators of coactivator binding.

Other molecular modeling techniques may also be employed in accordance with this invention. See, for example, Cohen et al, J. Med. Chem. (1990) 33:883-894); Navia et al., Curr. Opin. Struct. Biol. (1992) 2:202-210). For example, where the structures of test compounds are known, a model of the test compound may be superimposed over the model of the structure of the invention. Numerous methods and techniques are known in the art for performing this step, any of which may be used. See, for example, Farmer, "Drug Design," Aliens, E.J., ed., 10:119-143 (Academic Press, New York, 1980); U.S. Patent No. 5,331,573; U.S. Patent No. 5,500,807; Verlinde, Structure, (1994) 2:577-587); and Kuntz et al., Science, (1992) 257:1078-1082). The model building techniques and computer evaluation systems described herein are not a limitation on the present invention.

Using these computer modeling systems, a large number of compounds may be quickly and easily examined and expensive and lengthy biochemical testing avoided. Moreover, the need for actual synthesis of many compounds can be substantially reduced and/or effectively eliminated. Using such methods, two series of compounds have been designed to fit these criteria. Series one is a set of conformationally constrained peptides representing analogs of the second NR box of GRIPl. These peptides were synthesized using known methods ["Peptide Synthesis Protocols," (Methods in Molecular Biology, Volume 35), Eds. M. Pennington, and V. Dunn, Humana Press, 1994] and were shown to have the properties described in Figure 20. Of the set of designed peptides, TG-17 (peptide number 9) exhibited the degree of helical character expected of a mimic of the coactivator peptide structure. These data reveal that TG17 is highly helical relative to the others. Series two represents the compounds from the virtual libraries described above.

Using such methods, scaffolds have been designed to fit these criteria. By applying the stated restrictions of the coactivator binding site and the coactivator, as exemplified by the NR-box of GRIPl, to the full set of compounds in all of the cited databases, a set of scaffolds are determined. For example, two scaffolds are shown in Figure 24. These scaffolds have been fully optimized using this computational methodology. Their structures have been analyzed to optimize their fit into the coactivator binding site, and to determine the ability to synthesize compounds comprising these scaffolds. By slight variations in the computational methods, many more scaffolds become available.

After fully optimizing the scaffolds through computational methodology, the scaffolds will be synthesized to determine whether any compounds have the desired function. The function is determined by using one of the assays herein described. The compounds are tested for their ability to affect the interaction of receptor and coactivator. A matrix is generated that delineates the effects of each substituent in each position. This data is further analyzed to discern which substituents confer the desired effects upon library members. This set of relationships between structure of compound and effect perceived by assay is described as a "structure activity relationship," or S AR.

A set of covalently conformationally constrained peptides representing analogs of the second NR box of GRIPl has been designed. By covalently conformationally constrained is meant the covalent joining of amino acid side chain functionalities to restrict the conformations available to the peptide. These peptides were synthesized using known methods [Peptide Synthesis Protocol] and were shown to have the properties described in Figure 20. Of this set of designed peptides, TG-17 (peptide number 9) exhibited the degree of helical character expected of a mimic of the coactivator peptide structure. These data reveal that TG17 is highly helical relative to the other designed peptides. Figures 25-32 represent examples of designed compounds. For each compound, the amino acid, chemical structure and IC 50 value are shown. The IC 50 value reflects the ability of the compound to competitively inhibit the interaction of hTR and GRIPl.

It is possible to determine the unique features of molecules involved in binding selectively to one nuclear receptor as compared to other nuclear receptors by comparing features of molecules that show preferential complementarity for different receptors. The aspects of a molecule that confer specificity of binding to a particular nuclear receptor may not be apparent from examining structure alone. In these cases, the structure data may be combined with functional data to gain an understanding of what leads to specificity. Understanding specificity in these terms permits the design and development of therapeutics useful in treating nuclear receptor-based disorders.

Compounds identified through modeling can be screened in an assay characterized by binding of the compound to a coactivator binding site of interest for coactivator binding activity, such as a biologically based assay. Screening can be in vitro and/or in vivo. Preferred assays include cell-free competition assays and cell culture based assays. The biological screening preferably centers on activity-based response models, binding assays (which measure how well a compound binds to the receptor), and bacterial, yeast and animal cell lines (which measure the biological effect of a compound in a cell). The assays can be automated for high capacity - high throughput screening (HTS) in which large numbers of compounds can be tested to identify compounds with the desired activity.

As an example, in vitro binding assays can be performed in which compounds are tested for their ability to block the binding of a coactivator protein, fragment, fusion or peptide thereof, to a coactivator binding site of interest. For cell and tissue culture assays, they may be performed to assess a compound's ability to block function of cellular coactivators, such as members of the pl60 family of coactivator proteins, such as SRC-1, AIB1, RAC3, p/CIP, and GRIPl and its homologues TIF 2 and NcoA-2, and those that exhibit receptor and or isoform-specific binding affinity. In a preferred embodiment, compounds of the invention bind to a nuclear receptor coactivator binding site with greater affinity than the cellular coactivator proteins. Tissue profiling and appropriate animal models also can be used to select compounds. Different cell types and tissues also can be used for these biological screening assays. Suitable assays for such screening are described herein and in Shibata et al. (Recent Prog. Horm. Res. 52:141-164 (1997)); Tagami et al. (Mol. Cell Biol (1997) 77(5):2642-2648); Zhu et al. (J. Biol Chem. (1997) 272(14):9048-9054); Lin et al. (Mol. Cell Biol. (1997) 77(10):6131-6138); Kakizawa et al. (J. Biol. Chem. (1997) 272(38):23799-23804); and Chang et al. (Proc. Natl. Acad. Sci. USA (1997) 94(17):9040-9045), which references are incorporated herein in their entirety by reference. For example, coactivators or binding fragments thereof can be expressed and/or assayed for binding as for GRIPl (Hong et al., MCB supra; and Hong et al., PNAS supra) and/or SRC-1 (Spencer et al, Nature (1997) 359:194-198; Onate et al., Science (1995) 270:1354-1357), incorporated by reference.

An assay for the determination of relative ability of potential agonists and antagonists of coactivator binding has been established. This assay uses a fluorescently labeled peptide (peptide 2 as shown in Figure 20) which represents the second NR box of GRIPl as a probe for coactivator binding. Binding is detected by monitoring changes in fluorescence polarization of the probe. Potential agonists or antagonists are evaluated by their ability to displace this probe. Using this assay, the peptides shown in Figure 20 were evaluated. The results of this study are shown in Figure 21. TG-17, (peptide number 9) was shown to be a strong antagonist of coactivator binding.

Another assay that can be used to determine the relative strength of potential agonists and antagonists is the GST pulldown method of monitoring the interaction of a coactivator and a receptor. Using this assay (Fig. 22), TG-17 (peptide number 9) also exhibited a significant degree of antagonistic character. Thus, TG17 is an example of an efficient antagonist of coactivator binding.

The compounds selected can have agonist and/or antagonistic properties. The compounds also include those that exhibit new properties with varying mixtures of agonist and antagonist activities, depending on the effects of altering coactivator binding in the context of different activities of nuclear receptors, either hormone-dependent or hormone-independent, which are mediated by proteins other than coactivators, and which interact with the receptors at locations other than the coactivator binding site. The compounds also include those, which through their binding to receptor locations that are conformationally sensitive to hormone binding, have allosteric effects on the receptor by stabilizing or destabilizing the hormone-bound conformation of the receptor, or by directly inducing the same, similar, or different conf ormational changes induced in the receptor by the binding of hormone.

Of particular interest is use of such compounds in a method of modulating nuclear receptor activity in a mammal by administering to a mammal in need thereof a sufficient amount of a compound that fits spatially and preferentially into a coactivator binding site of a nuclear receptor of interest. By "modulating" is intended increasing or decreasing activity of a nuclear receptor. For example, pre-clinical candidate compounds can be tested in appropriate animal models in order to measure efficacy, absorption, pharmacokinetics and toxicity following standard techniques known in the art. Compounds exhibiting desired properties are then tested in clinical trials for use in treatment of various nuclear receptor-based disorders. These include ER-based disorders, such as postmenopausal symptoms and cancer resulting from loss of estrogen production, and osteoporosis and cardiovascular disease stemming from traditional estrogen replacement therapy. Others include TR-based disorders including cardiovascular disease, metabolic disorders, hyperthyroidism, glaucoma and skin disorders. GR-based disorders include Type IJ diabetes and inflammatory conditions such as rheumatic diseases.

The invention also provides for cocrystals made from nuclear receptor ligand binding domains with a molecule bound to the coactivator binding site. As exemplified in the Examples, TR LBDs are co-crystallized with a peptide molecule comprising a coactivator NR-box 2 peptide sequence bound to the coactivator binding site, and the hormone/ligand T₃.

Crystals are made from purified nuclear receptor LBDs that are usually expressed by a cell culture, such as E. coli. Preferably, different crystals (cocrystals) for the same nuclear receptor are separately made using different coactivators-type molecules, such as protein fragments, fusions or small peptides. The coactivator-type molecules preferably contain NR-box sequences necessary for binding to the coactivator binding site, or derivatives of NR-box sequences. Other molecules can be used in co-crystallization, such as small organics that bind to the coactivator or hormone binding site(s). Heavy atom substitutions can be included in the LBD and/or a co-crystallizing molecule.

After the three dimensional structure of the cocrystal is determined, the structural information can be used in computational methods to design synthetic compounds for the nuclear receptor, and further structure-activity relationships can be determined through routine testing using the assays described herein and known in the art.

Since nuclear receptor LBDs may crystallize in more than one crystal form, the structure coordinates of such receptors or portions thereof, as provided in Appendix 1, are particularly useful for solving the structure of those other crystal forms of nuclear receptors. They may also be used to solve the structure of mutants or co-complexes of nuclear receptors having sufficient structural similarity.

One method that may be employed for this purpose is molecular replacement. In this method, the unknown crystal structure, may be determined using the structure coordinates of this invention as provided in Appendix 1. This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

Atomic coordinate information gleaned from the crystals of the invention can be stored. In a preferred embodiment, the information is provided in the form of a machine- readable data storage medium. This medium contains information for constructing and/or manipulating an atomic model of a coactivator binding site or portion thereof. For example, the machine readable data for the coactivator binding site comprises structure coordinates of amino acids corresponding to human TR amino, acids selected from C-terminal helix 3 (Ile280, Thr281, Val283, Val284, Ala287, and Lys288), helix 4 (Phe293), helix 5 (Gln301, Ile302, Leu305, Lys306), helix 6 (Cys309), and helix 12 (Pro453, Leu454, Glu457, Val458 and Phe459), or a homologue of the molecule or molecular complex comprising the site. The homologues comprise a coactivator binding site that has a root mean square deviation from the backbone atoms of the amino acids of not more than 1.5 A. A preferred molecule or complex represents a compound bound to the coactivator binding site.

The machine-readable data storage medium can be used for interative drug design and molecular replacement studies. For example, a data storage material is encoded with a first set of machine-readable data that can be combined with a second set of machine- readable data. For molecular replacement, the first set of data can comprise a Fourier transform of at least a portion of the structural coordinates of the nuclear receptor or portion thereof of interest, and the second data set comprises an X-ray diffraction pattern of the molecule or molecular complex of interest. Using a machine programmed with instructions for using the first and second data sets a portion or all of the structure coordinates corresponding to the second data can be determined.

Protein for crystals and assays described herein can be produced using expression and purification techniques described herein and known in the art. For example, high level expression of nuclear receptor LBDs can be obtained in suitable expression hosts such as E. coli. Expression of LBDs in E. coli, for example, includes the TR LBD and other nuclear receptors, including members of the steroid/thyroid receptor superfamily, such as the receptors ER, AR, MR, PR, RAR, RXR and VDR. Yeast and other eukaryotic expression systems can be used with nuclear receptors that bind heat shock proteins as these nuclear receptors are generally more difficult to express in bacteria, with the exception of ER, which can be expressed in bacteria. Representative nuclear receptors or their ligand binding domains have been cloned and sequenced: human RAR-α, human RAR-γ, human RXR-α, human RXR-α, human PPAR-α, human PPAR-β, human PPAR-γ, human VDR, human ER (as described in Seielstad et al, Molecular Endocrinol, (1995) 9:647-658, incorporated herein by reference), human GR, human PR, human MR, and human AR. The LBD for each of these receptors has been identified.

Coactivator proteins can be expressed using techniques known in the art, particularly members of the pi 60 family of coactivator proteins that have been cloned and/or expressed previously, such as SRC-1, AIB1, RAC3, p/CIP, and GRIPl and its homologues TIF 2 and NcoA-2. A preferred method for expression of coactivator protein is to express a fragment that retains transcriptional activation activity using the "yeast 2- hybrid" method as described by Hong et al. (PNAS supra; and MCB supra), for GRIPl expression, which reference is herein incorporated by reference.

The proteins can be expressed alone, as fragments of the mature or full- length sequence, or as fusions to heterologous sequences. For example, TR can be expressed without any portion of the DBD or amino-terminal domain. Portions of the DBD or amino-terminus can be included if further structural information with amino acids adjacent the LBD is desired. Generally, for the TR the LBD used for crystals will be less than 300 amino acids in length. Preferably, the TR LBD will be at least 150 amino acids in length, more preferably at least 200 amino acids in length, and most preferably at least 250 amino acids in length. For example the LBD used for crystallization can comprise amino acids spanning from Met 122 to Val 410 of the rat TR-α or Glu 202 to Asp 461 of the human TR-β.

Typically the LBDs are purified to homogeneity for crystallization. Purity of LBDs can be measured with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), mass spectrometry (MS) and hydrophobic high performance liquid chromatography (HPLC). The purified LBD for crystallization should be at least 97.5 % pure, preferably at least 99.0% pure, more preferably at least 99.5% pure.

Initially, purification of the unliganded receptor can be obtained by conventional techniques, such as hydrophobic interaction chromatography (HPLC), ion exchange chromatography (HPLC), and heparin affinity chromatography.

To achieve higher purification for improved crystals of nuclear receptors, especially the TR subfamily and TR, the receptors can be ligand-shift-purified using a column that separates the receptor according to charge, such as an ion exchange or hydrophobic interaction column, and then bind the eluted receptor with a ligand, especially an agonist. The ligand induces a change in the receptor's surface charge such that when re- chromatographed on the same column, ligand-bound receptor is separated from unliganded receptor. Usually saturating concentrations of ligand are used in the column and the protein can be preincubated with the ligand prior to passing it over the column. The structural studies detailed herein indicate the general applicability of this technique for obtaining super-pure nuclear receptor LBDs for crystallization.

Purification can also be accomplished by use of a purification handle or "tag," such as with at least one histidine amino acid engineered to reside on the end of the protein, such as on the N-terminus, and then using a nickel or cobalt chelation column for purification. (Janknecht et al, Proc. Natl. Acad. Sci. USA, (1991) 55:8972-8976) incorporated by reference.

Typically purified LBD, such as TR LBD, is equilibrated at a saturating concentration of ligand at a temperature that preserves the integrity of the protein. Ligand equilibration can be established between 2 and 37°C, although the receptor tends to be more stable in the 2-20°C range. Preferably crystals are made with the hanging drop methods detailed herein. Regulated temperature control is desirable to improve crystal stability and quality. Temperatures between 4 and 25 °C are generally used and it is often preferable to test crystallization over a range of temperatures. The crystals are then subjected to vapor diffusion and bombarded with x-rays to obtain x-ray diffraction pattern following standard procedures.

For co-crystallization with a peptide that binds to the coactivator binding site, various concentrations of peptides containing a sequence that binds to a coactivator binding site of a nuclear receptor of interest can be used in microcrystallization trials, and the appropriate peptides selected for further crystallization. Any number of techniques, including those assays described herein can assay peptides for binding to the coactivator binding site of a nuclear receptor of interest. In a preferred embodiment, a NR-box 2 sequence-containing peptide is used for crystallization with TR LBD. A preferred peptide contains a NR-box (SEQ ID NO: 1) LxxLL motif, and suitable flanking sequences necessary for binding and forming complex with coactivator binding site of the nuclear receptor of interest, such as a TR LBD. The binding peptides are then tested in crystallization trials at various concentrations and ratios of concentrations with a nuclear receptor of interest, for example, as described herein and in the Examples. For crystallization trials with TR LBD, the hanging drop vapor diffusion method is preferred. Conditions of pH, solvent and solute components and concentrations and temperature can be adjusted, for instance, as described in the Examples. In the handing drop method, to obtain suitable crystals for x-ray diffraction analysis, seeding of prepared drops with microcrystals of the complex can be used. Collection of structural information can be determined by molecular replacement using the structure of TR LBD determined herein or previously by Wagner et al., supra. The structure is refined following standard techniques known in the art.

There are many uses and advantages provided by the present invention. For example, the methods and compositions described herein are useful for identifying peptides, peptidomimetics or small natural or synthetic organic molecules that modulate nuclear receptor activity. The compounds are useful in treating nuclear receptor-based disorders. Methods and compositions of the invention also find use in characterizing structure/function relationships of natural and synthetic coactivator compounds.

The following examples illustrate various aspects of this invention. These examples do not limit the scope of this invention. EXAMPLES

Example 1 Expression and purification of wild-type and mutant nuclear receptors and coactivators

A. Human TRβ LBD

Human TRβ LBD (His6-E202-D461) was expressed and purified as described (Shiau et al., Gene (1996) 779(2):205-10). Briefly, the protein was expressed from pET (e.g., pET3 and pET28) in BL21DE3 at 14°C, induced at OD(600nm) 0.7 with ImM IPTG and incubation was extended for 24 hours. Cells were harvested and lysed in 50mM sodium-phosphate buffer (pH 8.0), 0.3M NaCl, 10% glycerol, 25mM β- merceptoethanol and O.lmM PMSF as described above. The lysate was cleared by ultracentrifugation (Ti45, 36000 rpm, lh, 4°C), loaded on a Talon column equilibrated in the sodium phosphate buffer described above, washed with 12mM imidazole and eluted with an imidazole gradient (12 - 300 mM). TRβ LBD containing fractions were loaded in 0.6M ammonium sulfate on a TSK-phenyl hydrophobic interaction column and eluted with a reverse ammonium sulfate gradient [0.6 - 0 M] in 50% glycerol and 10% acetonitrile. Fractions containing TRβ LBD were tested for hormone binding, pooled and incubated with a 3-fold molar excess of T₃ (Sigma). The hydrophobic interaction run was repeated with liganded receptor under the same conditions. Liganded receptor, which elutes earlier than unliganded receptor, was collected and buffer changed to 20mM Hepes pH7.0, 3mM DTT and O.lμM T₃ using NAP columns (Pharmacia). For crystallization, the protein was concentrated by ultrafiltration (Millipore UFV2BGC10 concentrators) to a final concentration of 9mg/ml. The yield was about 9.5mg protein per liter bacterial culture.

B. Human TR mutants

Thirty-seven thyroid receptor mutants were created by synthesizing double- stranded oligonucleotides which encode the mutant sequence and which have ends allowing them to be ligated as a cassette using pairs of the Nsil, Pstl, Sstl, AlwNI, Apol, PflMI, BstXI, BseRI, BsmFI, PvuJJ, Nspl, Smal, Pmll, BglU and Bsml restriction sites of the hTRβl cDNA sequence, or the 3' plasmid polylinker Sail, or BamHI restriction sites. The hTRβl sequences thus mutated were subcloned into the pCMX vector encoding the full- length 461 amino acid hTRβl sequence. Some of the mutations of the hTRβl in the CMX vector and all three mutations of the hERα in the pSG5-ER-HEGO vector (Tora et al., EMBO (1989) 5:1981) were created using Quick Change Site-Directed Mutagenesis Kits (Stratagene). The mutated sequences were verified by DNA sequencing using Sequenase Kits (Stratagene).

C. Human ERα LBD

The human ERα-LBD 297-554 was overexpressed as described previously (Seielstad, et al., supra) in BL21(DE3)pLysS cells transformed with a modified pET-23d- ERG vector that contained the sequence Met- Asp-Pro fused to residues 297 to 554 of the hERα (provided by Paul Sigler of Yale University). Clarified bacterial lysates were adjusted to 3 M in urea and 0.7 M in NaCl and then applied to a 10-ml column of estradiol- Sepharose (Greene, et al., Proc. Natl. Acad. Sci. USA (1980) 77:5115-5119; Landel, et al., Mol. Endocrinol. (1994) 5:1407-1419; Landel, et al., J. Steroid Biochem. Molec. Biol. (1997) 63:59-73).

To carboxymethylate the solvent-accessible cysteines, the bound hERα-LBD was treated with 5 mM iodoacetic acid in 10 mM Tris, pH 8.1, 250 mM NaSCN (Hegy, et al., Steroids (1996) (57:367-373). Protein was eluted with 3 x 10-5 M ligand (either DES or OHT) in 30-100 ml of 50 mM Tris, 1 mM EDTA, 1 mM DTT and 250 mM NaSCN, pH 8.5. The yield of hERα-LBD was typically close to 100% (Seielstad, et al., Biochemistry (1995) 34:12605-12615). The affinity-purified material was concentrated and exchanged into 20 mM Tris, 1 mM EDTA, 4 mM DTT, pH 8.1 by ultrafiltration. The protein was bound to a Resource Q column (Pharmacia) and then eluted with a linear gradient of 25-350 mM NaCl in 20 mM Tris, pH 8.1, 1 mM DTT. The hERα-LBD-ligand complexes eluted at 150-200 mM NaCl. Pooled fractions were concentrated by ultrafiltration and analyzed by SDS-PAGE, native PAGE, and electrospray ionization mass spectrometry.

D. Human ER mutants

To test the importance of the NR box peptide/LBD interface observed in the crystal, a series of site-directed mutations were introduced into the ERα LBD. These mutations were designed either to simultaneously perturb the structural integrity and the nonpolar character of the floor of the binding groove (lie 358->Arg, Val 376->Arg and Leu 539->Arg) or to prevent the formation of the capping interactions (Lys 362->Ala and Glu 542->Lys). Fusions of glutathione-S -transferase (GST) to the wild-type and mutant LBDs were analyzed for their ability to bind ³⁵S-labeled GRIPl in the absence of ligand or in the presence of DES or OHT.

S-labeled GRIPl was incubated with either immobilized GST, immobilized wild type GST-hERα LBD, or immobilized mutant GST-LBDs in the absence of ligand or in the presence of DES or OHT. The bound GRTPl was quantitated after SDS-PAGE. I358R, mutant LBD containing a Ile->Arg substitution at residue 358; K362A, mutant LBD containing a Lys->Ala substitution at residue 362; V376R, mutant LBD containing a Val- >Arg substitution at residue 376; L539R, mutant LBD containing a Leu->Arg substitution at residue 539; E542K, mutant LBD containing a Glu->Lys substitution at residue 542.

In the absence of ligand or in the presence of OHT, fusions to the wild-type protein and all of the mutant LBDs showed no detectable binding to GRIPl. The lie 358- >Arg, Val 376->Arg and Leu 539->Arg mutants were all unable to interact with coactivator in the presence of agonist, confirming the importance of the packing interactions observed in the crystal. Disruption of either the N- or C-terminal capping interaction also compromised GRIPl binding in the presence of agonist. Only the wild-type GST-LBD was able to recognize the coactivator in the presence of DES.

E. Human ER LBD-GST Fusion Protein

A fusion between glutathione-S -transferase (GST) and amino acids 282-595 of hERα was constructed by subcloning the EcoRI fragment from pSG5 ERα-LBD (Lopez et al., submitted manuscript) into pGEX-3X (Pharmacia). The JJe 358-> Arg, Lys 362- >Ala, and Leu 539->Arg mutations were introduced into the GST-LBD construct using the QuikChange Kit (Stratagene) according to the manufacturer's instructions. The Val 376- >Arg and Glu 542->Lys mutations were created in the GST-LBD construct by subcloning the Bsml Hindiπ fragments of derivatives of pSG5-ER-HEGO (Tora, et al., supra) into which these mutations had already been introduced. All constructs were verified by automated sequencing (University of Chicago Cancer Research Center DNA Sequencing Facility). F. Radiolabeled full-length receptors and coactivator proteins

Wild-type (WT) or mutant pCMV-hTRβl vector and the pSG5-GPJPl and pCMX-SRC-la vectors were used to produce radiolabeled full-length receptors and coactivator proteins using the TNT coupled Reticulocyte Lysate System (Promega) and [³⁵S]-Met (DuPont). GST-GRIPl (amino acids 721-1221), GST-GRIPl (amino acids 563- 1121), GST-SRC-la (amino acids 381-882), GST- hTRβl (full-length, WT or mutants, WT provided by. C. Costa), and the GST-hRXRα (full-length provided by. C. Costa), fusion proteins were produced in E. coli strain HB101 as per the manufacturer's protocol (Pharmacia Biotech).

G. Coactivator GRIPl 563-767 His6 GST fusion protein

GRIPl 563-767 was cloned as a Bam Hl-Xho I fragment derived from pGΕX-2TK GPJPl 563-1121 into the corresponding sites of pGEX-4Tl. A His6-tag was added by inserting a Xho I-Nae I fragment of pET23a into Xho I-Bsa Al sites of this pGEX- 4T1 construct yielding pGEX GRIPl 563-767His6. Mutants of GRIPl 563-767 were generated by PCR or single stranded mutagenesis using oligonucleotides carrying the mutations and a pSG5 GRIPl vector as template." The mutations were confirmed by sequence analysis and integrated into pGEX GRIPl 563-767His6 as NgoMI - Xho I fragments. The GRIPl 563-767 His6 GST fusion protein was expressed in HB101 at 37°C. Protein expression was induced with ImM JPTG at an optical density (600 nm) of 0.7 and extended for 4 hours after induction. Cells were harvested by centrifugation, resuspended in sonication buffer (20mM TrisHCl pH 8.0, 0.1M NaCl, 10%glycerol, O.lmM PMSF and protease inhibitors (Complete, EDTA free, Boehringer Mannheim)). The resuspended cells were freeze-thawed once, incubated on ice with O.lmg/ml lysozyme for 20 minutes and lysed per sonication. The lysate was cleared by ultracentrifugation (Ti 45, 36000rpm, lh 4°C), the supernatant filtered (Costar 0.2μm top filter) and loaded on a Talon column (Clontech). The column was washed with 10 column volumes of sonication buffer supplemented with 12mM imidazole and eluted with an imidazole gradient [12 - lOOmM]. At this step the fusion proteins are about 95% pure. Imidazole was removed by gelfiltration on NAP columns (Pharmacia), and protein concentrations determined using the Biorad protein assay. Equal concentrations of the different derivatives of the fusion fragment were incubated with glutathione agarose (lh, 4°C) which was equilibrated in binding buffer (sonication buffer supplemented with ImM DTT, ImM EDTA and 0.01% NP-40). Beads were washed with at least 20 volumes of this buffer, diluted in binding buffer with 20% glycerol to 40%, frozen in aliqots and stored at -70°C.

H. Coactivator GRIPl 563-767 His6

GRIPl 563-767 was cloned as a Bam HI - Xho I fragment derived fron pGEX GRIPl 563-767His6 into corresponding cloning sites of pET23a yielding pETGRIPl 563-767His6. The fragment was expressed in BL21DE3. Expression, cell lysis and Talon purification was identical as described for GST GRIPl 563-767His6. The protein eluted from a Talon column in two fractions, one at 12mM and one between 40 and 70mM imidazole. In the earlier eluting fraction the fragment was associated with a 70 kDa protein which was removed by a MonoQ run in 50mM TrisHCl pH7.5, 10% glycerol, ImM EDTA, ImM DTT, O.lmM PMSF and protease inhibitors. GRIPl 563-767His6 eluted in the flow through and was concentrated by ultrafiltration. At this step the protein was more than 95% pure.

Example 2 Peptide Synthesis

Coactivator peptides were obtained using standard techniques. All peptides were HPLC purified and analyzed by mass spectroscopy. Peptide concentrations were either determined spectroscopically using the tyrosine signal (A₂₇₆ = 1450 M-lcm-1) or by amino acid analysis following standard techniques.

Example 3 Binding Assays With Nuclear Receptors And Coactivators

A. GST-GRIP pull-down assays and peptide competition assays

Binding experiments were performed by mixing glutathione beads containing 10 μg of GST fusion proteins (Coomassie Plus Protein Assay Reagent, Pierce) with 1-2 μl of the [³⁵S]-labeled wild-type or mutant hTRβl (25 fmoles, 4000 cpm of receptor), or coactivators in 150 μl of binding buffer (20 mM HEPES, 150 mM KC1, 25 mM MgCl₂, 10% glycerol, 1 mM dithiothreitol, 0.2 mM phenylmethylsulfonyl fluoride, and protease inhibitors) containing 2 mg/ml BSA for 1.5 hrs in the presence or absence of 1 μM T₃. Beads were washed 3 times with 1 ml of binding buffer and the bound proteins were separated using 10% SDS-PAGE and visualized by autoradiography. Binding was quantitated by phosphorimaging using ImageQuant (Molecular Dynamics).

For in vitro binding studies GR, TR and their derivatives were translated in the presence of [ S]methionine using the TNT Coupled Reticulocyte System (Promega). Separate translations were performed in the presence and absence of lOμM dexamethasone or lμM RU486 for GR and lOμM triiodothyronine for TR. Expression was quantified by phosphoimager analysis (BAS2000, Fuji). For all binding assays 50μl of a 20% bead suspension containing either 1.6 or 4.0 μM bound purified GST GRTPl fragment (either 568-767 or 563-1121) was incubated with 0.2μl or lΛμlin vitro transcribed and translated TR or GR, respectively. Binding was performed in the binding buffer described above supplemented with 20 μg/ml BSA and appropriate hormone. The chosen GST GRIPl fragment concentrations were sufficient to bind either 70 or 100% of the TR derivatives. The reaction was incubated at 4°C under rotation for 2 hours. In case of competition experiments, the appropriate concentration of peptides were added to the reaction before addition of receptors. However, no differences in the results were noted by adding the peptides after half of the incubation of the GST GRIPl fragment with nuclear receptors. This demonstrates that equilibrium is reached under the chosen conditions. Beads were washed five times with 200μl binding buffer + BSA at 4°C before elution of the bound proteins in 20μl SDS loading buffer. Eluted beads and input labeled protein were subjected to SDS-PAGE. The fraction of bound nuclear receptors was determined by phosphoimager analysis.

B. GST-hTRβl pull-down assays

Assay and analysis was performed as for Example 3 A. In vitro binding of [³⁵S]-labeled full-length GRIPl, [³⁵S]-labeled full-length SRC-la, and [³⁵S]-labeled full- length hRXRα, to GST- hTRβl wild-type (WT) and mutants was performed. Mutants V284R, K288A, I302R, L454R, and E457K all bound to hRXRα with an affinity equivalent to wild type hTR. All of these mutants showed decreased ability to bind GRIPl and SRC- la, as expected from the results of Example 3 A. The same results were obtained when a GST-SRC1 construct including SRC-la amino acids 381-882 was tested for binding of [³⁵S]-Met-labeled full-length hTRβ 1 WT and mutants (data not shown).

C. GST-hERα LBD pull-down assays

The wild-type and mutant GST-hERα LBDs were expressed in BL21(DE3) cells. Total ligand binding activity was determined by a controlled pore glass bead assay (Greene, et al., Mol. Endocrinol. (1988) 2:714-726) and protein levels were monitored by western blotting with a monoclonal antibody to hERα (H222). Cleared extracts containing the GST- hERα LBDs were incubated in buffer alone (50 mM Tris, pH 7.4, 150 mM NaCl, 2 mM EDTA, 1 mM DTT, 0.5% NP-40 and a protease inhibitor cocktail) or with 1 μM of either DES or OHT for 1 hour at 4°C. Extract samples containing thirty pmol of GST-LBD were then incubated with 10 μl glutathione-Sepharose-4B beads (Pharmacia) for 1 hour at 4°C. Beads were washed five times with 20 mM HEPES, pH 7.4, 400 mM NaCl, and 0.05% NP-40. ³⁵S-labeled GRJJPl was synthesized by in vitro transcription and translation using the TNT Coupled Reticulocyte Lysate System (Promega) according to the manufacturer's instructions and pSG5-GRIPl as the template. Immobilized GST- hERα LBDs were incubated for 2.5 hours with 2.5 μl aliquots of crude translation reaction mixture diluted in 300 μl of Tris-buffered saline (TBS). After five washes in TBS containing 0.05% NP-40, proteins were eluted by boiling the beads for 10 minutes in sample buffer. Bound ³⁵S-GRIP1 was quantitated by fluorography following SDS-PAGE.

D. Fluorescent polarization binding assays

Assays are performed by mixing the receptor, hormone, coactivator peptide probe, and potential modulator. The probe concentration was held constant at 10 nM; thyroid hormone concentration was held constant at lOmM; Htrbetal concentration was held constant at ImM; and potential modulator concentration was varied across the range of 0.1 nM to 50 μM.

It was shown experimentally that the binding of probe to receptor was completely saturable and reached equilibrium within ten minutes. In addition, competition experiments using native GRIPl peptides revealed that full competitive displacement of probe by modulator'was also reached within ten minutes. The validity of several controls was established: a positive control (competition by unlabeled GRIPl NR Box peptide), and negative controls for ligand dependence of probe binding (no thyroid hormone) and for unsuccessful competition (a sequence scrambled NR box peptide that breaks up the leucine triad). The effects of pH and salt concentration upon the system, and determination of an optimal buffer (HEPES, Ph 7.5; 10 Mm NaCl, 140 Mm KC1, 1 Mm DTT, 1 Mm EDTA, protease inhibitors) have also been studied. The experiment is carried out with simultaneous monitoring of both overall fluorescence intensity and fluorescence polarization for each sample to ensure no perturbations arise in overall fluorescence intensity.

Experimentally, potential modulators can be evaluated by pre-equilibrating the receptor, probe, and hormone for as set period of time, for example, one hour. Then a set of samples can be titrated with increasing concentrations of each modulator, and evaluated for displacement of the probe after a set period of time, for example, one hour. All experiments can be carried out in quadruplicate, with each iteration containing the positive and negative competition controls and ten dose points. The data can then be analyzed using Klotz plots. IC50 values are determined using nonlinear regression analysis. Further analysis of binding data can involve Scatchard or Hill plots to verify the inhibitory constant and presence of a single class or multiple classes of binding sites. The various parameters of the experiment can be varied depending upon the dissociation constant of the receptor coactivator pair or the identity of the receptor or coactivator.

Electrophoretic mobility shift assays

GRIPl, a mouse pl60 coactivator, recognizes the ERα LBD in a ligand- dependent manner. The binding of agonists to the ERαLBD promotes recruitment of GRIPl, whereas binding of antagonists prevents this interaction (Norris, et al., J. Biol. Chem. (1998) 273:6679-88). While agonist-bound receptor will bind to all three of the NR boxes from GRIPl, ERα strongly prefers NR-box 2 (Ding, et al., Mol. Endocrinol. (1998) 72:302-13).

An electrophoretic mobility shift assay was used to directly assess the ability of the NR-box 2 peptide to bind the purified ERα LBD in the presence of either DES or OHT. Eight microgram samples of purified Herα-LBD bound to either DES or OHT were incubated in the absence of the peptide, i.e., buffer alone, or in the presence of either a 2- fold or 10-fold molar excess of the GRIPl NR-box 2 peptide. The binding reactions were performed on ice for 45 minutes in 10 μl of buffer containing 20Mm Tris, Ph 8.1, lMm DTT, and 200Mm NaCl and then subjected to 6% native PAGE. Gels were stained with GELCODE Blue Stain reagent (Pierce).

In the presence of the NR-box 2 peptide, the migration of the DES-Herα- LBD complex was retarded. In contrast, peptide addition had no effect on the mobility of the OHT-Herα-LBD complex. Hence, this peptide fragment of GRTPl possesses the ligand-dependent receptor binding activity characteristic of the full-length protein.

Example: 4 Transfection Assays With TR and Herα

HeLa cell transfection and assay conditions are described (Webb et al., Mol Endocrinol (1995) 9:443). For TR assays, 5 μg of the reporter ρ(DR-4)₂ -TK-LUC consisting of two copies of the DR-4 element (a direct repeat of the consensus TR response element (TRE) spaced by 4 base pairs) placed upstream of a minimal (-32/+45) thymidine kinase gene promoter linked to luciferase (LUC) coding sequences were used. A reporter containing palindromic TREs gave the same results (data not shown). Also, 2 μg of the hTRβl expression vector, Pcmx-TR (WT or mutant), and 0.5 μg transfection control vector, Pj3LacZ, which contains the SV40 promoter linked to the β-galactosidase gene, were used. Other cells co-transfected with vector or receptor constructs can be used for same purpose. Alternative cells expressing sufficient levels of an endogenous receptor(s), or cells selected that express a single reporter, can be used for transfection assays, including MCF-7 cells expressing ER (Webb et al., supra) , and GC cells expressing TR (Norman et al., J. Biol. Chem. (1989) 26^"4: 12063-12073).

For Herα assays, 5 μg of estrogen responsive reporter plasmid encoding chloramphenicol acetyltransferase (CAT), Pere-collTATA (Sadovsky, et al, Mol Cell Biol. (1995) 75:1554), 0.5 μg expression vector encoding full-length Herα , Psg5-er HEGO (WT or mutants), and 2 μg of pj31acz, were used. For the experiments of Figures 2 and 4, 0.5 μg of a full-length GRTPl expression vector, Psg5-GRIP1, was also included in the transfection. Transfected cells were treated with or without 1 μM T₃ or E , as indicated. After culturing for 24 hrs, the LUC or CAT activities were assayed and the β-galactosidase activities were also assayed to correct for differences in transfection efficiencies. The triplicate points were averaged and standard deviations were less than 10%.

Example 5 Hormone Binding Assays For Wild-Type And Mutant TRs

The T₃ binding affinity constants (Kd) for in vitro -translated WT and mutant TRs were measured using [¹²⁵I] 3,5,3' triiodo-L-thyronine ([¹²⁵I]T₃) in gel filtration binding assays as described (Apriletti et al., Protein Expr. Purif. (1995) 6:363). Both the Kd and standard enor (S.E.) values were calculated using the Prism computer program (GraphPad Software, Inc.). Mutations are indicated by the single-letter amino acid abbreviations, with the native residue name, followed by the primary sequence position number, and then the mutated residue name. The affinity of the WT TR is 81 + 12 Pm. The relative affinity was determined by dividing the WT Kd by each mutant Kd. The 37 mutants tested with their relative affinities are: E217R (123%), E227R (109%), K242E (92%), E267R (117%), H271R (123%), T277R (7%), T281R (145%), V284R (105%), D285A (89%), K288A (98%), C294K (94%), E295R (118%), C298A (87%), C298R (141%), E299A (171%), I302A (86%), I302R (99%), K306A (6%), K306E (6%), P384R (164%), A387R (107%), E390R (151%), E393R (146%), L400R (95%), H413R (109%), H416R (153%), M423R (156%), R429A (48%), S437R (170%), L440R (174%), V444R (89%), T448R (234%), E449R (36%), P453E (32%), L454R (26%), L456R (46%), E457K (71%).

Example 6 Coactivator Binding Assays For Wild-Type And Mutant TRs

Wild type (WT) TR and most of the TR mutants liganded to 3,5,3 '-triiodo-L- thyronine (T₃) bind equally well to the coactivator, GRIPl. In all cases, GRIPl binding was hormone-dependent (data not shown). Mutations L454R and E457K in surface residues of helix 12 abolish GRTPl binding (Figure 1). Mutations in two residues of helix 3, V284R and K288A, and two residues of helix 5, 1302R and K306A, also impair binding (Figure 1). Five mutations with diminished GRIPl binding (V284R, K288A, I302R, L454R, and E457K) also show decreased binding to another coactivator, SRC- la (data not shown). Thus, these results show that two different coactivators recognize the same TR surface residues.

Example 7 TR Residues Involved In Ligand-Dependent Transcription Activation In Context Of A

Cell

Residues involved in ligand-mediated transcription activation were identified by testing the TR mutants of Example 8 in HeLa cells. T₃ increased reporter gene activity 5-fold in cells expressing either WT TR or mutated TRs showing normal GRIPl binding (representative mutants are shown in Figure 1. By contrast, TR mutants with diminished or absent GRIPl binding (V284R, K288A, I302R, K306A, L454R, and E457K) show a diminished or absent response to T₃ which correlates with the GRIPl binding defect. Overexpression of GRTPl increases activation by the WT TR and rescues activation by TR mutants roughly in proportion to the severity of the defect of GRTPl binding and activation (Figure 2). These results suggest that the same residues are required for coactivator binding, function of the endogenous coactivator(s) in HeLa cells, and responsiveness of TRs to GRTPl.

Example 8 Effect of TR Mutations On Other Receptor Functions

The effects of the mutations on other receptor functions also were examined . All of the mutants bound radiolabeled thyroid hormone (Kd values, 6%-234% that for native receptor); occasional lower values were expected because some residues have partially buried side chains. None of the residues that decrease GRTPl binding affected TR binding to a GST-RXR fusion protein or to DNA using three different DNA half-site anangements and testing with or without added RXR (data not shown). Some mutations that affect GRTPl binding occur in a region spanning helices 3-5, which has been suggested as important for TR/RXR heterodimerization (O'Donnell et al., supra; Lee et al., Mol. Endocrinol. (1992) 6: 1867- 1873). In contrast, however, the above results indicate that these residues do not contribute to TR/RXR heterodimerization. Further, TRs mutated in the CBS residues retain the ability of WT TR of T₃-dependent inhibition of the activity of the Jun and Fos transcription factors at an AP-1 site (Saatcioglu et al., supra), suggesting that the CBS residues do not participate in TR actions mediated through these proteins. These data indicate that the mutational effects are specific, the amount of input labeled TR in the different reactions is comparable, and the levels of expression of the mutant TRs are comparable to those of WT receptors.

Example 9 Coactivator Binding Site In ER

Three separate mutations (K362A, V376R, and E542K) were created in human estrogen receptor-α (Herα) which align to three of the effective positions in Htrβl (K288A, I302R, and E457K). All three mutations diminish GRTPl binding and abolish transcriptional activation (Figure 3), and mutant V376R, with 10% residual GRTPl binding, was rescued partially by overexpression of GRTPl (Figure 4). As a control, the ER mutants demonstrated a normal hormone-dependent ability to activate a vitellogenin-LUC hybrid reporter gene, GL45, which responds to the ER amino-terminal activation function (Berry et al., EMBO J (1990) 9:2811-2818) (data not shown). The finding that similar residues are required for GRTPl binding and transcription activation activity in the TR and ER suggests that the coactivator binding site residues are similar in different nuclear receptors.

Example 10 Coactivator NR-Box Binding Affinity For TR

To study the interaction between nuclear receptors and GRTPl in vitro, a fragment of GRTPl (563-767) was purified that contains all three NR-boxes (Figures 6 and 7). The fragment was found to be highly soluble and, in agreement with a secondary structure prediction using PhD, displays a mainly alpha-helical far UV-CD spectrum (data not shown). Three of the four helices predicted for the fragment include the NR-boxes at their C-terminus, suggesting that these boxes are part of amphipathic alpha-helices. These results show that the NR-boxes of GRTPl are contained in a soluble, alpha-helical 24Kd fragment.

Binding assays show that GRTPl NR-boxes 1, 2 and 3, interact differentially with hTRβ LBD (Figure 7). A GST-fusion of the GRTPl (563-767) fragment strongly binds TR (Kd or EC50 ) in a ligand depend fashion. Replacement of the hydrophobic residues of NR-box 3 with alanine does not reduce binding of TR significantly, whereas similar replacement of NR-box 2 results in loss of TR binding of about 50%. By titrating the amount of GRTPl fragment, about a 4-fold stronger binding of TR for NR-box 2 (EC50 = 1.0 μM) over NR-box 3 (EC50 = 4.0 μM) was estimated. In the absence of functional NR-boxes 2 and 3, almost no binding to TR was detected suggesting that under these experimental conditions NR-box 1 is not a cognate binding site for TR. Full length TR or TR-LBD bound GRTPl equally. These results show that TR recognizes GRTPl NR-box 2 and 3, with preference for NR-box 2.

Example 11 Coactivator NR-Box Binding Affinity For GR

GR also was found to bind GRTPl (563-767) in a ligand-dependent manner (Figure 8). However, in contrast to TR, extension of GRTPl (563-767) to residue 1121 increases binding to GR about 3 -fold suggesting an additional binding site on GRTPl for GR. Binding of the larger fragment remains ligand-dependent; no interaction can be observed in the presence of the GR partial antagonist RU486. These results are in agreement with in vivo 2-hybrid GR GRTPl interaction studies. In the presence of ligand no difference was detected in the binding of GRTPl by full length GR or a deletion mutant of GR that lacks the N-terminal activation domain AF-1. However in the absence of ligand, binding of GR to GRTPl (563-1121) increased by about 10-fold indicating that sequences in the GR N-terminus are able to suppress binding of unliganded GR to this additional binding site in GRTPl. Additionally, GR did not bind to a GRTPl (563-767) mutant in which both NR-box 2 and 3 are replaced by alanines, and binds most strongly to a fragment that lacks a functional NR-box 2. As with TR, GR does not recognize NR-box 1. In contrast to TR, the GR prefers NR-box 3 to NR-box 2. These results demonstrate that GR prefers binding to NR-box 3 and interacts with an additional GRTPl site within the CREB (Camp - response - element binding protein) - binding protein (CBP) binding site.

Example 12 Coactivator Peptide Binding Affinity For TR

To investigate whether the preference of TR for NR-box 2 is dependent on the sequence or structural context of the NR-boxes, competition studies on the interaction of GRTPl with hTRβ LBD were performed using coactivator peptides containing different NR- boxes (NR-box 2 peptide (residues 11-23 of SEQ TD NO: 6) EKHKILHRLLQDS, and NR- box 3 peptide (residues 9-21 of SEQ ID NO: 7) ENALLRYLLDKDD) (Figure 9). Consistent with the interaction of Htr LBDβ with GRTPl (563-767) NR-box mutants, a peptide containing NR-box 1 competes the interaction of GRTPl with hTRβ LBD only at very high concentrations (EC50 = 130 μM). Peptides containing either NR-box 2 or 3 compete GRTPl (563-767) efficiently and display the preference of hTRβ LBD for NR-box 2 (EC50 (NR-box 2) = 1.5 μM, EC50 (NR-box 3) = 4 μM). The apparent affinities (EC50) for peptides of NR-box 2 and 3 are comparable with the analogous GRTPl (563-767) NR- box mutants suggesting that the preference of TR for NR-boxes is solely dependent on the sequence and independent of the structural context of the NR-boxes.

Peptides of NR-box 2 or 3 compete GRTPl (563-767) containing functional NR-boxes 2 and 3 or a mutant of this fragment that contains only a functional NR-box 2 with comparable affinity. Thus, while TR can bind both NR-box 2 and 3, in a GRTPl coactivator peptide fragment containing both boxes, TR preferentially binds NR-box 2.

These results show the preference of TR for NR-box 2 is sequence dependent.

The same types of assays for TR competition are performed to assess coactivator peptide binding affinity for GR. The peptide concentrations are normalized relative to TR for obtaining comparable dose response curves.

Example 13 Binding Affinity of TR For Extended Coactivator Peptides

Sequence identity between all three central NR-boxes of the pi 60 coactivator family is limited to the conserved leucine residues of the (SEQ ID NO: 1) LxxLL motif (Figure 6). However, the sequence conservation of a particular NR-box can extend into neighboring residues. To investigate the contribution of these neighboring residues to affinity and specificity of the different NR-boxes for TR, the ability of peptides containing individual NR-boxes with different lengths of adjacent sequences to compete with the interaction of GRTPl (563-767) with hTRβ LBD were compared (Figure 10).

A peptide consisting of the minimal motif of NR-box 3/residues 12-17 of SEQ ID NO: 7; LLRYLL) does not compete the TR LBD interaction with GRTPl (563- 767). A peptide consisting of the NR-box 2 (residues 15-20 of SEQ JD NO: 6; TLHRLL) also does not sufficiently compete the interaction (data not shown). Extending peptides containing a (SEQ ID NO: 1) LxxLL motif to include adjacent residues increased affinity for both NR-box motifs and magnified the preference of TR for NR-box 2 (NR-box 2 peptides: (residues 11-23 SEQ TO NO: 6) EKHKILHRLLQDS and (residues 7-23 of SEQ ID NO: 6) TSLKEKHKILHRLLQDS; and NR-box 3 peptides: (residues 8-24 of SEQ ID NO: 7) KENALLRYLLDKDDTKD and (residues 5-24 of SEQ JD NO: 7) PKKKENALLRYLLDKDDTKD). A chimeric peptide containing the NR-box 3 motif in the context of the NR-box 2 flanking sequences (SEQ TD NO: 31; TSLKEKHKLLRYLLQDSS) binds like a NR-box 2 peptide.

These results demonstrates that preference of TR for NR-box 2 is at least partially due to features of the bound peptide (residues 15-20 of SEQ ID NO: 6; TLHRLL), but that their affinity and specificity is modulated by adjacent sequences.

Example 14 Binding Affinity of TR and GR for Mutant Coactivator

A) TR affinity for IlxxLL motif residues

To investigate the role of the hydrophobic residues in NR-box 2, individual residues of the (residues 15-20 of SEQ JD NO: 6) TLHRLL motif were replaced by alanine in the background of GRTPl (563-767) containing a non-functional NR-box 3 (Figure 11). Surprisingly, replacement of any of the conserved leucines prevents binding to TR almost completely. Only replacement of the nonconserved isoleucine exhibited a lessened but still severe impact on the affinity of NR-box 2 for TR. As replacement of a single leucine by alanine is sufficient to overcome the interaction of both the remaining hydrophobic residues and adjacent sequences with hTRβ LBD, it appears that their contribution to the affinity of NR-box 2 for hTRβ LBD is cooperative rather than additive.

Similar results were obtained by competing the interaction of hTRβ LBD with the GRTPl (563-767) NR-box 3 mutant using peptides in which either TL, HR or LL of the NR-box 2 motif are replaced by alanines (Figure 11). Whereas the peptides containing the TL or LL replacement failed to interact with the hTRβ LBD even at very high concentrations, in agreement with a proposed alpha-helical structure of the motif, replacement of the "HR spacer" by alanines showed a marginal effect on the affinity of the peptide for TR-LBD.

Replacement of single leucine residues of NR-box 2 by phenylalanine reduced the affinity of NR-box 2 peptides for TR LBD about 100-fold, replacement of the isoleucine about 10-fold (Figure 11). Therefore, the interaction of TR with GRTPl relies not simply on the hydrophobicity of the (SEQ ID NO: 1) LxxLL motif, but also on positive contributions by the leucine residues themselves.

These results demonstrate that single mutations of the conserved leucines in the (SEQ JD NO: 1) LxxLL motif strongly reduce affinity of GRTPl for hTRβ LBD.

Collectively, the above examples demonstrate that peptides containing NR- boxes, particularly NR-box 2, reproduce the affinity and specificity of the interaction of GRTPl (563-767) with hTRβ LBD.

B) TR affinity of FxxLW and FxxAL motif residues

The three conserved leucines of the NR-box 2 (SEQ JD NO: 2) IlxxLL motif are embedded in the hydrophobic cleft of the hTRβ LBD:NR-box 2 interaction surface, whereas the non conserved isoleucine is located on the rim of this cleft where structural changes can be more easily accommodated (See Example 18). In agreement with this structure, replacement of this residue by alanine or phenylalanine reduced binding to hTRβ LBD to a less extent than the comparable mutations of the conserved leucine residues. The surface generated by the three conserved leucines (L690, L693, L694) of the NR-box 2 peptide (residues 12-24 of SEQ ID NO: 6) 686-KHKILHRLLQDSS-698 is highly complementary to the coreesponding binding site in the hTRβ LBD (Figures 16 and 17). Comparison of this binding site to other nuclear receptors shows that it contains a structural motif that is unique, highly conserved and present in all known structures of nuclear receptor LBDs (Wurtz et al., Nat Struct Biol. (1996) 3:87-94; Wagner et al., supra; Renaud et al, Nature (1995) 375:681-689; Bourguet et al., Nature (1995) 375:377-382; and Brzozowski et al, Nature (1997) 359:753-758).

Interaction of highly conserved hydrophobic motifs, which are part of amphipathic alpha-helices, with complementary hydrophobic surfaces resembles a feature observed for the interaction of several other transcriptional activators with their target proteins (p53:MDM2, VP16:TAFIL31 or CREB:KTX-CBP). However, the motifs of p53 (FxxLW), VP16 (FxxAL) and CREB (YxxTL) differ from the (SEQ JD NO: 1) LxxLL motif of nuclear receptor coactivators. A Fxxxh motif may be generally involved in interaction with TAFTI31, where "h" represents any hydrophobic residue. Though with respect to the known structures, complementarity of the interacting hydrophobic surfaces identified here seem to be a common feature of these interactions, cross-reactions between different motifs are possible. For instance, VP16, p53, and p65 (FxxFL) are able to functionally interact with TAFIT31, or p53 and E2F1-DP1 (FxxLL) both interact with MDM2. These interactions are sensitive to mutations in the Fxxxh motif. Therefore it appears that either complementarity of the hydrophobic surfaces is not an absolute requirement or that induced fitting of the interacting surfaces is possible.

Based on these observations, studies were performed to determine whether GRTPl interacts with TAFII31 or MDM2. However, no interaction was detected. GRTPl mutants changing NR-box 2 ( SEQ JD NO: 1; LxxLL) to VP16 ( SEQ ID NO: 4; FxxAL) or p53 (SEQ JD NO: 3; FxxLW) like binding sites also failed to bind TAFTI31 or MDM2 demonstrating that the presence of the correct binding site is not sufficient to create binding (data not shown). Moreover, peptides containing the VP16 or p53 binding sites are not able to compete the interaction of GRTPl with TR, even in very high concentration, but do compete the interaction with GR (data not shown). The affinity of this interaction is weak, but comparable to affinity of a peptide of NR-box 2 that, in the context of a GRTPl mutant lacking NR-box 3, binds GR in vivo (Ding et al., supra). This binding is only about ten times less than a peptide containing NR-box 3, GR's primary binding site.

As shown above, GR binds GRTPl (563-767) with about one-fifth the affinity than a comparable amount of TR. Thus, the high concentration of NR-box 3 peptide required to compete the interaction of GR with GRTPl (563-767) may rather reflect a weak affinity of GR for the peptide rather than a particular strong interaction of GR with GRTPl (563-767).

These results suggest that at least on the peptide level, other hydrophobic motifs besides (SEQ JD NO: 1) LxxLL can interact with the coactivator binding site, but that it is receptor dependent. C) TR affinity for residues adjacent to IlxxLL motif

Peptides containing a FxxLL motif bind TR but with two orders of magnitude lower affinity than a (SEQ JD NO: 1) LxxLL motif (Figure 11). To test whether the additional changes in the hydrophobic motif or adjacent sequences of the VP16 peptide prevent its binding to TR, a chimeric peptide containing the NR box-2 motif (SEQ JD NO: 1) LxxLL in the context of the VP16 sequence was constructed. This peptide binds to TR but with an about 100-fold lower affinity than the original NR-box 2 peptide. Thus, the inability to bind the VP16 peptide appears to be due to the combination of an imperfect hydrophobic motif and the incompatibility of TR to adjacent sequences of the VP16 motif.

As the interaction of the chimeric peptide with GR was comparable to the original NR-box 2 and VP16 peptides, this incompatibility appears due to TR-specific features in the NR-box interaction surface. These results show sequences adjacent the NR- box motif LxxLL can reduce binding of NR-box 2 to TR, but not GR.

Example 15 Crystallization and Structure Determination of NR LBD Complexes

A) Crystallization of hTRβ LBD with T^ and GRIPl NR-box 2 Peptide

Several peptides containing GRTPl NR-box 2 were tested in crystallization trials with the hTRβ LBD. The complex of the hTRβ LBD with the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) produced crystals that were dependent on both the presence and the concentration of the peptide. Without the peptide, the hTRβ LBD precipitated immediately. However, nucleation was erratic, but could be overcome through seeding of prepared drops with microcrystals of the hTRβ LBD:GRTP1 NR-box 2 peptide complex. Structure of the hTRβ LBD:GRTP1 NR-box 2 peptide complex was determined by molecular replacement using the structure of the hTRβ LBD determined previously (Wagner et al., supra), and refined to a resolution of 3.6 A (Table 1). The refined model consists of residues K211-P254 and V264-D461 of monomer 1 of the hTRβ LBD, residues K211-P254 and G261-D461 of monomer 2 of the hTRβ LBD, and the GRTPl NR-box 2 peptides (residues 14-24 of SEQ JD NO: 6) 688- KTLHRLLQDSS-698, and (residues 14-22 of SEQ JD NO: 6) 688-KTLHRLLQD-696 (Appendix 1). Briefly, the complex between the hTRβ LBD and the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ ID NO: 6) was prepared by mixing (equal) volumes of a solution of 9mg ml hTRβ LBD in 20Mm HEPES Ph 7.4 with a solution of 14 Mm GRTPl in 0.4Mm ammonium acetate Ph 4.72, and incubating the mixture on ice for 1 hour. Crystals were obtained after 2 days at 4°C using hanging drop vapor diffusion from a drop containing 1.5μl of hTRβ LBD:GRTP1 complex, prepared as described, and 0.5μl 15%PEG 4K, 0.2M sodium citrate Ph 4.9, suspended above a reservoir containing 10% PEG 4K, 0.1M ammonium acetate, and 0.05 M sodium citrate (Ph 5.6). After allowing the drop to equilibrate for 1 hour, 0.2μl of 10-3 to 10-5 dilutions of microcrystals in reservoir buffer were introduced to provide nucleation. Crystals are of space group P3121 (a=95.2, b=95.2, c=137.6) and contain two molecules of the hTRβ LBD and two molecules of the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6).

Table 1. Data collection, phasing, and refinement statistics

R •,syπr ,= ∑_h ∑i I i_h,i u (7_h( I / Σ for the intensity (I) of i observations of reflection h.

Correlation coefficient ; ^■■ Σ_hEo²Ec² - Eo²Ec²l [∑_h (Eo₂ ■ 2x2-, 1/2

Eo ∑_h (Ec"-EcT]

Translation function (t_a, t_b, ...) = ∑_h (|£ø(h)|² - ∑h <\Eo^\²>) (Ec (h,t_a ,tb,...)|² - <|£c(h)|²) where E₀ represents the normalized observed structure factor amplitudes, and E_c represents the normalized structure factors for the search model in a triclinic unit cell with dimensions identical to that of the crystal. The reported peak height represents the value of the function for the translation (t_a, t_b) of the NCS monomers, divided by the rms value of the translation function density.

R factor = Σ | _obs - _caIc | / Σ | _obs |.

R_free is calculated the same as R factor, except only for 10% of the reflections that were set aside for cross validation and not used in refinement. B) Crystallization of Herα LBD with DES and GRIPl NR-box 2 Peptide

Crystals of a DES-Herα LBD-GRTPl NR-box 2 peptide complex were obtained by hanging drop vapor diffusion. Prior to crystallization, the DES-Herα LBD (residues 297-554) complex was incubated with a 2-4 fold molar excess of the GRTPl NR- box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) for 7-16 hr. Two μL samples of this solution were mixed with equal volume samples of reservoir buffer consisting of 25-27% (w/v) PEG 4000, 90 Mm Tris (Ph 8.75-9.0) and 180 Mm Na Acetate and suspended over wells containing 800 μL of the reservoir buffer. After 4-7 days at 19- 21°C, rod-like crystals were obtained. The coactivator complex crystals lie in the spacegroup P2χ with cell dimensions a=54.09, b=82.22, c=58.04 and β=l 11.34. Two molecules each of the DES-LBD and the coactivator peptide form the asymmetric unit. A 200 μm x 40 μm x 40 μm crystal was transferred to a cryosolvent solution containing 25% (w/v) PEG 4000, 10% (w/v) ethylene glycol, 100 Mm Tris (Ph 8.5), 200 Mm Na Acetate and 10 μM peptide and frozen in an N₂ stream at -170°C in a rayon loop. Diffraction data from this crystal were measured at -170°C using a 300 mm MAR image plate at the Stanford Synchrotron Radiation Laboratory (SSRL) at beamline 7-1 at a wavelength of 1.08 A. The diffraction images were processed with DENZO and scaled with SCALEPACK (Otwinowski, et al., Methods Enzymol. (1997) 276:307-326) using the default -3σ cutoff.

C) Crystallization of Herα LBD with OHT

Crystals of the Herα LBD (residues 297-554) complexed to OHT were obtained by the hanging drop vapor diffusion method. Equal volume aliquots (2 μL) of a solution containing 3.9 mg/Ml protein-ligand complex and the reservoir solution containing 9% (w/v) PEG 8000, 6% (w/v) ethylene glycol, 50 Mm HEPES (Ph 6.7) and 200 Mm NaCl were mixed and suspended over 800 μL of the reservoir solution. Hexagonal plate-like crystals formed after 4-7 days at 21-23°C. Both crystal size and quality were improved through microseeding techniques. These crystals belong to the space group P6₅22 with cell parameters a=b=58.24 A and c=277.47 A. The asymmetric unit consists of a single Herα LBD monomer; the dimer axis lies along a crystallographic two-fold. A single crystal (400 μm x 250 μm x 40 μm) was briefly incubated in a cryoprotectant solution consisting of 10% (w/v) PEG 8000, 25% (w/v) ethylene glycol, 50 Mm HEPES (Ph 7.0) and 200 Mm NaCl and then flash frozen in liquid N₂ suspended in a rayon loop. Diffraction data were measured at -170°C using a 345 mm MAR image plate at SSRL at beamline 9-1 and at a wavelength of 0.98 A. The diffraction images were processed with DENZO and scaled with SCALEPACK (Otwinowski, et al., supra) using the default -3σ cutoff.

Example 16 Structure Determination and Refinement of NR LBD Complexes

A) Structure of hTRβ LBD with T^ and GRIPl NR-box 2 Peptide

Data were measured using Cu Ka radiation from an R-axis generator at 50 Kv and 300 Ma with a 0.3Mm collimator and a Ni filter. Reflections were measured using an R-Axis II detector and integrated with Denzo, and equivalent reflections scaled using Scalepack (Otwinowski and Minor, "Processing of x-ray diffraction data collected in oscillation mode." In Macromolecular Crystallography, Part A (ed. C.W. Carter, Jr. and R.M. Sweet), pp. 307-326. Academic Press, New York, NY). Possible rotation function solutions were calculated using normalized amplitudes in AMORE from a model of hTRβ LBD with the ligand, T₃, omitted; translation function solutions were subsequently determined using TFFC for the two rotation solutions with the highest correlation coefficients. For two hTRβ LBD molecules in the asymmetric unit, the calculated solvent content is 52%. After rigid body refinement of the two hTRβ LBD molecules, electron density maps were calculated. Strong positive density present in both the anomalous and conventional difference Fourier maps for the iodine atoms of the T₃ ligand confirmed the conectness of the solution. The iodine atoms for both T₃ ligands were modeled as a rigid body, and the structure refined with strict NCS symmetry using CNS. Both 2FoFc and FoFc electron density maps showed interpretable density, related by the NCS operator, near H12 of both molecules of the hTRβ LBD. The electron density could be modeled as a short α-helix, and the observed side chain density was used to tentatively assign the sequence and direction to the chain. The refined model consists of residues of the hTRβ LBD, and peptide residues of the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6). Atomic coordinates of the hTRβ LBD:GRP1 site 2 peptide complex are attached as Appendix 1.

B) Structure of Herα LBD with DES and GRIPl NR-box 2 Peptide

Initial efforts to determine the structure of the DES-Herα LBD-NR box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) complex utilized a low resolution (3.1 A) data set (data not shown). A self -rotation search implemented with POLARRFN ("The CCP4 suite: programs for protein crystallography", Acta Crystallogr. (1994) D50:760-763) indicated the presence of a noncrystallographic dyad. The two LBDs in the asymmetric were located by molecular replacement in AmoRe (CCP4, 1994) using a partial polyalanine model of the human RARγ LBD (Renaud, et al., supra) as the search probe (R=58.2%, CC=35.6% after placement of both monomers). Given that the model at this point was both inaccurate (r.m.s.d. 1.7 A between this model and the final model based on Cα positions) and incomplete (accounting for only -45% of the total scattering matter in the asymmetric unit), an aggressive density modification protocol was undertaken. Iterative cycles of two-fold NCS averaging in DM (CCP4, 1994) interspersed with model building in MOLOC (Muller, et al., Bull. Soc. Chim. Belg. (1988) 97:655-667) and model refinement in REFMAC (Murshudov, et al., Acta Crystallogr. (1997) D53:240-255) (using tight NCS restraints) were used to quickly build a model of the LBD alone. For this procedure, MAMA (Kleywegt, et al., "Halloween...masks and bones. In From First Map to Final Model", Bailey, et al, eds., Warrington, England, SERC Daresbury Laboratory, 1994) was used for all mask manipulations and PHASES (Furey, et al., PA33 Am. Cryst. Assoc. Mtg. Abstr. (1990) 18:73) and the CCP4 suite (CCP4, 1994) were used for the generation of structure factors and the calculation of weights.

However, although the DES-Herα LBD-NR complex model accounted for -90% of the scattering matter in the asymmetric unit, refinement was being hampered by severe model bias. The high-resolution data set of the DES-Herα LBD-NR-box 2 peptide complex became available when the R_fr_ee of the OHT-Herα LBD model was -31%. Both monomers in the asymmetric unit of the DES complex crystal were relocated using AmoRe and the incompletely refined OHT-Herα LBD model (with helix 12 and the loop between helices 11 and 12 removed) as the search model. The missing parts of the model were built and the rest of the model was conected using MOLOC and two-fold averaged maps generated in DM. Initially, refinement was carried out with REFMAC using tight NCS restraints. At later stages, the model was refined without NCS restraints using the simulated annealing, minimization and B -factor refinement protocols in X-PLOR and a maximum- likelihood target. All B-factors were refined isotropically and anisotropic scaling and a bulk solvent correction were used. The R_free set contained a random sample of 6.5% of all data. In refinement, all data between 27 and 2.03 A (with no σ cutoff) were used. The final model was composed of residues 305-549 of monomer A, residues 305-461 and 470-554 of monomer B, residues 687-697 of peptide A, residues 686-696 of peptide B, 164 waters, two carboxymethyl groups and a chloride ion. According to PROCHECK, 93.7% of all residues in the model were in the core regions of the Ramachandran plot and none were in the disallowed regions. Thus, the structure of the DES-Herα LBD-NR-box 2 peptide complex has been refined to a crystallographic R-factor of 19.9% (R_free=25.0%) using data to 2.03 A resolution.

Tie 689 from the peptide interacts with three receptor residues (Asp 538, Glu 542 and Leu 539). The γ-carboxylate of Glu 542 forms hydrogen bonds to the amides of residues 689 and 690 of the peptide. A water-mediated hydrogen bond network is formed between the imidazole ring of His 377, the γ-carboxylate of Glu 380, and the amide of Tyr 537. Three residues (Glu 380, Leu 536 and Tyr 537) interact with each other through van der Waals contacts and/or hydrogen bonds. Intriguingly, mutations in each these three residues dramatically increase the transcription activity of unliganded ERα LBD (Eng, et al., Mol. Cell. Biol. (1997) 17:4644-4653); Lazennec, et al., Mol. Endocrinol. (1997) 11:1375-86; White, et al., EMBO J. (1997) 16:1427-35). Atomic coordinates of DES-LBD- peptide complex are attached as Appendix 2.

Table 2. Summary of Crystallographic Statistics

Ligand

Data Collection DES OHT

Space group P2ι P6₅22

Resolution 2.03 1.90

Observations 104189 269253

Unique 30265 23064

Completeness (%) 98.4 99.1

Rsym(%)^a 7.8 7.0

Average I/σl 9.8 16.1

Refinement

Number of non-hydrogen atoms 4180 2070

Rcryst (%) /R&ee (%) 19.9/25.0 23.0/26.1

Bond r.m.s. deviation (A)0.006 0.006

Angle r.m.s. deviation (°)1.05 1.05

Average B factor (A²) 34.0 40.4

Rs m =∑i I Ii- <Ii> I / ∑A where <Iι> is the average intensity over symmetry equivalents

Rcryst = Σ I F₀ - F_c I / ∑ I F₀ 1

C) Structure of Herα LBD-OHT complex

The OHT complex data set was then collected. Starting with one of the monomers of the preliminary low-resolution DES-Herα LBD-NR-box 2 peptide model as the search probe, molecular replacement in AmoRe was used to search for the location of LBD in this crystal form in both P6_t22 and P6₅22. A translation search in P6₅22 yielded the conect solution (R=53.8%, CC=38.2%). In order to reduce model bias, DMMULTI (CCP4, 1994) was then used to project averaged density from the DES complex cell into the OHT complex cell. Using MOLOC, a model of the Herα LBD was built into the resulting density. The model was refined initially in REEMAC and later with the simulated annealing, positional and B -factor refinement protocols in X-PLOR (Brunger, X-PLOR Version 3.843, New Haven, Connecticut: Yale University, 1996) using a maximum- likelihood target (Adams, et al., Proc. Natl. Acad. Sci. USA (1997) 94:5018-23). Anisotropic scaling and a bulk solvent conection were used and all B-factors were refined isotropically. Except for the R_fj._ee set (a random sampling consisting of 8% of the data set), all data between 41 and 1.9 A (with no σ cutoff) were included. The final model consisted of residues 306-551, the ligand and 78 waters. According to PROCHECK (CCP4, 1994), 91.6% of all residues in the model were in the core regions of the Ramachandran plot and none were in the disallowed regions. Thus, the structure of the OHT-Herα LBD complex has been refined against data of comparable resolution (1.90 A) to a crystallographic R- factor of 23.0% (R_free=26.2%). Atomic coordinates of OHT-Herα LBD complex are attached as Appendix 3.

Example 17 Structural Analysis of hTRβ LBDrGRIP 1 NR-Box 2 Peptide Complex

A) Structure of cocrystal complex (contents of asu)

The asymetric unit (asu) of the crystal contains two monomers of the hTRβ LBD and two molecules of the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6), which observes the NCS relation of the two TR monomers (Figure 12). The structure of the hTRβ LBD, which closely resembles that of the Rtrα LBD (Wagner et al., supra), consists of twelve alpha-helices and two β-strands organized in three layers, resembling an alpha-helical sandwich. The only significant difference between the hTRβ LBD and the Rtrα LBD is disorder in the loop between helices HI and H3. The GRTPl NR-box 2 peptide forms an amphipathic α-helix of about 3 turns, preceded by 2 residues and followed by 3 residues in extended coil conformation.

The relation of the two monomers of the hTRβ LBD is primarily translational, and does not resemble the homodimer structures reported for the Hrxr, or the Her (Bourguet et al., supra; Brzozowski et al., supra). Furthermore, the interface between the two monomers does not involve residues necessary for formation of the physiological TR dimer. Instead, one of the cocrystal peptides appears to bridge the interaction between the two monomers. The hydrophobic face of the alpha-helix of the cocrystal peptide contacts monomer 1 of the hTRβ LBD at H3, H5, and HI 2, while the hydrophilic face contacts monomer 2 at the hairpin turn preceding strand S3. The second cocrystal peptide also contacts monomer 2 at H3, H5, and H12, and the two cocrystal peptides observe the same NCS relation as TR LBD monomers.

The common interface between both cocrystal peptides and the hTRβ LBD buries the hydrophobic residues that define the cocrystal peptide (SEQ JD NO: 1) LxxLL sequence motif, residues Tle689, Leu690, Leu693, and Leu694; against the surface of the receptor LBD (Figures 16 and 17). The presence of the second peptide in the crystal, duplicating the interactions of the hydrophobic residues, suggests those interactions are specific and drive the interaction of the peptide with the hTRβ LBD, while the hydrophilic interactions provide a fortuitous crystal contact and account for the dependence of crystallization on the presence and concentration of the peptide.

B) Structure of the GRIPl NR-box 2 peptide

The GRTPl NR-box 2 peptide used in the crystallization is 13 amino acids long (residues 12-24 of SEQ JD NO: 6; 686-KΗKTLHRLLQDSS-698). For the NR-box 2 peptide in monomer 1 (peptide 1), 12 amino acids are ordered in the crystal. Residues K688 - Q694 form an amphipathic helix, with residues K686-H687 and D695-S698 on either end in extended coil conformations. For the NR-box 2 peptide in monomer 2 (peptide 2), residues K688 - Q694 again form an amphipathic helix, but the ends of the peptide are disordered. While the resolution of the current data prevents absolute assignment of hydrogen bonds, it is evident from the periodicity of the side chain density that the central residues form an alpha-helix. In the absence of TR the far UV-CD spectrum of the GRTPl NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) appears to be random coil (data not shown). Stable helix formation may thus be induced by the interaction of the hydrophobic amino acids with the receptor LBD as it has been proposed in other proteimprotein interactions, such as p53:MDM2 (Kussie et al., Science (1996) 274:948-953), VP16:TAF31 (Uesugi et al., Science (1996) 277:1310-1313), and CREB:KIX-CBP (Radhakrishnan et al., Cell (1997) 97:741-752). C) Structure of the hTRβ LBD:GRIP1 NR-box 2 peptide interface

The hTRβ LBD of the cocrystal contributes residues from three helices, H3, H5, and H12 to the interface, which pack against one another to create a hydrophobic cleft. The residues lining the cleft are 1280, T281, V283, V284, A287, and K288 from H3; Q301, 1302, L305, and K306 from H5; and L454, E457, V458, and F459 from H12. A cysteine residue (C309) from H6 appears to provide a partial surface that is buried deep within the bottom of the cleft.

The GRTPl NR-box 2 peptide 686-KHKILHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) binds at the junction of H3 and H12. Leu690 of the bound peptide inserts into a shallow but defined depression at the base of the cleft, making van der Waals contact with L454 and V458 of H12, while peptide residue Tle689 packs against L454 of H12 outside the edge of the cleft; L454, then, interdigitates between the two residues. One further turn C-terminal along the alpha-helix, L693 and L694 of the bound peptide pack into complementary pockets within the hydrophobic cleft. Peptide residue L693 forms van der Waals contact with V284 of H3, while peptide residue L694, bound more deeply in the cleft, makes contact with F298 and L305 of H4 and H5. The hydrophobic interactions of the GRTPl NR-box 2 peptide with the hTRβ LBD are observed for both cocrystal peptides 1 and 2 in their respective monomers of the crystal dimer complex, suggesting that the interactions are specific to the peptide, and not induced by crystallization.

Example 18 Overall Structure of the DES-Herα-LBD-NR-box 2 Peptide Complex

The asymmetric unit of the DES-Herα LBD-NR-box 2 peptide 686- KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) complex crystals contains the same noncrystallographic dimer of LBDs that has been observed in the previously determined structures of the LBD bound to both E and RAL (Brzozowski, et al., supra and Tanenbaum, et al., supra). Beyond the flexible loops between helices 2 and 3 and helices 9 and 10, the two LBDs of the dimer adopt similar structures (r.m.s.d. 0.47 A based on Cα positions). The conformation of each LBD complexed with DES closely resembles that of the LBD bound to E₂ (Brzozowski, et al., supra); each monomer is a wedge shaped molecule consisting of three layers of eleven to twelve helices and a single beta hairpin. In each LBD, the hydrophobic face of helix 12 is packed against helices 3,.5/6 and 11 covering the ligand binding pocket. One NR-box 2 peptide is bound to each LBD in a hydrophobic cleft composed of residues from helices 3, 4, 5 and 12 and the turn between 3 and 4. The density for both peptides in the asymmetric unit is continuous and unambiguous. Residues 687 to 697 from peptide A and residues 686 to 696 from peptide B have been modeled; the remaining residues are disordered. Given that each peptide lies within a different environment within the crystal, it is striking that from residues He 689 to Gin 695 each peptide forms a two turn, amphipathic α helix. Flanking this region of common secondary structure, the peptides adopt dissimilar random coil conformations.

Example 19 Structure of the OHT-Herα LBD Complex

The binding of OHT induces a conformation of the Herα LBD that differs in both secondary and tertiary structural organization from that driven by DES binding. In the DES complex, the main chain from residues 339 to 341, 421 to 423, and 527 to 530 form parts of helices 3, 8 and 11 respectively. In contrast, these regions adopt an extended conformation in the OHT complex. In addition, the composition and orientation of helix 12 are different in the two structures. Helix 12 in the DES complex consists of residues 538 to 546 whereas helix 12 in the OHT complex consists of residues 536 to 544. Most dramatically, rather than covering the ligand binding pocket as it does in the DES complex, helix 12 in the OHT complex occupies the part of the coactivator binding groove formed by residues from helices 3, 4, and 5, and the turn connecting helices 3 and 4. This alternative conformation of helix 12 appears to be similar to that observed in the RAL complex (Brzozowski, et al., supra).

Example 20 Coactivator Binding Site Structure And Function

TR coactivator binding site

The above examples demonstrate that nuclear receptors, exemplified by TR, GR and ER, are recognized by specific coactivators that bind thereto through a coupling surface comprising a hydrophobic cleft and a charged hydrophobic perimeter. Identification and characterization of this coupling surface and the coactivator binding site of nuclear receptors offers a new target for the design and selection of compounds that modulate binding of coactivator to nuclear receptors.

Residues forming the coactivator binding site were found to cluster within a surprisingly small area with well-defined borders (see, e.g., Figures 5, 14, and 15). As is shown in above Examples, mutated residues nearby this area do not affect coactivator binding or transcriptional activation. Additionally, the coactivator binding assays and structural analyses demonstrated that NR-box containing proteins and peptides bind to this site. These results also showed that the GRTPl coactivator protein binds to the site through a highly (SEQ JD NO: 1) LxxLL.

The structural analyses showed that residues contacting a conserved leucine residue of the (SEQ JD NO: 1) LxxLL motif included V284, F293, 1302, L305 and L454. Residues within 4.5A of an atom of the bound peptide included T281, V284, K288, F293, Q301, 1302, L305, K306, P453, L454 and E457. Structural analyses also revealed two other features of the site: a hydrophobic residue from helix 12 (Phe459) that contributes to local packing, and a cysteine residue contributed by helix 6 (Cys309) that provides a partial surface buried deep within the site. Mutational analyses showed that residues which block GRTPl and SRC-1 coactivator binding when mutated are residues V284, K288, 1302, K306, L454, and V458. Mutated residues likely to undergo a conformational change upon hormone binding included Leu454 and Glu457. Thus, the site identified by mutational, binding assays and crystallography conesponds to a surprisingly small cluster of residues on the surface of the LBD that define a prominent hydrophobic cleft formed by hydrophobic residues conesponding to human TR residues of C-terminal helix 3 (Tle280, Val283, Val284, and Ala287), helix 4 (Phe293), helix 5 (Lle302 and Leu305), helix 6 (Cys309), and helix 12 (Leu454, Val458 and Phe459). Collectively, the Examples indicate that residues forming the site are amino acids conesponding to human TR residues of C-terminal helix 3 OQe280, Thr281, Val283, Val284, Ala287, and Lys288), helix 4 (Phe293), helix 5 (Gln301, Tle302, Leu305, Lys306), helix 6 (Cys309), and helix 12 (Pro453, Leu454, Glu457, Val458 and Phe459). The coactivator binding site is highly conserved among the nuclear receptor super family (Figure 19).

The coactivator binding site of TR contains charged and hydrophobic residues at its periphery, but only hydrophobic residues at its center (see, e.g., Figures 5 and 18). The hydrophobic cleft at the center of the site may play a significant role in driving the coactivator binding reaction. The site is comprised of two parts (Figure 18), right). Residues contained in helices 3, 5 and 6 (Figure 18, yellow residues) likely form a constitutive part, since their positions are identical in all nuclear receptor structures reported, including the liganded, activated states of the TR, RAR, and ER, the unliganded RXR, and the inhibitor-liganded ER. By contrast, the residues of helix 12 (Figure 18, red residues) are differently positioned in the active and inactive states reported. Thus the coactivator binding site for the nuclear receptors is likely to be formed in response to an active hormone by positioning helix 12 against a scaffold formed by helices 3-6. Because the coactivator binding site is so small, it is easy to understand how even slight changes in the position of helix 12, which may, for example, be induced by an antagonist ligand, could impair coactivator binding, and thus receptor activation.

A) ER coactivator binding site

Binding of the NR-box 2 peptide 686-KHKILHRLLQDSS-698 (residues 12- 24 of SEQ JD NO: 6) to the ERα LBD buries 1000 A² of predominantly hydrophobic surface area from both molecules. The NR-box 2 peptide binding site is a shallow groove composed of residues Leu 354, Val 355, He 358, Ala 361 and Lys 362 from helix 3; Phe 367 and Val 368 from helix 4; Leu 372 from the turn between helices 3 and 4; Gin 375, Val 376, Leu 379 and Glu 380 from helix 5; and Asp 538, Leu 539, Glu 542 and Met 543 from helix 12. The floor and sides of this groove are completely nonpolar, but the ends of this groove are charged. Therefore, structural characterization of the binding site of the NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) to the ERα LBD, which is the same NR-box 2 peptide utilized to crystallize the T₃-TR LBD, supports the findings for TR that residues forming the coactivator binding site of nuclear receptors is composed of a well defined hydrophobic cleft and a charged hydrophobic perimeter. These residues are highly conserved among the nuclear receptor super family (Figure 19). Structural characterization of the coactivator peptide-bound ER LBD also supports the concept of exploiting the slight differences among the coactivator binding sites of nuclear receptors in designing and identifying compounds that target specific nuclear receptors.

The ERα LBD interacts primarily with the hydrophobic face of the NR-box 2 peptide 686-KHKTLHRLLQDSS-698 (residues 12-24 of SEQ JD NO: 6) α helix formed by the side chains of Tie 689 and the three (SEQ JD NO: 1) LxxLL motif leucines (Leu 690, Leu 693 and Leu 694). The side chain of Leu 690 is deeply embedded within the groove and forms van der Waals contacts with the side chains of He 358, Val 376, Leu 379, Glu 380 and Met 543. The side chain of Leu 694 is similarly isolated within the groove and makes van der Waals contacts with the side chains of He 358, Lys 362, Leu 372, Gin 375, Val 376 and Leu 379. In contrast, the side chains of both De 689 and the second NR box leucine, Leu 693, rest against the rim of the groove. The side chain of Tie 689 lies in a shallow depression formed by the side chains of Asp 538, Leu 539 and Glu 542. The side chain of Leu 693 makes nonpolar contacts with the side chains of Tie 358 and Leu 539.

The charged and polar side chains which form the hydrophilic face of the peptide helix project away from the ERα receptor and either interact predominantly with solvent or form symmetry contacts. None of the side chains of the polar and charged residues outside the helical region of either peptide in the asymmetric unit, with the exception of Lys 688 of peptide B, is involved in hydrogen bonds or salt bridges with its associated ERα LBD monomer. The ε-amino group of Lys 688 of peptide B hydrogen bonds to the side chain carboxylate of Glu 380 of monomer B. This interaction is presumably a crystal artifact; the main chain atoms of the N-terminal three residues of peptide B are displaced from monomer B and interact extensively with a symmetry-related ERα LBD.

In addition to interacting with the hydrophobic face of the peptide helix, the ERα LBD stabilizes the main chain conformation of the NR box peptide by forming capping interactions with both ends of the peptide helix. Glu 542 and Lys 362 are positioned at opposite ends of the peptide binding site. The side chains of Glu 542 and Lys 362 form van der Waals contacts with main chain and side chain atoms at the N- and C- terminal turns of the peptide helix respectively. These interactions position the stabilizing charges of the γ-carboxylate of Glu 542 and ε-amino group of Lys 362 near the ends of the NR box peptide helix. The side chain carboxylate of Glu 542 hydrogen bonds to the amides of the residues of N-terminal turn of the peptide helix (residues 688 and 689 of peptide A; residues 689 and 690 of peptide B). Similarly, the ε-amino group of Lys 362 hydrogen bonds to the carbonyls of the residues of the C-terminal turn of the peptide helix (residue 693 of peptide A; residues 693 and 694 of peptide B). Except for the orientation of helix 12, the structure of the peptide binding groove of the ERα LBD is almost identical in the DES and OHT complexes. The region of this groove outside of helix 12 is refened to herein as the "static region" of the NR box binding site. Helix 12 in the OHT complex and the NR box peptide helix in the DES complex interact with the static region of the coactivator recognition groove in strikingly similar ways.

Helix 12 mimics the hydrophobic interactions of the NR box peptide with the static region of the groove with a stretch of residues (residues 540 to 544) that resembles an NR box ((residues 6-10 of SEQ JD NO: 43) LLEML instead of (SEQ JD NO: 1) LxxLL). The side chains of Leu 540 and Met 543 lie in approximately the same locations as those of the first and second motif leucines (Leu 690 and Leu 693) in the peptide complex. Leu 540 is inserted into the groove and makes van der Waals contacts with Leu 354, Val 376 and Glu 380. Met 543 lies along the edge of the groove and forms van der Waals contacts with the side chains of Leu 354, Val 355 and He 358. The side chain position of Leu 544 almost exactly overlaps that of the third NR box leucine, Leu 694. Deep within the groove, the Leu 544 side chain makes van der Waals contacts with the side chains of De 358, Lys 362, Leu 372, Gin 375, Val 376 and Leu 379.

Helix 12 in the OHT complex is also stabilized by N- and C-terminal capping interactions. Lys 362 interacts with the C-terminal turn of helix 12 much as it does with the equivalent turn of the peptide helix. The Lys 362 side chain packs against the C- terminal turn of the helix 12 with its ε-amino group hydrogen bonding to the carbonyls of residues 543 and 544. Given that the capping interaction at the N-terminal turn coactivator helix is formed by a helix 12 residue (Glu 542), the N-terminal turn of helix 12 in the antagonist complex is forced to interact with another residue, Glu 380. The Glu 380 γ- carboxylate forms van der Waals contacts with Tyr 537 and interacts with the amide of Tyr 537 through a series of water-mediated hydrogen bonds.

In addition to forming these "NR box-like" interactions, helix 12 also forms van der Waals contacts with areas of the ERα LBD outside of the coactivator recognition groove. The side chain of Leu 536 forms van der Waals contacts with Glu 380 and Trp 383 and that of Tyr 537 forms van der Waals contacts with His 373, Val 376 and Glu 380. As a result of these contacts, helix 12 in the OHT complex buries more solvent accessible surface area (-1200 A²) than the NR box peptide in the DES-ERα LBD-peptide complex.

Example 21 Covalently Conformationally Constrained Peptides

For small flexible peptides, such as peptide hormones, and disordered regions of larger proteins, such as the NR boxes of the pl60 coactivators, the entropic cost of organizing the peptide backbone into the required fold is high. The introduction of constraints into the system has been widely utilized to both define active conformations and increase affinity for receptors A number of approaches have been reported for constraining peptides to pseudohelical conformations. These approaches have included conformational restriction using sterically demanding amino acids chimeric peptide motifs, covalent crosslinks between side chains and others. These methods have been applied to dissection of the molecular details of protein ligand interactions; particularly in the cases of opioid receptors, parathyroid hormone receptors, [54, 55, 57, 64] other membrane receptors, [21, 32, 65, 66] transcription factors, [24-26, 59, 67-69] and other systems of biological interest. [32, 34, 65, 70-73] One of the most successful approaches has involved the formation of macrolactams including the side chain of lysine and glutamic acid or aspartic acid in an i to i+3, i to i+4 of the i to Ϊ+7 relationship [19, 32-34, 40, 47, 49-51, 53-57, 64]. Studies with bridged calcitonin analogs [34, 74] and opioid receptor ligands [18, 60] have clearly shown that the helix stabilizing abilities of covalent constraints vary with the flanking sequences and the bridging group, and that these effects cannot be predicted by a particular model.

A series of methods covalently constraining the NR boxes to a pseudo- helical conformation were evaluated. Examination of the structure of the second NR box of GRTPl bound to the hTRβ revealed several potential sites for incorporation of such lactam constraints that did not appear likely to perturb the α-helical geometry of the peptide or sterically occlude binding to the TR. A series of these compounds (see Figure 20) were synthesized by solid phase peptide synthesis. Thus, elaboration of a preloaded Wang resin by the standard Fmoc protocols gave the linear 13 amino acid peptide which contains allyl ester protected acid groups and allyloxycarbamate (alloc) protected lysines that can be deprotected in the presence of the other blocking groups and the resin. Selective removal of the orthogonal protecting groups with palladium catalysis revealed the acid and amine functionalities which were then coupled with PyBOP to form the first lactam bridges. Finally, concomitant deprotection of all remaining protecting groups and cleavage from the polymer resin gave the desired constrained peptides. After purification by RP-HPLC, the structures were confirmed by MALDI mass spectrometry, giving the expected exact mass, and MSⁿ sequencing.

Examination of the circular dichroism spectra of these compounds in aqueous solution indicated that most constraints did not enforce a particularly high degree of α-helical character upon the peptides (Figure 20). However, one peptide, TG-17 9, did exhibit significant helicity based upon the ratios of ellipticy at 192, 209, and 222 nm. Further structural study of this compound using NOES Y NMR techniques revealed four amide proton resonances that show amide-amide (i, i+1) crosspeaks characteristic for peptide amides in an α-helical fold. This result was reinforced by the observation of coupling of these signals with α-backbone protons with coupling constants of approximately 4.5 Hz, well within the range normally exhibited by α-helical segments of proteins. This study confirmed the presence of helical conformation in ca. 30% of the peptide. Such data could arise either from a single stable conformation of the constrained peptide or from averaging the data from several energetically accessible conformers that were rapidly interconverting. Over the temperature range of 4 °C to 50 °C, the helicity induced in peptide 9 by the constraint was constant while peptide 1 showed no helical character, even at the lower temperatures. TGI 7 thus enforces helical character in macrolactam region of the peptide and this constraint induces a single dominant conformation.

Example 22 Helical Analog of GRIPl NR Box as Efficient Competitor for Binding to hTRBeta

The effects of the covalent helical constraint upon the effective ability of the peptides to compete for binding to hTRβ was studied. This was initially assayed using the fluorescence anisotropy assay (Figure 21). In the assay, probe (2) does not bind to TR in the absence of thyroid hormone indicating that the hTRβ was functioning normally. Linear peptide 1 successfully competed for binding to hTRβ with the labeled probe and the success of this competition was dependent upon an intact NR box with scrambled peptide 3 not competing for binding to the receptor. The relative inhibitory abilities of the constrained peptides closely mirrored the relative degree of α-helical character exhibited in the CD studies. Thus, TG-17 (9) was the only constrained peptide to exhibit significantly increased competitive ability relative to the linear probe. The rest of the materials (peptides 4-8) ranged from not significantly better than linear peptide 1 to significantly worse than 1. These results indicate that the binding of the NR box to the receptor does indeed involve an induced fit of the peptide into a helical conformation. Furthermore, they indicate that a conformationally rigid analog of the NR box that presents the leucine triad in the conect geometry will bind to the receptor with a higher affinity than the linear NR box peptide. The observed 15-fold increase in binding constant is in good agreement with prior results using similar constraints in other systems.

Exhibit 23 TG17 Blocks the Interaction of the Nuclear Receptor Interaction Domain of GRIPl and hTRβ

The ability of TGI 7 to block a more intact interaction than the simple binding of coactivator peptide was evaluated. This property was tested using the semiquantitative GST pulldown assay (Figure 22). In this assay, the binding of hTRβ to the immobilized GRTPl NTD was dependent upon the presence of T3, indicating that the receptor was functioning normally (Lanes 2 and 3). This control also indicates that the overall efficiency of pulldown is approximately 10%, in comparison to a normalized loading control (Lane 1). The interaction of receptor and co-activator could be blocked by the linear NR Box peptide 1 at high but not low concentrations (Lanes 4 and 5), although saturation has not been achieved at the highest concentration tested (100 μM). The interaction was not blocked by the sequence-scrambled peptide 3, even at high concentrations (Lane 6). These controls indicate that the interaction behaves normally under these assay conditions. Increasing concentrations of TG-17 (9) successfully blocked binding of the receptor to the immobilized GRTPl NTD with complete saturation having been reached by a concentration of 10 μM. Thus, the results of the semi-quantitative assay with intact proteins minor those of the peptide binding assay and indicate that TG-17 (9) can efficiently block the interaction of the receptor and coactivator proteins. Example 24 TG-17 Can Be Efficiently Produced In A Library Format.

It has been established that TG-17 functions as a competitive inhibitor of GRTPl binding. Its synthesis was adapted to the format needed for the production of combinatorial libraries. The coupling reactions, deprotections, lactam formation, and cleavage reaction were optimized so that the material can be produced in good yield (approximately 60%) and purity (>85%) after cleavage and purification by precipitation in the block. The parallel synthesis of ten samples of TG-17 carried out on the 50 μM scale in ten wells of a Robbins 96 well parallel synthesis apparatus. A set of peptides can be produced in less than a week. Analysis of these samples after cleavage and purification by precipitation revealed the same degree of purity as with other manual syntheses (>85%). When the resulting inhibitors were tested in the fluorescence assay, they revealed a high degree of homogeneity in response, showing less than twofold variation in IC₅₀. The effects of peptide length were also evaluated. The constrained peptide can be shortened to a total length of 9 residues without any loss of binding affinity. However, shortening the peptide can result in a substantial increase in the side reaction of dimerization during the macrolactam formation and also significantly lowers the efficiency of purification by precipitation. Thus in a prefened embodiment, the length of the peptide is as shown in TG- 17, which gives good purity peptide without requiring additional purification after precipitation.

Example 25 The Design of Scaffolds and Peptidomimetics

The geometric information from the crystal structure of the GRTPl peptide bound to hTRβl was used to design chemical scaffolds that present pendant substituents to the three pockets normally occupied by the leucine side chains of the LxxLL triad. CAVEAT was used to search databases of three-dimensional molecules using queries formed from geometric descriptors defined by vectors from the alpha and beta carbons of leucines 690, 693 and 694 of GRTPl. Searches were performed over databases obtained from Molecular Design Ltd. (MDL), the Available Chemical Directory (ACD), Pergamon's Comprehensive Medicinal Chemistry (CMC), and the MDL Drug Data Report (MDDR). DOCK 4.0.1 was used to remove potential scaffolds that matched the vector queries but which had Van der Waals clashes with the receptors. This procedure generated several potential scaffolds of which two were chosen for further optimization (Figure 23).

Libraries of compounds from scaffolds were designed to approximate the conect geometry of the GRTPl helix to find leads that can be optimized into useful competitive inhibitors. To direct these synthetic efforts, docking methods were used to define a subset of functional groups that might enhance binding of the scaffolds to the desired pocket. CombiDOCK was used to evaluate several virtual combinatorial libraries. Libraries containing combinations of functional groups at the linkage points of the scaffold were created and docked to the receptor site. This led to the definition of the general structures in Figure 23.

The screening of these libraries provided some insight into the theoretically prefened methods of linking and substituting the scaffolds. With respect to the hexahydrocarbazole scaffold, the substituent attached to the intracyclic nitrogen at Rl could be either a small alkyl chain or a larger carbamate. While the single best scoring molecule had a carbamate, the libraries containing a methyl group at this position gave the best average score. The carbamate materials are attractive because they may produce more strongly binding libraries. However, the methyl group may have significant advantages with regards to the synthesis of the libraries. Both groups should be accessible by synthesis and the proposed routes presented below could be modified to accommodate either group. At the side chain position R2, the amide groups produce the best average scoring libraries, while the methyl amine shown gave the single best fitting molecule. Again, both groups are available from the proposed methods. Finally, at the R3 position, the ether linkage was prefened and the deep nanow pocket strongly favored aromatic rings. An evaluation of the solubility parameters (ClogP) of all members of this virtual library revealed that this scaffold provides an average value for library members that is well within the accepted range (ca. 5). The presence of the tertiary amine affords some solubility on the proper face of the molecule to preserve the amphipathic character of the molecule. If further improvements are required, the angular methyl group could be substituted with a charged or polar group.

The dibenzoazocine scaffold fits somewhat differently in the pocket with the scaffold itself binding into the hydrophobic cleft. In all three positions, the docking results favored a hydrocarbon linker with no apparent advantage being offered by heteroatoms or more complex linkages. In the Rl and R3 positions, the favored groups were aromatic rings, which could take advantage of some deep nanow pockets. All of the conesponding molecules that were visually inspected have the Rl substituent bound into the SI pocket of the protein. The pocket appears to be deeper than the R2 and R3 pockets. The R2 pocket benefited little from increased substitution with a simple ethyl group consistently providing the best average results. Computational evaluation of the expected solubility parameters for this scaffold revealed that library members are considerably more hydrophobic than was the case for the hexahydrocarbazole scaffold. Improvements to subsequent materials might include the use of heteroatoms in the linkers or formation of the quaternary ammonium salt.

Example 26 Evaluation Of The Differences Between The NR Box Binding Pockets Of Htrβl. Herα,

And PPARv

The differences among binding pockets on different nuclear receptors were evaluated to determine how these differences could be utilized by synthetic inhibitors to provide specificity. The structure of the nuclear receptor*coactivator complexes were aligned in a common frame of reference by performing an RMS fit of the alpha and beta carbons of the leucine residues of the LxxLL motif of the peptide coactivator. Initial visual inspection of molecular surfaces, with potentials projected onto the surfaces, seemed to indicate that the receptor sites from hTRβl and PPARγ are quite similar to each other while that of hERα was quite distinct. However, differences in the SI pocket may afford selective binding of ligands to these sites. The SI pockets of hTRβl and PPARγ are distinctly different, with the PPARγ pocket being the larger of the two. Computational docking studies have shown that hTRβl prefers planar rings such as benzene in this pocket, and that larger saturated rings such as cyclohexane do not score well. Visual inspection of the S2 pocket of PPARγ suggests that rings the size of cyclohexane may preferentially bind there. Thus, libraries of organic molecules with larger substituents at the PI position may bind PPARγ selectively over hTRβl. The S 1 pocket of hERα is larger, shallower, and less distinct than the conesponding pockets of hTRβl and PPARγ. The charge distribution on the surface of each of the proteins in the binding pocket ranges from neutral to electronegative. The least apparent charge is located on the surface of PPARγ , while the greatest is located on hERα, suggesting polar groups and electrostatic interactions as potentially useful for differentiating between these pockets. The S2 pocket is similar with respect to size, shape and charge for all three proteins. However, the S2 pocket of hTRβl is longer than that of both PPARγ and hERα and may afford some advantage for selectivity. The hERα protein appears to possess a secondary pocket between SI and S2 which suggests that larger, bifurcated substituents might be used at the R2 position of scaffolds to obtain specificity for the hERα receptor site. The S2 pocket appears to possess a partial positive charge in all three protein-binding sites. The S3 pocket of PPARγ is relatively indistinct with respect to shape when compared to conesponding pockets of the other two binding sites. The hERα binding site contains a ridge between S3 and SI pockets that is not present in hTRβl. The hERα S3 pocket is also slightly larger and deeper than the S3 pocket of hTRβl. Again, the potentials projected onto the surfaces of the S3 pockets appear to be quite similar. While the differences between the sites are sometimes subtle, compounds may be developed that bind selectively to each of these sites.

Identification and characterization of the coactivator binding site for TR, and extension of this information to other nuclear receptors shows that this site is common for all nuclear receptors identified to date. Additionally, sequence and structural comparison, coupled with the Examples showing differential specificity for coactivator binding to TR, GR and ER, reveal that minor differences between the receptors, such as found in helix 12, are likely to influence specificity of a coactivator for different types of nuclear receptors. Thus, the Examples presented herein demonstrate that information derived from the structure and function of the TR coactivator binding site can be applied in design and selection of compounds that modulate binding of coactivator proteins to nuclear receptors for all members of the nuclear receptor super family. Further, the Examples demonstrate that libraries of compounds from scaffolds designed to approximate the conect geometry of the NR-box helix can be utilized to find leads that can be optimized into useful nuclear receptor modulators. REFERENCES

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All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

The invention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

Appendix 1

Atomic Coordinates for Human TR-^β Complexed With T₃, and a GRIPl NR-box 2 Peptide

REMARK full length numbering •REMARK all residue names correct REMARK peptide sequence

REMARK two molecules of TRB - CHAIN A and CHAIN B REMARK two molecules of T3 - CHAIN J and CHAIN K REMARK two molecules of GRIP-1 peptide - CHAIN X and CHAIN Y REMARK chain X lies between A and B REMARK chain Y interacts with B only REMARK residues differing between A and B include: REMARK A 217 Glu, A 252 Gin, A 263 Lys (missing side chains) .REMARK B 237 Ser, B239 His, B 394 Lys (missing side chains) REMARK additionally Gly 261, Gly 262 are not visible in chain A REMARK residues differing between X and Y include: REMARK A 692 Arg

REMARK additionally, residues Ly ^•ss 668888,, Lys 689; Ser 697 , Ser 698 REMARK are not visible in chain Y

ATOM 1 N LYS A 211 52.546 23. 912 35. ,239 1.00 45. ,76 7

ATOM 2 CA LYS A 211 52.944 24. 345 36. ,586 1.00 43. .42 6

ATOM 3 C LYS A 211 52.035 23. 665 37. 836 1.00 35. 68 6

ATOM 4 0 LYS A 211 51.511 22. 556 37. 763 1.00 33. 58 8

ATOM 5 CB LYS A 211 52.610 25. 825 36. 779 1.00 46. 72 6

ATOM 6 N PRO A 212 51.678 24. 182 39. 199 1.00 35. 64 7

ATOM 7 CD PRO A 212 52.082 25. 474 ^' 39. 842 1.00 38. 60 6

ATOM 8 CA PRO A 212 50.809 23. 379 40. 166 l.oo- 38. 35 6

ATOM 9 CB PRO A 212 50.670 24. 194 41. 440 1.00 38. 95 6

ATOM 10 CG PRO A 212 51.455 25. 469 41. 255 1.00 42. 00 6

ATOM 11 C PRO A 212 49.433 23. 097 39. 594 1.00 38. 78 6

ATOM 12 O PRO A 212 48.920 23. 949 38. 802 1.00 34. 64 8

ATOM 13 N GLU A 213 48.901 21. 948 40. 014 1.00 40. 31 7

ATOM 14 CA GLU A 213 47.609 21. 419 39. 529 1.00 43. 87 6

ATOM 15 CB GLU A 213 47.943 20. 307 38. 520 1.00 45. 16 6

ATOM 16 CG GLU A 213 49.125 20. 708 37. 601 1.00 47. 60 6

ATOM 17 CD GLU A 213 49.284 19. 828 36. ,353 1.00 50. 68 6

ATOM 18 OE1 GLU A 213 49.355 18. ,547 36. .474 1.00 59. .18 8

ATOM 19 OE2 GLU A 213 49.356 20. ,368 35. .180 1.00 49. .06 8

ATOM 20 C GLU A 213 46.711 20. .988 40. .747 1.00 45. .96 6

ATOM 21 O GLU A 213 47.111 21. .136 41. .910 1.00 43, .13 8

ATOM 22 N PRO A 214 .45.463 20, .460 40 .515 1.00 46, .52 7

ATOM 23 CD PRO A 214 44.985 20 .184 39 .148 1.00 46 .44 6

ATOM 24 CA PRO A 214 44.447 20 .124 41 .596 1.00 47 .52 6

ATOM 25 CB PRO A 214 43.249 19 .629 40 .816 1.00 45 .40 6

ATOM 26 CG PRO A 214 43.588 19 .674 39 .327 1.00 49 .89 6

ATOM 27 C PRO A 214 44.787 19 .082 42 .625 1.00 45 .70 6

ATOM 28 O PRO A 214 45.816 18 .466 42 .535 1.00 44 .49 8

ATOM 29 N THR A 215 43.915 18 .876 43 .606 1.00 45 .24 7

ATOM 30 CA THR A 215 44.161 17 .890 44 .686 1.00 49 .36 6

ATOM 31 CB ^' THR A 215 44.163 18 .586 46 .093 1.00 44 .86 6

ATOM 32 OGi THR A 215 42.878 18 .447 46 .728 1.00 52 .26 8

ATOM 33 CG2 THR A 215 44.514 20 .031 45 .974 1.00 39 .43 C ATOM 34 C THR A 215 42.934 16.995 44.667 1.00 52.51 6

ATOM 35 O THR A 215 41.816 17.501 44.691 1.00 53.48 8

ATOM 36 N ASP A 216 43.118 15.683 44.607 1.00 58.81 7

ATOM 37 CA ASP A 216 41.973 14.740 44.615 1.00 61.51 6

ATOM 38 CB ASP A 216 42.386 13.451 45.343 1.00 70.57 6

ATOM 39 CG ASP A 216 42.399 12.283 44.475 1.00 78.07 6

ATOM 40 OD1 ASP A 216 41.532 12.161 43.586 1.00 82.31 8

ATOM 41 OD2 ASP A 216 43.293 11.436 44.684 1.00 86.55 8

ATOM 42 C ASP A 216 40.640 15.311 45.268 1.00 58.42 6

ATOM 43 0 ASP A 216 39.598 14.840 44.924 1.00 56.85 8

ATOM 44 N GLU A 217 40.673 16.270 46.217 1.00 54.92 7

ATOM 45 CA GLU A 217 39.502 16.937 46.856 1.00 53.37 6

ATOM 46 CB GLU A 217 39.943 17.459 48.216 1.00 51.02 6

ATOM 47 C GLU A 217 39.113 18.144 45.956 1.00 53.55 6

ATOM 48 O GLU A 217 37.905 18.394 45.695 1.00 54.33 8

ATOM 49 N GLU A 218 40.162 18.895 45.511 1.00 49.20 7

ATOM 50 CA GLU A 218 39.933 20.073 44.661 1.00 45.94 6

ATOM 51 CB GLU A 218 41.232 20.855 44.304 1.00 43.43 6

ATOM 52 CG GLU A 218 41.907 21.579 45.479 1.00 40.86 6

ATOM ^' 53 CD GLU A 218 43.061 22.446 45.074 1.00 39.88 6

ATOM 54 OE1 GLU A 218 43.895 22.019 44.232 1.00 37.61 8

ATOM 55 OE2 GLU A 218 43.183 23.583 45.599 1.00 34.01 8

ATOM 56 C GLU A 218 39.249 19.647 43.390 1.00 44.71 6

ATOM 57 O GLU A 218 38.302 20.291 42.964 1.00 45.31 8

ATOM 58 N TRP A 219 39.720 18.553 42.797 1.00 44.02 7

ATOM 59 CA TRP A 219 39.109 18.061 41.574 1.00 46.97 6

ATOM 60 CB TRP A 219 39.799 16.793 41.074 1.00 48.42 6

ATOM 61 CG TRP A 219 40.879 17.029 40.141 1.00 54.61 6

ATOM 62 CD2 TRP A 219 40.755 17.256 38.733 1.00 55.24 6

ATOM 63 CE2 TRP A 219 42.067 17.523 38.245 1.00 53.67 6

ATOM 64 CE3 TRP A 219 39.691 17.234 37.828 1.00 54.55 6

ATOM 65 CDl TRP A 219 42.159 17.159 40.447 1.00 55.75 6

ATOM 66 NE1 TRP A 219 42.895 17.485 39.339 1.00 54.43 7

ATOM 67 CZ2 TRP A 219 42.330 17.851 36.895 1.00 52.54 6

ATOM 68 CZ3 TRP A 219 39.943 17.535 36.509 1.00 55.17 6

ATOM 69 CH2 TRP A 219 41.239 17.820 36.029 1.00 55.59 6

ATOM 70 C TRP A 219 37.646 17.743 41.812 1.00 47.32 6

ATOM 71 O TRP A 219 36.788 18.028 40.978 1.00 43.56 8

ATOM 72 N GLU A 220 37.376 17.142 42.965 1.00 49.91 7

ATOM 73 CA GLU A 220 36.021 16.769 43.316 1.00 53.57 6

ATOM 74 CB GLU A 220 36.052 16.055 44.649 1.00 58.18 6

ATOM 75 CG GLU A 220. 35.149 14.930 44.672 1.00 73.13 6

ATOM 76 CD GLU A 220 35.735 13.935 45.442 1.00 80.06 6

ATOM 77 OE1 GLU A 220 36.886 13.575 45.173 1.00 82.12 8

ATOM 78 OE2 GLU A 220 35.078 13.478 46.378 1.00 82.78 8

ATOM 79 C GLU A 220 35.161 18.026 43.381 1.00 50.51 6

ATOM 80 O GLU A 220 33.991 18.010 42.995 1.00 49.94 8 _.

ATOM 81 N LEU A 221 35.761 19.120 43.865 1.00 43.71 7

ATOM 82 CA LEU A 221 35.047 20.398 43.951 1.00 42.81 6

ATOM 83 CB LEU A 221 35.935 21.510 44.510 1.00 39.21 6

ATOM 84 CG LEU A 221 35.375 22.908 44.353 1.00 36.34 6

ATOM 85 CDl LEU A 221 33.941 22.929 44.836 1.00 36.93 6

ATOM 86 CD2 LEU A 221 36.226 23.910 45.122 1.00 24.18 6 > > > > ; > ι-3 1-3 ι >-3 > > > > > t-3 ι-3 HI HI HI HI HI HI HI > t-3 > HI t-3 t-3 HI HI Hi >t-3 HI t- HI HI t-3 Hi >HI > > >

Hi ι-3 3 > t-3 > > t-3 H H > > >

HI t-3 t-3 H HI HI t-3 o O o o O O O O O O O o O O O O o o ooooooooooooooooooooo HI HI HI > O O o o o o o o o

S s s s s s s s s s s s s 2 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s

M M M n ω ω ω ω ω ω M M M M M M ^M M ^{M M μ H μ H H H O O O O O O O O O O Φ} ^ ^ ^ * ^ ^ ^{ω o lo oo c} ^ ffi J ^ U W H O ^ CO ^ (n Ui ^ U M H O a CO ^ m Ul fc W ⁾ H O ^ ⁽B ~J m W * U ) H O ⁽C C(⁾ l (Ji Ui *> U M H O tf) C z o o

O O 25 O O O p Z O o n o o π o o o o z

CD O Cl CD > ιx w rc HI H Hi H H < < < < < Hi HI HI H Hi tr

M H trt t-^| t-^| t→ t-^, t→ t→ t-' tr¹ 5E 5E rc 5E > > > 5E i i a i i tr¹ tr¹ ir¹ tr¹ tr¹ Ir¹ t→ f f (r¹ P

50 0 50 0 50 50 50 tr¹ tr¹ tr¹ tr¹ tr¹ 50 5σ 5θ 5σ Λ Λ c ω w Λ W CΛ Λ -q n w M Ki -^Ii D > > > > ■

w ω ifl o co co o ω

rvi _Ni K_i K_i o o t o M ^ ^ ^ M M M Co c c c co w co co c c co c w co

» m W _Λ W ^ m W (n -J J O Oo ω H N3 H O θ ω o r H H ^O O ^ O ^ ^H O θ ^H O H H H N3 M U ω

(-> -J ui ω co cri oo yj ω _^i α) ^J (T\ C»J CO O O CO Cn vO > t-' .t^ C ^σι ^ '^ ^O ^ O ₎ O 00 Lπ O O θ σι C0 00 l-' -J *. |-' >Λ i ~J t-' σι O CO O O J^ CO h- ' O iJD π cπ <n oo -j oo *> o fc O H O i σi o ω ^i i vo ifl ϋi o ω w o ω *. i m w o uι o tD Ui ono ω ω o ω N i t\) -J LO -J o o αⁱ M iD m ω o co φ CO CTl l-^J CO -J d-. |\) O l£> tsJ CO I

Cπ Cπ ιfc> * Pi H ω i U3 Lπ o

H oo m

C_O M C ^ ^ _OO M O ^ _{CO C}^ ^ 3 0 O O ^ ^ C^ ^ C^ OO Cr. Oθ σ> U3 CO U3 0 U3 CO crι lo Uι CO H M Λ ∞ ^|i' Cft O W3 N σι ^ !^ ° ^ S ^M, ^ ∞ ω ∞ -J Ui M ui m ^ Λ ω N o u o si Λ O i£₎ l O ₍n N U' ffl m *' W m U O * H O CΛ -J M l N m l i£> M M ^i m H ^ j ω iD σi H ω ϋi N μ μ ω ω o m αi ω m Λ Ho

^ co w o O ^ oo o^ o^ σ. ^ ∞ c^ σi ∞ σ. ^ oo σi σ. cr. o c . -J OD m cr,

ATOM 140 CG HIS A 229 28.250 26.333 33.929 1.00 28.39 6

ATOM 141 CD2 HIS A 229 29.025 26.081 32.838 1.00 28.83 6

ATOM 142 ND1 HIS A 229 27.386 27.368 33.542 1.00 30.47 7

ATOM 143 CE1 HIS A 229 27.654 27.692 32.280 1.00 26.95 6

ATOM 144 NE. I HIS A 229 28.635 26.934 31.840 1.00 31.27 7

ATOM 145 C HIS A 229 26.225 24.541 34.312 1.00 38.40 6

ATOM 146 O HIS A 229 25.591 25.227 33.528 1.00 41.49 ^•8

ATOM 147 N VAL A 230 26.519 23.256 34.113 1.00 38.55 7

ATOM 148 CA VAL A 230 26.088 22.554 32.916 1.00 40.40 6

ATOM 149 CB VAL A 230 26.890 21.256 32.701 1.00 44.68 6

ATOM 150 CGI VAL A 230 26.557 20.656 31.345 1.00 39.39 6-

ATOM 151 CG2 VAL A 230 28.381 21.509 32.817 1.00 42.18 6

ATOM 152 C VAL A 230 24.603 22.239 32.900 1.00 44.28 6

ATOM 153 O VAL A 230 23.959 22.316 31.847 1.00 45.94 8

ATOM 154 N ALA A 231 24.072 21.862 34.059 1.00 45.59 7

ATOM 155 CA ALA A 231 22.669 21.500 34.175 1.00 47.84 6

ATOM 156 CB ALA A 231 22.482 20.582 35.374 1.00 45.08 6

ATOM 157 C ALA A 231 21.792 22.734 34.314 1.00 48.04 6

ATOM 158 O ALA A 231 20.565 22.647 34.324 1.00 49.95 8

ATOM 159 N THR A 232 22.436 23.894 34.384 1.00 47.26 7

ATOM 160 CA THR A 232 21.722 25.161 34.528 1.00 43.64 6

ATOM 161 CB THR A 232 22.112 25.832 35.850 1.00 41.93 6

ATOM 162 OG1 THR A 232 23.467 26.283 35.791 1.00 39.10 8

ATOM 163 CG2 THR A 232 21.990 24.846 37.008 1.00 29.80 6

ATOM 164 C THR A 232 22.055 26.114 33.387 1.00 43.97 6

ATOM 165 O THR A 232 21.679 27.279 33.436 1.00 40.55 8

ATOM 166 N ASN A 233 22.783 25.625 32.381 1.00 48.62 7

ATOM 167 CA ASN A 233 23.134 26.468 31.231 1.00 58.62 6

ATOM 168 CB ASN A 233 24.626 26.283 30.880 1.00 62.44 6

ATOM 169 CG ASN A 233 25.141 27.355 29.927 1.00 68.35 6

ATOM 170 OD1 ASN A 233 24.822 28.544 30.096 1.00 65.50 8

ATOM 171 ND2 ASN A 233 25.951 26.951 28.959 1.00 74.29 7

ATOM 172 C ASN A 233 22.241 26.035 30.073 1.00 65.06 6

ATOM 173 O ASN A 233^' 22.312 24.900 29.604 1.00 69.47 8

ATOM 174 N ALA A 234 21.381 26.954 29.646 1.00 68.80 7

ATOM 175 CA ALA A 234 20.423 26.708 28.564 1.00 70.98 6

ATOM 176 CB ALA A 234 19.748 28.015 28.186 1.00 71.43 6

ATOM 177 C ALA A 234 20.988 26.062 27.308 1.00 73.83 6

ATOM 178 O ALA A 234 22.041 26.419 26.822 1.00 74.33 8

ATOM 179 N GLN A 235 20.227 25.096 26.819 1.00 75.07 7

ATOM 180 CA GLN A 235 20.562 24.363 ■ 25.629 1.00 76.32 6

ATOM 181 CB GLN A 235 20.328 25.239 24.391 1.00 76.98 6

ATOM 182 CG GLN A 235 18.887 25.292 23.908 1.00 77.07 6

ATOM 183 CD GLN A 235 17.896 25.420 25.019 1.00 80.85 6

ATOM 184 OE1 GLN A 235 17.668 24.448 25.768 1.00 82.01 8

ATOM 185 NE2 GLN A 235 17.313 26.596 25.149 1.00 78.80 7

ATOM 186 C GLN A 235 21.960 23.840 25.573 1.00 77.15 6

ATOM 187 0 GLN A 235 22.386 23.458 24.508 1.00^' 76.06 8

ATOM 188 N GLY A 236 22.676 23.766 26.687 1.00 77.46 7

ATOM 189 CA GLY A 236 24.053 23.245 26.627 1.00 78.37 6

ATOM 190 C GLY A 236 24.923 23.491 25.390 1.00 79.43 6

ATOM 191 O GLY A 236 24.917 24.565 24.844 1.00 79.47 8

ATOM 192 N SER A 237 25.739 22.526 24.991 1.00 77.98 7 ^ ^ _H^ H H HI Hi Hi Hl Hi HI HI Hi H H Hi H H H H Hl H H H H H H H H o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o g o g p o o o o o o o o o o p o p o

K)

. - z t-^| t-^| t t-^< t-^, t-^, tw→ - - - > - ^l t t-^| t-^| t-^| t- -..^| ^-⁾ l ^→ l ^→ H 3 H ^t3 H H ^ ^t3 rf ι-3 H ^t3 H a 3: 3: ϊ a a 3: _H. _{« H}. co to co c -H IM I I CΛ CO C .. c.o. c.o. c .o. c .o. c .o. . .. ._* ._^ ._* ¹ t . 50 50 0 0 0 0 0 50 0 50 5 50 0 M H t H D PJ cn cn CΛ Λ Z Z Z S Z Z Z Z - ω ω co ω co w c/- n O O ^hα ^|xi t> ^ro ^fα ^ftJ ^fo O ^,τ^{j ,}O ' T co co cn co co co co co co co 5o 50 50 5

^ NJ No W NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ M NJ NJ NJ N M NJ NJ M NJ NJ NJ NJ NJ M NJ NJ NJ NJ N^ ₄-_> 4-. 4^ 4^ 4-, 4-. 4-. 4-» 4^ 4-. 4s. 4-. 4-. 4-. 4-. 4-. 4-. 4-. 4^S. 4^ 4-. 4 4-. 4^ CO C ω co CO CO CO CO CO W NJ NJ W NJ NJ NJ M μ-' μ-' μ-' μ-' μ-' μ-' O O O O O O O O O UJ UJ UJ UJ UJ UJ U UJ UJ UJ UJ UJ UJ UJ ∞

fc ui co cn σi ω ω i O UJ 4-. 4-. O C NJ C oo o Nj co cn oo μ-' μ

M M W M M M W M M M M NJ M W M NJ NJ ^ KJ M M M NO IJ C C M 4-, -_* 4-. σ σ σ. 4-. cπ NJ Co c c cπ cπ ^ cn ^ -J ^ ^ cn -J C CT c ^ μ-> *- μ-> 00 CO ~J CO CO 4-. O cπ μ-> cπ 0 O N n >c UJ cπ NJ cπ CD Ui en CO 0 CO n μ-¹ NJ 4-> CO CO ^j UJ ^1 μ-¹ μ-¹

CTl UJ 4-. UJ CD 00 00 NJ NJ 0 NJ < ι ~J 4-. CD lit CO NJ o 4-. 00 00 0 cn 0 NJ cn J 4-> 4-. μ-¹ NJ en cn UJ 4-.

NJ J μ-¹ CO CO 4-. μ-¹ O CTl μ-> NJ CO O CO UJ 00 O ~J NJ 0 0 μ-¹ NJ cπ CO 00 μ-¹ NJ NJ en 0 cπ cn cn CO CO CO NJ 4-.

CD cn CTl 0 NJ ^ 0 ^J 4=. 4-. cπ CO ^1 CO NJ CO cπ e

NJ NJ μ-> NJ NJ μ-> μ-¹ μ-¹ μ-¹ μ-¹ μ-> μ-> μ-¹ μ-> μ-> μ-¹ μ-> μ-¹ μ-¹ μ-¹ μ-¹ μ-> μ-¹ μ-¹ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ μ-> μ-» -> NJ NJ μ-¹ NJ

0 μ-¹ NJ NJ NJ N

NJ O I ⁾ 0 O 00 00 en -J CTl 4-. cπ < ι CTl ~J cπ cn -j -J ^1 ^j -0 CD UJ UJ 0 O O μ μ-¹ μ-> NJ μ-¹ μ-> O O CO CO UJ J Nl μ-¹ (71 00 CO μ-> ( l 0 -j μ-> NJ cπ Tl cπ cπ CO ϋ O 0 CH -J =» J μ-¹ NJ cn 0 μ-> CO 4-. UJ

~J 0 UJ cπ UJ CO

NJ cπ <x> CO -J 0 -J cπ CO cπ cn ~j CO en cn ~J 00 en Cπ O 4-. 00 0 en NJ Co ^•J cπ CTl

O 4-. NJ CO μ-> 4-. CTl co Cn UJ O NJ CO CO ~j CO 4=- NJ en 4-. cn O 0 D cπ cπ *> cn C UJ 4-. cπ μ-¹ J en cπ

0 00 Cπ cπ 4-. co O μ μ-¹ ^j CD NJ D μ-¹ NJ μ-¹ CO C Cπ 00 en Co cπ J C

CO co cπ ^1 NJ μ-¹ cn CO UJ c μ-< μ-> μ-> μ-¹ μ-¹ μ-¹ μ-¹ μ-> μ-> μ-¹ μ-¹ μ-> μ-> μ-> μ-" μ-¹ μ-» μ-¹ l-¹ μ-¹ μ-¹ μ-¹ μ-> μ-» μ-¹ μ-> μ-> μ-> μ-> μ-> μ-¹ μ-¹ μ-> μ-> t-> μ-¹ μ-¹ μ-¹ μ-¹ μ-■ μ-¹ μ-" μ-¹ μ-> μ-¹ μ-¹

0 O 0 0 0 0 0 0 0 0 0 0 O σ 0 0 0 0 0 0 0 0 0 0 0 0 0 O 0 0 0 O 0 0 0 0 0 0 O 0 *

0 0 0 0 0 σ O σ 0 0 0 O 0 0 0 O O O 0 0 0

0 O O • • • •

0 O 0 O 0 0 0 O O

0 O 0

0 O 0

O O 0 0 0 O 0 O 0 O O 0 O 0 O σ

^ ~j -j cn O CTl O CTl -J ^1 CTl cn cn cn cn -~J -j ^1 cn en en cn ^1 UJ UJ UJ UJ UJ UJ UJ J CO CO -j -j ^] 4-.

4-. 4-. .t. ^1 ^J CTl 4-. CTl μ-> μ-> σ -J ^j cn cπ n NJ I-¹ !£> CTl cπ -j μ-» O -J cn cn ^1 45. cπ Cπ 4~.

CO UJ ~0 ^1 4-.

4-. CO Cπ 45. 0 O cπ cπ cπ cπ cπ O c

4-. 4-. O π UJ CO σ> * CO μ-¹ UJ cπ cn NJ μ-¹ NJ CO 00 en cn μ-¹ CO NJ 4-. μ-¹ CO μ-¹ cn 0 co C 4-, μ^j NJ NJ CO cn CTl NJ 00 UJ CO CO UJ σ CD CO μ-¹ y CO cπ CO O 0 ^1 NJ cπ CO 00 cn cπ en 0

UJ O CO

^1 NJ UJ 4-. cn 4-. CO O

O 0 O cn O cn cπ O c

^1 cn cn cn m σi ^ ∞ cri i ∞ σⁱ m m ^ ∞ crⁱ J σⁱ m σⁱ crⁱ m ^ co σⁱ m c^ ^ w m cri m σi cri m ^i ω m i ^% , _™ _

"' uⁱ -^j u^j cn i ai ^ m m m oi i co m co

ATOM 246 C LYS A 242 18.143 28.291 18.483 1.00 66.28 6

ATOM 247 O LYS A 242 17.102 28.923 18.592 1.00 67.61 8

ATOM 248 N ARG A 243 19.334 28.813 18.204 1.00 64.19 7

ATOM 249 CA ARG A 243 19.617 30.219 17.975 -1.00 62.43 6

ATOM 250 CB ARG A 243 21.070 30.274 17.463 1.00 60.12 6

ATOM 251 CG ARG A 243 21.665 31.636 17.305 1.00 40.00 6

ATOM 252 CD ARG A 243 23.213 31.599 17.267 1.00 40.00 6

ATOM 253 NE ARG A 243 23.826 31.217 15.996 1.00 40.00 7

ATOM 254 CZ ARG A 243 25.113 31.439 15.714 1.00 40.00 6

ATOM 255 NH1 ARG A 243 25.905 32.041 16.616 1.00 40.00 7

ATOM 256 NH2 ARG A 243 25.592 31.097 14.520 1.00 40.00 7

ATOM 257 C ARG A 243 18.639 30.789 16.950 1.00 62.97 6

ATOM 258 O ARG A 243 18.662 30.390 15.784 1.00 63.96 8

ATOM 259 N LYS A 244 17.771 31.692 17.393 1.00 62.41 7

ATOM 260 CA LYS A 244 16.790 32.309 16.498 1.00 61.57 6

ATOM 261 CB LYS A 244 15.368 31.974 16.962 1.00 63.68 6

ATOM 262 CG LYS A 244 15.102 30.471 17.104 1.00 71.29 6

ATOM 263 CD LYS A 244 13.641 30.167 17.468 1.00 73.83 6

ATOM 264 CE LYS A 244 13.182 30.908 18.737 1.00 74.71 6

ATOM 265 NZ LYS A 244 13.951 30.536 19.970 1.00 73.32 7

ATOM 266 C LYS A 244 17.009 33.806 16.501 1.00 59.30 6

ATOM 267 0 LYS A 244 16.562 34.514 17.399 1.00 56.34 8

ATOM 268 N PHE A 245 17.705 34.264 15.468 1.00 57.06 7

ATOM 269 CA PHE A 245 18.045 35.692 15.333 1.00 59.01 6

ATOM ^■270 CB PHE A 245 18.825 35.947 14.049 1.00 59.62 6

ATOM 271 CG PHE A 245 19.908 34.979 13.834 1.00 66.60 6

ATOM 272 CDl PHE A 245 19.618 33.714 13.399 1.00 67.17 6

ATOM 273 CD2 PHE A 245 21.198 35.309 14.139 1.00 69.25 6

ATOM 274 CE1 PHE A 245 20.614 32.794 13.255 1.00 69.92 6

ATOM 275 CE2 PHE A 245 22.189 34.385 13.994 1.00 70.50 6

ATOM 276 CZ PHE A 245 21.897 33.126 13.552 1.00 70.89 6

ATOM 277 C PHE A 245 16.856 36.620 15.340 1.00 60.68 6

ATOM 278 0 PHE A 245 15.946 36.516 14.528 1.00 62.37 8

ATOM 279 N LEU A 246 16.919 37.558 16.272 1.00 60.10 7

ATOM 280 CA LEU A 246 15.884 38.554 16.437 1.00 59.44 6

ATOM 281 CB LEU A 246 16.227 39.510 17.585 1.00 57.43 6

ATOM 282 CG LEU A 246 15.100 ^'40.384 18.086 1.00 54.41 6

ATOM 283 CDl LEU A 246 14.010 39.474 18.640 1.00 52.43 6

ATOM 284 CD2 LEU A 246 15.575 41.325 19.151 1.00 51.69 6

ATOM 285 C LEU A 246 15.717 39.330 15.135 1.00 62.05 6

ATOM 286 0 LEU A 246 16.706 39.609 14.430 1.00 59.85 8

ATOM 287 N PRO A 247 14.473 39.668 14.784 1.00 63.33 7

ATOM 288 CD PRO A 247 13.263 39.314 15.534 1.00 64.44 6

ATOM 289 CA PRO A 247 14.198 40.421 13.558 1.00 63.56 6

ATOM 290 CB PRO A 247 12.687 40.671 13.600 1.00 64.42 6

ATOM 291 CG PRO A 247 12.161 39.922 14.729 1.00 64.90 6

ATOM 292 C PRO A 247 14.996 41.733 13.496 1.00 61.94 6

ATOM 293 0 PRO A 247 15.159 42.455 14.486 1.00 61.60 8

ATOM 294 N GLU A 248 15.506 42.006 12.299 1.00 61.33 7

ATOM 295 CA GLU A 248 16.280 43.197 11.976 1.00 63.50 6

ATOM 296 CB GLU A 248 16.481 43.273 10.437 1.00 66.94 6

ATOM 297 CG GLU A 248 17.012 44.671 9.966 1.00 68.70 6

ATOM 298 CD GLU A 248 16.981 44.939 8.471 1.00 40.00 6 ATOM 299 OE1 GLU A 248 16.432 44.144 7.644 1.00 40.00 8

ATOM 300 OE2 GLU A 248 17.509 46.015 8.086 1.00 40.00 8

ATOM 301 C GLU A 248 15.624 44.489 12.458 1.00 64.19 6

ATOM 302 O GLU A 248 16.298 45.395 12.918 1.00 65.56 8

ATOM 303 N ASP A 249 14.300 44.545 12.323 1.00 64.36 7

ATOM 304 CA ASP A 249 13.493 45.703 12.673 1.00 63.33 6

ATOM 305 CB ASP A 249 12.088 45.531 12.116 1.00 62.97 6

ATOM 306 CG ASP A 249 11.277 44.527 12.870 1.00 64.63 6

ATOM 307 OD1 ASP A 249 11.687 43.352 12.963 1.00 64.84 8

ATOM 308 OD2 ASP A 249 10.183 44.880 13.395 1.00 66.52 8

ATOM 309 C ASP A 249 13.371 46.062 14.130 1.00 64.31 6

ATOM 310 O ASP A 249 13.310 47.250 14.468 1.00 64.73 8

ATOM 311 N ILE A 250 13.274 45.049 14.997 1.00 63.09 7

ATOM 312 CA ILE A 250 13.133 45.318 16.418 1.00 64.39 6

ATOM 313 CB ILE A 250 13.035 44.034 17.214 1.00 65.79 6

ATOM 314 CG2 ILE A 250 12.001 44.104 18.336 1.00 64.78 6

ATOM 315 CGI ILE A 250 12.611 42.860 16.341 1.00 65.28 6

ATOM 316 CDl ILE A 250 11.753 41.852 17.088 1.00 65.08 6

ATOM 317 C ILE A 250 14.404 46.104 17.276 1.00 65.21 6

ATOM 318 O ILE A 250 15.155 45.506 18.047 1.00 64.05 8

ATOM 319 N GLY A 251 14.670 47.529 17.299 1.00 65.48 7

ATOM 320 CA GLY A 251 15.871 48.326 18.042 1.00 67.32 6

ATOM 321 C GLY A 251 16.595 49.110 16.895 1.00 68.52 6

ATOM 322 O GLY A 251 17.528 48.616 16.266 1.00 65.49 8

ATOM 323 N GLN A 252 16.162 50.356 16.557 1.00 72.26 7

ATOM 324 CA GLN A 252 16.541 50.930 15.207 1.00 74.10 6

ATOM 325 CB GLN A 252 15.316 50.844 14.295 1.00 75.82 6

ATOM 326 C GLN A 252 16.995 52.403 15.084 1.00 77.17 6

ATOM 327 O GLN A 252 17.572 52.955 15.986 1.00 76.50 8

ATOM 328 N ALA A 253 16.374 53.372 13.908 1.00 80.78 7

ATOM 329 CA ALA A 253 16.687 54.725 13.567 1,00 83.70 6

ATOM 330 CB ALA A 253 16.381 54.956 12.093 1.00 83.23 6

ATOM 331 C ALA A 253 16.15? 55.960 14.345 1.00 85.59 6

ATOM 332 O ALA A 253 15.317 56.721 13.798 1.00 85.69 8

ATOM 333 N PRO A 254 16.384 56.155 16.264 1.00 35.05 7

ATOM 334 CD PRO A 254 17.102 55.053 16.908 1.00 33.97 6

ATOM 335 CA PRO A 254 16.002 • 57.231 17.219 1.00 35.89 6

ATOM 336 CB PRO A 254 16.534 56.756 18.563 1.00 33.94 6

ATOM 337 CG PRO A 254 17.146 55.441 18.349 1.00 33.31 6

ATOM 338 C PRO A 254 16.717 58.498 16.731 1.00 37.75 6

ATOM 339 O PRO A 254 17.838 58.804 17.100 1.00 38.78 8

TER

ATOM 1 N LYS A 263 18.045 57.462 23.875 1.00 61.71

ATOM . 2 CA LYS A 263 16.824 56.712 24.215 1.00 64.36

ATOM 3 CB LYS A 263 15. .758 57. .004 23. .141 1. .00 63. ,50 6

ATOM 4 C LYS A 263 16. .841 55. .180 24. .429 1. .00 63. .41 6

ATOM 5 O LYS A 263 17. ,877 54, .542 24. .409 1. .00 61. .93 8

ATOM 6 N VAL A 264 15. .615 54. .664 24. .654 1. .00 61. .15 7

ATOM 7 CA VAL A 264 15. .292 53, .229 24. .856 1, .00 59. .46 6

ATOM 8 CB VAL A 264 14. .251 52, .974 25. .978 1. .00 59. .03 6

ATOM 9 CGI VAL A 264 14, .229 51 .494 26, .368 1, .00 53, .79 6

ATOM 10 CG2 VAL A 264 14, .449 53 .818 27, .142 1, .00 55. .32 6

ATOM 11 C VAL A 264 14, .590 52 .820 23. .554 1. .00 60. .96 6 S _{o o oo o o o o o}ooooooooooooooooooooooooooooooooooooooooo

cn cn cn cn cn cπ cπ cπ cπ cπ cπ cπ cn Ln cπ 4-. 4-. 4s. ^ 4=. 4-. 4-. 4-. 4-. 4-. w ω u ^j w ω ω i^j ω M M l i M M M M W M M

Λ W M μ o ω co i m ui Ji W M H o lO CO ^ Tl Ul fe W M H O ^j co -J m uι *> U N⁾ μ o »o co ⁾ (ri uι ji U M o ιt) co ^ (jι uι * ω CO z

5C 5E 5E 5E jc co o c co co co t J T) iTJ O πj j UJ nj ηj O iio > > > > Cl O O O Cl Q Cl O Ω t-¹ t-¹ t-^, t-^, t-^, t-^, t-' t-¹ > ^ ' > μπ H H H M H B M W K 5C 5S t-< tr" t^"1 tr¹ t l→ t PJ PJ PJ PJ PJ PJ PJ PJ CO CO CΛ C O CO O C

Iβ M ω ω M » 3 W » ϊ » B W H H H EI Ifl W H H H > > > > Gr'σ-'σα→ tc-' tσ→ tσ-'αt-' lσ→

G G G G G C C G O O 'U TJ O ^rO O T5 > M ( W ( N) I fO M ui ui ui n ui ui ui ui

i — i i — > ( — » i — ' t — ' i — ' i — ' μ^j μ-^{i j} -' μ-> μ-> ι-' μ-' μ-' μ-> μ-' μ-' μ-> μ-^, μ-' μ-^Λ μ-' HJ

_{O O (}_i |_i __l |_i -J 00 UJ O NJ NJ NJ CO μ^J CO NJ NJ NJ NJ NJ N3 ⁴-. NJ μ-' 0 0 -~J UJ O^O UJ UJ CO UJ UJ UJ UJ CO UJ UJ O c ~o _^J NJ c o c -J ~J J U N o NJ H ^ ω w i ⁱfl co ⁱiⁱ H ^ -α ⁱ υⁱ ^ Λ. -J H ω Λ ω w Φ n w ω H ω M i w u -J M co uJ Oo _ ,. ,^.. .„ *, .^.. "- --^ ' ' '-' ^• ' '" θ μ-' Co co NJ μ-' μ-' μ-^> u 4-. co o uJ cn cπ - NJ π u co NJ UJ O ω u_{i ^}J C ω co - iπ ^ co j- i j αj ui io n -J f cn o co ^j αi ^i oj M u, 4=. o co cn u μ^j -J cπ 4^ o μ-' 4s. u cπ co cn t-' cn 4^ cπ NJ cπ cn NJ co n J O H O M M N ω ω ^ Λ uⁱ ^ m ^ W i i ^ m m Λ αⁱ m ϋⁱ m A ^ fc m uⁱ ^ m m i m J o N io φ o co io co o o μ μ- ' co m ) ^ ^ ιc w J co ω o o co Λ iB ω ^ w o μ N⁾ ^ W Λ fli ^ iv uⁱ co m θs o3 σι μ iD μ ⁽D «⁾ co o o o N) J ∞ μ-> ω ^ -. o^ 4-. cn ω M μ-' ^ ^j cn ^ o M n -J 4^ J s^, cπ ∞ oo -J o^ C^ μ-_> C_jι 00 NJ C0 μ-' 4-. ∞ C0 OT < 4^ NJ O Cπ UJ Cn Cπ Cπ cτι ∞ ^ NJ C^ ^ -^ NJ Cπ C0 4-, C0 NJ 4^

M NJ NJ NJ M NJ W N N W NJ W CO O CO NJ NJ NO M NJ N M W M Is M NJ M -' ^μ-' -' W l W o N U Λ ffl Ui uι oι <Λ ⁽J ^ m o o co ffi θ5 oι ⁱΛ ^ ^ ω w w H i ^ ^ θ H N^{) Λ )} i αι uⁱ A t, ι_Λ ^j w N c, ιo θ H M ω

4^ C0 4-. Ct5 00 Cπ Cn -^ NJ 0 ^ 4^ Cπ O C0 4-. UJ O NJ -J c CO CO UJ CO O UJ ∞ Cπ O ∞ CO O C^ oo J n ^ co c cr> uJ -. cri ra Nj ^ o w o co ^ -j c o ^ OT --J n ro J O OT n v5 cπ -J L NJ n ^ n c cx3 α-. o μ- c cτ Co ^ -J co o ^ co c ^ ^ ∞ cn c o ω

-J cn cn cπ U_i -. 4-. cπ _(j cπ <_jι Cπ -. ^ ω co w ω 4-. s. . 4i 4^ 4^ Λ s. cn cn <^ O ∞ ∞ μ- O ∞ UJ CO μ- NJ Co NJ J O ∞ NJ ^ ∞ O O Co μ- π π J CO ∞

∞ u π m μ^ ^ ^ c> μ-' μ-' -J Cπ -. μ-' u -. U 4^ cn ^ _;^ θ -. ω ∞ ^ NJ ^ cn 4 ∞ NJ Cn uJ Cπ Cn cτ, <-π NJ cπ ∞ 4-. o σι Cθ θ c^ NJ O co 4-. -^j o cn <^

en en cn en ^ ∞ cτι ∞ c m ^ oo crι cτι σi c (^ c^ cΛ σ cn ^ ∞ o m

ATOM 65 ND1 HIS A 271 9.673 41.732 21.199 1.00 71.98 7

ATOM 66 CE1 HIS A 271 8.936 41.242 20.209 1.00 73.91 6

ATOM 67 NE2 HIS A 271 9.495 40.132 19.764 1.00 73.59 7

ATOM 68 C HIS A 271 12.402 40.416 24.745 1.00 48.33 6

ATOM 69 O HIS A 271 12.707 39.225 24.728 1.00 48.39 8

ATOM 70 N PHE A 272 13.029 41.334 25.487 1.00 41.34 7

ATOM 71 CA PHE A 272 14.130 41.001 26.384 1.00 39.44 ^•6

ATOM 72 CB PHE A 272 15.077 42.194 26.512 1.00 36.67 6

ATOM 73 CG PHE A 272 15.953 42.413 25.282 1.00 33.39 6

ATOM 74 CDl PHE A 272 16.619 43.615 25.093 1.00 33.14 6

ATOM 75 CD2 PHE A 272 16.138 41.394 24.346 1.00 38.28 6

ATOM 76 CE1 PHE A 272 17.454 43.807 23.988 1.00 38.26 6

ATOM 77 CE2 PHE A 272 16.973 41.585 23 . 244 1.00 43.28 6

ATOM 78 CZ PHE A 272 17.634 42.786 23.068 1.00 39.74 6

ATOM 79 C PHE A 272 13.650 40.528 27.764 1.00 40.75 6

ATOM 80 O PHE A 272 14.081 39.476 28.227 1.00 35.51 8

ATOM 81 N THR A 273 12.756 41.266 28.428 1.00 41.64 7

ATOM 82 CA THR A 273 12.290 40.854 29.757 1.00 45.97 6

ATOM 83 CB THR A 273 11.651 42.025 30.506 1.00 51.52 6

ATOM 84 OG1 THR A 273 10.442 42.422 29.859 1.00 45.74 8

ATOM 85 CG2 THR A 273 12.601 43.211 30.565 1.00 49.73 6

ATOM 86 C THR A 273 11.267 39.731 29.664 1.00 46.23 6

ATOM 87 O THR A 273 10.854 39.183 30.680 1.00 41.21 8

ATOM 88 N LYS A 274 10.849 39.412 28.440 1.00 46.21 7

ATOM 89 CA LYS A 274 9.871 38.362 28.211 1.00 54.53 6

ATOM 90 CB LYS A 274 9.414 38.405 26.773 1.00 54.36 6

ATOM 91 C LYS A 274 10.498 37.015 28.515 1.00 56.88 6

ATOM 92 O LYS A 274 9.789 36.044 28.759 1.00 57.98 8

ATOM 93 N ILE A 275 11.836 36.973 28.491 1.00 56.48 7

ATOM 94 CA ILE A 275 12.609 35.746 28.767 1.00 52.64 6

ATOM 95 CB ILE A 275 13.444 35.346 27.543 1.00 49.15 6

ATOM 96 CG2 ILE A 275 12.568 34.829 26.429 1.00 47.42 6

ATOM 97 CGI ILE A 275 14.238 36.532 27.026 1.00 45.31 6

ATOM 98 CDl ILE A 275 15.001 36.242 25.771 1.00 37.22 6

ATOM 99 C ILE A 275 13.541 35.870 29.982 1.00 51.78 6

ATOM 100 O ILE A 275 14.014 34.873 30.503 1.00 49.80 8

ATOM 101 N ILE A 276 13.790 37.107 30.415 1.00 51.76 7

ATOM 102 CA ILE A 276 14.681 37.389 31.537 1.00 52.58 6

103 CB ILE 55.04 6

ATOM A 276 14.691 38.877 31.844 1.00

ATOM 104 CG2 ILE A 276 13.311 39.340 32.261 1.00 53.28 6

ATOM 105 CGI ILE A 276 15.675 39.206 32.976 1.00 57.31 6

ATOM 106 CDl ILE A 276 17.096 38.942 32.655 1.00 60.32 6

ATOM 107 C ILE A 276 14.323 36.644 32.828 1.00 50.70 6

ATOM 108 O ILE A 276 15.177 36.458 33.691 1.00 55.55 8

ATOM 109 N THR A 277 13.072 36.209 32.963 1.00 47.33 7

ATOM 110 CA THR A 277 12.631 35.523 34.158 1.00 42.59 6

ATOM 111 CB THR A 277 11.098 35.456 34.217 1.00 44.97 6

ATOM 112 OG1 THR A 277 10.545 36.777 34.102 1.00 46.38 8

ATOM 113 CG2 THR A 277 10.657 34.838 35.539 1.00 37.17 6

ATOM 114 C THR A 277 13.211 34.118 34.304 1.00 39.84 6

ATOM 115 0 THR A 277 13.796 33.796 35.365 1.00 40.55 8

ATOM 116 N PRO A 278 13.055 33.261 33.288 1.00 38.20 7

ATOM 117 CD PRO A 278 12.370 33.534 32.023 1.00 36.34 6 ≤ ≤ _{H H H}3 Hϊ H Hl H Hl H H H H H H HI H H H H H >-3 H H H o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o'o o o o o o o o o o o o o o o

μ-> μ-> t-¹ ^ ^ ^j ^ |--ⁱ H-ι μ^{j J} μ-' μ-ⁱ μ-' μ-' -' -' μ-' μ^j μ-ι ₁-^J |— i μ^ i-' μ-' μ-' μ-' μ-'

~J cn cn cn cn cn cn o J OO -~j cn cn *>. co NJ o w co i m ui ^ w M H O ^ ∞ i m uⁱ ^ u M o i^β O ^sJ m ui Δ ω M H o iD ffl i m ui Λ i i o iii

O Ω Z O Ω Ω Ω Ω Ω 2! O Ω Ω Ω Ω Ω Z O Ω Z Ω Ω Ω Ω Z O Ω Ω O Ω Ω O Ω Ω Ω Ω Ω Ω 3 O Ω Ω Ω ^• o Ω Ω Ω D Q n a > O Ω CD > 5E 5E PJ O Ω CD > Ω Ω CD > O Ω Ω D > z CD > Ω CD

NJ NJ NJ NJ μ-> μ-¹ μ-> NJ

> > < < < < < < < < > > > > H ^l-3 H H H ^lHl ^l-3 M M M a3 > > HD Ό O TI co O CO > > > > > > > > ^ 5O 50 5O 5O O 0 0 50 50 5O O X 5i: 3 p pC 5i 5i: _t t^H ^ M t^:i 50 50 0

13 tτ3 TJ tr¹ Q θ θ £π Ω Ω Ω Ω Ω Ω Ω 50 5σ 50 50 50 50 5σ pJ PJ pJ PJ PJ P pj pJ O O O O

> > > > > > ^ 5=^, 3=' ^ >' > >' > > > t >

W M M M K) N M N N N N M M M W ^ N ^{M M M M M N N M M M M M M N M |VJ} ^ W M N Iv N f f M N | NJ NJ NJ NJ NJ NJ NJ NJ CO ∞ CO OO OO CO OO OO ∞ OO OO CO OO OO OO CXl OO CO ∞ CO CO ∞ OO OO ∞ OD αj CO OO ∞ cπ cn cn 4^ 4i. s. -. 4i *. fc l ) U U U⁾ W U ω M '^• W" 'M- W'" MM MN N W M M Wl MM MM HH hH ¹ μ -* H μ-» μμ- > μμ- > o n rθ- i rO- i t O— > rO-, ,O-. O,-. ,O-, UJ UJ UJ UJ UJ OO OO OO OO

NJ μⁱ H M i NvJ NJ NJ NJ NJ NJ NJ M NJ μ-' μ-' M M μ-' μ-' μ-' μ-' M μ-' μ-' μ-^j μ-' μ-' -^ l— ■ t—' μ-' i— r- r— r-

C lD W O W l l l UJ UJ NJ θ θ θo o u co ∞ U co ^ ^ ^ s. ^ cn cτι co -^j c cn ^J cn ^J _^-i co -J i m m ui M u cn NJ O Cn cn 4-. oo NJ cn co uJ Cn NJ M μ H U CO O μ θ O H M H 01 Uⁱ t> θ ω vl Uι cθ μ μ M M U) cn 4-. o cn cn co o cn -J Cn ?°, c0 -J NJ -J NJ Cπ -J NJ 00 -0 ~J 4-. NJ O UJ ~J C0 00 NJ O UJ ~^j ^ι co ^j cn -^j -. cπ u U cπ -. μ-^ι cn uJ c o co cπ rι NJ NJ -j oo cn 4-. o ~J cπ ^w _Cr, _^j μ-_> o uJ cπ NJ NJ UJ μ-' UJ NJ cπ co co cn O CO NJ O CO UJ NJ Cn NO CO Cn NJ Cn 00 4s. Cn cn CO NJ uJ cn uJ o co 4s. cn ~J cn cn t-' co co

NJ NJ W NJ NJ CO C_O CO CO CO CO CO CO CO CO CO CO W NJ CO NJ NJ M NO NJ M NJ CO NJ CO CO CO CO CO CO CO CO Cn ^ CXJ ∞ J M O O O O O O CO CO M M O ∞ UJ O CO UJ UJ ^ ∞ UJ UJ O UJ O O O M NJ NJ CO OO cn Cπ C^ i. ^

NJ OO NJ CΠ O C 4-. CO CΠ UJ -J UJ ⁴s. cn -. ∞ -^ n cn ∞ cn o ^θ co -' o cn N^{J θ 4}^ ω c o o ∞ c -. co NJ n ω n Nj o ^ co 4-. u en co c cn cn NJ 4-. UJ μ ω m ω o^j ω co ω ω M ^ N m ^ ffl ^ ^ ^ co ⁱo ^{μ μ} m ^ m o o ω co m ^μ w ^μ π S S u ω

*> M σι m i *. μ ui i H i κ⁾ un c n ^ NJ uι N c^ -J c ⁴^ ∞ c σ c ∞ c^ uJ cn Nύ ∞

C0 4-. 4-. 4-. 4-. 4=» 4 4^ 4-. C0 4^ CO C C C C C CO CO CO CO C CO CO CO CO CO CO C CO CO C C CO C W U^ O M N U O U σi ∞ ^ ∞ ^ -J ^ O M NJ NJ ^ ^ cn o ∞ ^ ^ C^

O C0 C0 C0 C0 C0 UJ Cn NJ C0 NJ 4-. Cn UJ UJ O C0 M Cn C0 C0 UJ O -J w -j Λ co t ω μ W Λ N ^ ^U_{j j}^ ^ -J O NJ 4-. Cn cn 4a. 4s. C UJ NJ UJ ^J Cn CO Cn J Cπ ^l UJ NJ Cπ μ^j ~J co CO O O C0 4S. NJ O

NJ en -J Cπ Co o cπ co uJ NJ UJ Co co N^j μ-' ~J θ cπ θ cn ^^] NJ -J ~J CO O ^μ 00 UoJ ω^ ^μ Co ^s. ω 00 ^ ~J u μ-^K> c^n o ^ ⁱo ω ^μ S m ffl w 4i 4-. c ~J o c

^J NJ NJ Cn CO Cn cn O UJ NJ co μ-> cn co cn UJ 4-. μ-> μ-> μ-> μ-> μ-¹ μ-> μ-¹ μ-> -ⁱ ι_» μ-¹ μ-> μ-¹ μ-¹ μ->

O o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o σ o o o o o o o o o

CO CO NJ NJ NJ CO NJ CO NJ CO CO CO NJ NJ NJ CO CO CO CO cn -j en cπ CO C^O C⁰ NJ NJ C⁰ 4-. C^O C0 C C CO C0 NJ CO Cn OO - 00 0 4^ UJ O C NJ CO OO UJ O Cn 4-w UJ NJ 00 00 co Λ N cπ u NJ cn ^i c o NJ NJ NJ CO CO CO C CO CO CO CO CO

M 4-. cn cπ en cπ uJ Co co o co ~o -^j co cπ NJ

NJ CO -J NJ OO CΠ NJ NJ M J 4-. cπ NJ cn 0 -J 00 NJ CO CO s. NJ

CD NJ Cn J UJ t-¹ M -J 4=> en 00 0 00 4-. 0 cn t-> cπ UJ 4s. ιb αi H cn cn -J UJ cπ ∞ -^j o c^{P 4}-^> cn ∞ ∞ u^J θ uJ UJ ^μ-^> co o π 4 _^1 σi co ~ o cπ cn cn cn -J ∞ σ OT σ, o σ, ^ ∞ o c cn c c ^ ∞ o ^ ^ c ^ o^ c σ ^

ATOM 171 CG ASP A 285 17.083 26.277 39.149 1.00 38.15 6

ATOM 172 OD1 ASP A 285 16.484 25.743 40.110 1.00 34.70 8

ATOM 173 OD2 ASP A 285 16.431 26.828 38.231 1.00 34.43 8

ATOM 174 C ASP A 285 20.751 26.449 40.305 1.00 36.70 6

ATOM 175 O ASP A 285 21.106 25.389 40.808 1.00 37.96 8

ATOM 176 N PHE A 286 21.604 27.300 39.737 1.00 35.96 7

ATOM 177 CA PHE A 286 23.029 27.022 39.704 1.00 37.10 6

ATOM 178 CB PHE A 286 23.754 28.009 38.793 1.00 37.97 6

ATOM 179 CG PHE A 286 25.252 28.027 38.987 1.00 36.50 6

ATOM 180 CDl . PHE A 286 25.963 26.849 38.974 1.00 36.75 6

ATOM 181 CD2 ! PHE A 286 25.931 29.218 39.199 1.00 33.83 6

ATOM 182 CE1 . PHE A 286 27.331 26.860 39.161 1.00 39.55 6

ATOM 183 CE2 : PHE A 286 27.307 29.233 39.387 1.00 38.08 6

ATOM 184 CZ PHE A 286 28.008 28.052 39.371 1.00 34.44 6

ATOM 185 C PHE A 286 23.631 27.105 41.083 1.00 36.83 6

ATOM 186 O PHE A 286 24.317 26.192 41.504 1.00 35.61 8

ATOM 187 N ALA A 287 23.393 28.228 41.752 1.00 37.33 7

ATOM 188 CA ALA A 287 23.917 28.448 43.087 1.00 36.34 6

ATOM 189 CB ALA A 287 23.523 29.828 43.555 1.00 36.40 6

ATOM 190 C ALA A 287 23.346 27.393 44.027 1.00 38.76 6

ATOM 191 O ALA A 287 23.994 26.973 44.981 1.00 41.98 8

ATOM 192 N LYS A 288 22.114 26.979 43.735 1.00 38.28 7

ATOM 193 CA LYS A 288 21.429 25.971 44.538 1.G0 45.26 6

ATOM 194 CB LYS A 288 19.994 25.746 44.054 1.00 48.35 6

ATOM 195 CG LYS A 288 19.025 26.819 44.464 1.00 51.43 6

ATOM 196 CD LYS A 288 17.628 26.246 44.682 1.00 60.23 6

ATOM 197 CE LYS A 288 17.135 25.478 43.485 1.00 62.81 6

ATOM 198 NZ LYS A 288 17.196 26.327 42.268 1.00 64.69 7

ATOM 199 C LYS A 288 22.120 24.632 44.536 1.00 43.31 6

ATOM 200 O LYS A 288 21.961 23.857 45.462 1.00 45.66 8

ATOM 201 N LYS A 289 22.865 24.366 43.467 1.00 41.70 7

ATOM 202 CA LYS A 289 23.571 23.120 43.351 1.00 40.67 6

ATOM 203 CB LYS A 289 23.655 22.708 41.877 1.00 42.25 6

ATOM 204 CG LYS A 289 22.271 22.492 41.247 1.00 39.53 6

ATOM 205 CD LYS A 289 22.331 21.606 40.012 1.00 43.19 6

ATOM 206 CE LYS A 289 20.941 21.362 39.447 1.00 45.74 6

ATOM 207 NZ LYS A 289 20.273 20.165 40.006 1.00 52.49 7

ATOM 208 C LYS A 289 24.948 23.185 44.003 1.00 41.50 6

ATOM 209 O LYS A 289 25.642 22.184 44.080 1.00 39.77 8

ATOM 210 N LEU A 290 25.312 24.370 44.490 1.00 40.68 7

ATOM 211 CA LEU A 290 26.594 24.583 45.149 1.00 39.33 6

ATOM 212 CB LEU A 290 27.153 25.972 44.829 1.00 36.14 6

ATOM 213 CG LEU A 290 27.358 26.290 43.365 1.00 34.81 6

ATOM 214 CDl LEU A 290 27.945 27.675 43.208 1.00 29.07 6

ATOM 215 CD2 LEU A 290 28.267 25.242 42.757 1.00 33.45 6

ATOM 216 C LEU A 290 26.434 24.405 46.652 1.00 40.08 6

ATOM 217 O LEU A 290 25.803 25.235 47.333 1.00 42.00 8

ATOM 218 N PRO A 291 27.028 23.333 47.210 1.00 40.27 7

ATOM 219 CD PRO A 291 27.851 22.330 46.519 1.00 39.65 6

ATOM 220 CA PRO A 291 26.905 23.096 48.659 1.00 38.28 6

ATOM 221 CB PRO A 291 27.755 21.860 48.911 1.00 35.88 6

ATOM 222 CG PRO A 291 28.202 21.355 47.585 1.00 34.19 6

ATOM 223 C PRO A 291 27.327 24.298 49.522 1.00 40.05 6 ATOM 224 O PRO A 291 26.571 24.739 50.391 1.00 41.33 8

ATOM 225 N MET A 292 28.522 24.843 49.299 1.00 40.59 7

ATOM 226 CA MET A 292 29.021 25.957 50.097 1.00 42.86 6

ATOM 227 CB MET A 292 30.313 26.475 49.477 1.00 43.28 6

ATOM 228 CG MET A 292 31.269 25.378 49.050 1.00 50.35 6

ATOM 229 SD MET A 292 32.895 26.096 48.757 1.00 51.17 16

ATOM 230 CE MET A 292 33.812 24.647 48.074 1.00 54.63 6

ATOM 231 C MET A 292 27.984 27.066 50.149 1.00 41.05 6

ATOM 232 O MET A 292 27.986 27.886 51.057 1.00 39.66 8

ATOM 233 N PHE A 293 27.080 27.078 49.172 1.00 39.30 7

ATOM 234 CA PHE A 293 26.030 28.091 49.114 1.00 40.92 6

ATOM 235 CB PHE A 293 25.398 28.107 47.715 1.00 40.98 6

ATOM 236 CG PHE A 293 24.348 29.168 47.524 1.00 42.78 6

ATOM 237 CDl PHE A 293 24.654 30.493 47.747 1.00 44.40 6

ATOM 238 CD2 PHE A 293 23.071 28.833 47.116 1.00 43.66 6

ATOM 239 CE1 PHE A 293 23.701 31.478 47.564 1.00 39.83 6

ATOM 240 CE2 PHE A 293 22.112 29.819 46.930 1.00 46.21 6

ATOM 241 CZ PHE A 293 22.430 31.146 47.155 1.00 45.18 6

ATOM 242 C PHE A 293 24.979 27.772 50.164 1.00 45.54 6

ATOM 243 O PHE A 293 24.686 28.576 51.034 1.00 42.01 8

ATOM 244 N CYS A 294 24.426 26.572 50.062 1.00 47.05 7

ATOM 245 CA CYS A 294 23.386 26.125 50.962 1.00 50.15 6

ATOM 246 CB CYS A 294 22.944 24.733 50.524 1.00 45.90 6

ATOM 247 SG CYS A 294 22.303 24.663 48.829 1.00 51.50 16

ATOM 248 C CYS A 294 23.825 26/125 52.423 1.00 51.38 6

ATOM 249 O CYS A 294 23.008 25.954 53.322 1.00 53.83 8

ATOM 250 N GLU A 295 25.119 26.327 52.645 1.00 49.72 7

ATOM 251 CA GLU A 295 25.666 26.384 53.996 1.00 52.53 6

ATOM 252 CB GLU A 295 27.103 25.830 54.015 1.00 57.40 6

ATOM 253 CG GLU A 295 27.182 24.309 54.061 1.00 69.63 6

ATOM 254 CD GLU A 295 26.660 23.747 55.342 1.00 78.49 6

ATOM 255 OE1 GLU A 295 27.291 23.946 56.412 1.00 82.82 8

ATOM 256 OE2 GLU A 295 25.590 23.086 55.335 1.00 85.30 8

ATOM 257 C GLU A 295 25.653 27.831 54.488 1.00 48.54 6

ATOM 258 O GLU A 295 26.365 28.184 55.426 1.00 49.82 8

ATOM 259 N LEU A 296 24.804 28.631 53.846 1.00 43.79 7

ATOM 260 CA LEU A 296 24.670 30.034 54.159 1.00 45.42 6

ATOM 261 CB LEU A 296 25.062 30.864 52.923 1.00 41.04 6

ATOM 262 CG LEU A 296 26.438 30.658 52.315 1.00 42.74 6

ATOM 263 CDl LEU A 296 26.447 31.030 50.861 1.00 40.99 6

ATOM 264 CD2 LEU A 296 27.437 31.454 53.086 1.00 39.44 6

ATOM 265 C LEU A 296 23.239 30.366 54.548 1.00 45.56 6

ATOM 266 O LEU A 296 22.301 29.660 54.148 1.00 43.07 8

ATOM 267 N PRO A 297 23.050 31.405 55.365 1.00 46.99 7

ATOM 268 CD PRO A 297 24.121 32.241 55.930 1.00 47.12 6

ATOM 269 CA PRO A 297 21.700 31.811 55.787 1.00 49.61 6

ATOM 270 CB PRO A 297 21.937 32.990 56.738 1.00 49.91 6

ATOM 271 CG PRO A 297 23.401 33.155 56.872 1.00 51.28 6

ATOM 272 C PRO A 297 20.864 32.212 54.558 1.00 49.59 6

ATOM 273 O PRO A 297 21.402 32.684 53.556 1.00 51.66 8

ATOM 274 N CYS A 298 19.545 32.035 54.655 1.00 51.02 7

ATOM 275 CA CYS A 298 18.618 32.369 53.567 1.00 52.86 6

ATOM 276 CB CYS A 298 17.201 31.877 53.915 1.00 54.57 6

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ATOM 596 CG GLN A 340 19.087 44.146 17.767 1.00 41.10 6

ATOM 597 CD GLN A 340 18.876 42.705 17.305 1.00 48.84 6

ATOM 598 OE1 . GLN A 340 19.826 41.888 17.309 1.00 50.53 8

ATOM 599 NE2 ! GLN A 340 17.650 42.393 16.907 1.00 54.25 7

ATOM 600 C GLN A 340 19.779 45.750 21.263 1.00 41.50 6

ATOM 601 O GLN A 340 18.998 46.444 21.923 1.00 42.72 8

ATOM 602 N LEU A 341 20.758 45.026 21.806 1.00 42.00 7

ATOM 603 CA LEU A 341 20.952 44.947 23.243 1.00 38.10 6

ATOM 604 CB LEU A 341 22.209 44.145 23.575 1.00 36.66 6

ATOM 605 CG LEU A 341 22.361 43.804 25.029 1.00 39.94 6

ATOM 606 CDl LEU A 341 21.219 42.884 25.410 1.00 34.98 6

ATOM 607 CD2 LEU A 341 23.685 43.128 25.284 1.00 40.95 6

ATOM 608 C LEU A 341 21.072 46.321 23.860 1.00 36.37 6

ATOM 609 O LEU A 341 20.484 46.588 24.892 1.00 37.89 8

ATOM 610 N LYS A 342 21.848 47.184 23.209 1.00 33.29 7

ATOM 611 CA LYS A 342 22.089 48.546 23.679 1.00 35.17 6

ATOM 612 CB LYS A 342 23.057 49.242 22.721 1.00 34.97 6

ATOM 613 CG LYS A 342 23.655 50.536 23.240 1.00 40.00 6

ATOM 614 CD LYS A 342 24.673 51.109 22.245 1.00 34.48 6

ATOM 615 CE LYS A 342 25.514 52.229 22.873 1.00 37.54 6

ATOM 616 NZ LYS A 342 26.655 52.634 21.987 1.00 42.32 7

ATOM 617 C LYS A 342 20.796 49.349 23.774 1.00 38.29 8

ATOM 618 O - LYS A 342 20.345 49.711 24.861 1.00 36.23 8

ATOM 619 N ASN A 343 20.223 49.622 22.603 1.00 39.25 7

ATOM 620 CA ASN A 343 18.993 50.385 22.485 1.00 40.19 6

ATOM 621 CB ASN A 343 18.521 50.373 21.033 1.00 37.96 6

ATOM 622 CG ASN A 343 19.664 50.550 20.052 1.00 39.22 6

ATOM 623 OD1 ASN A 343 20.428 51.537 20.125 1.00 42.37 8

ATOM 624 ND2 ASN A 343 19.773 49.612 19.125 1.00 42.19 7

ATOM 625 C ASN A 343 17.928 49.748 23.375 1.00 40.12 6

ATOM 626 O ASN A 343 17.010 50.417 23.859 1.00 36.01 8

ATOM 627 N GLY A 344 18.073 48.433 23.568 1.00 40.95 7

ATOM 628 CA GLY A 344 17.152 47.670 24.394 1.00 39.25 6

ATOM 629 C GLY A 344 17.039 48.092 25.842 1.00 38.26 6

ATOM 630 O GLY A 344 16.072 47.724 26.512 1.00 35.69 8

ATOM 631 N GLY A 345 18.017 48.857 26.329 1.00 35.89 7

ATOM 632 CA GLY A 345 17.964 49.301 27.706 1.00 34.00 6

ATOM 633 C GLY A 345 19.273 49.199 28.443 1.00 38.64 6

ATOM 634 O GLY A 345 19.469 49.888 29.441 1.00 38.14 8

ATOM 635 N LEU A 346 20.170 48.337 27.973 1.00 39.52 7

ATOM 636 CA LEU A 346 21.444 48.180 28.649 1.00 36.05 6

ATOM 637 CB LEU A 346 22.124 46.876 28.209 1.00 35.72 6

ATOM 638 CG LEU A 346 21.355 45.617 28.501 1.00 34.89 6

ATOM 639 CDl LEU A 346 22.295 44.413 28.422 1.00 44.09 6

ATOM 640 CD2 LEU A 346 20.786 45.721 29.902 1.00 34.84 6

ATOM 641 C LEU A 346 22.358 49.361 28.396 1.00 33.52 6

ATOM 642 O LEU A 346 23.267 49.653 29.178 1.00 35.58 8

ATOM 643 N GLY A 347 22.087 50.056 27.295 1.00 30.47 7

ATOM 644 CA GLY A 347 22.909 51.192 26.931 1.00 33.01 6

ATOM 645 C GLY A 347 24.360 50.768 26.747 1.00 30.72 6

ATOM 646 O GLY A 347 24.669 49.775 26.082 1.00 30.89 8

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ATOM 808 OE1 . GLU A 369 38.337 26.744 29.994 1.00 42.05 8

ATOM 809 OE2 GLU A 369 40.158 26.795 31.218 1.00 42.03 8

ATOM 810 C GLU A 369 34.953 28.471 33.821 1.00 25.57 6

ATOM 811 O GLU A 369 34.987 29.256 34.760 1.00 20.56 8

ATOM 812 N VAL A 370 33.967 28.463 32.921 1.00 25.39 7

ATOM 813 CA VAL A 370 32.849 29.396 33.029 1.00 25.99 6

ATOM 814 CB VAL A 370 31.763 29.131 31.987 1.00 26.15 6

ATOM 815 CGI VAL A 370 30.609 30.093 32.183 1.00 27.65 6

ATOM 816 CG2 VAL A 370 32.306 29.251 30.592 1.00 17.70 6

ATOM 817 C VAL A 370 32.245 29.209 34.412 1.00 26.49 6

ATOM 818 O VAL A 370 32.012 30.170 35.147 1.00 28.16 8

ATOM 819 N ALA A 371 31.988 27.947 34.739 1.00 21.01 7

ATOM 820 CA ALA A 371 31.393 27.554 36.011 1.00 19.57 6

ATOM 821 CB ALA A 371 31.441 26.039 36.145 1.00 18.62 6

ATOM 822 C ALA A 371 32.116 28.211 37.177 1.00 23.48 6

ATOM 823 O ALA A 371 31.531 28.989 37.931 1.00 32.67 8

ATOM 824 N LEU A 372 33.401 27.893 37.305 1.00 22.89 7

ATOM 825 CA LEU A 372 34.217 28.447 38.369 1.00 23.28 6

ATOM 826 CB LEU A 372 35.675 27.996 38.178 1.00 27.76 6

ATOM 827 CG LEU A 372 35.943 26.524 38.415 1.00 21.18 6

ATOM 828 CDl LEU A 372 37.356 26.171 38.049 1.00 27.64 6

ATOM 829 CD2 LEU A 372 35.675 26.204 39.880 1.00 20.90 6

ATOM 830 C LEU A 372 34.098 29.966 38.396 1.00 21.34 6

ATOM 831 O LEU A 372 33.828 30.572 39.439 1.00 23.16 8

ATOM 832 N LEU A 373 34.288 30.561 37.223 1.00 24.42 7

ATOM 833 CA LEU A 373 34.214 32.007 37.074 1.00 23.78 6

ATOM 834 CB LEU A 373 34.296 32.360 35.575 1.00 22.18 6

ATOM 835 CG LEU A 373 34.784 33.726 35.165 1.00 31.52 6

ATOM 836 CDl LEU A 373 36.000 34.084 35.962 1.00 31.93 6

ATOM 837 CD2 LEU A 373 35.103 33.720 33.693 1.00 30.24 6

ATOM 838 C LEU A 373 32.904 32.480 37.720 1.00 25.69 6

ATOM 839 O LEU A 373 32.895 33.410 38.532 1.00 30.13 8

ATOM 840 N GLN A 374 31.814 31.800 37.368 1.00 26.24 7

ATOM 841 CA GLN A 374 30.487 32.104 37.896 1.00 21.60 6

ATOM 842 CB GLN A 374 29.454 31.121 37.335 1.00 24.57 6

ATOM 843 CG GLN A 374 29.310 31.145 35.821 1.00 21.02 6

ATOM 844 CD GLN A 374 28.224 30.201 35.331 1.00 22.86 6

ATOM 845 OE1 GLN A 374 28.037 30.042 34.123 1.00 24.07 8

ATOM 846 NE2 GLN A 374 27.515 29.590 36.249 1.00 25.59 7

ATOM 847 C GLN A 374 30.421 32.039 39.422 1.00 20.66 6

ATOM 848 O GLN A 374 29.717 32.832 40.048 1.00 24.47 8

ATOM 849 N ALA A 375 31.136 31.074 40.004 1.00 16.26 7

ATOM 850 CA ALA A 375 31.155 30.889 41.445 1.00 17.16 6

ATOM 851 CB ALA A 375 31.805 29.568 41.780 1.00 19.53 6

ATOM 852 C ALA A 375 31.907 32.025 42.108 1.00 25.13 6

ATOM 853 O ALA A 375 31.397 32.646 43.034 1.00 23.81 8

ATOM 854 N VAL A 376 33.122 32.277 41.611 1.00 24.57 7

ATOM 855 CA VAL A 376 33.959 33.354 42.118 1.00 25.80 6

ATOM 856 CB VAL A 376 35.101 33.658 41.164 1.00 26.48 6

ATOM 857 CGI VAL A 376 35.926 34.812 41.697 1.00 23.20 6

ATOM 858 CG2 VAL A 376 35.959 32.429 40.952 1.00 19.08 6

ATOM 859 C VAL A 376 33.107 34.599 42.312 1.00 25.69 6 H H H H H H H HI H Hi H Hl H H H H Hl ⁱHl H HI H^l H H H H H H H H ^t-3 H H H ι-3 HI H HI H Hι HI H Hi t-3 H !-3 H Hl H Hl ι-3 H! Hi o oo o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

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NJ O ∞ UJ C0 C0 4s O O ∞ 4s 4-. cn M C0 UJ 4s M O W Cn C0 4S M Cπ C0 00 Cπ 4s 4s O C^ Cn UJ M v^

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NJ 03 0D 4-. UJ W Cn vD Cr> Cn 4s 0 4s M NJ W O C^ NJ 4s O CO CTl UJ CO O CO Cπ O CO C^ Cn Cπ θ M M M ^ ∞ NJ 4s

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-^J c ^ c en c cn ^ ∞ cn ∞ ∞ σ^ϊ CΛ σ^ϊ ^ ∞ σ oo on c -- ∞ on ∞ c^ c -^ cn -J co cn cn cn cn cn cn -J

ATOM 913 NH2 ARG A 383 28.194 38.992 42.918 1-00 35.46 7

ATOM 914 C ARG A 383 27.523 ,2.989 50.216 1-00 44.96 6

ATOM 915 O ARG A 383 27.744 42.344 51.260 1.00 45.60 8

ATOM 916 N PRO A 384 26.852 44.144 50.223 1.00 45.33 7

ATOM 917 CD PRO A 384 26.625 44.964 49.027 1.00 46.85 6

ATOM 918 CA PRO A 384 26.298 44.738 51.446 1.00 47.37 6

ATOM 919 CB PRO A 384 25.841 46.130 51.012 1.00 46.90 6

ATOM 920 CG PRO A 384 26.075 46.229 49.567 1.00 46.41 6

ATOM 921 C PRO A 384 25.158 43.919 52.049 1.00 48.29 6

ATOM 922 O PRO A 384 24.404 43.264 51.329 1.00 48.34 8

ATOM 923 N GLY A 385 25.039 43.983 53.383 1.00 49.88 7

ATOM 924 CA GLY A 385 23.991 43.270 54.113 1.00 50.35 6

ATOM 925 C GLY A 385 24.347 41.852 54.495 1.00 50.70 6

ATOM 926 O GLY A 385 23.614 41.204 55.244 1.00 53.48 8

ATOM 927 N LEU A 386 25.466 41.371 53.955 1.00 49.04 7

ATOM 928 CA LEU A 386 25.901 40.017 54.215 1.00 50.53 6

ATOM 929 CB LEU A 386 27.224 39.751 53.492 1.00 45.17 6

ATOM 930 CG LEU A 386 27.152 39.592 51.993 1.00 48.26 6

ATOM 931 CDl LEU A 386 28.542 39.439 51.404 1.00 41.68 6

ATOM 932 CD2 LEU A 386 26.302 38.374 51.682 1.00 38.40 6

ATOM 933 C LEU A 386 26.045 39.776 55.691 1.00 52.13 6

ATOM 934 O LEU A 386 26.296 40.692 56.459 1.00 53.67 8

ATOM 935 N ALA A 387 25.861 38.522 56.077 1.00 53.42 7

ATOM 936 CA ALA A 387 25.976 38.129 57.470 1.00 56.01 6

ATOM 937 CB ALA A 387 24.802 37.234 57.854 1.00 56.47 6

ATOM 938 C ALA A 387 27.289 37.385 57.659 1.00 55.52 6

ATOM 939 O ALA A 387 28.275 37.940 58.134 1.00 53.75 8

ATOM 940 N CYS A 388 27.273 36.120 57.253 1.00 56.03 7

ATOM 941 CA CYS A 388 28.412 35.236 57.370 1.00 59.57 6

ATOM 942 CB CYS A 388 27.923 33.803 57.172 1.00 59.23 6

ATOM 943 SG CYS A 388 26.397 33.431 58.009 1.00 58.64 16

ATOM- 944 C CYS A 388 29.482 35.581 56.328 1.00 62.18 6

ATOM 945 O CYS A 388 29.720 34.821 55.400 1.00 67.88 8

ATOM 946 N VAL A 389 30.110 36.747 56.495 1.00 60.78 7

ATOM 947 CA VAL A 389 31.173 37.212 55.590 1.00 57.70 6

ATOM 948 CB VAL A 389 31.740 38.567 56.024 1.00 57.09 6

ATOM 949 CGI VAL A 389 32.795 39.037 55.041 1.00 59.03 6

ATOM 950 CG2 VAL A 389 30.640 39.598 56.171 1.00 53.98 6

ATOM 951 C VAL A 389 32.297 36.182 55.550 1.00 57.77 6

ATOM 952 O VAL A 389 32.358 35.336 54.662 1.00 60.94 8

ATOM 953 N ALA A 390 33.182 36.292 56.528 1.00 52.68 7

ATOM 954 CA ALA A 390 34.347 35.431 56.684 1.00 48.41 6

ATOM 955 CB ALA A 390 34.703 35.321 58.185 1.00 45.19 6

ATOM 956 C ALA A 390 34.224 34.040 56.082 1.00 47.63 6

ATOM 957 O ALA A 390 35.107 33.597 55.348 1.00 51.95 8

ATOM 958 N ARG A 391 33.117 33.366 56.391 1.00 47.11 7

ATOM 959 CA ARG A 391 32.879 32.018 55.885 1.00 51.64 6

ATOM 960 CB ARG A 391 31.520 31.498 56.383 1.00 54.22 6

ATOM 961 CG ARG A 391 31.267 30.012 56.059 1.00 64.20 6

ATOM 962 CD ARG A 391 29.930 29.489 56.602 1.00 73.80 6

ATOM 963 NE ARG A 391 29.787 28.044 56.454 1.00 79.76 7

ATOM 964 CZ ARG A 391 30.573 27.140 57.043 1.00 84.27 6

ATOM 965 NH1 ARG A 391 31.598 27.535 57.806 1.00 85.28 7 ATOM 966 NH2 ARG A 391 30.340 25.840 56.849 1.00 86.84 7

ATOM 967 C ARG A 391 32.922 31.986 54.358 1.00 48.18 6

ATOM 968 O ARG A 391 33.494 31.080 53.756 1.00 49.57 8

ATOM 969 N ILE A 392 32.281 32.993 53.762 1.00 45.01 7

ATOM 970 CA ILE A 392 32.196 33.148 52.319 1.00 48.77 6

ATOM 971 CB ILE A 392 31.224 34.297 51.963 1.00 46.45 6

ATOM 972 CG2 ILE A 392 31.241 34.582 50.479 1.00 42.35 •6

ATOM 973 CGI ILE A 392 29.791 33.953 52.402 1.00 49.69 6

ATOM 974 CDl ILE A 392 28.792 35.039 52.113 1.00 51.09 6

ATOM 975 C ILE A 392 33.554 33.356 51.641 1.00 50.90 6

ATOM 976 O ILE A 392 33.914 32.605 50.732 1.00 52.21 8

ATOM 977 N^' GLU A 393 34.298 34.374 52.071 1.00 50.43 7

ATOM 978 CA GLU A 393 35.592 34.684 51.471 1.00 50.30 6

ATOM 979 CB GLU A 393 36.437 35.561 52.387 1.00 53.97 6

ATOM 980 CG GLU A 393 36.558 36.966 51.844 1.00 62.18 6

ATOM 981 CD GLU A 393 37.546 37.777 52.564 1.00 67.69 6

ATOM 982 OE1 GLU A 393 38.149 38.741 52.119 1.00 66.42 8

ATOM 983 OE2 GLU A 393 37.856 37.640 53.729 1.00 70.64 8

ATOM 984 C GLU A 393 36.341 33.429 51.230 1.00 49.31 6

ATOM 985 O GLU A 393 36.755 33.089 50.125 1.00 49.53 8

ATOM 986 N LYS A 394 36.552 32.730 52.303 1.00 46.07 7

ATOM 987 CA LYS A 394 37.265 31.543 52.078 1.00 45.76 6

ATOM 988 CB LYS A 394 37.396 30.800 53.373 1.00 43.85 6

ATOM 989 CG LYS A 394 38.207 31.617 54.394 1.00 40.00 6

ATOM 990 CD LYS A 394 39.372 32.374 53.705 1.00 40.00 6

ATOM 991 CE LYS A 394 40.136 33.265 54.681 1.00 40.00 6

ATOM 992 NZ LYS A 394 41.516 33.602 54.162 1.00 40.00 7

ATOM 993 C LYS A 394 36.568 30.778 50.966 1.00 46.69 6

ATOM 994 O LYS A 394 37.215 30.427 49.988 1.00 49.13 8

ATOM 995 N TYR A 395 35.269 30.514 51.095 1.00 4-6.57 7

ATOM 996 CA TYR A 395 34.553 29.823 50.022 1.00 43.33 6

ATOM 997 CB TYR A 395 33.059 30.123 50.076 1.00 48.44 6

ATOM 998 CG TYR A 395 32.275 29.236 50.994 1.00 53.83 6

ATOM 999 CDl TYR A 395 31.010 29.598 51.415 1.00 56.43 6

ATOM 1000 CE1 TYR A 395 30.266 28.769 52.252 1.00 59.73 6

ATOM 1001 CD2 TYR A 395 32.790 28.033 51.428 1.00 56.47 6

ATOM 1002 CE2 TYR A 395 32.054 27.198 52.265 1.00 62.60 6

ATOM 1003 CZ TYR A 395 30.787 27.565 52.687 1.00 63.18 6

ATOM 1004 OH TYR A 395 30.059 26.753 53.528 1.00 64.46 8

ATOM 1005 C TYR A 395 35.120 30.356 48.716 1.00 37.30 6

ATOM 1006 O TYR A 395 35.643 29.601 47.908 1.00 34.10 8

ATOM 1007 N GLN A 396 35.029 31.670 48.522 1.00 31.92 7

ATOM 1008 CA GLN A 396 35.563 32.273 47.305 1.00 34.81 6

ATOM 1009 CB GLN A 396 35.403 33.801 47.329 1.00 32.64 6

ATOM 1010 CG GLN A 396 36.088 34.485 46.162 1.00 29.57 6

ATOM 1011 CD GLN A 396 35.616 35.891 45.927 1.00 29.46 6

ATOM 1012 OE1 GLN A 396 35.599 36.726 46.862 1.00 34.65 8

ATOM 1013 NE2 GLN A 396 35.245 36.173 44.689 1.00 27.21 7

ATOM 1014 C GLN A 396 37.035 31.909 47.167 1.00 37.13 6

ATOM 1015 O GLN A 396 37.511 31.590 46.080 1.00 37.36 8

ATOM 1016 N ASP A 397 37.751 31.970 48.285 1.00 38.61 7

ATOM 1017 CA ASP A 397 39.164 31.642 48.298 1.00 40.37 6

ATOM 1018 CB ASP A 397 39.757 31.869 49.704 1.00 40.51 6 S g S g ^ ^ ^ ^ ^ H ^ _M Hl Hi Hl HI HI H H H n n o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

O CD O O O O O N ._J N._J N._J N._J NJ NJ NJ c c .n_ .. co N O

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> M M M x X

M M M M M M M M M ^μ 50 50 50 50 5 5 50 50 50 50 50 tn >tn M >tn tή co ω co ω ω ω ω ω ω ω cΛ ω ω c/i ω ω cj co co co ω ω < > > > ^ > ?^:' > >' > *^, 3^:;' > > ' > > > 3

4s 4s 4s. 4s 4s. 4s 4s. 4s. 4s. 4s 4s 4s 4-. 4s M M M M M M M M M M M M M O O O O O O

4s 4s 4S 4s 4s 4s CO CO CO CO CO CO C CO CO CO NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ M M M M M M M M M O O O O O O O O O O O vO vO UJ UJ UJ UJ

∞ Cπ cΛ C^ -J ^ ^ -J O M O UJ UJ CO OO -J CJO -J NJ M W CO C Cn (J-l Cn ^ -J O UJ UJ OO CX) -J O^

>-- cn 4S M W --I UJ Cn U C0 W σ^ N C0 N0 W W O σ^ C 4s 00 vD μ-' O --] 4 c C0 σi C0 4s. ^ O UJ CO C OO NJ -J 4S OO UJ NJ O N CX> UJ C0 σι C0 CJ 00 M W O C CΛ C0 vD 4S vn NJ W CO Cπ σι C s c θ 4 0 cn σ 4s ^ -J uj μ- ^l 4s _^j o cn uJ cn i—' UJ NJ CO _vO Cn Cn 4S vD W C^ 4 ^ CO C s 4i CTl vO 4S C» UJ ^ s OJ O NJ O OO UJ Cn - O -J NJ ^■~J ' "NJ- -J C0 C0 4s M Cπ NJ NJ O 00 C C0 NJ

C CO CO CO CO CO C C CO M W CO W W W W W M NJ W W M W W W W W W ^ W W N INJ N NJ W W N N^ C0 W s C0 W M M O O v0 CX> O UJ 00 UJ 00 00 00 -J OT C0 C0 ∞ αJ -J 0 Cπ Cπ UJ O M M 4s. Cπ 4^S C0 C0 Cn C0 4^

M vl J H co *■ ω vi i^β ^ ω m Λ m w m ^ J i o ^ o ^ ffl vi μ vi o^j m io co N μ ϋⁱ ϋi ω ^ M ω ^ ^ ^ ^ n M ui ui in in CO CO M CO M M O _OT -. W U C^ ^ CΛ U vO U1 0 ∞ 4s σϊ CO ∞ M s ^(jn π W W -J W J CO NJ cπ CO M CO M ∞ M 4S. -J θ σι 0n O C^ W C0 O 4s O 4S O 4s W C0 C0 σι C0 M 4s Cπ Cn 4-. ^ μ-. O -J O -J O 4s CD --J NJ C0 μ-¹ cn cn WM W NWJ NMJ NWJ NCOJ NCnJ CNπJ M^ W^

cn cn cn cn cn -_J ∞ en -] cn -J cn σι cn σΛ -J OT cn -J cn --J σ c^ cn cn -^

ATOM 1178 O VAL A 414 48.427 33.029 28.409 1.00 55.49 8

ATOM 1179 N THR A 415 49.706 33.863 26.733 1.00 56.28 7

ATOM 1180 CA THR A 415 50.721 34.484 27.557 1.00 57.83 6

ATOM 1181 CB THR A 415 51.268 35.675 26.758 1.00 59.64 6

ATOM ^"'1182 OG1 . THR A 415 51.605 36.754 27.636 1.00 66.69 8

ATOM 1183 CG2 ! THR A 415 50.197 36.158 25.745 1.00 59.42 6

ATOM 1184 C THR A 415 50.146 35.049 28.879 1.00 56.98 6

ATOM 1185 O THR A 415 48.933 35.146 29.051 1.00 55.70 8

ATOM 1186 N HIS A 416 51.C68 35.330 29.795 1.00 57.44 7

ATOM 1187 CA HIS A 416 50.808 36.011 31.047 1.00_# 57.34 6

ATOM 1188 CB HIS A 416 51.346 37.422 30.708 1.00^* 61.35 6

ATOM 1189 CG HIS A 416 51.872 38.237 31.821 1.00 69.78 6

ATOM 1190 CD2 HIS A 416 53.114 38.297 32.390 1.00 71.42 6

ATOM 1191 ND1 HIS A 416 51.135 39.263 32.416 1.00 72.49 "7

ATOM 1192 CE1 HIS A 416 51.914 39.884 33.290 1.00 75.50 6

ATOM 1193 NE2 HIS A 416 53.099 39.323 33.291 1.00 73.91 7

ATOM 1194 C HIS A 416 49.261 35.892 31.297 1.00 53.79 6

ATOM 1195 O HIS A 416 48.499 36.779 30.902 1.00 52.81 8

ATOM 1196 N PHE A 417 48.806 34.779 31.911 1.00 48.05 7

ATOM 1197 CA PHE A 417 47.355 34.428 32.061 1.00 47.99 6

ATOM 1198 CB PHE A 417 47.165 32.954 31.996 1.00 46.11 6

ATOM 1199 CG PHE A 417 45.835 32.590 31.399 1.00 44.27 6

ATOM 1200 CDl PHE A 417 45.680 32.720 30.046 1.00 41.79 6

ATOM 1201 CD2 PHE A 417 44.758 32.135 32.164 1.00 40.23 6

ATOM 1202 CE1 PHE A 417 44.498 32.397 29.422 1.00 44.30 6

ATOM 1203 CE2 PHE A 417 43.540 31.802 31.529 1.00 36.80 6

ATOM 1204 CZ PHE A 417 43.427 31.928 30.144 1.00 40.69 6

ATOM 1205 C PHE A 417 46.427 34.836 33.196 1.00 46.69 6

ATOM 1206 O PHE A 417 46.147 36.004 33.331 1.00 43.35 8

ATOM 1207 N TRP A 418 45.906 33.801 33.909 1.00 45.14 7

ATOM 1208 CA TRP A 418 44.982 33.867 35.065 1.00 44.89 6

ATOM'^' 1209 CB TRP A 418 45.545 33.099 36.255 1.00 42.24 6

ATOM 1210 CG TRP A 418 44.959 33.452 37.598 1.00 47.11 6

ATOM 1211 CD2 TRP A 418 43.724 32.924 38.149 1.00 46.98 6

ATOM 1212 CE2 TRP A 418 43.534 33.565 39.413 1.00 48.94 6

ATOM 1213 CE3 TRP A 418 42.777 31.986 37.688 1.00 45.23 6

ATOM 1214 CDl TRP A 418 45.434 34.350 38.512 1.00 46.24 6

ATOM 1215 NE1 TRP A 418 44.588 34.407 39.608 1.00 50.63 7

ATOM 1216 CZ2 TRP A 418 42.441 33.270 40.238 1.00 45.46 6

ATOM 1217 CZ3 TRP A 418 41.686 31.706 38.500 1.00 44.50 6

ATOM 1218 CH2 TRP A 418 41.511 32.335 39.753 1.00 47.55 6

ATOM 1219 C TRP A 418 44.908 35.324 35.398 1.00 43.88 6

ATOM 1220 O TRP A 418 43.797 35.839 35.702 1.00 43.17 8

ATOM 1221 N PRO A 419 46.084 35.976 35.461 1.00 43.55 7

ATOM 1222 CD PRO A 419 47.467 35.482 35.400 1.00 41.52 6

ATOM 1223 CA PRO A 419 46.009 37.396 35.758 1.00 41.48 6

ATOM 1224 CB PRO A 419 47.436 37.884 35.535 1.00 39.21 6

ATOM 1225 CG PRO A 419 48.261 36.696 35.223 1.00 39.25 6

ATOM 1226 C PRO A 419 44.960 38.090 34.817 1.00 36.28 6

ATOM 1227 O PRO A 419 44.208 38.978 35.237 1.00 37.08 8

ATOM 1228 N LYS A 420 44.915 37.701 33.540 1.00 35.96 7

ATOM 1229 CA LYS A 420 43.977 38.287 32.575 1.00 40.82 6

ATOM 1230 CB LYS A 420 44.314 37.805 31.155 1.00 40.78 6 ≤ S ≤ 2 S ≤ ≤ _μ3 _{μ μ}3 _μ3 H H H H H H H H H H H H H o o o o o o o o o o o o o o o o o o o o g g g g g g g g g g g g g g g o g o o o o o o o o o o o o o o o

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 -> -> t-> -¹ )-*

M W W W M NJ NJ W NJ W NJ W W W W M W NJ M NJ NJ NO NJ NJ NJ NJ W NJ W W W W NJ W W W NJ NJ W NJ NJ M W W NJ W NJ m m α_i co _{j vi vi vi vi J} -_J ^ -_J ^ oi m m m m m m m m m ^ w w w w ui w 4s 4s 4s, 4s. " 4S 4S CO CO CO C CO C C CO

CO NJ M O UJ 00 -J CΛ Cn 4s C0 NJ _M O uj oo -J cn cn 4s Co Nj M o uJ oo -vj cn cn 4s co NJ M O uJ oo - c n 4s o NJ θ vθ oo ~J c cn 4s co N

O Ω Ω O Ω Ω O Ω O Ω Ω Ω Z O Ω Z Ω Ω Ω Ω Ω Z O Ω Ω CO Ω Ω Ω Z O Ω Ω Ω Ω Ω Ω O Ω Ω Ω Ω Ω Ω O Ω Z Ω Ω

Cl fl tB O Ω D > IN J σ Ω CD PJ O Ω CD > O α Ω CD > NJ M σ σ Ώ CD > tsi PJ α NJ M NJ M NJ M

H H H H H H H < < < < < < < tn tn tn 2 2 2 2 2 2 2 2 tn tn tn tn tn t^-, tn tn tn tn tn tn ιn tn _ι. χ > $* > > ^μ< P PJ PJ PJ PJ tn tn tn tn

PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ : 5₀ 5₀ 0 50 50 O 5 M tn t tn tn t m CO cό c/i CO CΛ CO CO CO CO HI HI H HI HI π H HI G G G G G G G G G α G G G G G CO CO O O

_Δ *. _ι^" Λ * ι^ ι^ *' ^ ^ ^ ^Λ ^ ^ ^β ^ ^ * ^Λ ^ ^ ^{Λ Λ} ^ ^ ^{Λ fc Λ ,,>} '^,i '^,:' '^,> '^,:' *' *' *' *' *' ^Λ ^ * 'ⁱ ι ιt« ιfc ^ Λ ιt^ ιli ^

W W W NJ W W NJ NJ NJ NJ NJ M NJ NJ NJ N N W NJ W NJ NO NJ M NJ W W W W NJ W NJ W NJ NJ NJ NJ W NJ NJ NJ W W σι m m m m m Λ Ui uι ^ uι ^ ui π Λ J- ^ * ^ ^ ^ ^ ^ ω ω ⁾ ω ω ω ω ω M W N N) M M M M μ μ μ _{H H} μ μ _{O O O O O}

u u ω ω t_Λ) ω u ω Λ -> ^ Λ ji ω Λ Λ *. j- *, t. _{Λ ω <i} j_i CO 4s 4s. 4s 4s 4s 4s 4s. 4s. 4s _s n -J ∞ - oo co j co co NJ θ θ vD θ c NJ W UJ o μ M μ M vl vi ui

₁— C0 C₀ C0 NJ Cn ^J C0 μ-^» CO -J C0 4s cπ UJ 4s. C μ^ 4s 4s O UJ 4s π cn cn N co ^μ-> 4s. cn cn 4s Nj uJ

O cn cn o o cπ u^j O 4s O Cπ NJ M Cn NJ C0 cn uJ NJ 00 4s. μ-ι co c

-J _^I UJ 4S O U? C0 Cn Cπ C0 4s 4s O - • -_J co N_{J U}J _UJ M cπ o oo -^j cn -J M UJ oo M θo o 4s^, cπ cn Nj ^μj cπ cπ co 4s ~ cn μ-' cn o oo co 4s

4_S 4_S 4_S 4_S 4_{S 4S} 4_S. 4_{S 4S} C C_O C_O C_O C C_O C_O CO C C C CO C C0 4S 4S S 4S 4S 4S. 4^ I^ CO CO (^ C^ 4_S C0 Cn C₀ C0 NJ M O O CΛ CD 00 v0 UJ UJ UJ v0 UJ UJ ⁰0 ∞ UJ UJ M O W C⁰ M M M ^CD UJ UJ σ, ^vJ Cn -J -J ^ cn c^

O 0 cn cπ 0 NJ o cn 00 ^j o o cn cn 4s O w co cn -J cn 4s, co ₄s co ₄s cn o uJ UJ Cπ 4s co NJ u θ NJ Cn NJ UJ -J θ co cπ O ID M ~J μ -j co NJ μ-» uJ cn uj cπ cn co co N --] NJ Cπ UJ NJ UJ UJ Cn M NJ CO M 00 cπ co cn M cn UJ NJ M CO C0 CO NJ CO CO Cn C0 cn 4s cπ _{o σι} v. y3 ₀₀ Cπ NJ O ^! OO CO OO NJ CO Cn o M o cn -J O 4s 4s. 4s 00 C0 M -vJ cn NJ 4s. M M co co co co co co co co co ui co co co co co co w w co co co co co co co co co co co co co co co co co co co co ω cn c^ ^ ∞ v -j ^ ^ ^ --ι uj ∞ σ^ cπ 4s 4s UJ θ M W c co s Λ M Co s s cn cπ --ι c^ uj

M _θ rn C0 C0 M 4S. M ∞ C0 O 00 ^vJ W Cn -J C0 ⁴s 4s σ^ ^4S U^J C Cn ⁰⁰ cn ^4s O ^M Cπ W Cπ Cπ C0 ^ UJ UJ -J C0 ∞ ^M 4s. oo u^j cn NJ uJ UJ NJ cn NJ

O M M CO cn n NJ W ^s w u cn ^θo w o w oo cπ cπ w ^{! UJ} - ⁴ -' ^(j-^{i W M} n ^{M θθ N NJ} u^j ^J c co c o CO NJ NJ M M 4S O0 CS NJ -J 0

Cn M n o O Cn 4s VJD M UJ 0 4-. C^ UJ UJ 4s. ^ W CO Cπ ∞ C Cπ Cn 4s OD UJ Cn θD -J UJ O UJ C O CO M M NJ ^l CO M cn co cn co cπ NJ Oo NJ Co cn

)-* -> i~> t-¹ I-* M M M M M M μ-i μ-> μ-i

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 r-. r-. o r-. -. δ o o δ o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o δ o δ δ o § § §. § § § § u u ^₎ ω _J w ω l) _W M ^) M ^) w ^J ω ^) u c) ω ω w ^) lJ ^ π w π C_O W O C_O M N_{J M} ∞ U_J ∞ CO O UJ M ∞ CO O O NJ M UJ π vJ

M cπ its o co '-J cn co o J co s UJ cn NJ NJ O - J O n NJ CΠ co M M o ω o -J s c_Jϊ M Ui ω W M 4s M ω w cJ M j N - c c <jn c σ, ra m iJi oo m m i iJ) m m m m oi -J O oi i m oi m m m -J ⁽- m m m <ri m m σi -I σi m

≤ ≤ S ≤ ≤ μ3 H μ ^μ3 ^μ3 H H H H H H H H! H! H H H H^l H H H H H H H H H H

S r^ o n o n Ω O Ω O O O O O O O O O O O O O O O O g o g g O O O O O O O O O O O O O O O O O O O O O

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

^ π _{i i i}._{i f}o _to ω co co co co co co co co co co co co co co co co co co co co co co co co co co co ω

CO CO O CO CO CO CO N W W W NJ NJ NJ NJ W W M M M M M M M M M M O O O O O O O O OO OO OO UUJJ UCDD UUJJ UvOJ UUJJ UCD^ vO UJ UD UD CO CO OO CO CO Cn Cπ 4s C0 NJ M θ UJ 00 _vJ Cn Cπ 4s C0 NJ M O UJ C0 -J Cn Cn 4S C0 NJ M o uJ co -J cn cn 4s co NJ M θ uj co ^J cn cπ 4s co Nj M θ u co -vj cn cπ

Z O Ω Ω Ω Z O Ω Ω Z O Ω Ω Ω Ω Ω Ω Z O Ω Ω O Ω Ω Ω Z O Ω Z Z Ω Z Ω Ω Ω Ω O Ω Ω Ω Ω Ω Ω Z O O O O Ω Ω Ω CD D Ω Ω CD PJ α Ω CD 5C 5E tsι PJ D Ω CD > α Ω D > o σ Ω CD ;>

M M NJ NJ M NJ M NJ M

Ω ^ ^ ^ ^ ^ Ω Ω Ω M M M M M M M 2 2 2 2 2 2 2 2 > > > > > > > > tn tn tn t t-^< tn tn tn > ι > > > > > tn tn tn m tn tn tn tn tn -tn t -n t .n tn tn tn tn tn p^j p^j p^j p p^j p p^j n 5o ^ 50 50 50 50 50 5o 50 50 50 p p p^j tn ^j p^j p^j pj co o co co o co o ^{" " '} > μ μ< μ ^μμ PtJl PPJJ PPJJ PPJJ PPJJ PPJ] PMJ Pt^IJJ Ht-3^I Ht-3 HH! Hi-3 HHι HHI HH! HH^I: ΩO ΏΩ ΏΩ ΩΩ ΏΩ ΏΩ ΩΩ ΩΩ ΩΩ ΩΩ ΏΩ G G G G G G G G TJ TJ TJ TJ TJ TJ TJ > >

CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO W NJ NJ NJ W W W W W NJ NJ W NJ W 4s ω ω ω ω C0 NJ W W W M M M M M M M M O O O O O O O O UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ UJ ∞ ∞ ∞ 00 rø ∞ ∞

W M W M NJ NJ NJ NJ M W NJ M W CO M M NJ CO W CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO W

-J cπ cn co -J vJ Cπ cn cn ^vJ rΛ -J UJ O -J 00 00 O UJ O W C0 C0 W M M O M C0 M C0 4s C0 NJ NJ M NJ O M O NJ NJ M M C0 NJ C0 -J Cn Cn Cπ Cπ

^ m θJ 4s (j-ι 4s 4s ^ co co -vJ UJ θ rΛ UJ UJ M 4s co UJ Cπ UJ -O C^ UJ O O J UJ Cθ θ Cπ co Cπ cπ θ O N) UJ NJ μ^j u^j uj NJ cn cn - uj co cπ o NJ ^1 cn CO NJ M M UJ 4S CO M Cn ∞ 4s W Cn Cn C0 Cn M 4s W C0 4s 4s 4s 4s UJ O UJ NJ vD C0 M Cn NJ Cπ 00 -J NJ O _v ω W σϊ C0 s M 4s ∞ UJ O UJ UJ ^ M NJ 4s O π π M O ^ n 4s 4s UJ O CO -vJ C CO ∞ 4S ^ ₁χ) O NJ Nj oo cn Co co oo co cn M

4s 4s 4s 4s 4s 4s 4s 4s C0 4^S 4s 4s 4^S 4s 4S. 4-. 4S 4-. 4s C0 C0 CO CO 4s 4^ c_β u_j co -4 -_vj Λ π ^j o θ M W N^j co ω m S Mc_jn Cθπ Sv0 c4sπ, ∞M OO ^(j M W W M C0 O NJ M 4S C0 O O 4S C0 ~J W -J ^vJ UJ C0 ω

4s 4s NJ O UJ UJ UJ rΛ Cπ O O Cn O O CO W C CΛ

CO CO CO CO CO CO CO C CO CO CO CO CO C C C CO CO CO CO CO CO C CO CO CO CO C0 4S 4S 4S ^ 4S 4^ c ∞ ∞ uj co ∞ -_vj -_vJ cΛ π 4s s M NJ W o co 4s. π π n c^ CΛ cπ σ, c^ co en co 4s cn co u -~J UJ NJ μ-' cπ NJ UJ -J co cn cπ uJ CD 4s. co u^j ι-' --J μ^j co cπ o co o NJ M O UJ UJ O CO UJ M OO Cπ vJ Co uJ NJ cn co co cπ co o cn o o cn co cn CO M O M Cn Cπ UJ C0 M O 4s C0 -J M Cn 4s Cn C0 00 C0 C0 C0 C0 O O O Cn UJ 4S 4s cn C0 cn 4s M 4s cπ 4s CO o UJ 4s O Cn NJ -J 4s C0 NJ M UJ O 4S 4s Cn ^vJ O 4s C0 M M -J O Cn -J UJ -vJ O O M μ ⁽) ui vi μ

4S. -J CD M UJ C UJ CO O 4s. N co cn 4. _^j co o

M μ-¹ M μ-^{1 μ}-¹ M M M M oooooo oooooooooooooooooooooooooooooooo ooooooooooo ooo oooooo oooooooooooooooooooo^ooooooooooo o oo o o oo o ooooo oo

CO C_θ

W

M m M o

M

-J oo en en m _v co m m -J ∞ m m m m m m J co m m m iTi σi m ^ co m vi vj m vj φ ^ ^ ^ vj ω

ATOM 1337 CA CYS A 434 26.371 49.616 35.996 1.00 34.34 6

ATOM 1338 CB CYS A 434 27.047 "3.612 34.711 1.00 35.20 6

ATOM 1339 SG CYS A 434 27.789 50.811 34.285 1.00 54.48 16

ATOM 1340 C CYS A 434 24.974 49.198 35.612 1.00 34.09 6

ATOM ^""1341 O CYS A 434 24.107 50.040 35.415 1.00 34.89 8

ATOM 1342 N HIS A 435 24.756 47.898 35.447 1.00 34.30 7

ATOM 1343 CA HIS A 435 23.453 47.423 35.042 1.00 35.44 6

ATOM 1344 CB HIS A 435 23.404 45.904 35.104 1.00 31.76 6

ATOM 1345 CG HIS A 435 22.099 45.351 34.675 1.00 32.03 6

ATOM 1346 CD2 HIS A 435 21.697 44.790 33.519 1.00 28.61 6

ATOM 1347 ND1 HIS A 435 20.941 45.482 35.452 1.00 28.48 7

ATOM 1348 CE1 HIS A 435 19.912 45.025 34.759 1.00 33.27 6

ATOM 1349 NE2 HIS A 435 20.345 44.597 33.583 1.00 31.57 7

ATOM 1350 C HIS A 435 22.400 47.974 35.972 1.00 32.74 6

ATOM 1351 O HIS A 435 21.304 48.284 35.565 1.00 32.87 8

ATOM 1352 N ALA A 436 22.777 48..046 37.241 1.00 31.01 7

ATOM 1353 CA ALA A 436 21.910 48.563 38.266 1.00 29.91 6

ATOM 1354 CB ALA A 436 22.661 48.595 39.580 1.00 21.23 6

ATOM 1355 C ALA A 436 21.475 49.969 37.884 1.00 33.86 6

ATOM 1356 O ALA A 436 20.296 50.298 37.910 1.00 36.10 8

ATOM 1357 N SER A 437 22.453 50.795 37.532 1.00 35.19 7

ATOM 1358 CA SER A 437 22.172 52.167 37.140 1.00 33.03 6

ATOM 1359 CB SER A 437 23.441 52.815 36.603 1.00 35.31 6

ATOM 1360 OG SER A 437 23.203 54.151 36.193 1.00 44.99 8

ATOM 1361 C SER A 437 21.110 52.158 36.055 1.00 38.39 6

ATOM 1362 O SER A 437 20.049 52.745 36.204 1.00 37.54 8

ATOM 1363 N ARG A 438 21.432 51.483 34.956 1.00 37.32 7

ATOM 1364 CA ARG A 438 20.534 51.379 33.821 1.00 39.30 6

ATOM 1365 CB ARG A 438 21.114 50.402 32.786 1.00 42.97 6

ATOM 1366 CG ARG A 438 22.343 50.911 32.051 1.00 41.72 6

ATOM 1367 CD ARG A 438 21.955 52.134 31.251 1.00 45.23 6

ATOM 1368 NE ARG A 438 20.964 51.839 30.237 1.00 45.66 7

ATOM 1369 CZ ARG A 438 20.063 52.718 29.809 1.00 49.71 6

ATOM 1370 NH1 ARG A 438 20.046 53.958 30.318 1.00 50.91 7

ATOM 1371 NH2 ARG A 438 19.198 52.354 28.865 1.00 46.86 7

ATOM 1372 C ARG A 438 19.147 50.922 34.240 1.00 42.37 6

ATOM 1373 O ARG A 438 18.147 51.297 33.625 1.00 40.58 8

ATOM 1374 N PHE A 439 19.080 50.120 35.298 1.00 42.25 7

ATOM 1375 CA PHE A 439 17.803 49.624 35.763 1.00 42.81 6

ATOM 1376 CB PHE A 439 17.975 48.794 37.013 1.00 42.18 6

ATOM 1377 CG PHE A 439 16.739 48.053 37.413 1.00 42.48 6

ATOM 1378 CDl PHE A 439 16.198 47.111 36.562 1.00 47.09 6

ATOM 1379 CD2 PHE A 439 16.105 48.320 38.613 1.00 39.76 6

ATOM 1380 CE1 PHE A 439 15.047 46.427 36.905 1.00 49.17 6

ATOM 1381 CE2 PHE A 439 14.940 47.630 38.963 1.00 45.10 6

ATOM 1382 CZ PHE A 439 14.411 46.683 38.098 1.00 46.36 6

ATOM 1383 C PHE A 439 16.921 50.803 36.075 1.00 44.79 6

ATOM 1384 O PHE A 439 15.830 50.903 35.554 1.00 40.26 8

ATOM 1385 N LEU A 440 17.410 51.681 36.951 1.00 42.77 7

ATOM 1386 CA LEU A 440 16.660 52.871 37.344 1.00 42.96 6

ATOM 1387 CB LEU A 440 17.546 53.824 38.150 1.00 37.19 6

ATOM 1388 CG LEU A 440 17.943 53.297 39.500 1.00 36.97 6

ATOM 1389 CDl LEU A 440 18.620 54.389 40.316 1.00 33.65 6 2 ≤ S 2 S μ μ! ≤ μ3 μ3 H 3 H H H H H H H H! HI H

S r rn n o o o o o o o o o o o o o o o o o o o o o g o o g o o o o o o o o o o o o o o o o o o o

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

-ⁱ V-> -' b- -¹ t-' i-' i-' )-' -ⁱ l-ⁱ L-^l t-> t-' -' i-> μ-> -ⁱ -ⁱ M μ->

M M M -> -> t 4s 4_S 4s 4s 4s. 4s 4s 4s 4s. 4^ 4s 4s

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NJ M NJ M NJ M M NJ

TJ Ω Ω Ω Ω Ω Ω Ώ Ω Ώ Ω Ω Ώ Ώ Ω Ώ < < < tn tn m tn tn tn tn tn ιn 2 2 2 2 2 2 2 2 X X X x x x pπ x X tn in 50 K m tn m > ; ; >- >-< t-< J PJ PJ PJ PJ PJ PJ PJ M M PJ PJ O G G G tn tn tn m tn tn co co co co co co co co co H H HI H H H HJ HJ CO CO co CΛ o Co co o c o G G p > > > > > > > > > > > ^'P > > > > > > > > > > > > > > > > p > ^,p

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TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ TJ ^•TJ T TJ TJ TJ TJ TJ tn tn tn m tn in t-i t-i Ω Ω Ω Ω Ω Ω Ω Ω Ω 50 50 50 5 2 5 50 50 50 50 50 50 3: 3 5C X X X 5 X X 3J X PJ PJ PJ PJ PJ PJ PJ PJ O o 6 o O O O O O d d O PJ M W W PJ PJ RJ PJ PJ P^J PJ G G G G G G G G G G G G a G G G G

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00 on n cπ NJ 4s.

00 4s 00 rn (j-l C0 Cn C0 M W 4s W Cn 4s M σι M' O v0 O C0 4s. UJ O NJ 4s UJ Cn uJ w u_{j j} c^ o cn w J UJ c cn co cn M NJ cn NJ -v NJ NJ 4s s c NJ n cπ NJ M

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ATOM 1496 C PRO A 453 10.015 40.084 39.532 1-00 50.99 6

ATOM 1497 0 PRO A 453 10.876 40.900 39.838 1-00 54.17 8

ATOM 1498 N LEU A 454 10.255 38.781 39.423 1.00 51.21 7

ATOM 1499 CA LEU A 454 11.585 38.298 39.674 1.00 47.17 6

ATOM ^{^}1500 CB LEU A 454 11.813 36.962 38.975 1.00 44.44 6

ATOM 1501 CG LEU A 454 13.167 36.375 39.289 1.00 41.33 6

ATOM 1502 CDl LEU A 454 13.524 36.638 40.720 1.00 35.93 6

ATOM 1503 CD2 LEU A 454 13.169 34.907 38.992 1.00 34.79 6

ATOM 1504 C LEU A 454 12.541 39.375 39.182 1.00 42.^'25 6

ATOM 1505 O LEU A 454 13.477 39.718 39.886 1.00 40.82 8

ATOM 1506 N PHE A 455 12.270 39.957 38.011 1.00 39.29 7

ATOM 1507 CA PHE A 455 13.133 41.005 37.473 1.00 41.81 6

ATOM 1508 CB PHE A 455 12.527 41.592 36.192 1.00 47.22 6

ATOM 1509 CG PHE A 455 13.433 42.565 35.467 1.00 56.97 6

ATOM 1510 CDl PHE A 455 14.715 42.189 35.135 1.00 57.23 6

ATOM 1511 CD2 PHE A 455 12.999 43.840 35.126 1.00 59.40 6

ATOM 1512 CE1 PHE A 455 15.557 43.059 34.466 1.00 56.58 6

ATOM 1513 CE2 PHE A 455 13.848 44.716 34.452 1.00 61.^'80 6

ATOM 1514 CZ PHE A 455 15.129 44.322 34.126 1.00 59.94 6

ATOM 1515 C PHE A 455 13.273 42.085 38.534 1.00 45.12 6

ATOM 1516 O PHE A 455 14.361 42.323 39.034 1.00 39.95 8

ATOM 1517 N LEU A 456 12.155 42.735 38.849 1.00 43.92 7

ATOM 1518 CA LEU A 456 12.122 43.803 39.840 1.00 44.08 6

ATOM 1519 CB LEU A 456 10.680 44.251 40.093 1.00 50.20 6

ATOM 1520 CG LEU A 456 10.062 45.242 39.144 1.00 55.79 6

ATOM 1521 CDl LEU A 456 8.598 45.432 39.450 1.00 54.70 6

ATOM 1522 CD2 LEU A 456 10.807 46.548 39.295 1.00 53.01 6

ATOM 1523 C LEU A 456 12.739 43.355 41.136 1.00 44.65 6

ATOM 1524 O LEU A 456 13.597 44.022 41.685 1.00 45.93 8

ATOM 1525 N GLU A 457 11.973 41.761 41.851 1.00 44.56 7

ATOM 1526 CA GLU A 457 12.475 41.179 43.105 1.00 46.37 6

ATOM 1527 C GLU A 457 14.005 41.236 43.132 1.00 43.60 6

ATOM 1528 O GLU A 457 14.583 41.724 44.117 1.00 42.69 8

ATOM 1529 CB GLU A 457 12.024 39.723 43.223 1.00 50.16 6

ATOM 1530 CG GLU A 457 11.114 39.476 44.427 1.00 20.00 6

ATOM 1531 CD GLU A 457 10.807 37.994 44.648 1.00 20.00 6

ATOM 1532 OE1 GLU A 457 11.673 37.099 44.311 1.00 20.00 8

ATOM 1533 OE2 GLU A 457 9.683 37.639 45.172 1.00 20.00 8

ATOM 1534 N VAL A 458 14.928 41.078 41.903 1.00 43.21 7

ATOM 1535 CA VAL A 458 16.412 41.094 41.868 1.00 44.98 6

ATOM 1536 CB VAL A 458 16.881 40.306 40.642 1.00 44.83 6

ATOM 1537 CGI VAL A 458 18.365 40.106 40.698 1.00 49.72 6

ATOM 1538 CG2 VAL A 458 16.185 38.979 40.558 1.00 40.89 6

ATOM 1539 C VAL A 458 17.130 42.420 41.877 1.00 42.72 6

ATOM 1540 O VAL A 458 18.061 42.617 42.658 1.00 42.88 8

ATOM 1541 N PHE A 459 16.713 43.325 41.010 1.00 44.53 7

ATOM 1542 CA PHE A 459 17.385 44.606 40.892 1.00 48.18 6

ATOM 1543 CB PHE A 459 17.281 45.104 39.494 1.00 43.60 6

ATOM 1544 CG PHE A 459 17.915 44.190 38.547 1.00 40.79 6

ATOM 1545 CDl PHE A 459 17.325 42.983 38.244 1.00 41.01 6

ATOM 1546 CD2 PHE A 459 19.153 44.483 38.054 1.00 39.48 6

ATOM 1547 CE1 PHE A 459 17.988 42.081 37.441 1.00 40.62 6

ATOM 1548 CE2 PHE A 459 19.814 43.589 37.257 1.00 36.87 6 ATOM 1549 CZ PHE A 459 19.233 42.385 36.940 1.00 36.39 6

ATOM 1550 C PHE A 459 16.837 45.648 41.744 1.00 52.71 6

ATOM 1551 O PHE A 459 17.492 46.682 42.017 1.00 51.34 8

ATOM 1552 N GLU A 460 15.606 45.422 42.161 1.00 62.92 7

ATOM -1553 CA GLU A 460 15.066 46.428 42.965 1.00 69.33 6

ATOM 1554 CB GLU A 460 13.552 46.352 43.094 1.00 72.95 6

ATOM 1555 CG GLU A 460 12.978 47.767 42.957 1.00 78.35 6

ATOM 1556 CD GLU A 460 12.246 48.261 44.157 1.00 82.97 6

ATOM 1557 OE1 . GLU A 460 12.471 47.759 45.281 1.00 88.28 8

ATOM 1558 OE2 GLU A 460 11.422 49.200 44.017 1.00 84.80 8

ATOM 1559 C GLU A 460 15.736 46.245 44.272 1.00' 71.87 6

ATOM 1560 O GLU A 460 16.187 45.170 44.691 1.00 74,51 8

ATOM 1561 N ASP A 461 15.790 47.373 44.917 1.00 78.50 7

ATOM 1562 CA ASP A 461 16.415 47.505 ^• 46.173 1.00 84.19 6

ATOM 1563 CB ASP A 461 16.394 48.981 46.471 1.00 85.82 6

ATOM 1564 CG ASP A 461 16.801 49.786 45.276 1.00 89.62 6

ATOM 1565 OD1 ASP A 461 16.692 49.344 44.086 1.00 93.00 . 8

ATOM 1566 OD2 ASP A 461 17.239 50.923 45.482 1.00 93.04 8

ATOM 1567 C ASP A 461 15.639 46.703 47.214 1.00 86.80 6

ATOM 1568 O ASP A 461 16.245 45.748 47.731 1.00 88.70 8

ATOM 1569 OXT ASP A 461 14.457 47.026 47.451 1.00 88.70 8

TER

ATOM 1 CB LYS B 211 -20.802 66.251 39.780 1.00 46.72 6

ATOM 2 CG LYS B 211 -19.566 65.345 39.922 1.00 56.48 6

ATOM 3 CD LYS B 211 -18.264 66.114 40.045 1.00 60.93 6

ATOM 4 CE LYS B 211 -18.043 67.067 38.886 1.00 61.95 6

ATOM 5 NZ LYS B 211 -19.008 68.224 38.903 1.00 69.93 7

ATOM 6 C LYS B 211 -22.418 67.861 40.818 1.00 35.68 6

ATOM 7 O LYS B 211 -23.356 67.113 40.454 1.00 33.58 8

ATOM 8 N LYS B 211 -20.742 66.675 42.239 1.00 45.76 7

ATOM 9 CA LYS B 211 -20.998 67.285 40.894 1.00 43.42 6

ATOM 10 N PRO B 212 -22.610 69.205 41.068 1.00 35.64 7

ATOM 11 CD PRO B 212 -21.526 70.177 41.287 1.00 38.60 6

ATOM 12 CA PRO B 212 -23.943 69.861 41.036 1.00 38.35 6

ATOM 13 CB PRO B 212 -23.657 71.320 41.420 1.00 38.95 6

ATOM 14 CG PRO B 212 -22.226 71.474 41.551 1.00 42.00 6

ATOM 15 C PRO B 212 -24.798 69.772 39.807 1.00 38.78 6

ATOM 16 O PRO B 212 -24.350 70.045 38.696 1.00 34.64 8

ATOM 17 N GLU B 213 -26.058 69.424 40.032 1.00 40.31 7

ATOM 18 CA GLU B 213 -27.081 69.290 39.003 1.00 43.87 6

ATOM 19 CB GLU B 213 -27.895 68.004 39.265 1.00 45.16 6

ATOM 20 CG GLU B 213 -27.032 66.709 39.286 1.00 47.60 6

ATOM 21 CD GLU B 213 -27.807 65.421 39.199 1.00 50.68 6

ATOM 22 OE1 GLU B 213 -28.847 65.244 39.886 1.00 59.18 8

ATOM 23 OE2 GLU B 213 -27.382 64.516 38.442 1.00 49.06 8

ATOM 24 C GLU B 213 -27.924 70.576 39.080 1.00 45.96 6

ATOM 25 O GLU B 213 -27.624 71.467 39.859 1.00 43.13 8

ATOM 26 N PRO B 214 -28.987 70.698 38.308 1.00 46.52 7

ATOM 27 CD PRO B 214 -29.484 69.635 37.446 1.00 46.44 6

ATOM 28 CA PRO B 214 -29.843 71.907 38.302 1.00 47.52 6

ATOM 29 CB PRO B 214 -30.799 71.639 37.210 1.00 45.40 6

ATOM 30 CG PRO B 214 -30.530 70.257 36.805 1.00 49.89 6

ATOM 31 C PRO B 214 -30.574 72.330 39.535 I.00 45.70 6 ATOM 32 O PRO B 214 -30.597 71.595 40.483 1.00 44.49 8

ATOM .33 N THR B 215 -31.180 73.515 39.506 1.00 45.24 7

ATOM 34 CA THR B 215 -31.965 74.036 40.652 1.00 49.36 6

ATOM 35 CB THR B 215 -31.443 75.420 41.091 ^•1.00 44.86 6

ATOM 36 OG1 . THR B 215 -32.249 76.464 40.534 1.00 52.26 8

ATOM 37 CG2 ! THR B 215 -30.011 75.617 40.659 1.00 39.43 6

ATOM 38 C THR B 215 -33.386 74.239 40.114 1.00 52.51 6

ATOM 39 O THR B 215 -33.562 74.868 39.078 1.00 53.48 8

ATOM 40 N ASP B 216 -34.387 73.741 40.829 1.00 58.81 7

ATOM 41 CA ASP B 216 -35.795 73.865 40.435 1.00 61.51 6

ATOM 42 CB ASP B 216 -36.674 74.005 41.650 1.00^*70.57 6

ATOM 43 CG ASP B 216 -37.675 72.981 41.710 1.00 78.07 6

ATOM 44 OD1 ASP B 216 -38.228 72.588 40.652 1.00 82.31 8

ATOM 45 OD2 ASP B 216 -37.983 72.567 42.830 1.00 86.55 8

ATOM 46 C ASP B.216 -35.920 75.123 39.648 1.00 58.42 6

ATOM 47 O ASP B 216 -36.847 75.317 38.827 1.00 56.85 8

ATOM 48 N GLU B 217 -34.954 75.979 39.984 1.00 54.92 7

ATOM 49 CA GLU B 217 -34.851 77.259 39.353 1.00 53.37 6

ATOM 50 CB GLU B 217 -34.104 78.264 40.251 1.00 51.02 6

ATOM 51 CG GLU B 217 -34.151 79.689 39.679 1.00 40.00 6

ATOM 52 CD GLU B 217 -34.301 80.745 40.739 1.00 40.00 6

ATOM 53 OE1 GLU B 217 -34.089 80.443 41.945 1.00 40.00 8

ATOM 54 OE2 GLU B 217 -34.625 81.921 40.411 1.00 40.00 8

ATOM 55 C GLU B 217 -34.232 77.163 37.957 1.00 53.55 6

ATOM 56 O GLU B 217 -34.815 77.612 37.018 1.00 54.33 8

ATOM 57 N GLU B 218 -33.063 76.572 37.839 1.00 49.20 7

ATOM 58 CA GLU B 218 -32.318 76.385 36.608 1.00 45.94 6

ATOM 59 CB GLU B 218 -30.965 75.793 36.981 1.00 43.43 6

ATOM 60 CG GLU B 218 -30.065 76.728 37.801 1.00 40.86 6

ATOM 61 CD GLU B 218 -28.713 76.159 38.072 1.00 39.88 6

ATOM 62 OE1 GLU B 218 -28.606 74.967 38.449 1.00 37.61 8

ATOM 63 OE2 GLU B 218 -27.707 76.901 37.945 1.00 34.01 8

ATOM 64 C GLU B 218 -33.014 75.475 35.610 1.00 44.71 6

ATOM 65 O GLU B 218 -32.935 75.686 34.405 1.00 45.31 8

ATOM 66 N TRP B 219 -33.669 74.439 36.131 1.00 44.02 7

ATOM 67 CA TRP B 219 -34.368 73.490 35.290 1.00 46.97 6

ATOM 68 CB TRP B 219 -35.046 72.408 36.119 1.00 48.42 6

ATOM 69 CG TRP B 219 -34.195 71.230 36.374 1.00 54.61 6

ATOM 70 CD2 TRP B 219 -34.048 70.120 35.478 1.00 55.24 6

ATOM 71 CE2 TRP B 219 -33.076 69.248 36.063 1.00 53.67 6

ATOM 72 CE3 TRP B 219 -34.615 69.771 34.252 1.00 54.55 6

ATOM 73 CDl TRP B 219 -33.399 71.019 37.415 1.00 55.75 6

ATOM 74 NE1 TRP B 219 -32.697 69.838 37.236 1.00 54.43 7

ATOM 75 CZ2 TRP B 219 -32.635 68.075 35.431 1.00 52.54 6

ATOM 76 CZ3 TRP B 219 -34.214 68.603 33.643 1.00 55.17 6

ATOM 77 CH2 TRP B 219 -33.234 67.758 34.214 1.00 55.59 ^' 6

ATOM 78 C TRP B 219 -35.409 74.199 34.459 1.00 47.32 6

ATOM 79 O TRP B 219 -35.561 73.914 33.277 1.00 43.56 8

ATOM 80 N GLU B 220 -36.126 75.130 35.084 1.00 49.91 7

ATOM 81 CA GLU B 220 -37.158 75.874 34.402 1.00 53.57 6

ATOM 82 CB GLU B 220 -37.811 76.820 35.373 1.00 58.18 6

ATOM 83 CG GLU B 220 -39.251 76.812 35.221 1.00 73.13 6

ATOM 84 CD GLU B 220 -39.824 76.858 36.489 1.00 80.06 6 ATOM 85 OE1. GLU B 220 -39.485 75.995 37.324 1-00 82.12 8

ATOM 86 OE2 '. GLU B 220 -40.635 77.740 36.718 1.00 82.78 8

ATOM 87 C GLU B 220 -36.539 76.645 33.250 1.00 50.51 6

ATOM 88 O GLU B 220 -37.160 76.793 32.195 1.00 49.94 8

ATOM 89 N LEU B 221 -35.312 77.135 33.^55 1.00 43.71 7

ATOM 90 CA LEU B 221 -34.604 77.884 32.411 1.00 42.81 6

ATOM 91 CB LEU B 221 -33.214 78.324 32.865 1.00 39.21 6

ATOM 92 CG LEU B 221 -32.321 78.833 31.754 1.00 36.34 6

ATOM 93 CDl . LEU B 221 -33.G73 79.843 30.927 1.00 36.93 6

ATOM 94 CD2 LEU B 221 -31.058 79.446 32.331 1.00 24.18 6

ATOM 95 C LEU B 221 -34.454 77.011 31.192 1.00 43.46 6

ATOM 96 O LEU B 221 -34.819 77.406 30.104 1.00 45.25 8

ATOM 97 N ILE B 222 -33.878 75.829 31.398 1.00 39.09 7

ATOM 98 CA ILE B 222 -33.687 74.857 30.330 1.00 35.47 6

ATOM 99 CB ILE B 222 -33.224 73.516 30.871 1.00 33.74 6

ATOM 100 CG2 ILE B 222 -33.204 72.488 29.776 1.00 28.86 6

ATOM 101 CGI ILE B 222 -31.840 73.631 31.493 1.00 33.33 6

ATOM 102 CDl ILE B 222 -31.435 72.419 32.264 1.00 34.85 6

ATOM 103 C ILE B 222 -34.991 74.627 29.598 1.00 34.26 6

ATOM 104 O ILE B 222 -35.082 74.832 28.392 1.00 31.90 8

ATOM 105 N LYS B 223 -35.992 74.183 30.346 1.00 39.49 7

ATOM 106 CA LYS B 223 -37.300 73.892 29.785 1.00 44.43 6

ATOM 107 CB LYS B 223 -38.351 73.876 30.882 1.00 50.81 6

ATOM 108 CG LYS B 223 -39.693 73.358 30.411 1.00 62.51 6

ATOM 109 CD LYS B 223 -40.795 73.532 31.449 1.00 72.22 6

ATOM 110 CE LYS B 223 -42.163 73.249 30.827 1.00 74.55 6

ATOM 111 NZ LYS B 223 -43.268 73.378 31.837 1.00 75.78 7

ATOM 112 C LYS B 223 -37.648 74.942 28.755 1.00 42.81 6

ATOM 113 O LYS B 223 -38.337 74.661 27.796 1.00 40.36 8

ATOM 114 N THR B 224 -37.146 76.156 28.979 1.00 39.89 7

ATOM 115 CA THR B 224 -37.353 77.293 28.074 1.00 39.93 6

ATOM 116 CB THR B 224 -36.956 78.609 28.776 1.00 40.57 6

ATOM 117 OG1 THR B 224 -37.646 78.740 30.028 1.00 39.27 8

ATOM 118 CG2 THR B 224 -37.273 79.805 27.893 1.00 38.11 6

ATOM 119 C THR B 224 -36.521 77.094 26.789 1.00 39.96 6

ATOM 120 O THR B 224 -37.043 76.677 25.756 1.00 36.67 8

ATOM 121 N VAL B 225 -35.231 77.421 26.888 1.00 38.02 7

ATOM 122 CA VAL B 225 -34.263 77.295 25.801 1.00 38.12 6

ATOM 123 CB VAL B 225 -32.869 77.015 26.348 1.00 38.19 6

ATOM 124 CGI VAL B 225 -31.863 76.983 25.226 1.00 36.77 6

ATOM 125 CG2 VAL B 225 -32.483 78.050 27.353 1.00 41.76 6

ATOM 126 C VAL B 225 -34.656 76.191 24.843 1.00 37.52 6

ATOM 127 O VAL B 225 -34.621 76.364 23.638 1.00 36.77 8

ATOM 128 N THR B 226 -35.005 75.046 25.410 1.00 34.02 7

ATOM 129 CA THR B 226 -35.423 73.887 24.638 1.00 34.67 6

ATOM 130 CB THR B 226 -35.677 72.707 25.574 1.00 30.56 6

ATOM 131 OG1 THR B 226 -34.432 72.225 26.084 1.00 32.20 8

ATOM 132 CG2 THR B 226 -36.413 71.595 24.874 1.00 20.99 6

ATOM 133 C THR B 226 -36.664 74.170 23.803 1.00 36.41 6

ATOM 134 O THR B 226 -36.633 74.054 22.578 1.00 39.64 8

ATOM 135 N ALA B 227 -37.746 74.542 24.480 1.00 39.20 7

ATOM 136 CA ALA B 227 -39.008 74.861 23.822 1.00 36.93 6

ATOM 137 CB ALA B 227 -39.914 75.631 24.785 1.00 38.06 6 S S S S S 2 _{M μ3 μ3 μ3}βμ μ^μaμ_{3 H} μ μ₃μ_{3 H}

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ATOM 164 C ARG B 282 -34.556 80.919 13.622 1.00 34.81 6

ATOM 165 O ARG B 282 -35.008 81.034 14.753 1.00 36.03 8

ATOM 166 N VAL B 283 -33.288 81.183 13.289 1.00 31.71 7

ATOM 167 CA VAL B 283 -32.304 81.667 14.249 1.00 30.16 6

ATOM 168 CB VAL B 283 -30.993 82.029 13.559 1.00-29.00 6

ATOM 169 CGI VAL B 283 -30.015 82.617 14.557 1.00 28.64 6

ATOM 170 CG2 VAL B 283 -30.385 80.816 12.915 1.00 28.28 6

ATOM 171 C VAL B 283 -32.848 82.884 14.994 1.00 32.50 6

ATOM 172 O VAL B 283 -32.619 83.057 16.185 1.00 33.48 8

ATOM 173 N VAL B 284 -33.573 83.728 14.265 1.00 30.96

ATOM 174 CA VAL B 284 -34.177 84.925 14.844 1.00 29.14 6

ATOM 175 CB VAL B 284 -34.672 85.892 13.751 1.00 31.27 6

ATOM 176 CGI VAL B 284 -35.278 87.129 14.371 1.00 24.21 6

ATOM 177 CG2 VAL B 284 -33.554 86.270 12.812 1.00 30.51 6

ATOM 178 C VAL B 284 -35.336 84.498 15.747 1.00 28.89 6

ATOM 179 O VAL B 284 -35.491 84.994 16.860 1.00 27.29 8

ATOM 180 N ASP B 285 -36.143 83.564 15.250 1.00 28.76 7

ATOM 181 CA ASP B 285 -37.299 83.057 15.983 1.00 35.32 6

ATOM 182 CB ASP B 285 -38.129 82.098 15.111 1.00 33.29 6

ATOM 183 CG ASP B 285 -38.881 82.795 14.013 1.00 38.15 6

ATOM 184 OD1 ASP B 285 -39.660 83.729 14.305 1.00 34.70 8

ATOM 185 OD2 ASP B 285 -38.741 82.406 12.821 1.00 34.43 8

ATOM 186 C ASP B 285 -36.863 82.339 17.257 1.00 36.70 6

ATOM 187 O ASP B 285 -37.606 82.304 18.237 1.00 37.96 8

ATOM 188 N PHE B 286 -35.663 81.755 17.235 1.00 35.96 7

ATOM 189 CA PHE B 286 -35.134 81.053 18.401 1.00 37.10 6

ATOM 190 CB PHE B 286 -33.870 80.262 18.052 1.00 37.97 6

ATOM 191 CG PHE B 286 -33.079 79.818 19.258 1.00 36.50 ^'6

ATOM 192 CDl PHE B 286 -33.704 79.168 20.294 1.00 36.75 6

ATOM 193 CD2 PHE B 286 -31.721 80.063 19.343 1.00 33.83 6

ATOM 194 CE1 PHE B 286 -32.987 78.769 21.401 1.00^'39.55 6

ATOM 195 CE2 PHE B 286 -30.997 79.662 20.456 1.00 38.08 6

ATOM 196 CZ PHE B 286 -31.632 79.013 21.486 1.00 34.44 6

ATOM 197 C PHE B 286 -34.808 82.023 19.504 1.00 36.83 6

ATOM 198 O PHE B 286 -35.246 81.845 20.631 1.00 35.61 8

ATOM 199 N ALA B 287 -34.005 83.027 19.169 1.00 37.33 7

ATOM 200 CA ALA B 287 -33.599 84.035 20.132 1.00 36.34 6

ATOM 201 CB ALA B 287 -32.644 85.008 19.469 1.00 36.40 6

ATOM 202 C ALA B 287 -34.831 84.769 20.657 1.00 38.76 6

ATOM 203 O ALA B 287 -34.882 85.193 21.814 1.00 41.98 8

ATOM 204 N LYS B 288 -35.820 84.912 19.779 1.00 38.28 7

ATOM 205 CA LYS B 288 -37.066 85.584 20.112 1.00 45.26 6

ATOM 206 CB LYS B 288 -37.983 85.690 18.898 1.00 48.35 6

ATOM 207 CG LYS B 288 -37.577 86.756 17.916 1.00 51.43 6

ATOM 208 CD LYS B 288 -38.806 87.359 17.226 1.00 60.23 6

ATOM 209 CE LYS B 288 -39.680 86.308 16.564 1.00 62.81 6

ATOM 210 NZ LYS B 288 -38.897 85.460 15.614 1.00 64.69 7

ATOM 211 C LYS B 288 -37.846 84.901 21.191 1.00 43.31 6 «

ATOM 212 O LYS B 288 -38.650 85.532 21.857 1.00 45.66 8

ATOM 213 N LYS B 289 -37.618 83.604 21.345 1.00 41.70 7

ATOM 214 CA LYS B 289 -38.313 82.849 22.351 1.00 40.67 6

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ATOM 746 CA LEU B 360 -19.741 65.729 17.889 1.00 35.44 6

ATOM 747 CB LEU B 360 -20.706 66.817 17.405 1.00 34.16 6

ATOM 748 CG LEU B 360 -20.263 68.255 17.575 1.00 34.59 6

ATOM 749 CDl LEU B 360 -21.394 69.181 17.212 1.00 33.53 6

ATOM 750 CD2 LEU B 360 -19.869 68.486 19.010 1.00 31.69 6

ATOM 751 C LEU B 360 -20.464 64.397 17.924 1.00 38.72 6

ATOM 752 O LEU B 360 -21.021 64.011 18.958 1.00 38.29 8

ATOM 753 N SER B 361 -20.466 63.708 16.791 1.00 40.96 7

ATOM 754 CA SER B 361 -21.106 62.416 16.721 1.00 45.67 6

ATOM 755 CB SER B 361 -20.532 61.630 15.551 1.00 46.45 6

ATOM 756 OG SER B 361 -20.750 62.314 14.322 1.00 51.81 8

ATOM 757 C SER B 361 -20.895 61.638 18.018 1.00 44.49 6

ATOM 758 O SER B 361 -21.696 60.793 18.362 1.00 46.67 8

ATOM 759 N SER B 362 -19.811 61.953 18.726 1.00 41.44 7

ATOM 760 CA SER B 362 -19.453 61.309 19.972 1.00 42.13 6

ATOM 761 CB SER B 362 -17.962 61.510 20.234 1.00 42.61 6

ATOM 762 OG SER B 362 -17.164 61.025 19.158 1.00 51.87 8

ATOM 763 C SER B 362 -20.228 61.812 21.174 1.00 38.41 6

ATOM 764 O SER B 362 -20.602 61.025 22.035 1.00 38.01 8

ATOM 765 N PHE B 363 -20.455 63.123 21.228 1.00 34.55 7

ATOM 766 CA PHE B 363 -21.150 63.735 22.346 1.00 32.96 6

ATOM 767 CB PHE B 363 -21.006 65.245 22.285 1.00 31.99 6

ATOM 768 CG PHE B 363 -19.578 65.719 22.378 1.00 29.97 6

ATOM 769 CDl PHE B 363 -19.286 67.058 22.447 1.00 30.61 6

ATOM 770 CD2 PHE B 363 -18.536 64.800 22.391 1.00 32.02 6

ATOM 771 CE1 PHE B 363 -17.966 67.489 22.543 1.00 33.67 6

ATOM 772 CE2 PHE B 363 -17.221 65.222 22.484 1.00 30.91 6

ATOM 773 CZ PHE B 363 -16.927 66.557 22.554 1.00 29.33 6

ATOM 774 C PHE B 363 -22.617 63.361 22.482 1.00 30.52 6

ATOM 775 O PHE B 363 -23.142 63.331 23.596 1.00 32.19 8

ATOM 776 N ASN B 364 -23.279 63.075 21.361 1.00 33.51 7

ATOM 777 CA ASN B 364 -24.683 62.701 21.377 1.00 38.03 6

ATOM 778 CB ASN B 364 -24.855 61.369 22.111 1.00 42.32 6

ATOM 779 CG ASN B 364 -24.008 60.271 21.524 1.00 53.11 6

ATOM 780 OD1 ASN B 364 -24.183 59.895 20.344 1.00 59.51 8

ATOM 781 ND2 ASN B 364 -23.102 59.746 22.325 1.00 55.95 7

ATOM 782 C ASN B 364 -25.494 63.771 22.091 1.00 31.89 6

ATOM 783 O ASN B 364 -26.279 63.471 22.990 1.00 30.28 8

ATOM 784 N LEU B 365 -25.306 65.018 21.673 1.00 27.62 7 -

ATOM 785 CA LEU B 365 -26.005 66.144 22.280 1.00 29.36 6

ATOM 786 CB LEU B 365 -25.402 67.443 21.743 1.00 27.54 6

ATOM 787 CG LEU B 365 -23.897 67.453 21.738 1.00 38.91 6

ATOM 788 CDl LEU B 365 -23.391 68.766 21.190 1.00 34.47 6

ATOM 789 CD2 LEU B 365 -23.393 67.214 23.143 1.00 34.24 6

ATOM 790 C LEU B 365 -27.496 66.074 21.987 1.00 26.23 6

ATOM 791 O LEU B 365 -27.911 65.790 20.863 1.00 27.06 8

ATOM 792 N ASP B 366 -28.296 66.321 23.022 1.00 25.23 7

ATOM 793 CA ASP B 366 -29.752 66.320 22.878 1.00 26.07 6

ATOM 794 CB ASP B 366 -30.441 65.651 24.076 1.00 29.68 6

ATOM 795 CG ASP B 366 -30.221 66.374 25.360 .1.00 35.74 6

ATOM 796 OD1 ASP B 366 -30.277 67.617 25.387 1.00 36.78 8

ATOM 797 OD2 ASP B 366 -30.017 65.711 26.410 1.00 41.23 8

ATOM 798 C ASP B 366 -30.230 67.752 22.740 1.00 27.70 6 ATOM 799 O ASP B 366 -29.552 68.678 23.171 1-00 31.94 8

ATOM 800 N ASP B 367 -31.409 67.913 22.142 1-00 29.18 7

ATOM 801 CA ASP B 367 -32.031 69.225 21.930 1.00 32.72 6

ATOM 802 CB ASP B 367 -33.558 69.106 22.071 1.00 38.04 6

ATOM 803 CG ASP B 367 -34.172 68.166 21.081 1.00 42.43 6

ATOM 804 OD1 . ASP B 367 -34.051 68.373 19.854 1.00 35.95 8

ATOM 805 OD2 ! ASP B 367 -34.829 67.188 21.504 1.00 51.42 8

ATOM 806 C ASP B 367 -31.496 70.238 22.959 1.00 33.71 6

ATOM 807 O ASP B 367 -30.791 71.188 22.624 1.00 38.30 8

ATOM 808 N THR B 368 -31.858 69.997 24.218 1.00 31.06 7

ATOM 809 CA THR B 368 -31.453 70.822 25.344 1.00 26.28 6

ATOM 810 CB THR B 368 -31.567 70.020 26.643 1.00 27.30 6

ATOM 811 OG1 THR B 368 -32.916 69.578 26.824 1.00 33.42 8

ATOM 812 CG2 THR B 368 -31.143 70.855 27.824 1.00 25.16 6

ATOM 813 C THR B 368 -30.025 71.315 25.181 1.00 21.13 6

ATOM 814 O THR B 368 -29.746 72.508 25.150 1.00 23.17 8

ATOM, 815 N GLU B 369 -29.123 70.354 25.072 1.00 21.32 7

ATOM 816 CA GLU B 369 -27.711 70.634 24.932 1.00 28.00 6

ATOM 817 CB GLU B 369 -26.947 69.306 24.878 1.00 32.79 6

ATOM 818 CG GLU B 369 -27.229 68.433 26.130 1.00 36.29 6

ATOM 819 CD GLU B 369 -26.689 67.051 26.083 1.00 41.03 6

ATOM 820 OE1 GLU B 369 -26.960 66.318 25.102 1.00 42.05 8

ATOM 821 OE2 GLU B 369 -25.992 66.645 27.048 1.00 42.03 8

ATOM 822 C GLU B 369 -27.428 71.527 23.731 1.00 25.57 6

ATOM 823 O GLU B 369 -26.780 72.549 23.886 1.00 20.56 8

ATOM 824 N VAL B 370 -27.922 71.154 22.548 1.00 25.39 7

ATOM 825 CA VAL B 370 -27.710 71.968 21.355 1.00 25.99 6

ATOM 826 CB VAL B 370 -28.457 71.429 20.130 1.00 26.15 6

ATOM 827 CGI VAL B 370 -28.255 72.358 18.953 1.00 27.65 6

ATOM 828 CG2 VAL B 370 -28.014 70.021 19.788 1.00 17.70 6

ATOM 829 C VAL B 370 -28.238 73.346 21.676 1.00 26.49 6

ATOM 830 O VAL B 370 -27.580 74.351 21.445 1.00 28.16 8

ATOM 831 N ALA B 371 -29.450 73.362 22.213 1.00 21.01 7

ATOM 832 CA ALA B 371 -30.145 74.589 22.573 1.00 19.57 6

ATOM 833 CB ALA B 371 -31.414 74.246 23.335 1.00 18.62 6

ATOM 834 C ALA B 371 -29.256 75.501 23.401 1.00 23.48 6

ATOM 835 O ALA B 371 -28.936 76.613 22.989 1.00 32.67 8

ATOM 836 N LEU B 372 -28.860 75.008 24.571 1.00 22.89 7

ATOM 837 CA LEU B 372 -27.999 75.758 25.472 1.00 23.28 6

ATOM 838 CB LEU B 372 -27.606 74.860 26.658 1.00 27.76 6

ATOM 839 CG LEU B 372 -28.728 74.524 27.619 1.00 21.18 6

ATOM 840 CDl LEU B 372 -28.272 73.529 28.648 1.00 27.64 6

ATOM 841 CD2 LEU B 372 -29.198 75.801 28.284 1.00 20.90 6

ATOM 842 C LEU B 372 -26.769 76.268 24.722 1.00 21.34 6

ATOM 843 O LEU B 372 -26.439 77.454 24.762 1.00 23.16 8

ATOM 844 N LEU B 373 -26.111 75.349 24.023 1.00 24.42 7

ATOM 845 CA LEU B 373 -24.916 75.669 23.254 1.00 23.78 6

ATOM 846 CB LEU B 373 -24.525 74.446 22.396 1.00 22.18 6

ATOM 847 CG LEU B 373 -23.098 74.283 21.942 1.00 31.52 6

ATOM 848 CDl LEU B 373 -22.196 74.576 23.100 1.00 31.93 6

ATOM 849 CD2 LEU B 373 -22.873 72.889 21.457 1.00 30.24 6

ATOM 850 C LEU B 373 -25.235 76.902 22.405 1.00 25.69 6

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C0 O 4S O v! Cπ C0 θ μ^j vl UJ vl O UJ ^vl NJ UJ μ-^, UJ vl C0 M UJ NJ vl Cπ 4s C0 M Cn Cn M -J NJ C0 O C0 vl vl Cπ C0 4s CO M O M 4S NJ vl 00 4s CT M 00 C0 M M C0 NJ O 4s Cπ μ-' NJ C0 4s uJ Cπ -J 0⁰ 00 C0 Cn O O ^v0 ^C0 ^C0 C⁰ cn O

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M μ-> M M M M M M M M M M M M M M M M M M M M M M M M t-» M μ-> M M M μ-» t->

0 O O 0 O O O O O O 0 O O 0 O O 0 O O O O 0 0 0 O O O O O O 0 O 0 O O 0 0 O O 0 O O O O O O 0 0 O 0 O O 0 O O O O 0 0 0 O O O O O 0 0 O 0 0 0 O

O O O O 0 O O O 0 0 O O O O 0

4S Cπ cπ 4S 4S 4S 4s CO NJ NJ CO CO CO CO CO 4S CO CO O CO CO CO CO CO 4S CO CO CO CO C Cn 4s 4S CO CO on CO Co J J cπ Cπ 4s NJ UJ 00 on 4s vl vl CO O 0 M 4S O NJ O CO UJ on cπ vl M cn CO O J CO on NJ NJ CO Co CO C CO CO O CO vl vl en -J 4S CO O NJ 4S M 4S vl 4S cn co M co v] 4S vl co CO on M CO 4S CO 01 00 CD co vl UJ 00 O 4S cn NJ CO 00 NJ on C Cπ M U 0 cπ l

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M on Cπ -J M on 00 UJ M Co co 4S M Cπ on vl 4S M NJ O 0 cri cn cn cτι cτi cn vi ∞ cn on cn cn σι cτι -J ∞ cτi cι cτι cn cn cn cn cn cn -^ ,_{ι m} „ „ ^{uι uι} u^{i vj} U c ^vi-co cn on cn on vi co on oo

ATOM 1064 O LEU B 401 -24.576 74.900 34.427 1-00 45.14 3

ATOM 1065 N ALA B 402 -26.068 ^6.532 33.997 1.00 37.92 7

ATOM 1066 CA ALA B 402 -27.177 75.631 33.752 1.00 29.90 6

ATOM 1067 CB ALA B 402 -28.361 76.433 33.200 1.00 30.70 6

ATOM ^~1068 C ALA B 402 -26.779 74.521 32.773 1.00 28.88 6

ATOM 1069 O ALA B 402 -27.078 73.347 32.996 1.00 32.14 8

ATOM 1070 N PHE B 403 -26.091 74.908 31.698 1.00'31.07 7

ATOM 1071 CA PHE B 403 -25.655 73.970 30.673 1.00 29.90 6

ATOM 1072 CB PHE B 403 -24.847 74.715 29.607 1.00 27.03 6

ATOM 1073 CG PHE B 403 -24.557 73.908 28.359 1.00 26.97 6

ATOM 1074 CDl PHE B 403 -23.916 74.494 27.272 1.00 25.55 ,-

ATOM 1075 CD2 PHE B 403 -24.939 72.583 28.271 1.00 19.75 6

ATOM 1076 CE1 PHE B 403 -23.670 73.765 26.104 1.00 27.90 6

ATOM 1077 CE2 PHE B 403 -24.693 71.848 27.102 1.00 22.56 6

ATOM 1078 CZ PHE B 403 -24.057 72.439 26.020 1.00 22.24 6

ATOM 1079 C PHE B 403 -24.810 72.902 31.329 1.00 28.82 6

ATOM 1080 O PHE B 403 -25.092 71.726 31.205 1.00 26.00 8

ATOM 1081 N GLU B 404 -23.776 73.335 32.037 1.00 30.25 7

ATOM 1082 CA GLU B 404 -22.865 72.419 32.712 1.00 34.03 6

ATOM 1083 CB GLU B 404 -21.835 73.215 33.527 1.00 39.45 6

ATOM 1084 CG GLU B 404 -20.654 72.384 34.068 1.00 47.68 6

ATOM 1085 CD GLU B 404 -19.750 73.129 34.996 1.00 54.02 6

ATOM 1086 OE1 GLU B 404 -19.372 74.290 34.701 1.00 57.27 8

ATOM 1087 OE2 GLU B 404 -19.369 72.555 36.048 1.00 63.85 8

ATOM 1088 C GLU B 404 -23.645 71.509 33.642 1.00 36.01 6

ATOM 1089 O GLU B 404 -23.470 70.292 33.640 1.00 38.64 8

ATOM 1090 N HIS B 405 -24.492 72.131 34.458 1.00 29.56 7

ATOM 1091 CA HIS B 405 -25.306 71.387 35.405 1.00 31.69 6

ATOM 1092 CB HIS B 405 -26.245 72.324 36.173 1.00 33.75 6

ATOM 1093 CG HIS B 405 -25.536 73.185 37.163 1.00 34.75 6

ATOM 1094 CD2 HIS B 405 -24.234 73.286 37.524 1.00 34.58 6

ATOM 1095 ND1 HIS B 405 -26.223 74.101 37.969 1.00 32.43 7

ATOM 1096 CE1 HIS B 405 -25.334 74.703 38.769 1.00 36.15 6

ATOM 1097 NE2 HIS B 405 -24.139 74.222 38.511 1.00 39.84 7

ATOM 1098 C HIS B 405 -26.106 70.342 34.648 1.00 34.21 6

ATOM 1099 O HIS B 405 -26.087 69.160 35.006 ^' 1.00 37.06 8

ATOM 1100 N TYR B 406 -26.806 70.776 33.598 1.00 30.83 7

ATOM 1101 CA TYR B 406 -27.592 69.853 32.796 1.00 28.85 6

ATOM 1102 CB TYR B 406 -28.192 70.537 31.579 1.00 31.48 6

ATOM 1103 CG TYR B 406 -28.991 69.576 30.730 1.00 23.49 6

ATOM 1104 CDl TYR B 406 -30.179 69.047 31.196 1.00 19.42 6

ATOM 1105 CE1 TYR B 406 -30.893 68.128 30.441 1.00 23.80 6

ATOM 1106 CD2 TYR B 406 -28.525 69.152 29.496 1.00 21.81 6

ATOM 1107 CE2 TYR B 406 -29.241 68.228 28.740 1.00 24.64 6

ATOM 1108 CZ TYR B 406 -30.420 67.713 29.217 1.00 21.56 6

ATOM 1109 OH TYR B 406 -31.120 66.802 28.480 1.00 24.96 8

ATOM 1110 C TYR B 406 -26.697 68.725 32.304 1.00 24.24 6

ATOM llll O TYR B 406 -27.155 67.609 32.110 1.00 27.08 8

ATOM 1112 N ILE B 407 -25.422 69.056 32.084 1.00 25.76 7

ATOM 1113 CA ILE B 407 -24.428 68.092 31.628 1.00 33.75 6

ATOM 1114 ^' CB ILE B 407 -23.090 68.778 31.274 1.00 34.23 6

ATOM 1115 CG2 ILE B 407 -21.959 67.774 31.230 1.00 32.46 6

ATOM 1116 CGI ILE B 407 -23.214 69.514 29.936 1.00 43.30 6 H H ^ ^ H H ^ H H H H H H HI H H H HI HI H H H HI H^ ^ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 μ_ μ-ι μ-. μ-. μj μ-ι μ-ι μ-> M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M μ-ⁱ μ- ¹ _|__ μ_{J H}_₁ μ_ μ-ι μ. μ-. μ-, μ-ι μ-ι μ-ι μ-» μ-> M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M μ-ⁱ μ-

^ _On on rn cn cn cn cn cn cn cn cπ cn cn cπ cπ cn cn cn cn 4s 4s 4s 4s 4s 4^ 4s 4s 4s 4s co co (jj co w NJ μ- M _j c_{θ v}i on cπ ₄^ c NJ _{M θ} U_J Cv v] on cπ s co NJ M θ UJ ∞ vi c π ^s co NJ θ ^j ∞ v⁾ cn n 4s Nj M uJ oθ vj ^ o o co

O Ω Z O Z Ω Ω Ω O Z O Ω Z Ω Ω Ω Ω Ω Z O Ω z z Ω Z Ω Ω Ω Ω O Ω O Ω O Ω Ω Ω Ω Ω Ω Z O Ω Z O Ω Ω Ω Z O Ω W PI D D Ω tD N pJ α Ω CD 3; 33 CSl J σ Ω CD > 5C N Pl W D n tJ) D O Ω D

NJ NJ NJ NJ NJ M M NJ M ,

X X X X X X 3: x n t-3 3 ι-3 Hi HI H D=' ^I ' ^I M M M M x tn tn t

H x tn M t-c. 50 50 5 0 0 5 50 5 0 50 50 μ w co ω co co co co co tn in ω ω ω ω w ω Λ ω cΛ ω cΛ o o ij c ω 50 Z Z Z Z Z Z Z Z PJ PJ

CD CD CD IB CD CD CD CD I_j l_j CD CD CD Cα CD CD CD CD CD CD CD DJ CD CD ro ro CD DJ CD CD CD CD CD CD

4s 4s 4S 4s 4s 4s 4s 4s. 4s 4S. 4S. 4s 4S 4s 4s 4s. 4s 4s. 4s 4s 4s 4s 4s 4s. 4_, 4S 4s 4S 4s 4S 4-. 4s. 4s, 4S, 4S 4s ι-» μ-^l M M μ-ι μ-' -ⁱ M M -^{, ^} -^ι -' M -ⁱ M μ-ⁱ μ-ⁱ μ^ O O O O O O O O O O O O O O O O O O O O O O

NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ M M M M M μ-ⁱ μ-¹ O O O O O O O O O O O UJ UJ UJ J CD UJ UJ UJ UJ UJ UJ CO OO OO CO CO OO CO CO CO vl vl

I I I 1 I 1 I I I I I I I I I I 1 I I I I I I I I I I I I I I i I I i I I I I I I I I I I I I , , , , I M NJ M NJ NJ M NJ NJ NJ M NJ NJ NJ M NJ NJ W M NJ M M NJ M NJ NJ NJ M J NJ M NJ NJ CO CO CO CO CO CO NJ NJ NJ NJ M 0 0 4s 4s CO CO NJ M NJ NJ CO CO CTl On Cn 4_. C C0 4s Cn Cn v] UJ vl vl CO vJ on cn CJi v! vJ CO M M O M O vO CO vJ O^

M 00 O O M M Cn Cn O 4s. Cπ M NJ NJ O C0 CTl 4s. C5n 00 cn θ NJ UJ 4s M 4s C0 v] C0 Cn NJ O CD Cn cn M O vl Cn NJ l— > CTι C0 4s M NJ Cπ vl UJ M M O M UJ UJ vi cn cπ ( π θ M cn vi -v ∞ vi vi u oo -J θ cπ oo uj co NJ cπ oo 4s cn C0 NJ Cn M O 4s 00 M C0 0n C0 UJ vl N NJ vl v) UJ UJ NJ C0 UJ vl UJ 0 C0 4s O Cn C0 C0 UJ O UJ C0 4s NJ Cn NJ O ∞ 4s M NJ CD 00 Cn 4s 0n Cn 4s O O 4.rsv. 4.rsv C m0 C ^fπn N rvJ^{i t} N^>.J^ι 4 ^s <jJ O 4s. C0 vl C0 NJ 4s. 0n C0 4_. cn 4S. v0 O C0 M o o_Λ α^ σ_i c cn cn _Ti c c σ_{ϊ C}Ti π π n cin c^ m cTi σ c^

O O _v^ 4s ω 4s C M M NJ O M uJ uJ UJ O M NJ C M NJ C CO 0 s. s Cn ^ 0 ^

∞ Cn O NJ N CTl π Cn 4s O M CO NJ UJ ∞ Cπ NJ M O Cjπ θn NJ Cθ CO CO Cπ Cn -J Cπ ∞

UJ UJ C CO UJ O O UJ -J M UJ 4s 4s 4s ∞ 4s. 4s 4s NJ 4s on NJ vl cπ -J O^ ∞ 4s cO NJ Cn NJ M 4^S vJ CO CT, M Cn Cv M M M θn 4-. CO O CO M UJ 4s cn UJ M NJ -^ vJ ^ UJ Cn CO vJ 4S vJ UJ C^ CO CO Cn CTl UJ ∞ v^

θ _vθ vi cjn σι ∞ vi oθ vθ θ M M o cn cπ co co NJ NJ M n cιn o vi _∞ u θ M M 4s co co 4s co c cn π s 4^

Cn Cn CO Cθ Cn NJ vl CO M 4s NJ CO ∞ 4s CO UJ O σi 4s M vl CXI vl CO CO CO UJ 4s Cn vI M 4s 4-. CO Cn CO UJ ∞ M M vl M θn O vl 4s cn CO O M Cπ CO CTι OO NJ NJ M 4s 4s Uj vO M 4s 4s on J CO C0 4s 0 4s UJ O Cn v0 4s UJ OO CO UJ CO vl CO CO NJ 4-. UJ vl Ul , , ^ .-v , ι ^ ^{O "}^ ^O ** ^{α> 0} --¹ O O C0 O NJ O Cn - UJ 4s. cn M 4s on M M ∞ θ C^v vO vO Cn M O v1 Cl ^S v N^j S v 4? ω C μ-i M M μ- o o o o o o o o o o o o o 0 0 0 0 0 0 0 0 0 0 0 0 0 o o o o o o o o o o o o o o o 0 0 0 0 0 0 0 0 0 0 0 0 0 o o O O O O O O O O O O O O O O O O O O O O O O

4_S 4_S CO CO CO CO 4s 4s 4s cπ cπ cπ co co vi vi cn cπ cπ 4s. 4s. co co co co co co co 4s 4s 4s. Co cπ cπ cπ 4 4s. on cn 4 cn M C0 00 4s Cπ cn Cn 4s vl O 4s 00 N0 M 0n NJ C0 Cπ C0 cn 4s. cn NJ NJ M C0 C0 CO CO 4S CO C0 CO CO CO CO C0 CO C 00 co o 0 on -J 00 4s. Cπ Cπ NJ CO M M Cθ NJ vl vl Cn UJ

-J co cn - μ-ⁱ s. c M c σi s c^jn 4 M s uJ c u v⁾ vi μ-ι -^j c c co oo co 3 co μ-ι - oθ vi CO vl 4s J CT μ-i M NJ UJ cn NJ u ui N Ui ιo * m ^ ^ -J -J m co o o co a M ⁱB co θ ^j u ^A N⁾ i^v u u ^ y m ^ o3 ^ o oι ^ ω μ μ N ^ NJ M O co co cn vi cπ co co

00 on -J cn vi cn on on on -vi ∞ σi vi cn cn on cn on vi ∞ cn v vi cn -vr o^ o- ri cn vi oj cn ∞

o o o o o o o o o o o o o o o o o o o o o o o o o g g g^'g g g o o o o o o o o o o o o o o o o o o o o o

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

M μ-^, μ-ι μ- μ-^l μ-ι μ- M M μ- μ-ι μ-ι μ-ι μ-ⁱ M μ-' M μ-' -¹ M M

NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NO NJ NJ I^NJ NJ M M M M M μ-i μ-i M μ-¹ μ- μ-ⁱ μ-ⁱ M NJ NJ NJ M M M M M M M M M M O O O O O O O O O O O UJ UJ UJ UJ O UJ J CD UJ CO CO CO OO CO OO CO CO OO CO vl -J vl -J -j - -j vl vl NJ M O CD OO vi on cn 4s cj NJ M o uJ oθ vi cn cn 4s co N^j μ-^> o uJ co ^vi cn Cπ 4s co NJ M O J C0 vi cn n 4s co NJ -ⁱ o UJ 00 vi on cπ s co NJ M

Ω Ω Ω Ω Ω Ω Ω Z O Ω Ω Ω O Ω Ω Ω Ω Ω O O Z Ω Z Ω O Ω Ω Z O Ω Ω O o PJ PJ σ Ω CD N pj pj σ σ Ω CD ^ J J O O Ω D > Ω Ω Z O Ω Ω Ω Ω Ω Z O Ω Z Ω Z Ω Ω Ω Ω Ω Ω CD > Ω Ω CD J J D O Ω CD

M CO NJ NJ NJ M NJ M NJ M M NJ NJ M NJ NJ M M NJ t-3 Hi t-3 H HI H H Hi τ T TJ τj τ J : : : 3: 3 : : 3 X X Hi t-3 H H H HI HI < < < < 3: 3; 3: 3: 3: 3 3: 31 X 50 50 50 50 50 50 0 50 3: : 3: 3: 3: ; : : : : : M M M M 3; 3: : : : : 3: < < <

> > > M TJ TJ TJ TJ TJ Tj TJ TJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ PJ ω cΛ ω ω ω co co co CO CO 50 50 M M M M M M M M 0 0 50 0 5o tn m tn tn tn in tn co O O O CO O O co CO

CD IS Ij CD CD CD CD CD CD D CD CD cD CD CD CD CD CD I^j CD ω CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD CD D CD CD

4s. 4s 4S. 4S. 4s 4s 4s 4_. 4s 4s 4s. 4s 4s 4s 4S s 4s 4S 4S 4s 4s 4s 4S. 4s 4S μ-^■ t—' μ μ-ⁱ μ^ μ-ⁱ -ⁱ M μ-ⁱ μ-ⁱ M μ-ⁱ μ-ⁱ μ-ⁱ μ^ co co co co co co co co vi vi vi vi vi ^vi ^vi ^vi ^vi ^vi cn oⁱ σⁱ ffⁱ ffⁱ cn oⁱ σⁱ on n π cn cn cn cn cn cn 4s. 4s. 4s 4S 4s. 4s 4s CO CO CO CO CO CO CO co O

μ^ l j μ-. μ-i μ-. μ^j μ-. M M M NJ NJ NJ NJ M M M M M M M I 1 M I M M M M M M M M M M M M M M M M M M M M N o rvJ NJ NJ M vI O C0 UJ 0J 00 vl vl Cn v: M M O O v0 UJ C0 Tl Cπ 4s 4s UJ J O UJ O NJ C0 C0 C0 C0 M M NJ C0 4^S cn cn ∞ r— J Cn UJ NJ M O CTl 4s vl O M O NJ M NJ NJ M OO ^vj CO Cn M Cn ^v] vD CD M s U^T UJ CO UJ On 4s r v⁾ vl O O M W C_iJ M θn ^ UJ 0^ 4-. Cv 4S UJ NJ M v] CJ M ∞ CO Cπ 4-, 4^ CO CT, M uJ Cπ CO CT, M ∞ UJ ∞ 4^ CJ O C0 Cv NJ Cn M C» UJ -O UJ M C0 Cv O C0 NJ M 0n 4-. O O M 0n θ ∞ 4s (n 00 vl O 00 uJ uJ U^ _vi _{v] v] v}i _vi -j σ_\ c c^ σι cι σι cι σi Λ CΛ v rι θ^ cι σι o'i cn c^

NJ NJ 4-. NJ M O CO CO CO _vl on σ^ 4s cn 4s Cπ π o-. Cπ vJ cn cπ Cπ cTι π αι n _4s ^ _vl 4s o cn u_j co co 4s 4s co o uj _vo co co vl cn co uj 4s. cn M UJ 4s O UJ CO CO Cn M vl 4s. Cn cn NJ 4-. NJ _vi o cn uJ UJ θo cπ NJ Cθ M Cπ cn 4s cπ oo uJ NJ NJ vi ' - o M M UJ Cn co co NJ Co co cn Cn uJ cn on M 4s UJ M VI CΠ CMO C^VOI O^UJ N∞J ^UJ NJ ^VJ NJ CO NJ ∞ ^VJ C^U CO O. ^UJ S C^V N U ^V^ ^ S S UJ ^ ^

CO CO CO CO CO CO NJ NJ M NJ NJ NJ W NJ NJ NJ M M NJ M NJ CO CO CO CO CO l^J CO CO NJ NJ NJ CO NJ M rv M M O O O M O _vO UJ vl ∞ n CTi Cn vl cn vl OO OD UJ ∞ UJ NJ M O O UJ O O ∞ J. ∞ O U^

4s o ∞ on θ ∞ cn cn co 4s ∞ Cv ∞ ∞ co cv UJ cπ co cn co 4s M vi co cπ o^ NJ co N ω

C^ Oj Cn NJ M UJ O M Cv M CΛ UJ Cn UJ -vl UJ CO O vJ UJ M O CO CO O M Cπ CO uJ M Cπ NJ vl Cn cn 4S v] v^ NJ On O O OO Cu uD u^ O CO C^ CO UJ CO O α ^vl Cπ NJ M O ^uJ M ^ ^vl ^uJ C^{O v}J ^vI cn NJ vi vJ ∞ vO NJ ^ t^

M M M

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O ^ f-^ ^ ^ f-v ooooooo^{o o o o o o o o o o o o o o o o o o o o o o o o o o o o}σooδooδo§§§§§§g§§

4s 4s 4s 4s 4s 4s 4s 4^S M^ 4s. 4^ C0 4s 4s 4^S 4s 4-. 4s 4s Cn Cπ ^vl ^vI ^{v] v}l Cn CT^l Cπ cπ U^l Cn cπ σi Cπ Cπ cn CJl Cπ (π J^ ,-. _ c^ in Cv ^ - N ^ cn co cTi o ^ ^ o M ^ cn ^vj co N^j o co n NJ U M v^j v^ c -u, ^ _VJ S S N_J ^ M M W ^ S N_J C_V S M ∞ S W

M NJ vO UJ M NJ ∞ M C CΛ CTι ∞ CO NO -J W M vO O CO vJ UJ Cπ 4s 4s vl C C0 4s vJ UJ 4s. on v^ ∞ 4s C0 4s 00 M 4^S UJ 4s Cn UJ UJ O O C0 C0 -J M UJ Cπ M UJ M O UJ M ∞ Cπ 4s 4s O CO NJ UJ 4S C0 ∞ UJ ∞ v vJi MN^j uJ cn -vi co co co cn cn _un o^ c Ji vi co c cn cn c^ cn on on cn

ATOM 1223 NE1. TRP B 418 -17.690 74.071 31.368 1.00 50.63 7

ATOM 1224 CZ2 : TRP B 418 -19.819 75.109 30.571 1.00 45.46 6

ATOM 1225 CZ3 ! TRP B 418 -21.422 73.447 29.809 1.00 44.50 6

ATOM _1226 CH2 ! TRP B 418 -21.065 74.777 30.039 1.00 47.55 6

ATOM 1227 C TRP B 418 -16.502 ^■70.662 28.956 1.00 43.88 6

ATOM 1228 O TRP B 418 -16.671 71.424 27.986 1.00 43.17 8

ATOM 1229 N PRO B 419 -15.292 70.490 29.519 1.00 43.55 7

ATOM 1230 CD PRO B 419 -14.967 69.551 30.599 1.00 41.52 6

ATOM 1231 CA PRO B 419 -14.120 71.223 29.011 1.00 41.48 6

ATOM 1232 CB PRO B 419 -12.956 70.582 29.724 1.00 39.21 6

ATOM 1233 CG PRO B 419 -13.521 69.703 30.774 1.00 39.25 6

ATOM 1234 C PRO B 419 -14.035 71.067 27.479 1.00 36.28 6

ATOM 1235 O PRO B 419 -13.690 72.001 26.754 1.00 37.08 8

ATOM 1236 N LYS B 420 -14.330 69.871 26.976 1.00 35.96 7

ATOM 1237 CA LYS B 420 -14.278 69.609 25.538 1.00 40.82 6

ATOM 1238 CB LYS B 420 -14.452 68.103 25.271 1.00 40.78 6

ATOM 1239 CG LYS B 420 -13.349 67.214 25.830 1.00 48.62 6

ATOM 1240 CD LYS B 420 -13.565 65.746 25.480 1.00 55.12 6

ATOM 1241 CE LYS B 420 -12.427 64.892 26.017 1.00 53.26 6

ATOM 1242 NZ LYS B 420 -12.582 63.457 25.608 1.00 52.69 7

ATOM 1243 C LYS B 420 -15.414 70.374 24.875 1.00 40.29 6

ATOM 1244 O LYS B 420 -15.225 71.015 23.851 1.00 39.66 8

ATOM 1245 N LEU B 421 -16.591 70.300 25.499 1.00 38.33 7

ATOM 1.246 CA LEU B 421 -17.796 70.958 25.001 1.00 37.60 6

ATOM 1247 CB LEU B 421 -18.970 70.702 25.965 1.00 43.66 6

ATOM 1248 CG LEU B 421 -20.370 70.850 25.418 1.00 46.50 6

ATOM 1249 CDl LEU B 421 -20.529 69.890 24.255 1.00 45.15 6

ATOM 1250 CD2 LEU B 421 -21.383 70.538 26.486 1.00 51.31 6

ATOM 1251 C LEU B 421 -17.547 72.452 24.823 1.00 39.59 6

ATOM 1252 O LEU B 421 -17.975 73.035 23.836 1.00 40.66 8

ATOM 1253 N LEU B 422 -16.847 73.059 25.780 1.00 39.57 7

ATOM^' 1254 CA LEU B 422 -16.534 74.478 25.715 1.00 38.63 6

ATOM 1255 CB LEU B 422 -15.829 74.936 26.992 1.00 41.79 6

ATOM 1256 CG LEU B 422 -16.714 75.149 28.191 1.00 42.74 6

ATOM 1257 CDl LEU B 422 -15.911 75.685 29.360 1.00 42.89 6

ATOM 1258 CD2 LEU B 422 -17.783 76.162 27.813 1.00 39.27 6

ATOM 1259 C LEU B 422 -15.677 74.788 24.513 1.00 40.47 6

ATOM 1260 O LEU B 422 -15.823 75.846 23.917 1.00 47.83 8

ATOM 1261 N MET B 423 -14.789 73.853 24.168 1.00 34.27 7

ATOM 1262 CA MET B 423 -13.907 74.019 23.024 1.00 35.25 6

ATOM 1263 CB MET B 423 -12.920 72.858 22.922 1.00 32.56 6

ATOM 1264 CG MET B 423 -12.013 72.703 24.125 1.00 40.70 6

ATOM 1265 SD MET B 423 -10.345 72.007 23.784 1.00 47.65 ^' 16

ATOM 1266 CE MET B 423 -10.770 70.538 22.761 1.00 47.16 6

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ATOM 1272 CG LYS B 424 -17.257 70.879 20.843 1.00 30.07 6

ATOM 1273 CD LYS B 424 -16.444 70.510 19.611 1.00 33.22 6

ATOM 1274 CE LYS B 424 -15.795 69.136 19.706 1.00 28.75 6

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ATOM 1541 OE2: GLU B 457 -32.157 94.156 7.633 1.00 20.00 8

ATOM 1542 N VAL B 458 -27.428 90.413 7.281 1.00 43.21 7

ATOM 1543 CA VAL B 458 -26.706 89.739 8.351 1.00 44.98 6

ATOM .1544 CB VAL B 458 -27.075 88.255 8.432 1.00 44.83 6

ATOM 1545 CGI VAL B 458 -26.440 87.623 9.646 1.00 49.72 6

ATOM 1546 CG2 VAL B 458 -28.562 88.086 8.474 1.00 40.89 6

ATOM 1547 C VAL B 456 -25.190 89.822 8.311 1.00 42.72 6

ATOM 1548 O VAL B 458 -24.551 90.179 9.303 1.00 42.-88 8

ATOM 1549 N PHE B 459 -24.605 89.488 7.180 1.00 44.53 7

ATOM 1550 CA PHE B 459 -23.165 89.480 7.077 1.00 48.18 6

ATOM 1551 CB PHE B 459 -22.747 88.457 6.065 1.00 43.60 6

ATOM 1552 CG PHE B 459 -23.167 87.116 6.441 1.00 40.79 6

ATOM 1553 CDl PHE B 459 -24.494 86.750 6.368 1.00 41.01 6

ATOM 1554 CD2 PHE B 459 -22.263 86.286 7.009 1.00 39.48 6

ATOM 1555 CE1 PHE B 459 -24.892 85.540 6.889 1.00 40.62 6

ATOM 1556 CE2 PHE B 459 -22.649 85.091 7.527 1.00 36.87 6

ATOM 1557 CZ PHE B 459 -23.967 84.711 7.455 1.00 36.-39 6

ATOM 1558 C PHE B 459 -22.627 90.758 6 . 623 1.00 52.71 6

ATOM 1559 O PHE B 459 -21.414 91.050 6.791 1.00 51.34 8

ATOM 1560 N GLU B 460 -23.489 91.531 5.976 1.00 62.92 7

ATOM 1561 CA GLU B 460 -22.953 92.741 5.533 1.00 69.33 6

ATOM 1562 CB GLU B 460 -23.851 93.487 4.505 1.00 72.95 6

ATOM 1563 CG GLU B 460 -22.917 94.002 3.412 1.00 78.35 6

ATOM 1564 CD GLU B 460 -22.908 35.480 3.256 1.00 82.97 6

ATOM 1565 OE1 GLU B 460 -23.257 96.213 4.217 1.00 88.28 8

ATOM 1566 OE2 GLU B 460 -22.524 35.977 2.167 1.00 84.80 8

ATOM 1567 C GLU B 460 -22.790 93.576 6.786 1.00 71.87 6

ATOM 1568 O GLU B 460 -23.471 93.391 7.802 1.00 74.51 8

ATOM 1569 N ASP B 461 -21.796 94.449 6.696 1.00 78.50 7

ATOM 1570 CA ASP B 461 -21.401 95.328 7.701 1.00 84.19 6

ATOM 1571 CB ASP B 461 -20.182 96.032 7.125 1.00 85.82 6

ATOM 1572 CG ASP B 461 -19.261 95.066 6.463 1.00 89.62 6

ATOM 1573 OD1 ASP B 461 -19.670 93.929 5.982 1.00 93.00 8

ATOM 1574 OD2 ASP B 461 -18.084 95.361 6.387 1.00 93.04 8

ATOM 1575 C ASP B 461 -22.540 96.291 8.012 1.00 86.80 6

ATOM 1576 O ASP B 461 -23.063 96.176 9.139 1.00 88.70 8

ATOM 1577 OXT ASP B 461 -22.962 97.048 7.098 1.00 88.70 8

TER

ATOM 4002 Cl T3 J 1 ^• 20.152 36.643 29.561 1.00 22.34 6

ATOM 4003 C2 T3 J 1 19.021 41.567 29.283 1.00 21.84 6

ATOM 4004 C3 T3 J 1 18.880 37.086 29.226 1.00 23.43 6

ATOM 4005 C4 T3 J 1 18.249 42.606 28.776 1.00 22.31 6

ATOM 4006 C5 T3 J 1 18.747 38.372 28.866 1.00 24.83 6

ATOM 4007 C6 T3 J 1 17.938 43.621 29.664 1.00 25.16^' 6

ATOM 4008 C7 T3 J 1 19.799 39.296 28.753 1.00 24.65 6

ATOM 4009 C8 T3 J 1 18.330 43.594 31.028 1.00 21.93 6

ATOM 4010 C9 T3 J 1 21.101 38.940 29.075 1.00 25.09 6

ATOM 4011 CIO T3 J 1 19.063 42.558 31.465 1.00 23.66 6

ATOM 4012 Cll T3 J 1 21.254 37.600 29.456 1.00 23.12 6

ATOM 4013 C12 T3 J 1 19.459 41.490 •30.621 1.00 19.67 6

ATOM 4014 C13 T3 J 1 20.370 35.228 30.075 1.00 18.97 6

ATOM 4015 C15 T3 J 1 21.549 34.480 29.455 1.00 19.32 6

ATOM 4016 C17 T3 J 1 21.535 33.003 29.710 1.00 19.02 6 ATOM 4017 11 T3 J 1 16.898 39.029 28.661, 1.00 25.29 53

ATOM 4018 12 T3 J 1 17.058 45.327 29.154 1.00 26.49 53

ATOM 4019 13 T3 J 1 22.763 40.262 29.169 1.00 25.67 53

ATOM -4020 Nl T3 J 1 21.800 34.859 28.024 1.00 15.12 7

ATOM 4021 01 T3 J 1 17.934 44.682 31.806 1.00 21.79

ATOM 4022 02 T3 J 1 19.432 40.560 28.362 1.00 22.05

ATOM 4023 03 T3 J 1 21.911 32.260 28.776 1.00 20.38

ATOM 4024 04 T3 J 1 21.137 32.622 30.840 1.00 20.16

TER

ATOM 4025 Cl T3 K 1 -28.131 75.928 7.543 1.00 22.34

ATOM 4026 C2 T3 K 1 -24.676 77.673 4.318 1.00 21.84

ATOM 4027 C3 T3 K 1 -28.490 76.351 6.201 1.00 23.43

ATOM 4028 C4 T3 K 1 -24.217 77.893 2.989 1.00 22.31

ATOM 4029 C5 T3 K 1 -27.485 76.499 5.233 1.00 24.83

ATOM 4030 C6 T3 K 1 -23.545 79.124 2.700 1.00 25.16

ATOM 4031 C7 T3 K 1 -26.132 76.227 5.581 1.00 24.65

ATOM 4032 C8 T3 K 1 -23.382 80.104 3.772 1.00 21.93 6

ATOM 4033 C9 T3 K 1 -25.685 75.833 6.855 1.00 25.09 6

ATOM 4034 CIO T3 K 1 -23.867 79.823 5.042 1.00 23.66 6

ATOM 4035 Cll T3 K 1 -26.708 75.670 7.834 1.00 23.12 6

ATOM 4036 C12 T3 K 1 -24.521 ^"78.610 5.376 1.00 19.67 6

ATOM 4037 C13 T3 K 1 -29.211 ^'75.830 8.626 1.00 18.97 6

ATOM 4038 C15 T3 K 1 -29.181 567 9.488 1.00 19.32 6

ATOM 4039 C17 T3 K 1 -30.440 343 10.264 1.00 19.02 6

ATOM 4040 11 T3 K 1 -27.868 ^"^7.342 3. 316 1.00 25.29 53

ATOM 4041 12 T3 K 1 -22.732 79.619 0.850 1.00 26.49 53

ATOM 4042 13 T3 K 1 -23.602 75.792 ,334 1.00 25.67 53

ATOM 4043 Nl T3 K 1 -28.680 73.342 762 1.00 15.12 7

ATOM 4044 01 T3 K 1 -22.742 81.265 443 1.00 21.79

ATOM 4045 02 T3 K 1 -25.267 76.388 595 1.00 22.05

ATOM 4046 03 T3 K 1 -30.816 73.159 10.382 .00 20.38

ATOM 4047 04 T3 K 1 -31.028 75.359 10.729 ,00 20.16

TER

ATOM 1 C LYS X 686 13.868 40.176 48.888 00 40.00

ATOM 2 O LYS X 686 13.914 40.120 47.639 .00 40.00

ATOM 3 N LYS X 686 14.374 42.245 50.489 00 40.00 7

ATOM 4 CA LYS X 686 14.937 41.070 49.710 .00 40.00 6

ATOM 5 N HIS X 687 13.038 39.527 49.705 .00 40.00 7

ATOM 6 CA HIS X 687 11.891 38.518 49.521 1.00 40.00 6

ATOM 7 CB HIS X 687 10.639 3-9.000 50.212 1.00 40.00 6

ATOM 8 CG HIS X 687 10.981 39.526 51.563 1.00 40.00 6

ATOM 9 CD2 HIS X 687 11.021 38.908 52.753 1.00 40.00 6

ATOM 10 ND1 HIS X 687 11.354 40.844 51.754 1.00 40.00 7

ATOM 11 CE1 HIS X 687 11.614 40.994 53.034 1.00 40.00 6

ATOM 12 NE2 HIS X 687 11.422 39.847 53.646 1.00 40.00 7

ATOM 13 C HIS X 687 11.183 38.108 48.208 1.00 40.00 6

•ATOM 14 O HIS X 687 11.674 38.361 47.094 00 40.00 8

ATOM 15 N LYS X 688 10.064 37.458 48.649 ,00 40.00 7

ATOM 16 CA LYS X 688 8.911 36.858 47.931 .00 40.00 6

ATOM 17 CB LYS X 688 8.292 37.850 46.968 ,00 40.00 6

ATOM 18 C LYS X 688 9.246 35.573 47.161 1.00 40.00 6

ATOM 19 O LYS X 688 9.319 34.473 47.722 1.00 40.00

ATOM 20 N ILE X 689 9.426 35.754 45.865 1.00 40.00 oooooooooooogoggggooooooooooooo

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ATOM 1220 CZ TYR A 459 17.450 -9.514 15.941 1.00 72.93

ATOM 1221 OH TYR A 459 18.4:67 -8.687 16.351 1.00 74.56

ATOM 1222 C TYR A 459 13.649 -14.097 13.187 1.00 71.86

ATOM 1223 0 TYR A 459 13.380 -15.099 13.852 1.00 73.11

ATOM 1224 N THR A 460 12.981 -13.756 12.090 1.00 74.84

ATOM 1225 CA THR A 460 11.881 -14.567 11.589 1.00 77.66

ATOM 1226 CB THR A 460 11.246 -13.900 10.373 1.00 76.69

ATOM 1227 C THR A 460 12.436 -15.938 11.212 1.00 80.26

ATOM 1228 O THR A 460 11.684 -16.866 10.912 1.00 80.82

ATOM 1229 N PHE A 461 13.762 -16.051 11.231 1.00 82.69

ATOM 1230 CA PHE A 461 14.440 -17.299 10.905 1.00 85.63

ATOM 1231 CB PHE A 461 15.920 -17.034 10.630 1.00 85.47

ATOM 1232 C PHE A 461 14.284 -18.288 12.059 1.00 87.52

ATOM 1233 O PHE A 461 14.493 -17.940 13.224 1.00 86.53

ATOM 1234 N LEU A 462 13.914 -19.520 11.724 1.00 89.49

ATOM 1235 CA LEU A 462 13.711 -20.568 12.718 1.00 91.34

ATOM 1236 CB LEU A 462 12.961 -21.741 12.087 1.00 91.23

ATOM 1237 C LEU A 462 15.016 -21.060 13.340 1.00 92.05

ATOM 1238 O LEU A 462 16.042 -21.165 12.664 1.00 91.91

ATOM 1239 N SER A 463 14.966 -21.357 14.635 1.00 92.53

ATOM 1240 CA SER A 463 16.131 -21.855 15.358 1.00 92.96

ATOM 1241 CB SER A 463 16.033 -21.483 16.833 1.00 91.67

ATOM 1242 C SER A 463 16.189 -23.371 15.200 1.00 93.39

ATOM 1243 O SER A 463 15.156 -24.034 15.102 1.00 93.44

ATOM 1244 N SER A 464 17.399 -23.917 15.167 1.00 93.82

ATOM 1245 CA SER A 464 17.577 -25.355 15.015 1.00 93.85

ATOM 1246 CB SER A 464 17.284 -25.769 13.577 1.00 93.74

ATOM 1247 C SER A 464 18.997 -25.743 15.396 1.00 93.96

ATOM 1248 O SER A 464 19.815 -26.074 14.535 1.00 93.65

ATOM 1249 N THR A 465 19.279 -25.699 16.694 1.00 93.91

ATOM 1250 CA THR A 465 20.600 -26.036 17.212 1.00 93.79

ATOM 1251 CB THR A 465 20.952 -27.483 16.863 1.00 93.38

ATOM 1252 C THR A 465 21.640 -25.085 16.634 1.00 93.27

ATOM 1253 O THR A 465 21.302 -24.017 16.121 1.00 93.03

ATOM 1254 N LEU A 466 22.907 -25.479 16.723 1.00 93.26

ATOM 1255 CA LEU A 466 23.999 -24.665 16.207 1.00 92.34

ATOM 1256 CB LEU A 466 25.335 -25.338 16.498 1.00 91.59

ATOM 1257 C LEU A 466 23.829 -24.461 14.706 1.00 92.18

ATOM 1258 O LEU A 466 24.411 -23.545 14.125 1.00 92.67

ATOM 1259 N LYS A 467 23.028 -25.323 14.086 1.00 91.28

ATOM 1260 CA LYS A 467 22.772 -25.238 12.653 1.00 90.02

ATOM 1261 CB LYS A 467 21.740 -26.287 12.240 1.00 89.93

ATOM 1262 C LYS A 467 22.269 -23.841 12.308 1.00 88.35

ATOM 1263 O LYS A 467 23.032 -22.990 11.849 1.00 88.50

ATOM 1264 N SER A 468 20.981 -23.610 12.536 1.00 86.02

ATOM 1265 CA SER A 468 20.384 -22.315 12.252 1.00 84.10

ATOM 1266 CB SER A 468 18.901 -22.333 12.620 1.00 84.08

ATOM 1267 OG SER A 468 18.229 -23.378 11.937 1.00 83.03

ATOM 1268 C SER A 468 21.109 -21.230 13.040 1.00 83.39

ATOM 1269 O SER A 468 21.264 -20.105 12.565 1.00 83.48

ATOM 1270 N LEU A 469 21.558 -21.579 14.242 1.00 82.04

ATOM 1271 CA LEU A 469 22.276 -20.640 15.098 1.00 80.28

ATOM 1272 CB LEU A 469 22.595 -21.294 16.436 1.00 79.81

ATOM 1273 C LEU A 469 23.564 -20.174 14.419 1.00 79.18

ATOM 1274 O LEU A 469 24.111 -19.122 14.756 1.00 78.61

ATOM 1275 N GLU A 470 24.044 -20.969 13.466 1.00 76.69 r₃nn_{3 3}rnn3n₃n₃n₃n₃n2o3O3O₃O3O₃O3O3O3O3O3O3O3O3O3O3O3O3O3O3O33OO3O3O3O3O3O3O3O3O3O3O3O2O3O3O3O3O3O33333333

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H H H v _vl _vl Vl ι o _j 5 _ιl _ιl _'J _>l ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^{m m m m m m m m m m ffl m m m ft m m m m m} ^ ^{m |}Λ W IΛ «1 ffl ft lΛ m Λ r^ _{i K Ni i}- _i- _i-_J M H H H H O O O O O O O O O O D ij vO U UJ ω v^

NNJJ ttOO CO LO NJ H O CO OT _vl Cn ljϊ rf^ CO NJ H O vO ∞ Ω Z Ω Z Ω Ω Ω Ω Z Ω O O Ω Ω Ω Ω Z O Ω Ω to Ω Ω Ω O Ω Ω O Ω

Ω O Ω Z Ω Ω Ω Ω Ω Z O Ω O Ω Ω Ω Z O Ω O Ω tO to O Ω W > ta PJ O Ω CO to PJ α Ω D3 to tsj PJ α Ω co D Ω DO Ω O

CO H H to co H to * μ _ffi ;_τ< _!I! a _{Lj ff}i .ιl ffi W ffi Ω Ω Ω Ω Ω Ω Ω Ω Ω 33222233 Ω Ω Ω Ω in t^ d α α o tn to to vo ω ijj ϋj co ω α _to _to > > to to to to to to to to to > to > > to to to to to to > to > to to in in in in in in in iπ in Ln in in in in in in in in cn Lπ in iπ tn cn cπ w iπ in tn iπ Ln in i^ O CO w S w S M NJ W M tO NJ CO M tO M CO t tO W M W CO tO NJ tO CO NJ tO NJ O tO M CO tO M cπ n cπ rfs ^ ^ _Lt-. ^ _Lts _L> Lps L^ rf ι w ιo ω i i) ω w ω w

I I I l l l l l I I I I O O O H CO NJ CO NJ H J t-ⁱ J H O NJ H O μⁱ H O o o on rfs LO Lo co co H to co co o t-ⁱ t-ⁱ o o μ^j

H H tO Co tn cπ cπ co rfs cπ rfs Ln ^vi v oo cπ oo co UJ n o 0o0 o CO CO rf o rfs oo oo j NJ t- oo in LO to oo μ cπ o LO en rfs cπ cπ Co LO Lπ vl on Ln rfs rfs σi UJ v] LO n o O fs 03 cn co H i co oo ttoo o O CO 00 UJ rf i -J LO co in co in NJ on o NJ -j UJ CD UJ NJ U on to o NJ vl r oo on oo cn i-' co rfs co o cn on 00 rfs cn 4 H on on o J 00 vl CO H CO UJ - co vi n co o in H oo io cn co cn o co cn cn H o in rf O OO l LO - o o vi cn co rfs uj vj co H 00 cπ on vl vl rf CD on rfs rf l l l l l I I I I I I I I I I I I I ¹ I I I ¹ I ^I I I I I I I I I I I I I I I I I I I cn _Lts W io W H O O O O i-^J t io rf rfs co iNj c rfs Li Lt. 4> n cn vi v] vi vi vi c w o όn ^'oo r_fs w o iι ω ό t_u ^' _H iπ t-> W ι^ ω

S t H _vO _vo o io M _vi NJ O Oo c cn cn L oo o o i vO W ∞ NJ L o J H v^ co M rf _vθ rfs _{L L} rfs c» ιn ιn t_v rf^ oo o cD m .^ c rfs o o μ ω

I I I o co vi ι

S rfi H Cn O vl

_{H H} ^L-₁

O O O O O O O O

W CO W CO NJ W W tO U W tv tv W CO CO rfs rfs rfi W W NJ tO tO CO M lO LO CO CO N CO CO t tO tO NJ rfs rf^ ⁱ ovn ⁱu ⁱvvi ⁱv oo vo- ^vrf-s ,i t ,,o , o _ rf ^s cn .rfivs .rfrvs cn -vii vvii mcn ncoo tt--iⁱ -J rfs π C UJ rfs H m (o in m m ι u . . , - :_ _ . ^{l J l} ' ^{w ω} W to CO CO

Ln c c Ln rfs H t cn in t H vi tv rfs ui o rfs L co J M o M i- ω rfs o

LO LO cπ cπ rf^ H cπ tTi H vi to CO rfs UJ UJ O H UJ rfs rfs cO O O vl vi in oo rfs rf on in o co on cn rfs ^i rfs in rf -vi CO o σ oo on Lπ cD rfs v s cπ _vo o o w oo tπ ui _vj c UJ LO oo rf o on on J D 00 O J co oo oo on rf- CO tO v] H

H H H -0 vl vl vl vl vl -J vl -J v _l vl l vl v _l v -l - l . cn cn cn cn cn cn u oo vi on in rfs co co j cD vi e i rf

O Ω Ω Ω Z O Ω Ω Ω Z O Ω tO Ω Ω Z O Ω Z Ω Ω Ω Ω Ω O O Ω CO Ω Ω Ω Z O Ω O Ω Ω Z OΩOΩ_{Ω Ω Ω Ω Ω Ω Ω}ZPΩ_{Ω Ω} tj Ω to to W Ω to to N M O O ω PJ ϋ Ω CD to Ω CO to ffi tsi p a ta o o co D o

H to to H ι-> t H to to to to to in t7^, tr< F F Ω Ω Ω Ω Ω Ω t→ tn £ £ 3 2 2 ^ in c co cΛ co ^ ^ κ; κ; _t κ5 ι-< κJ μ; ι

Z Z Z Z Z m m to to to to to to w m to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to in Ln in in in in in w in Lπ in Lπ iπ in in in w in in cπ cn cn in iπ in υi in iπ iπ cn Lπ in L^

LO CO C_O O CO CO CO L_O LO CJ L_O LO LO LO LO NJ CO W co to NJ W t H H H H H O o o o o o co u u^j UJ UJ UJ U^j uJ UJ OT ∞ ∞ oo ∞ oo oo oo vi ^vi vi ^vi vi vi cn σi cn cn cn cn cn cn cn cn

I 1 I I I I I I

03 03 00 -j CO UJ UJ UJ OO UJ OO vl ^vi σι on ii NJ W io co Lo rfs 4s in ιn Lπ ιn C⁾ L^θ Lπ rfs on cπ cn ιn ι rf ιi ιo rf s . _{> W} to M t-ⁱ co o n cπ

-0 H on o cn on on cπ cπ o on cn cπ cn n o cn in

LΠ on in cn on in cn cπ cn o o cπ cπ o cπ o on o cn in o o to cπ cn to to

H o in to cπ

H o

H o o o o on on cn on on on on cn cn in cn in on in in in in cπ in in cπ cπ cπ in rf. in on cπ vl μ oo o on in o o on cn H in in -> H co in cπ in cπ t co o cn in o cπ o on o on NJ on on vl rfs UJ t-¹ CO Ln i H v! L0 Lπ to co to to in oo tO vi o to cn oo io vl O -0 00 H cπ rfs o in rf> oo vi cn co rfs co cπ on to co t-i rfs cn to cn oo on oo o in rfs oo co rfs rfs to on cD co cπ O vi M M Ui ϋi vi oo co ω w μ ω -j 00 rfs UJ 00 00 vl rfs in co O o o co co -^j cπ co vi cn rfs Ln vi co H

ATOM 1780 ND2 ASN A 532 -9.016 -10.836 -9.891 1.00 62.68

ATOM 1781 C ASN A 532 -7.247 -6.710-10.648 1.00 59.75

ATOM 1782 O ASN A 532 -7.487 -6.615-11.850 1.00 57.50

ATOM ₌ 1783 N VAL A 533 -6.507 -5.822 -9.992 1.00 59.39

ATOM 1784 CA VAL A 533 -5.954 -4.656-10.669 1.00 58.22

ATOM 1785 CB VAL A 533 -6.223 -3.371 -9.865 1.00 59.20

ATOM 1786 CGI VAL A 533 -6.181 -2.163-10.785 1.00 59.21

ATOM 1787 CG2 VAL A 533 -7.574 -3.467 -9.172 1.00 59.57

ATOM 1788 C VAL A 533 -4.452 -4.767-10.907 1.00 57.86

ATOM 1789 O VAL A 533 -3.846 -3.874-11.499 1.00 60.56

ATOM 1790 N VAL A 534 -3.852 -5.863-10.451 1.00 56.03

ATOM 1791 CA VAL A 534 -2.417 -6.063-10.621 1.00 54.11

ATOM 1792 CB VAL A 534 -1.767 -6.632 -9.341 1.00 54.02

ATOM 1793 CGI VAL A 534 -0.300 -6.950 -9.601 1.00 52.37

ATOM 1794 CG2 VAL A 534 -1.900 -5.635 -8.200 1.00 55.70

ATOM 1795 C VAL A 534 -2.089 -7.008-11.770 1.00 54.31

ATOM 1796 O VAL A 534 -2.519 -8.164-11.780 1.00 51.66

ATOM 1797 N PRO A 535 -1.315 -6.527-12.755 1.00 53.54

ATOM 1798 CD PRO A 535 -0.749 -5.172-12.874 1.00 54.28

ATOM 1799 CA PRO A 535 -0.949 -7.373-13.893 1.00 53.24

ATOM 1800 CB PRO A 535 0.011 -6.500-14.697 1.00 52.71

ATOM 1801 CG PRO A 535 -0.353 -5.102-14.319 1.00 53.19

ATOM 1802 C PRO A 535 -0.296 -8.664-13.411 1.00 54.25

ATOM 1803 O PRO A 535 0.121 -8.768-12.254 1.00 54.56

ATOM 1804 N LEU A 536 -0.203 -9.645-14.299 1.00 53.63

ATOM 1805 CA LEU A 536 0.382 -10.926-13.937 1.00 53.11

ATOM 1806 CB LEU A 536 -0.250 -12.046-14.763 1.00 51.88

ATOM 1807 CG LEU A 536 -0.686 -13.256-13.938 1.00 51.83

ATOM 1808 CDl LEU A 536 -1.953 -12.917-13.173 1.00 49.51

ATOM 1809 CD2 LEU A 536 -0.905 -14.449-14.854 1.00 53.43

ATOM 1810 C LEU A 536 1.895 -10.990-14.081 1.00 52.58

ATOM 1811 O LEU A 536 2.414 -11.501-15.075 1.00 55.33

ATOM 1812 N TYR A 537 2.601 -10.462-13.087 1.00 48.72

ATOM 1813 CA TYR A 537 4.057 -10.501-13.093 1.00 44.22

ATOM 1814 CB TYR A 537 4.627 -9.134-12.709 1.00 44.52

ATOM 1815 CG TYR A 537 4.331 -8.053-13.731 1.00 45.18

ATOM 1816 CDl TYR A 537 3.623 -6.905-13.376 1.00 43.77

ATOM 1817 CE1 TYR A 537 3.334 -5.915-14.317 1.00 45.23

ATOM 1818 CD2 TYR A 537 4.747 -8.187-15.058 1.00 46.91

ATOM 1819 CE2 TYR A 537 4.462 -7.202-16.008 1.00 43.93

ATOM 1820 CZ TYR A 537 3.757 -6.071-15.631 1.00 46.70

ATOM 1821 OH TYR A 537 3.472 -5.097-16.565 1.00 48.35

ATOM 1822 C TYR A 537 4.401 -11.562-12.056 1.00 41.29

ATOM 1823 O TYR A 537 4.330 -11.319-10.856 1.00 41.82

ATOM 1824 N ASP A 538 4.748 -12.748-12.540 1.00 40.34

ATOM 1825 CA ASP A 538 5.055 -13.896-11.691 1.00 38.84

ATOM 1826 CB ASP A 538 5.594 -15.037-12.554 1.00 43.47

ATOM 1827 CG ASP A 538 4.571 -15.531-13.566 1.00 47.67

ATOM 1828 OD1 ASP A 538 4.931 -16.373-14.416 1.00 49.33

ATOM 1829 OD2 ASP A 538 3.405 -15.073-13.511 1.00 48.07

ATOM 1830 C ASP A 538 5.991 -13.676-10.508 1.00 37.28

ATOM 1831 O ASP A 538 5.620 -13.964 -9.371 1.00 38.55

ATOM 1832 N LEU A 539 7.196 -13.200-10.766 1.00 33.83

ATOM 1833 CA LEU A 539 8.155 -12.959 -9.692 1.00 32.80

ATOM 1834 CB LEU A 539 9.419 -12.323-10.263 1.00 32.78

ATOM 1835 CG LEU A 539 10.561 -12.031 -9.292 1.00 30.93 ATOM 1836 CDl LEU A 539 10.913 -13.280 -8.492 1.00 33.81

ATOM 1837 CD2 LEU A 539 11.758 -11.538 -10.077 1.00 25.92

ATOM 1838 C LEU A 539 7.558 -12.050 -8.614 1.00 31.85

ATOM 1839 O LEU A 539 7.590 -12.367 -7.423 1.00 25.63

ATOM 1840 N LEU A 540 7.011 -10.917 -9.042 1.00 32.07

ATOM 1841 CA LEU A 540 6.411 -9.976 -8.111 1.00 31.03

ATOM 1842 CB LEU A 540 5.792 -8.800 -8.861 1.00 30.56

ATOM 1843 CG LEU A 540 5.124 -7.774 -7,945 1.00 31.12

ATOM 1844 CDl LEU A 540 6.092 -7.357 -6.838 1.00 29.76

ATOM 1845 CD2 LEU A 540 4.693 -6.572 -8.762 1.00 30.85

ATOM 1846 C LEU A 540 5.337 -10.660 -7.282 1,00 34.55

ATOM 1847 O LEU A 540 5.316 -10.522 -6.063 1.00 31.60

ATOM 1848 N LEU A 541 4.446 -11.388 -7.941 1.00 35.64

ATOM 1849 CA LEU A 541 3.378 -12.101 -7.245 1.00 37.84

ATOM 1850 CB LEU A 541 2.452 -12.771 -8.255 1.00 38.49

ATOM 1851 CG LEU A 541 1.244 -11.932 -8.678 1.00 39.80

ATOM 1852 CDl LEU A 541 0.476 -11.476 -7.448 1.00 40.02

ATOM 1853 CD2 LEU A 541 1.713 -10.733 -9.485 1.00 40.48

ATOM 1854 C LEU A 541 3.937 -13.147 -6.275 1.00 40.10

ATOM 1855 O LEU A 541 3.472 -13.254 -5.137 1.00 42.72

ATOM 1856 N GLU A 542 4.929 -13.915 -6.723 1.00 38.45

ATOM 1857 CA GLU A 542 5.535 -14.932 -5.868 1.00 39.59

ATOM 1858 CB GLU A 542 6.738 -15.566 -6.564 1.00 41.73

ATOM 1859 CG GLU A 542 6.396 -16.327 -7.831 1.00 48.34

ATOM 1860 CD GLU A 542 6.931 -17.747 -7.819 1.00 52.57

ATOM 1861 OE1 GLU A 542 8.049 -17.961 -7.298 1.00 52.70

ATOM 1862 OE2 GLU A 542 6.230 -18.647 -8.331 1.00 53.69

ATOM 1863 C GLU A 542 5.989 -14.299 -4.553 1.00 39.94

ATOM 1864 O GLU A 542 5.567 -14.710 -3.472 1.00 40.99

ATOM 1865 N MET A 543 6.844 -13.287 -4.663 1.00 38.29

ATOM 1866 CA MET A 543 7.380 -12.580 -3.503 1.00 38.11

ATOM 1867 CB MET A 543 8.242 -11.408 • -3.963 1.00 37.34

ATOM 1868 CG MET A 543 9.311 -11.797 • -4.953 1.00 40.59

ATOM 1869 SD MET A 543 10.829 -12.223 ■ -4.114 1.00 45.64

ATOM 1870 CE MET A 543 12.014 -11.399 • -5.151 1.00 42.61

ATOM 1871 C MET A 543 6.287 -12.064 ^■ -2.581 1.00 37.94

ATOM 1872 O MET A 543 6.413 -12.127 • -1.358 1.00 39.20

ATOM 1873 N LEU A 544 5.218 -11.544 ■ -3.175 1.00 39.44

ATOM 1874 CA LEU A 544 4.100 -11.013 -2.408 1.00 40.91

ATOM 1875 CB LEU A 544 3.087 -10.344 ■ -3.341 1.00 39.88

ATOM 1876 CG LEU A 544 1.775 -9.905 -2.688 1.00 42.70

ATOM 1877 CDl LEU A 544 2.060 -8.886 -1.586 1.00 37.35

ATOM 1878 CD2 LEU A 544 0.854 -9.317 -3.741 1.00 38.47

ATOM 1879 C LEU A 544 3.420 -12.120 -1.614 1.00 42.83

ATOM 1880 O LEU A 544 2.957 -11.899 -0.496 1.00 42.73

ATOM 1881 N ASP A 545 3.367 -13.313 -2.197 1.00 46.32

ATOM 1882 CA ASP A 545 2.746 -14.456 -1.539 1.00 50.65

ATOM 1883 CB ASP A 545 2.606 -15.617 -2.524 1.00 53.67

ATOM 1884 CG ASP A 545 1.703 -15.278 -3.691 1.00 57.35

ATOM 1885 OD1 ASP A 545 0.697 -14.568 -3.475 1.00 59.99

ATOM 1886 OD2 ASP A 545 1.999 -15.718 -4.824 1.00 59.68

ATOM 1887 C ASP A 545 3.559 -14.898 -0.327 1.00 50.74

ATOM 1888 O ASP A 545 3.004 -15.388 0.657 1.00 49.39

ATOM 1889 N ALA A 546 4.874 -14.723 -0.401 1.00 51.82

ATOM 1890 CA ALA A 546 5.750 -15.095 0.702 1.00 53.12

ATOM 1891 CB ALA A 546 7.180 -14.678 0.395 1.00 53.19

³ G Z_{O Ω Ω Ω Ω}ΩΩΩOΩΩΩΩΩΩΩOΩΩΩΩΩΩΩOOΩOΩZOΩ Ω Z Ω tD P ro H u W rP. in σi O 'o ⁱO 'ti 'O 'O ⁱD 'O 'i 'O 'o X Co to tsi PJ O

Ln rfs Lθ θ j μⁱ cn i oo j ι- co H ra α_. ω o- en Ω α o σ σ α o α o α σ α o o α o α α α o o £ £ £ E E £ ϊ w W M W M H P H H M M H M M H H tfl t H B H M H H H tS H M M ≥ ≥ .. α o ?o ?o ?o to ω ω ω ω to to oj to ω to ω vΩ to ω ω ω ω to m tJ CD C0 CD C0 CD to to to ' > ' > ' > to ω ω ω w w w m oi m w m m m m m m σi m m m m m m m m j cn w w Cn ll ln m Lπ Lπ H O O O O O O O O O O O O O O O O O O O O ^vO UJ ^UJ ^UJ uD ^CD CJ3 CJ3 0⁰ 03 00 00 ∞

OO μ-i μi H H H t-' l-' H ' ^I I I I I

"-" !O H N W Co co rf_ rfs rf CD ,^ L-J U co -_v i ij t H O O H to w n in in w rf^ θo o vi cn ιθ _v] UJ CD θ rf μi θo o3 Cπ H c vi rfs irι oo cπ o cD cθ vi CD CD vθ cn co t--^{ι i} rfs μi -v Cθ J θ rf u3 θo cO CJ Lo o uj rfs vi en J uJ vi cn ⁱ Cπ rfs Lo o

UJ vl rfs o ^ _{w oo} ^ _{ω C}n w J t-ι ∞ _ι 2 ^ 2 ⁰⁰

LO LΠ in H t H H UJ rfs Cn iO W rfs UJ M W M LO H Cn NJ -v vl vl CD rfs o CO tO Cn H UJ OO vl UJ ι cn oo cπ μⁱ

cn cn on cn cn σi fo co to co H J NJ CO CO tO CO CO LO LO CO CO NJ CO CO NJ -J vl -J vl vl

U _lf. W 01 _lϋ _lt ιt> μ μ μ UJ to H co UJ H NJ vl vl LO H UJ LO Lπ μⁱ tO t-' UJ vi oo n in Ol in in In rv c n in rfs o co -j UJ ιo co H o O rf ^v v^jl J oo o rfs i rf rfs μⁱ π ⁱ rfs μ-ⁱ co co H to o -J -v] o oo vi cπ rfs co oo t-' vi LΠ co o H cn o l co -vj to H Oo σi O LO Ln rfs uJ in rfs

ATOM 1948 CA LEU B 306 12.884 21.133 29.757 1.00 60.98

ATOM 1949 CB LEU B 306 11.884 21.200 30.913 1.00 61.23

ATOM 1950 CG LEU B 306 12.221 20.417 32.183 1.00 62.23

ATOM 1951 CDl LEU B 306 13.304 21.144 32.966 1.00 62.56

ATOM 1952 CD2 LEU B 306 10.965 20.258 33.027 1.00 64.31

ATOM 1953 C LEU B 306 13.660 19.819 29.803 1.00 58.39

ATOM 1954 O LEU B 306 14.570 19.654 30.614 1.00 58.56

ATOM 1955 N ALA B 307 13.293 18.881 28.933 1.00 54.82

ATOM 1956 CA ALA B 307 13.971 17.589 28.861 1.00 50.62

ATOM 1957 CB ALA B 307 13.092 16.584 28.143 1.00 51.30

ATOM 1958 C ALA B 307 15.303 17.719 28.122 l.'oo 46.84

ATOM 1959 O ALA B 307 16.196 16.885 28.274 1.00 45.62

ATOM 1960 N LEU B 308 15.431 18.769 27.320 1.00 43.46

ATOM 1961 CA LEU B 308 16.643 18.983 26.542 1.00 43.01

ATOM 1962 CB LEU B 308 16.413 20.100 25.526 1.00 41.32

ATOM 1963 CG LEU B 308 16.315 19.708 24.051 1.00 43.10

ATOM 1964 CDl LEU B 308 15.942 18.239 23.903 1.00 40.51

ATOM 1965 CD2 LEU B 308 15.287 20.602 23.375 1.00 39.80

ATOM 1966 C LEU B 308 17.874 19.297 27.385 1.00 42.11

ATOM 1967 O LEU B 308 19.000 19.102 26.932 1.00 44.34

ATOM 1968 N SER B 309 17.669 19.775 28.608 1.00 40.88

ATOM 1969 CA SER B 309 18.796 20.100 29.475 1.00 42.79

ATOM 1970 CB SER B 309 18.562 21.447 30.163 1.00 41.25

ATOM 1971 OG SER B 309 17.459 21.379 31.046 1.00 46.67

ATOM 1972 C SER B 309 19.072 19.028 30.529 1.00 42.60

ATOM 1973 O SER B 309 20.053 19.119 31.269 1.00 44.18

ATOM 1974 N LEU B 310 18.217 18.012 30.596 1.00 39.44

ATOM 1975 CA LEU B 31U 18.394 16.936 31.569 1.00 37.62

ATOM 1976 CB LEU B 310 17.205 15.969 31.499 1.00 38.84

ATOM 1977 CG LEU B 310 16.216 15.873 32.668 1.00 42.43

ATOM 1978 CDl LEU B 310 16.040 17.219 33.355 1.00 42.55

ATOM 1979 CD2 LEU B 310 14.881 15.380 32.138 1.00 39.69

ATOM 1980 C LEU B 310 19.691 16.174 31.285 1.00 34.11

ATOM 1981 O LEU B 310 20.111 16.070 30.139 1.00 34.41

ATOM 1982 N THR B 311 20.339 15.662 32.326 1.00 34.04

ATOM 1983 CA THR B 311 21.564 14.888 32.127 1.00 32.34

ATOM 1984 CB THR B 311 22.434 14.824 33.399 1.00 31.75

ATOM 1985 OG1 THR B 311 21.724 14.116 34.420 1.00 36.20

ATOM 1986 CG2 . THR B 311 22.782 16.212 33.893 1.00 31.05

ATOM 1987 C THR B 311 21.145 13.460 33..790 1.00 32.37

ATOM 1988 O THR B 311 19.967 13.117 31.899 1.00 28.16

ATOM 1989 N ALA B 312 22.106 12.628 31.396 1.00 33.23

ATOM 1990 CA ALA B 312 21.811 11.237 31.053 1.00 35.63

ATOM 1991 CB ALA B . 312 23.077 10.527 30.577 1.00 34.00

ATOM 1992 C ALA B 312 21.210 10.489 32.240 1.00 34.29

ATOM 1993 O ALA B 312 20.226 9.766 32.089 1.00 33.10

ATOM 1994 N ASP B 313 21.800 10.665 33.419 1.00 33.90

ATOM 1995 CA ASP B 313 21.304 9.994 34.615 1.00 34.19

ATOM 1996 CB ASP B 313 22.258 10.219 35.788 1.00 42.09

ATOM 1997 CG ASP B 313 23.494 9.358 35.700 1.00 44.87

ATOM 1998 OD1 ASP B 313 24.586 9.858 36.040 1.00 51.57

ATOM 1999 OD2 ASP B 313 23.377 8.184 35.290 1.00 46.79

ATOM 2000 C ASP B 313 19.925 10.520 34.971 1.00 31.99

ATOM 2001 O ASP B 313 19.056 9.768 35.426 1.00 32.03

ATOM 2002 N GLN B 314 19.733 11.819 34.763 1.00 29.38

ATOM 2003 CA GLN B 314 18.458 12.457 35.046 1.00 29.73

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ATOM 2172 C PRO B 336 -8.602 -23.324 27.954 1.00 44.54

ATOM 2173 O PRO B 336 -9.809 -23.342 28.179 1.00 44.14

ATOM 2174 N PHE B 337 -8.007 -22.350 27.274 1.00 39.18

ATOM . 2175 CA PHE B 337 -8.764 -21.223 26.742 1.00 38.25

ATOM 2176 CB PHE B 337 -7.850 -20.003 26.567 1.00 36.98

ATOM 2177 CG PHE B 337 -7.229 -19.517 27.846 1.00 36.81

ATOM 2178 CDl PHE B 337 -5.846 -19.511 28.002 1.00 38.89

ATOM 2179 CD2 PHE B 337 -8.023 -19.062 28.893 1.00 35.97

ATOM 2180 CE1 PHE B 337 -5.262 -19.059 29.185 1.00 36.85

ATOM 2181 CE2 PHE B 337 -7.449 -18.608 30.079 1.00 37.15

ATOM 2182 CZ PHE B 337 -6.064 -18.607 30.224 1.00 38.40

ATOM 2183 c PHE B 337 -9.420 -21.535 25.402 1.00 36.81

ATOM 2184 0 PHE B 337 -8.962 -22.399 24.658 1.00 36.26

ATOM 2185 N SER B 338 -10.504 -20.828 25.107 1.00 35.85

ATOM 2186 CA SER B 338 -11.198 -20.981 23.836 1.00 34.76

ATOM 2187 CB SER B 338 -12.713 -20.948 24.035 1.00 34.85

ATOM 2188 OG SER B 338 -13.164 -19.621 24.235 1.00 33.53

ATOM 2189 C SER B 338 -10.761 -19.761 23.037 1.00 34.99

ATOM 2190 O SER B 338 -10.143 -18.855 23.591 1.00 34.32

ATOM 2191 N GLU B 339 -11.075 -19.722 21.750 1.00 33.01

ATOM 2192 CA GLU B 339 -10.682 -18.579 20.950 1.00 33.94

ATOM 2193 CB GLU B 339 -11.146 -18.737 19.501 1.00 33.79

ATOM 2194 CG GLU B 339 -10.758 -17.553 18.623 1.00 39.11

ATOM 2195 CD GLU B 339 -10.865 -17.852 17.137 1.00 43.17

ATOM 2196 OE1 GLU B 339 -11.990 -17.785 16.600 1.00 45.28

ATOM 2197 OE2 GLU B 339 -9.824 -18.152 16.510 1.00 39.19

ATOM 2198 C GLU B 339 -11.265 -17.295 21.531 1.00 34.28

ATOM 2199 O GLU B 339 -10.575 -16.283 21.631 1.00 33.65

ATOM 2200 N ALA B 340 -12.535 -17.339 21.920 1.00 31.12

ATOM 2201 CA ALA B 340 -13.194 -16.164 22.469 1.00 29.10

ATOM 2202 CB ALA B 340 -14.696 -16.412 22.573 1.00 33.84

ATOM 2203 C ALA B 340 -12.639 -15.731 23.826 1.00 28.98

ATOM 2204 O ALA B ^' 340 -12.431 -14.541 24.060 1.00 30.48

ATOM 2205 N SER B 341 -12.407 -16.691 24.719 1.00 26.66

ATOM 2206 CA SER B 341 -11.882 -16.386 26.044 1.00 24.26

ATOM 2207 CB SER B 341 -11.867 -17.643 26.923 1.00 27.04

ATOM 2208 OG SER B 341 -10.851 -18.541 26.515 1.00 33.84

ATOM 2209 C SER B 341 -10.479 -15.793 25.960 1.00 23.97

ATOM 2210 O SER B 341 -10.171 -14.824 26.651 1.00 21.56

ATOM 2211 N MET B 342 -9.631 -16.368 25.114 1.00 26.83

ATOM 2212 CA MET B 342 -8.271 -15.865 24.954 1.00 27.24

ATOM 2213 CB MET B 342 -7.477 -16.758 24.001 1.00 30.45

ATOM 2214 CG MET B 342 -6.038 -16.300 23.802 1.00 35.35

ATOM 2215 SD MET B 342 -4.866 -17.667 23.777 1.00 44.57

ATOM 2216 CE MET B 342 -4..034 -17.341 22.244 1.00 41.37

ATOM 2217 C MET B 342 -8.322 -14.448 24.385 1.00 25.31

ATOM 2218 O MET B 342 -7.653 -13.541 24.874 1.00 26.67

ATOM 2219 N MET B 343 -9.114 -14.278 23.345 1.00 25.75

ATOM 2220 CA MET B 343 -9.262 -12.979 22.712 1.00 25.47

ATOM 2221 CB MET B 343 -10.210 -13.088 21.528 1.00 23.51

ATOM 2222 CG MET B 343 -9.540 -13.618 20.273 1.00 28.86

ATOM 2223 SD MET B 343 -8.325 -12.456 19.609 1.00 29.25

ATOM 2224 CE MET B 343 -9.344 -11.015 19.371 1.00 28.74

ATOM 2225 C MET B 343 -9.798 -11.966 23.712 1.00 25.37

ATOM 2226 O MET B 343 -9.360 -10.810 23.728 1.00 24.98

ATOM 2227 N GLY B 344 -10.739 -12.403 24.536 1.00 23.91 s _to to to to to to to to to to to to to to to to to to to > to to H Hi H HI H H H H H - t- H H Hi Hi Hi Hⁱ H H t.-3j . .j H.j H.j o SS O O O O O O O O O O O O O O O O O O O O O O O O

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ATOM 3740 O ASP B 538 -12.120 2.626 22.147 1.00 26.41

ATOM 3741 N LEU B 539 -11.637 2.309 24.313 1.00 20.76

ATOM 3742 CA LEU B 539 -10.312 2.911 24.150 1.00 19.65

ATOM .3743 CB LEU B 539 -9.567 2.991 25.496 1.00 17.48

ATOM 3744 CG LEU B 539 -8.116 3.511 25.469 1.00 16.46

ATOM 3745 CDl LEU B 539 -8.051 4.892 24.838 1.00 16.43

ATOM 3746 CD2 LEU B 539 -7.564 3.569 26.895 1.00 15.57

ATOM 3747 C LEU B 539 -9.484 2.127 23.127 1.00 16.75

ATOM 3748 O LEU B 539 -8.862 2.716 22.249 1.00 20.36

ATOM 3749 N LEU B 540 -9.487 0.803 23.239 1.00 18.23

ATOM 3750 CA LEU B 540 -8.743 -0.048 22.319 1.00 18.05

ATOM 3751 CB LEU B 540 -8.909 -1.528 22.701 1.00 16.38

ATOM 3752 CG LEU B 540 -8.188 -2.554 21.821 1.00 19.81

ATOM 3753 CDl LEU B 540 -6.679 -2.303 21.828 1.00 19.27

ATOM 3754 CD2 LEU B 540 -8.473 -3.952 22.327 1.00 18.00

ATOM 3755 C LEU B 540 -9.241 0.169 20.891 1.00 21.50

ATOM 3756 O LEU B 540 -8.449 0.293 19.964 1.00 20.41

ATOM 3757 N LEU B 541 -10.559 0.206 20.726 1.00 ^'22.40

ATOM 3758 CA LEU B 541 -11.164 0.419 19.413 1.00 23.27

ATOM 3759 CB LEU B 541 -12.686 0.429 19.527 1.00 25.12

ATOM 3760 CG LEU B 541 -13.410 -0.808 18.999 1.00 36.53

ATOM 3761 CDl LEU B 541 -14.910 -0.671 19.273 1.00 30.98

ATOM 3762 CD2 LEU B 541 -13.136 -0.971 17.508 1.00 31.93

ATOM 3763 C LEU B 541 -10.697 1.751 18.842 1.00 22.46

ATOM 3764 O LEU B 541 -10.359 1.845 17.666 1.00 26.29

ATOM 3765 N GLU B 542 -10.694 2.781 19.680 1.00 23.96

ATOM 3766 CA GLU B 542 -10.248 4.106 19.270 1.00 26.91

ATOM 3767 CB GLU B 54^ -10.250 5.050 20.468 1.00 30.84

ATOM 3768 CG GLU B 542 -11.166 6.245 20.347 1.00 37.20

ATOM 3769 CD GLU B 542 -11.138 7.105 21.597 1.00 39.98

ATOM 3770 OE1 GLU B 542 -12.223 7.385 22.144 1.00 39.92

ATOM 3771 OE2 GLU B 542 -10.028 7.494 22.034 1.00 38.96

ATOM 3772 C GLU B 542 -8.826 4.010 18.724 1.00 27.90

ATOM 3773 O GLU B 542 -8.530 4.492 17.634 1.00 29.32

ATOM 3774 N MET B 543 -7.945 3.388 19.499 1.00 26.41

ATOM 3775 CA MET B 543 -6.552 3.237 19.107 1.00 23.53

ATOM 3776 CB MET B 543 -5.749 2.591 20.247 1.00 24.60

ATOM 3777 CG MET B 543 -5.812 3.338 21.579 1.00 26.46

ATOM 3778 SD ' MET B 543 -5.373 5.084 21.467 1.00 29.45

ATOM 3779 CE MET B 543 -3.585 4.971 21.349 1.00 25.43

ATOM 3780 C MET B 543 -6.403 2.407 17.832 1.00 25.80

ATOM 3781 O MET B 543 -5.535 2.686 17.004 1.00 23.59

ATOM 3782 N LEU B 544 -7.254 1.394 17.673 1.00 27.74

ATOM 3783 CA LEU B 544 -7.202 0.522 16.499 1.00 26.32

ATOM 3784 CB LEU B 544 -8.069 -0.721 16.719 1.00 26.75

ATOM 3785 CG LEU B 544 -8.274 -1.632 15.502 1.00 28.12

ATOM 3786 CDl LEU B 544 -6.956 -2.294 15.136 1.00 26.36

ATOM 3787 CD2 LEU B 544 -9.330 -2.680 15.803 1.00 27.00

ATOM 3788 C LEU B 544 -7.672 1.252 15.250 1.00 26.97

ATOM 3789 O LEU B 544 -7.036 1.181 14.195 1.00 24.25

ATOM 3790 N ASP B 545 -8.787 1.961 15.372 1.00 30.37

ATOM 3791 CA ASP B 545 -9.338 2.702 14.244 1.00 32.34

ATOM 3792 CB ASP B 545 -10.668 3.346 14.637 1.00 36.61

ATOM 3793 CG ASP B 545 -11.818 2.370 14.565 1.00 42.73

ATOM 3794 OD1 ASP B 545 -12.858 2.624 15.211 1.00 47.39

ATOM 3795 OD2 ASP B 545 -11.676 1.342 13.863 1.00 46.96

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ATOM 1220 CA THR 460 32.018 14.474 9.366 1.00 62.25

ATOM 1221 CB THR 460 32.502 13.531 10.499 1.00 63.07

ATOM 1222 OG1 THR 460 33.474 12.613 9.983 1.00 67.80

ATOM 1223 CG2 THR 460 31.344 12.759 11.084 1.00 60.23

ATOM 1224 C THR 460 31.759 13.678 8.086 l^'.OO 63.54

ATOM 1225 O THR 460 32.457 12.708 7.782 1.00 63.91

ATOM 1226 N PHE 461 30.758 14.113 7.326 1.00 65.06

ATOM 1227 CA PHE 461 30.395 13.446 6.080 1.00 67.00

ATOM 1228 CB PHE 461 29.052 13.975 5.563 1.00 66.48

ATOM 1229 CG PHE 461 27.867 13.147 5.991 1.00 66.30

ATOM 1230 CDl PHE 461 26.657 13.754 6.312 1.00 65.58

ATOM 1231 CD2 PHE 461 27.963 11.760 6.085 1.00 '66.41

ATOM 1232 CE1 PHE 461 25.562 12.996 6.723 1.00 65.45

ATOM 1233 CE2 PHE 461 26.872 10.994 6.494 1.00 66.83

ATOM 1234 CZ PHE 461 25.670 11.616 6.814 1.00 65.12

ATOM 1235 C PHE 461 31.463 13.604 5.004 1.00 68.38

ATOM 1236 O PHE 461 32.181 14.606 4.962 1.00 68.98

ATOM 1237 N LEU 462 31.542 12.601 4.132 1.00 69.57

ATOM 1238 CA LEU 462 32.511 12.545 3.039 1.00 71.68

ATOM 1239 CB LEU 462 32.080 11.475 2.030 1.00 71.00

ATOM 1240 C LEU 462 32.810 13.856 2.304 1.00 72.40

ATOM 1241 O LEU 462 33.725 14.590 2.680 1.00 73.45

ATOM 1242 N SER 463 32.043 14.141 1.253 1.00 73.22

ATOM 1243 CA SER 463 32.262 15.343 0.449 1.00 72.61

ATOM 1244 CB SER 463 32.544 14.942 -1.005 1.00 73.38

ATOM 1245 C SER 463 31.126 16.362 0.491 1.00 71.17

ATOM 1246 O SER 463 30.455 16.528 1.511 1.00 72.05

ATOM 1247 N SER 464 30.932 17.049 -0.633 1.00 68.86

ATOM 1248 CA SER 464 29.892 18.063 -0.759 1.00 66.06

ATOM 1249 CB SER 464 30.514 19.457 -0.704 1.00 66.26

ATOM 1250 C SER 464 29.108 17.887 -2.060 1.00 63.72

ATOM 1251 O SER 464 28.657 18.862 -2.662 1.00 62.88

ATOM 1252 N THR 465 28.954 16.638 -2.493 1.00 60.93

ATOM 1253 CA THR 465 28.205 16.343 -3.709 1.00 57.47

ATOM 1254 CB THR 465 28.185 14.824 -4.004 1.00 57.80

ATOM 1255 OG1 THR 465 27.525 14.135 -2.934 1.00 54.75

ATOM 1256 CG2 THR 465 29.606 14.287 -4.149 1.00 57.49

ATOM 1257 C THR 465 26.767 16.824 -3.523 1.00 54.93

ATOM 1258 O THR 465 26.349 17.129 -2.407 1.00 54.26

ATOM 1259 N LEU 466 26.013 16.892 -4.614 1.00 51.85

ATOM 1260 CA LEU 466 24.625 17.330 -4.550 1.00 49.25

ATOM 1261 CB LEU 466 24.013 17.349 -5.956 1.00 48.74

ATOM 1262 CG LEU 466 22.953 18.415 -6.253 1.00 48.72

ATOM 1263 CDl LEU 466 22.156 18.002 -7.482 1.00 48.32

ATOM 1264 CD2 LEU 466 22.033 18.594 -5.057 1.00 48.14

ATOM 1265 C LEU 466 23.817 16.397 -3.650 1.00 ^' 48.16

ATOM 1266 O LEU 466 22.961 16.845 -2.883 1.00 45.90

ATOM 1267 N LYS 467 24.093 15.099 -3.750 1.00 46.47

ATOM 1268 CA LYS 467 23.399 14.100 -2.947 1.00 47.45

ATOM 1269 CB LYS 467 23.802 12.693 -3.395 1.00 49.38

ATOM 1270 CG LYS 467 22.829 11.602 -2.974 1.00 52.70

ATOM 1271 CD LYS 467 23.561 10.301 -2.682 1.00 56.48

ATOM 1272 CE LYS 467 23.105 9.180 -3.604 1.00 59.54

ATOM 1273 NZ LYS 467 24.150 8.117 -3.732 1.00 61.22

ATOM 1274 C LYS 467 23.738 14.284 -1.472 1.00 46.89

ATOM 1275 O LYS 467 22.884 14.108 -0.604 1.00 46.06 _μ_g t

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NJ M J M tO M M CO NJ M O α Ω

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I I I I M M M M

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^ v _ _ _ _ _ X X X X X X X X X K X X X X X X X K X K tύ K X X X X X X X X to to to g 3 g

H ^μ3 μ3 H ^μ3 ^μg 3 ^ μ3 _l_3 μ μ3 μ μ H μ t3 h. ^ H g ^μg g ^μg ^μg ^μg ^μ3 ^μg ^μl ^μ3 ^μ3 ^μ3 ^μ3 H g ^μa o o o o so o o O s O to to to ^ I.³ 3333333

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3 33 S 3S 3 3S 3 3S 3 3 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

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CO ln M CO -J LO CD M M M ln vl OO lπ rfs L^O M NJ o NJ cn M in ^J C^J U^j o rfs NJ cn NJ cn cn o rfs NJ vi iO vi cn cn cn uj uj M Uj in cn oo vi in u vi

UJ UJ _vi o uj σ M M ln oo cn M Uj rfs UJ vi rfs co o o ^vi e o ^vi cn cD vⁱ -^J i rfs O^J c o rfs in M c c oo Ln oo iπ o M ^ rfs in vi o uj ijJ vi iπ oo M vi m u Nj NJ cn ω io io rfs NJ o Lπ iπ M cn u on on o^. c» o co o co cD rfs rfs M N^j cn rfs io M 0³ M on Lo M M rf^ ctJ rfs uj Lo o cn rfs in io uj v] CJ

M tO tO tO NJ tO M H LO NJ NJ NJ tO I NJ M NJ NJ tO NJ NJ IO M NJ t CO CO tO CO NJ CO NJ NJ NJ tO CO NJ NJ NJ NJ NJ ι o iD ω o o vo D3 vi υ^j υ^j rf w o co o o to ω ι cn ι ^{v v} n σ. cn c ^v ι cD σ ^vi n c v3 oo vo cD W _j Lπ o _vO W c uj w H oo o c Ln o u co Lπ rf v vj O M UJ NJ M vj oo m J c oo _vi Ln Uj rfs M Lπ rfs iπ o io o -vi rf io oo v Ln rfs io cJ M M Oo ^vJ O O UJ OO vl vl vl UJ O U rfs oO Cn tO NJ CJ NJ CO NJ OO M rfs CO LO NJ o Lπ ^vi ιπ ιo u^j rf-. 3 io Lπ i ιπ σι J io ιπ rfs vj vj t rfs θ LD co oo cn rfs _vi σ^ co rfi O co ixi vi iπ cD rfs tO Lo in cD W cn co M NJ M O cn io o cn N^j vj cπ ^" o"^"■ NJ ^* v ^*i v ^"i o. ^•^ oo M tO M on M oo αj o in cn σi M H cn oo

M H H I-' H --' .^J .-¹ I-' H I-' M H H H H H I-' I-' H M H H M M H H M M M M M M H M M M M M H M M M μ-' I-' o o o oo o o o o oo o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o ooooooooo o o o

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O -> l-¹ * M M H M H M H M H l-' M H H H M H M M M M M μ-' M M M M M M M M H M M M M M M M H M M H M M M H H M M

K K K K K K W W W W W W W W K K K K K K K W W W W W W K K W W K ffi W W W K W W W K ffi W K W W W W W W W W K K K W Ω O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O w w w § w w κ w κ w κ w κ κ κ κ ffi κ m κ w w w w m w w κ κ w κ κ κ κ w κ κ m κ w w w κ w m κ w w κ m m w κ w w w cn σι cn cn cn cn on on cn Lπ ιn in ιn ιπ Lπ ιn ιπ ιn rfs rfs rf^s rf_ rfs rfs rfs rfs rf^s rfs cJ co co ιo c^j ιo CJ io Lo ω

00 vi cn iπ rfs co NJ M O u co -vi on cπ rfs ω NJ M O U^j ∞ ^vi cn in rfs co co M o u^J oo ^vi on in rfs L^O NJ M o u^j CD vi cn in rfs L M M O u rø

rfs NJ NJ NJ NJ M M LO NJ lO CJ lO LO CO M 1 M CJ LO M M NJ LO NJ NJ NJ LO NJ M CJ M M M M CJ NJ CJ NJ CJ O NJ CJ M

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NJ i I

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M rf-. ∞ cn to co uj ιn M Uj ω ui ιπ oo rfs Lπ NJ θ ω ∞ u cn cn o NJ M rfs vi cn M UJ iJ rfs M -θ NJ co ∞

CJ CJ rfs rfs CJ lO LO M M LO LO LO NJ M H lo NJ NJ tO tO M M M M I C tO NJ NJ CJ M CO CO CJ M CJ M M CJ NJ lo cD NJ on cD iπ Lo o o vi rfs oo oo in rfs in o oo cD CD Lπ v vi NJ o CO CO NJ CO M CO NJ

UJ U3 O3 Cn rfs U3 M vl M 00 CD CO CO vl M NJ UJ CJ NJ vl CI, M rf M UJ o on oo M rfs

M O M UJ vi uj uj rfs rfs o u σ^ o uJ iπ rfs M Co cn NJ NJ M c M io io co o -vi L^O Lπ M NJ C^J N cπ M

M io ^ UJ UJ iπ ιθ _u. M θ oo o on co M iπ cn oo o Lθ vi cn o on rfs in oo co cn Co cn Lπ io Lπ M cn oo NJ rfs rfs w co M Lo o vi c.o _{W W} o oι _W μ _M o ^„ μ . ω αi ^ ^ S S ^ ^ ^ S Ϊ K μ S ^ -^j io io u^j σⁱ u^j iD Co cπ NJ c co v. io υJ J . D S ^ ^ M ^ ^ ^ ^ ^ ^ ^ g S ^

H M M H M M H M M M M M M M M M M M H M M M M M M M M M M M M M M M M r- ⁱ l-ⁱ t-ⁱ M M M H

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O ooooooooooooo O O O O O O O O O O O O O O O ooooooooo ooooooooo o o o o o o o o O O O o o o o o o o o O O O

Lπ Lθ rfs cj. rfs rfs rfs rfs rfs rfs rfs in ιn ιπ ιn ιn ιn rfs w rfs C^j Lo ιo rf rfs ιo rfs cn uι _s co c^j rfs o ιo co in ιπ ιn rfs rfs j rfs w in in j t W ^v c rf^{i v}i J O H cn cn ω iπ ^vi u^j in ^vj ∞ ui o J J Oo rfs rfs ^ L iπ ∞ M M v^

Lπ o u_j io io M in uj io o oo M CJ CO NJ LO M vi u oo Nj rfs cn o -^v m M NJ -^vl -o m UJ O M O CO NJ vJ M CO OO O O rfs uj CO rf- O _vl OO OO v₎

0 - rf- U3 Cn LO UJ UJ NJ ln O vl UJ NJ C0 03 vl CJ M LO v] rf- vl vl CO J vl

M o in o co N rf vi cD j -vi ^j o o o c c io rfi rfs c vi cJ NJ to o cD o in to o

HETATM 2060 01 HOH 69 36.519 8.863 38.836 1.00 41.56

HETATM 2061 01 HOH 70 30 .111 14 .823 12 .793 1.00 44.58

HETATM 2062 01 HOH 71 26 .850 -6 .092 1 .594 1.00 40.15

HETATM 2063 01 HOH 72 20 .448 -3 .169 1 .055 1.00 42.50

HETATM- 2064 01 HOH 73 33 .896 3 .047 16 .172 1.00 46.39

HETATM 2065 Ol HOH 74 16, .884 0 .446 26 .043 1.00 61.50

HETATM 2066 01 HOH 75 18. .595 0. .296 27. .866 1.00 47.33

HETATM 2067 01 HOH 76 6. .166 21. .439 19. .124 1.00 47.94

HETATM 2068 01 HOH 77 18. .484 20. .060 16. .232 1.00 35.52

HETATM 2069 01 HOH 78 1. 985 23. ,265 29. 187 1.00 46.42

HETATM 2070 01 HOH 79 12. 729 30. 461 27. 530 1.00 62.79

END

Claims

WHAT IS CLAIMED IS:

1. An assay for screening test compounds for the capability to affect the coactivator binding to a nuclear receptor, said assay comprising: adding sufficient nuclear receptor such that the ratio of receptor concentration to dissociation constant of nuclear receptor with coactivator is about 1; adding a concentration of peptide hormone in a concentration about 100 fold greater than the hormone Kd; adding a concentration of labeled GRIPl peptide probe 100 fold lower than the nuclear receptor concentration; allowing the mixture to equilibrate; adding increasing concentrations of a test compound of interest to a concentration 100 fold lower than said receptor concentration; measuring the displacement of said probe by said test compound of interest using fluorescent anisotropy; and evaluating the strength of said test compound's ability to affect coactivator binding.

2. The assay of claim 1, wherein said probe concentration is about lOnM; said nuclear receptor concentration is about 1 muM; said peptide hormone concentration is about 10 muM; and said test compound concentration is varied from about .InM to about 50 muM.

3. The assay of claim 1, wherein the nuclear receptor is TR, the probe concentration is about 10 nM; the nuclear receptor concentration is about lmuM; and the peptide hormone concentration is about lOmuM.

4. The assay of claim 1, wherein the nuclear receptor is ER; the probe concentration is about InM; the nuclear receptor concentration is about 100 nM; and the peptide hormone concentration is about 1 muM.

5. A combinatorial library of compounds that modulate coactivator binding to a variety of nuclear receptors, said library comprising:

Compounds constructed of a common scaffold of the structure

And substituents R, Rl, R2, R3, and R4, wherein said substituents are selected from the group consisting of alkyl, aryl, and hetero substitutions.

6. A combinatorial library of compounds that modulate coactivator binding to a variety of nuclear receptors, said library comprising:

Compounds constructed of a common scaffold of the structure

And substituents R, Rl, R2, R3, and R4, wherein said substituents are selected from the group consisting of alkyl, aryl, and hetero substitutions.

7. A method of designing a test compound that modulates coactivator binding to a variety of nuclear receptors, said method comprising:

Modeling test compounds that fit spatially and electrostatically into a coactivator binding site of a nuclear receptor of interest using an atomic structural model of a nuclear receptor coactivator binding site or portion thereof; Measuring the extent of binding to each nuclear receptor;

Assigning scores to reflect the extent of conformational fit: Selecting said test compounds with the best conformational scores; Designing said test compound.

8. A method of designing a compound that binds selectively to a specific nuclear receptor, said method comprising: modeling test compounds that fit electrostatically into a coactivator binding site of a nuclear receptor of interest using an atomic structural model of a nuclear receptor coactivator binding site or portion thereof; measuring the extent of binding to each nuclear receptor; assigning scores to reflect the extent of binding; selecting a compound that exhibits preferential modeling scores to a specific receptor of interest; optimizing features that show preferential complementarity for said receptor of interest; and designing a compound that incorporates the features of the molecule showing preferential complementarity.

9. A covalently conformationally constrained peptide that modulates coactivator binding to a coactivator binding site of a nuclear receptor, said peptide comprising a peptide sequence of nine to thirteen amino acids in length.

10. The peptide of claim 9 wherein the amino acid sequence is set forth in Figure 26.

11. The peptide of claim 9 wherein the amino acid sequence is set forth in Figure 27.

12. The peptide of claim 9 wherein the amino acid sequence is set forth in

Figure 28.

13. The peptide of claim 9 wherein the amino acid sequence is set forth in Figure 29.

14. The peptide of claim 9 wherein the amino acid sequence is set forth in Figure 30.

5 15. The peptide of claim 9 wherein the amino acid sequence is set forth in

Figure 31.

16. A method of identifying a compound that modulates coactivator binding to a nuclear receptor, said method comprising: modeling test compounds that fit electrostatically into a nuclear 10 receptor coactivator binding site of interest using an atomic structural model of a nuclear receptor coactivator binding site or portion thereof, screening said test compounds in an assay characterized by binding of a test compound to a nuclear receptor coactivator binding site, and identifying a library or test compound that modulates coactivator 15 binding to said nuclear receptor.

17. A combinatorial library of compounds that modulate coactivator binding to a variety of nuclear receptors, said library comprising: A scaffold of the structure

and

Substituents, wherein the side chains of the amino acids are from those provided by natural and non-natural amino acids.

18. A combinatorial library of compounds that modulate coactivator binding to a variety of nuclear receptors, said library comprising: A scaffold of the structure

ana Substituents, wherein the side chains of the amino acids are from those provided by natural and non-natural amino acids.

19. An assay for screening test compounds that effect the binding of coactivators to nuclear receptors, said assay comprising: providing a mixture of nuclear receptor, labeled co-activator probe, ad ligand of said nuclear receptor; adding a test compound to said mixture; and measuring displacement of said probe.

20. The assay of claim 19, wherein said labeled coactivator probe is glucocorticoid receptor interacting protein (GRIPl).

22. The assay of claim 19, wherein said labeled coactivator probe is labeled with a fluorescent label.

23. The assay of claim 19, wherein said labeled coactivator probe is labeled with a radioactive label.

24. The assay of claim 19, wherein said nuclear receptor is thyroid hormone receptor, said ligand is thyroid hormone, and said co-activator probe is GRIPl.

25. The assay of claim 19, wheein said nuclear receptor is at a concentration near the K_D of said nuclear receptor and said ligand is at a concentration more than one hundred fold above the K_D of said hormone.

26. The assay of claim 24, wherein the concentration of said nuclear receptor is about 1 μM, the concentration of said ligand is about 10 μM, and the concentration of said labeled coactivator probe is about 10 nM.

27. A peptide that is an analog of GRIPl NR box, wherein said peptide has an α-helical conformation.

28. The peptide of claim 27, wherein said peptide is an inhibitor of the interaction of GRIPl and a nuclear receptor.

29. The peptide of claim 27, wherein said peptide is an inhibitor of GRIPl biding to a thyroid hormone receptor.

30. The peptide of claim 27, wherein said peptide is 9 to 13 amino acids in length.

31. The peptide of claim 27, wherein said peptide is TG-12.

32. The peptide of claim 27, wherein said peptide is TG-8.

33. The peptide of claim 27, wherein said peptide is TG-13.

34. The peptide of claim 27, wherein said peptide is TG-14.

. 35. The peptide of claim 27, wherein said peptide is TG-15.

36.. The peptide of claim 27, wherein said peptide is TG-16.

37. The peptide of claim 27, wherein said peptide is TG-17.

38. A combinatorial library, wherein said combinatorial library comprises a plurality of members said members being compounds constructed of a common scaffold that fits the coactivator binding pocket of a nuclear receptor.

39. The combinatorial library of claim 38, wherein said nuclear receptor is a thyroid hormone receptor.

40. A combinatorial library, wherein said combinatorial library comprises a plurality of members said members being compounds constructed of a common scaffold of the structure of a GRIPl α-helix.

41. The combinatorial library of claim 40, wherein said compounds modulate interaction of GRIPl and a nuclear receptor.

42. The combinatorial library of claim 40, wherein said compounds modulate interaction of GRIPl and a thyroid hormone receptor.

43. A combinatorial library wherein said combinatorial library comprises a plurality of compounds constructed of a common scaffold of the following structure:

where R_l5 R₂, and R₃ are independently selected from the group consisting of alkyl, aryl, and hetero substitutions.

44. The combinatorial library of claim 43, wherein Ri comprises an alkyl chain or a cabamate.

45. The combinatorial library of claim 44, wherein R_! comprises a methyl group.

46. The combinatorial library of claim 45, wherein R₂ comprises an amide group.

47. The combinatorial library of claim 43, wherein R₃ comprises an ether linkage linked to aromatic rings.

^8. A combinatorial library, wherein said combinatorial library comprises of compounds constructed of a common scaffold of the following structure:

where R_l5 R₂, and R₃ are selected from the group consisting of alkyl, aryl, and hetero substitutions. 9. The combinatorial library of claim fθ, wherein comprises an aromatic rings.

SO. The combinatorial library of claim ^ wherein R₃ comprises an aromatic rings.

5^"1. The combinatorial library of claim *{$, wherein R₂ comprises an ethyl group.

A compound that binds to the NR box binding site of a nuclear receptor, wherein said compound has the following structure:

5 3. A compound that binds to a nuclear receptor, wherein said compound has the following structure:

vT4. A compound that binds to the NR box binding site of a nuclear receptor, wherein said compound has the following structure:

_T5. A compound that binds to a nuclear receptor, wherein said compound has the following structure:

ζ 6. A compound that binds to the NR box binding site of a nuclear receptor, wherein said compound has the following structure:

. A compound that binds to a nuclear receptor, wherein said compound has the following structure:

r#. A compound that binds to the NR box binding site of a nuclear receptor, wherein said compound has the following structure:

" <f A compound that binds to a nuclear receptor, wherein said compound has the following structure: