CA2229426A1 - Crystalline frap complex - Google Patents

Abstract

The invention relates to the human protein FRAP, and in particular to the FKBP12-rapamycin binding domain thereof and to the ternary complex formed by the FRB domain, rapamycin and FKBP12. A new crystalline composition comprising the ternary complex, coordinates defining its three dimensional structure in atomic detail, and uses thereof are disclosed.

Description

W O 97/15659 PCTAUS96~16953 Crystalline FRAP Complex Copyright Notice A portion of the disdosure of this patent document contAin~ mAt~riAl whidh is subject to copyright ~roL~.Iion. The copyright owner has no objection to the f~rcimile reproduction by anyone of the patent document or patent disdosure, as it appears in the Patent and TrAr7.~m,7rk Of fice patent file or records, but otherwise reserves all copyright rights whatsoever.

Field of the Invention The invention relates to a complex, in crystalline form, of two proteins, FKBP12 and the FRB domain of FRAP, in association with rapamycin, a small organic molecule to whidl the proteins bind. The crystalline form of this ternary complex is particularly useful for the ~7.~ ....;..ation of the three-dimensional structure of the complex at the atomic level. The three dimensional structure provides infnrmArinn useful for the design of pharmaceutical compositions which inhibit the biological function of proteins sudh as FRAP whidh contain an FRB domain, particularly those biological functions mediated by molecular interactions involving rapamycin or other compounds capable of binding to an FRB domain.

Background Rapamycin (som~times called sirolimus) was first described in 1975 as an antifungal agent isolated from Slr~L>loll-yces hygroscopicus (Vezina, 1975; Sehgal, 1975). In 1987, the structurally related compound FK506 (sometimes called tacrolimus) was characterized as a potent immunosu~res~iv~ agent (Tanaka, 1987), and shortly thereafter, rapamycin was also shown to have potent imm7mo~uppressive activity. In spite of la~allLy~ 's immunosut,~les~ive activity and structural fiimil~rity to FK506, the two compounds suppress the imml~n~ response in completely different ways (Schreiber, 1992). FK506 inhibits the T cell receptor (TCR) signal and ~1~V~ activation of a resting helper T cell. Rapamycin inhibits the autocrine signaling pathway involving interleukin-2 (IL-2) and the IL-2 receptor (IL-2R). These latter signals c(,m~l~il the cell to a program of cell division by ~:oll.~ .icating with the components of the cell cycle m~hin~ry n.oc~ ry for DNA replication.
Both FK506 and rapamycin are potentially useful in the treatment of human disease.
FK506 has been ~ v~d by the FDA for use in treating the rejection of transplanted organs. A
similar use has been envisioned for rapamycin, and its ~7.~m-1n~trated activity in organ transpl,7nt~ti~ n and auloill-ll-ul-e animal models indicate a high clinical potential. Rapamycin has been shown to have anLilull-or activity against B16 melanocarcinoma, colon 26 tumor, EM
ependymoblastoma, CD8F1 mAmm~ry and colon 38 murine tumors (Sehgal, 1993). Rapamycin has also shown imm71nosuppressive activity in assays to measure ~l~v~l-Lion of development of e adjuvant arthritis, experimental allergic encephalomyelitis and al l ~ 7n~
uveolt:LilLiLis in the rat (Sehgal, 1993).

_ W O 97/15659 PCT~US96/16953The biological activity and structural novelty of both rapamycin and FK506 led to a search for their cellular target(s), and the target of both compounds was identified as the plentiful cytoplasmic protein FKBP12 (for E1~506 kinding ~rotein) of 12 kDa molecular mass.
Since FK506 and rapamycin bound to the same target (Kd of 0.4 and 0.2 nM, respectively) and 5 affected different pathways, a new function was attributed to the FKBP12-ligand complex.
This new function arises from the ability of FKBP12-FK506 and FKBP12-rapamycin complexes, but not the individual components, to bind to and inhibit still other protein targets. The FKBP12-FK506 complex inhibits the phosphatase activity of calcineurin, a crucial component of the TCR pathway. Calcineurin is a serine/threonine phosphatase also called PP2B. The FKBP12-rapamycin complex inhibits the IL-2R signal by binding to a large (289kDa) protein named FRAP in humans (Brown et al, 1994) or RAFT in rats (Sabatini et al, 1994; Chiu et al, 1994).
The structural basis for the tight binding of FK506 and rapamycin by FKBP12 has been investigated by both X-ray diffraction and NMR techniques (Clardy, 1995). In particular, high resolution X-ray structures are available for FKBP12-FK506 (1.4 A resolution) and FKBP12-rapamycin (1.7 A resolution) (Van Duyne et al, 1991; Van Duyne et al, 1991a; Van Duyne et al, 1993). These structures reveal, among other things, the fold of FKBP12, the atomic details of the hydrophobic binding pocket, and the details of how F~C506 and rapamycin interact with the binding pocket. A structural analysis of the complex formed between FKBP12-FK506-20 calcineurin is also available (Griffith et al, 1995). That structure reveals how the portion of FK506 not involved in binding FKBP12 interacts with calcineurin and inhibits its phosphatase activity.
The biochemical charAct~ri~Ation of FRAP, the target of the FKBP12-rapamycin complex, remains incomplete. The C-terminal domain resembles a phosphatidylinositol tPI) kinase, but to 25 date no PI or protein kinase activity has been convincingly demonstrated. FRAP (RAFT, TOR) are members of a rapidly growing and important family of proteins that have been identified only recently (Zakian, 1995). ATM, TEL1, DNA-PK and MEC~ are some of the recently characterized members of this family of PIK-related kinases. (See e.g., Keith, 1995). ATM (for ataxia ~lngiectA~iA mutant) is responsible for a human autosomal hereditary disease 30 characterized by cerebellar degeneration, progressive mental retardation, uneven gait, dilation of blood vessels, immune defici~nei~s, premature aging and a hundredfold increase in cancer susceptibility (Zakian, 1995). Persons who are heterozygous in ATM are believed to be at elevated risk for cancer. Mutations to TEL1 lead to abnormally short telomeres, and in conjunction with other mutations can lead to sensitivity to X-rays, W radiation and 35 hydroxyurea. DNA-PK is, as the name suggests, a DNA-dependent protein kinase that recognizes damaged DNA, and hurnan cells without DNA-PK activity are radiation sensitive and repair deficient. MEC1 is required for both S-M and G2-M checkpoint progression as well as for meiotic recombination in yeast. Thus MEC1 is arguably the master checkpoint gene in yeast.

FRAP is a large protein (2549 amino acid residues), and only a small fraction can be involved in recognizing the FKBP12-rapamycin complex. Fortunately all of these residues are in one ~lr~m~in, and this domain, which is called the FKBP12-rapamycin binding (FRB) domain, is the protein used in this invention. It was i~t-n*fie~l through tryptic digests of FRAP and independently produced as an 11 kDa soluble protein (Chen et al, 1995) Unfortunately, until now, three-~imlon~ion~l structural details of the association of FKBP12-rapamycin with the FRB f7omAin of FRAP have remained completely unknown. In the absence of such three-~lim~n~i-)nal structural details, it has been impossible to design compounds based on that structure which would be capable of mimi~kin~ rapamycin's binding 10 to the FRB domain. We have now obtained crystals of that ternary complex and have determined its three dimensional structure. With this information, it is now possible for the first time to rationally design compounds capable of binding to an FRB domain and mimil king the pharmacological activity of ld~amycin. Such mimics may be used in place of rapamycin as immlmt)s~ essive agents or in other ph~rm~cological applications.
Summary of the Invention This invention centers on the FRB domain of human FRAP and begins with obtainingcrystals of human FKBP12-rd~alllycin-FRB of sllffi~ nt quality to ~letermine the three rlim~n~ional (tertiary) structure of the complex by X-ray diffraction methods.
In considering our work, it should be appreciated that obtaining protein crystals in any case is a somewhat unpredictable art, especially in cases in which the practitioner lacks the guidance of prior sllcc~ in preparing and/or crystalizing any closely related proteins.
Obtaining our first crystals of the ternary complex was therefore itself an unexpected result. In 1ition, our data represents the first detailed information available on the three ~lim~n~iona 25 structure of FRAP or of any of the PIK-related kinases and revealed an unpredicted array of surface features.
Our results are useful in a number of applications. As previously mentioned, the atomic details of how the FKBP12-rapamycin complex interacts with the FRB domain is essential for the structure-based design of ld~dllly~ill analogs. As noted above, rapamycin has several 30 promising dinical in~ Ation~, and improved ld~ yei~- analogs would be useful therapeutic agents. This structure can be used as an essential starting point in prerlit ting, via homology modeling, the structures of related proteins which contain homologous FRB domains, including other members of the PIK-related kinase family.
Furthermore, the structure shows in atomic detail--how a small organic m~l~c~
35 rapamycin, can be used to hold two proteins, FKBP12 and FRB, in close proximity. As such, this structure contains important lessons for the design of hetero~im~ri7ing agents.
Thus, the knowledge obtained co~c.orning the FRB of FRAP can be used to model the tertiary structure of related proteins. By way of example, the structure of renin has been modeled using the tertiary structure of endothiapepsin as a starting point for the derivation.

CA 02229426 1998-03-ll W O 97/15659 PCT~US96/16953 Model building of cercarial elastase and tophozoite cysteine protease were each built from known serine and cysteine proteases that have less than 35% sequence identity. The result,~nt models were used to design inhibitors in the low micromolar range. (Proc. Natl. Acad. Sci. 1993, 90, 3583). Furthermore, alternative methods of tertiary structure determination that do not rely 5 on X-ray diffraction techniques and thus do not require crystallization of the protein, such as NMR techniques, are simplified if a model of the structure is available for refinement using the additional data gathered by the alternative technique. Thus, knowledge of the tertiary structure of the FRB region of FRAP provides a significant window to the structure of other proteins containing a homologous FRB domain, including the other PIK-related kinases.
Accordingly, one object of this invention is to provide a composition, in crystalline form, comprising a protein containing an FRB domain. The protein may have a bound ligand or may be part of a complex with a second protein molecule and a shared ligand. For instance, the crystalline composition may contain a complex containing a first protein having a peptide sequence derived or selected from that of an FKBP12 protein, e.g., human FKBP12; a second protein having a peptide sequence derived or selected from that of an FRB ~1omAin of a PIK-related kinase family member, e.g. the FRB domain of human FRAP; and a ligand such as rapamycin which is capable of binding to both proteins to form a ternary complex. Such a crystalline composition may contain one or more heavy atoms, e.g., one or more lead, mercury, gold and/or selenium atoms. Such a heavy atom d~livaliv~ may be obtained, for example, by expressing a gene encoding the protein of interest under con.1i*ons p~ UUil~g the incorporation of one or more heavy atom labels (e.g. as in the incorporation of selenomethionine), reacting the protein with a reagent capable of linking a heavy atom to the protein (e.g. trimethyl lead acetate) or soaking a substance containing a heavy atom into the crystals.
Pl~ d crystalline compositions of this invention are capable of diffracting x-rays to a resolution of better than about 3.5 A, and more preferably to a resolution of 2.7 A or better, and are useful for r~ l;lL~llg the three-tlimen~ional structure of the mAl~riAl (The smaller the number of angstroms, the better the resolution.) Crystalline compositions of this invention specifically include those in which the crystals are charat t~ori7erl by the structural coordinates of the FRB protein set forth in the accompan,ving Appendix I or charact~ri7eri by coordinates having a root mean square deviation th~l~Lolll, with respect to backbone atoms of amino acids listed in Appendix I, of 1.5 A or less.
Furthermore, our crystalline compositions include cr,vstals characteri_ed by the structural coordinates of both the FRB and FKBP12 proteins set forth in Appendix I, optionally including a molecule of ra~a, . Ly~ll as defined structurally by the accompanying coordinates therefor.
Structural coordinates of a crystalline composition of this invention may be stored in a machine-readable form on a machine-readable storage m~ lm, e.g. a computer hard drive, diskette, DAT tape, etc., for display as a three-dimensional shape or for other uses involving computer-assisted manipulation of, or co~ u~alion based on, the structural coordinates or the three-dimensional structures they define. For example, data defining the three dimensional structure of a composition of this invention or a portion thereof co~L,.il.illg an FRB domain-C(Jll~dillillg protein of the PIK-related kinase family, or portions or structurally similar homologues of such proteins, may be stored in a machine-readable storage medium, and may be displayed as a graphical three-~imPn~ nal representation of the protein structure, typically using a cum~ult:l capable of reading the data from said storage me~ m and programmed with instructions for creating the representation from such data. This invention thus Pn~ omrasses a machine, such as a computer, having a memory which contains data ~ the structural coordinates of a crystalline composition of this invention, e.g. the coordinates set forth in Appendix I, together with additional optional data and instructions for manipulating such data. Such data may be used for a variety of purposes, such as the ~ irlAtion of other related structures and drug discovery.
A first set of such machine readable data may be combined with a second set of machine-readable data using a machine progr~mmPrl with instructions for using the first data set and the second data set to detPrmine at least a portion of the coordinates corresponding to the second set of machine-readable data. For instance, the first set of data may comprise a Fourier transform of at least a portion of the coordinates for the complex set forth in Appendix I, while the second data set may comprise X-ray diffraction data of a mol~ lP or m~ lP(~nlAr complex.
More specifically, one of the objects of this invention is to provide three-~lim~ncionAl structural information on the FRB domain of FRAP, of other members of the PIK-related kinase family which ~-ontAing homologous FRB domains, and of homologs or variants thereof, preferably in association with a bound ligand or bound ligand:protein complex (such as FKBP12-rapamycin). To that end, we provide for the use of the structural coordinates of a crystalline composition of this invention, or portions thereof, to solve, e.g. by molecular rep~AcPmPnt~ the three dimensional structure of a crystalline form of another such protein, protPin ligAn~l complex, or protPin ligAnd:protein complex. Doing so involves obtaining x-ray diffraction data for crystals of the protein or complex for which one wishes to determine the three dimensional structure. Then, one ~l~tPrmines the three-dimensional structure of that protein or complex by analyzing the x-ray diffraction data using molecular replAt~PmPnt techniques with reference to the previous structural coordinates. As described in US Patent No.
5,353,236, for instance, molecular replAc~m~nt uses a molecule having a known structure as a starting point to model the structure of an unknown crystalline sample. This technique is based on the principle that two molecules which have similar structures, orientations and positions in the unit cell diffract similarly. ~olPcl~lAr replA~ PmPnt involves pt~sitioning the known structure in the unit cell in the same location and orientation as the unknown structure. Once positioned, ~ 35 the atoms of the known structure in the unit cell are used to ~ Alcl~lAte the structure factors that would result from a hypothetical diffraction exp~rim~nt. This involves rotating the known structure in the six dimensions (three angular and three spatial dimensions) until alignment of the known structure with the expPrimf~ntAl data is achieved. This approximate structure can be fine-tuned to yield a more accurate and often higher resolution structure using various CA 02229426 1998-03-ll W O 97/15659 PCT~US96/16953 refinement techniques. For instance, the resultant model for the structure defined by- the expPrimPntAl data may be subjected to rigid body rP*mPmPnt in which the model is subjected t~>
limited additional rotation in the six ~lim~nsions yielding positioning shifts of under about 5%.
The refined model may then be further refined using other known rPfinPmPnt methods.
For example, one may use molecular replA(~PmPnt to exploit a set of coordinates such as set forth in Appendix I to dePrtninp the structure of a crystalline co-complex of the FRB
domain, FKBP12 and a ligand other than ld~all.ycin. Likewise one may use that same approach to determine the three dimensional structure of a complex of FKBP12, rapamycin and a protein collld~ g a modified FRAP FRB domain or an FRB domain from a homolog of FRAP.
Another object of the invention is to provide a method for rle~ g the three-dimensional structure of a protein containing an FRB domain, or a complex of the protein with a ligand therefor, using homology modeling techniques and structural coordinates for a composition of this invention. Homology modeling involves constructing a model of an unknown structure using structural coordinates of one or more related proteins, protein 15 ~lomAinS and/or subdomains. Homology modeling may be conducted by fitting common or homologous portions of the protein or peptide whose three dimensional structure is to be solved to the three ~imPnsional structure of homologous structural PlPmPntS. Homology modeling can indude rebuilding part or all of a three ~limPnsional structure with replAcPmPnt of amino acids (or other components) by those of the related structure to be solved. The structural coordinates 20 obtained for the related protein or complex may be stored, displayed, manipulated and otherwise used in like fashion as those for the ternary complex of FKBP12-rapamycin-FRB set forth in Appendix I.
Crystalline compositions of this invention thus provide a starting mAtPriAl, and their three rlimPnsional structure coordinates a point of reference, for use in solving the three-dimensional 25 structure of other proteins containing an FRB ~lomAin homologous to that of FRAP, as well as complexes co~ g such a protein. Sequence similarity may be determined using any conventional similarity matrix. (See e.g. Dayhoff,1979; Greer, 1981; and Gonnet, 1992). Proteins containing at least one FRB domain having at least 15% peptide sequence identity or similArity with respect to our FRB, as d~ led by any of the approaches described above, are30 consiLlPred FRAP homologs for the purpose of this disclosure.
By way of further example, the three dimensional structure defined by the machine readable data for the FRB domain (with or without the FKBP12 component) may be computationally evaluated for its ability to associate with various chemical entities. The term "(~hPmi~Al entity", as used herein, refers to chemical compounds, complexes of at least two 35 (~hPmi--Al compounds, and fragments of such compounds or complexes.
For instance, a first set of machine-readable data ~lPfining the 3-D structure of FRAP or a FRAP homolog, or a portion or complex thereof, is combined with a second set of machine-readable data defining the structure of a ~ hPmi~Al entity or moiety of interest using a machine progrAmmP-l with instructions for evaluating the ability of the chemical entity or moiety to WO 97/15659 PCT/IJS96/lC953 associate with the FRAP or FRAP homolog protein or portion or complex thereof and/or the location and/or orientation of such association. Such methods provide insight into the location, oriPntAhon and energetics of association of protein surfaces with such (~hPmirAl PnhhPs ~~hPmicAl entities that are capable of mimi-~king rapamycin's ability to associate with 5 FRAP or a FRAP homolog should share part or all of rapamycin's phArmACologic activities, e.g.
immllno~ r~ ive activity, but may be designed for more convenient or ecf~nomi~ Al preparation, improved phArmAcQkineti~s~ reduced side effects, etc. Such rh(~mi~Al entities therefore include potential drug c~AndidAtPs.
The three dimensional structure defined by the data may be displayed in a graphic~
10 format permiting visual inspection of the structure, as well as visual inspection of the association of the protein component(s) with rapamycin or other f~hPmicAl entities.
Alternatively, more quanliLdlive or computational methods may be used. For example, one method of this invention for evaluating the ability of a ~h~mi~Al entity to associate with any of the molecules or moleclllAr complexes set forth herein comprises the steps of: (a) employing 15 c(~ uLdtional means to perform a fitting operation between the ~ hPmicP~l entity and a binding pocket or other surface feature of the molecllle or molecular complex; and (b) analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket.
This invention further provides for the use of the structural coordinates of a crystalline 20 composition of this invention, or portions thereof, to identify reactive amino acids, such as cysteine residues, within the three-~im~nsionAl structure, preferably within or adjacent to a ligand binding site; to generate and visualize a molecular surface, such as a water-acc~s~sihle surface or a surface comprising the space-filling van der Waals surface of all atoms; to calculate and visualize the size and shape of surface features of the protein or complex, e.g., ligand 25 binding pockets; to locate potential H-bond donors and acc~L~ within the three-dimensional structure, preferably within or adjacent to a ligand binding site; to calculate regions of hydrophobicity and hydrophilicity within the three-~imf~n~ionAl structure, preferably within or adjacent to a ligand binding site; and to calculate and visualize regions on or adjacent to the protein surface of favorable interaction energies with respect to selected functional groups of 30 i . ll~ l (e.g. amino, hydroxyl, carboxyl, methylene, alkyl, alkenyl, aromatic carbon, aromatic rings, heteroaromatic rings, etc.). One mdy use the ~re~ Ig approaches for characterizing the FRB domain-containing protein and its interactions with moieties of potential ligands to design or select compounds capable of specific covalent attA(-hm~nt to reactive amino acids (e.g., cysteine) and to design or select compounds of compl~m~ntAry characteristics (e.g., size, shape, 35 charge, hydrophobicity/hydrophilicity, ability to participate in hydrogen bonding, etc.) to surface features of the protein, a set of which may be preselected. Using the structural - coordinates, one may also predict or calculate the orientation, binding constant or relative affinity of a given ligand to the protein in the complexed state, and use that information to design or select compounds of improved affinity.

W O 97115659 PCT~US96/16953 Ir~ such cases, the structural coordinates of the FRAP or FRAP homolog protein, or portion or complex thereof, are entered in machine readable form into a machine progrAmme.l with instructions for carrying out the desired operation and contAining any necess_ry A.~l~litionAl data, e.g. data defining structural and/or functional characteristics of a potential ligand or 5 moiety thereof"lefining molecular characteristics of the various amino acids, etc.
One method of this invention provides for selecting from a rlAtAhAce of ~h~mi~Alstructures a compound capable of binding to FRAP or a FRAP homolog. The method starts with structural coordinates of a crystalline composition of the invention, e.g., coordinates defining the three ~limPn~ nAl structure of FRAP or a FRAP homolog or a portion thereof or a 10 complex thereof. Points associated with that three ~lim~n~ional structure are charAcff~ri7e.1 with respect to the favorability of interactions with one or more filn~tionAl groups. A database of chemical structures is then searched for ~An~ Ate compounds ~:~,nl~ining one or more functional groups disposed for favorable interaction with the protein based on the prior chara~t~ri7.Ation. Compounds having structures which best fit the points of favorable 15 interaction with the three rlim~n~ional structure are thus identified.
It is often preferred, although not required, that such sea~ g be conducted with the aid of a computer. In that case a first set of machine-readable data rl~fining the 3D structure of a FRAP or FRAP homolog protein, or a portion or protein-ligand complex thereof, is combined with a second set of machine readable data ~l~fining one or more moieties or functional groups 20 of illLelesl, using a machine progrAmm~l with instructions for identifying ~r~r~lled locations for favorable interaction between the functional group(s) and atoms of the protein. A third set of data, i.e. data defining the location(s) of favorable interaction between protein and functional group(s) is so generated. That third set of data is then combined with a fourth set of data defining the 3D structures of one or more chemical entities using a machine progrAmm~ with 25 instructions for identifying chemical entities conld~ lg functional groups so disposed as to best fit the locations of their respective favorable interaction with the protein.
Compounds having the structures selected or ~l~si~n~ by any of the foregoing means may be tested for their ability to bind to FRAP or a FRAP homolog, inhibit the binding of Fl; AP or a FRAP homolog to a natural or non-natural ligand therefor (e.g. FKBP12-rapamycin, in the case 30 of FRAP), and/or inhibit a biological function me~iAtell by FRAP or the FRAP homolog.
This invention also permits methods for designing a compound capable of binding to a FRAP or FRAP homolog based on the three rlim~n~ional structure of bound rapamycin. One such method involves graphically displaying a three-dimensional representation based on coordinates defining the three-~lim.on~ional structure of a FRAP or FRAP homolog protein or a 35 portion thereof complexed with a ligand such as the FKBP12:rapamycin complex. Interactions between portions of ligand and protein are charA~t~ri7:~1 in order to identify candidate moieties of the ligand for replAc~m~nt. One or more portions of the ligand which interact with the protein may be replaced with substitute moieties selected from a knowledge base of one or more ~An~ Atf~ substitute moieties, and/or moieties may be added to the ligand to permit additional -WC~ 97~1~;659 PC'rJUS96J~6953 interactions with the protein. Compounds first id~nhfierl by any of the methods described herein are also Pncompassed by this invention.

Brief Description of the Drawings FIG. 1 depicts aco~ uL~ system.
FIG. 2 depicts storage media of this invention.
FIG. 3 depicts a ribbon diagram of the three dimensional structure of the FKBP12:rapamycin:FRB domain complex, as defined by the coordinates of Appendix I.

10 Detailed Description of the Invention Despite the key role played by the FKBP12:rapamycin:FRAP complex in the IL-2/IL-2R
~ign~ling pathway, and despite the growing appreciation of the biological irnportance of the PIK-related kinase family, nothing was known of the three-dimensional al. l ,i l~~ re by which the FRB domain of FRAP (or of any FRAP homolog) engages the FKBP12:rapamycin complex 15 required for its biological activity. X-ray crystallographic techniques could in principle address such issues. However, notwithstanding the key biological functions m~liAte~l by FRAP, there have been no reports disclosing that suitable crystals had been or could be obtained, let alone reports disclosing any x-ray crystallographic data or other inforrnation rc nc~ming the three-~lim~nsional structure of any FRB domain. Even in the event that crystals had been obtained, 20 then-available three-~im~nsicn~l structural data relating to the FKBP12:rapamycin complex would not have been been sllffici~nt for solving the ternary complex structure, at least in part, because the initial electron density maps wouldn't have permitted the chain of FRB to be traced.
Even if parts of the chain could have been traced, they would not have refined under least-squares minimization techniques.
Nonetheless, we have sllrc~e~ in producing FKBP12 and FRAP FRB proteins, and have obtained crystals of their ternary complex with rapamycin. We have solved the three-~lim~nsinnal structure of the crystalline complex using x-ray diffraction techniques. In view of our successes as disclosed herein, it can now be said that proteins comprising FRB domains can be produced in stable form, purified, and cryst~lli7e~, and that their three-dimensional 30 structures can be ~1etemmin~ all using mAt~riAls and methods such as disclosed herein.
As mentioned elsewhere, FRAP is one of a number of PIK-related ldnase family members that contain an FRB domain. PIK-related kinase family members share regions of homology including lipid kinase homologous regions, kinase domains and, in at least a number of cases, FRB domains. The presence and boundaries of homologous regions in a protein sequence can be ~ 35 j~1~ntifierl by using a computer alignment program that identifies amino acid sequence homology to a known sequence or domain. For example, the FRB rlomAin (amino acids 2015 - 2114) of FRAP may be used for such analysis, but FRB ~lomAin~ from other proteins such as RAPT or TOR1 or TOR2 can be used as well. The alignment method typically used by such programs is the N~P~ mAn-Wunch ~lignm~nt. See e.g., "A General Method Applicable to the Search for SimilAriti~ in the Amino Acid Sequence of Two Proteins." Nee~llmAn, S.B.; Wunch, C.D. J. Mol.
Biol. 1970, 48, 443-453.
We expressed the FRAP FRB domain as a glutathione-S-transferase (GST) fusion protein.
The cDNA encoding residues 2015 - 2114 from human FRAP (Chen et al, 1995) was cloned into a pGEX vector and expressed in E coli, the resulting fusion protein was recovered and deaved to yield the FRB protein which was then purified, all as described in detail below.
FKBP12 protein was ~imil~rly obtained using a cDNA encoding residues 1 - 107 from human FKBP12 (stAn~lA~rt et al, 1990, Nature 346: 671-674 Other proteins co~ . ~lg an FRB domain may also be used, including larger FRAP
10 fragments contAining the FRB and flanking peptide sequence, including up to the entire FRAP
protein. Additionally, FRB proteins can be prepared by analogous means contAining homologous FRB regions from other proteins, in~ ing RAPT, TOR1, TOR2 or other members of the PIK-related kinase family. It should further be appreciated that other ~ r~ion systems may be readily employed., including, e.g., mAt~riAl~ and methods for expression in E. coli using 15 T7, maltose-binding protein fusion (MBP~, with epitope tags (His6, HA, myc, Flag) included or cleaved off. Baculoviral ~x~ression may be used, e.g. using pVL1393 or derivatives, for tFRB
~lomAin, fused (or not) to epitope tag or fusion partner such as GST. Conventional materials and methods for expression in mAmmAliAn, yeast or other cells may also be used.
Rapamycin may be prepared by known methods or may be obtained from commercial 20 sources. Rapamycin analogs such as disclosed, e.g., in Luengo et al, 1995, Chemistry & Biology 2(7):471~81, may be used in place of rapamycin, in forming complexes of this invention.
Complex formation, crystallization, X ray diffraction exp.onm~nt~ and inlel~re~dtion of the diffraction data were conducted as described in detail in the Experimental Examples below.
The resulting structural coordinates for a crystalline composition comprising 25 FKBP12:rapamycin:FRB of FRAP (one molecule of complex per asymmetric unit) are set forth in Protein Database format in Appendix I. Solving the X-ray crystal structure of the ternary complex allowed us to conduct the first three dimensional characterization of an FRB:ligand complex (viewing FKBP12:rapamycin as the "ligand"). The complex, depicted in schematic form in FIG. 3, involves an elaborate array of contacts between the two protein domains and 30 their mutual small molecule ligand. This work reveals the first structural in~ights into an FRB
domain-containing protein.

Structure of the Ternary Complex The ternary complex of FKBP12-rapamycin-PRB has overall dimensions of 60 ~ x 45 A x 35 35 ~ with the rapamycin sandwiched between PKBP12 and FRB. The PKBP12 structure is basically the same as in previously reported binary structures, with a five stranded anti parallel ,~-sheet and a short oc-helix. This binary structure was originally ~l~rmined in the PKBP12-FK506 complex and later in the FKBP12-rapamycin complex (Van Duyne et al, 1993).
The four helix bundle of FRB does not wrap around the effector site of FKBP12-rapamycin; it WO 97/15659 . PCTAUS96~16953 just touches the effector (i.e., FRB-binding) intPrfflce of the binary complex with few protein-protein interactions. All of the interactions between ld~amycin and FRB are hydrophobic interactions, and protein-protein interactions between FKBP12 and FRB are limited to the 80s loop and one side chain of the 40s loop of FKBP12 (Table 2). The solvent acc~s~ihle surface areas of FKBP12 and FRB are 5348 A and 5711 A, respectively. Since the solvent Arc~s~ihle surface area of the FKBP12-FRB complex (protein only) is 10342 A, binding results in a very modest 6% reduction of solvent Ac~ ihle surface area. Two long side chains in the 40s loop (Lys44 and Lys47) and three residues in the 80s loop (Thr85, Gly86 and His87) of FKBP12 appear to make crucial contact in the ternary complex. In the FRB site, two residues at the end 10 of al and the al-a2 loop (Arg2042 and Tyr2038) contact the 80s loop of FKBP12, and two residues in helix a4 (Tyr2105 and Asp2102) form direct or water-~nP-liAt~1 hydrogen bonds to the 40s loop of FKBP12. The loop-loop interaction between 80s loop (FKBP12) and the al-a2 loop (FRB) and the loop-helix interaction between 40s loop (FKBP12) and helix a4 are the main protein-protein interactions in this ternary complex and thus contribute all of the protein-15 protein binding force forming the ternary complex.

Structure of FRB domain of FR~P
The FRB domain of the FRAP forms a typical four helix bundle, which is one of the most common structural motifs in globular proteins. The overall clim~n~iQn~ of this domain are 45 A
20 x 30 A x 30 ~. All four helices (termed al-oc4) are connected with short lmcltorhAnd loops. The longest helix a3 (residues 2065-2091) has a bend at residue 2074 of 59~. Except for a small bent part of a3 (residues 1065-2073), all four helices have similar lengths (16-19 residues, about 30 A in length). The a2 helix also has a small bend around residues Glu2049, Val2050 and Leu2051 to form a 31o-helical turn rather than a normal a-helix. The angle between al and a2 25 is 22~ and the angle between a3 and a4 is 20~. The angles between these pairs are in the range of 40-60~, which indicates that this four helix bundle is close to the 'X' type int~rh~licAl Table 2 Intra-molecular hydrogen bonds and close contacts in the ternary complex Inter-helical int-~ractil~n.c in the FRB domain of FRAP
Distance (A ) His 2055 (a2) N~2 Tyr 2104 (a4) OH 2.85 His 2028 (al) N~2 Ser 2112 (c O~ 3.23 Close contacts of ...~a.lly-i.. and FRB domain of FRAP
Rapamycin FRB domain of FRAP Distance (A) c50 Thr 2098 o 3.13 c27 Ser 2035 o~3.39 C51 Ser 2035 o~ 3.38 I.,t~ ...c ofFKBP12and FRBdomainofFRAP
FKBP12 FRB domain o~ FRAP Distance (A) Lys 47 O Tyr 210S OH 2.56 Thr 85 O~l Arg 2042 NH1 3.10 Thr 85 O~1 Arg 2042 NH2 2.88 Gly 86 O Arg 2042 NH2 2.79 His 87 N~2 Tyr 2038 OH via H20 301 ~is 87 N~l Arg 2042 NH2 via H20 303 Lys 44 N~ Asp 2102 O~1 via H2O 310 pattern which is the alt~m~ting pattern of parallel and perpendicular helix-helix interactions (Harris et al, 1994). As usual, most of the hydrophobic and aromatic residues are located in the inter-helical int~rface and most of the hydrophilic residues are in the outside of the bundle, which is exposed to the solvent. Only two strong hydrogen bonds were found for the inter-helical interactions (Table 2) and could be key interactions mamLdi--. - -g the overall conformation of the four helix bundle. Helices al and a4, which have an int~rhf~ l angle of 44~, form a deep cleft on the molecular surface of this domain. This cleft is surrounded by six aromatic side chains forming the 'aromatic pocket' which has exquisite steric compl~mPnt~ry for the rapamycin effector domain binding.

Structure of FKBP12-rapamycin The structure of FKBP12 in the ternary complex is basically the same as that in the binary complex of FKBP12-rapamycin or FKBP12-FK506. The protein fold and the architecture of the secQn~l~ry structure are exactly the same as in the binary complex, and the interaction with rapamycin is also the same as that of the binary complex. The overall r.m.s. deviation between the FKBP12 in the ternary complex and that in the FKBP12-rapamycin complex is 1.14 A (0.49 for the main chain), and the deviation between FKBP12 in the ternary complex and that in the FKBP12-FK506 complex is 1.11 A (0.48 A for the main chain), which implies that binding of FKBP12:rapamycin to the FRAP FRB domain is not accompanied by significant changes in the conformation of the FRB binding site on FKBP12 or of the effector domain of rapamycin.
Even the 40s loop and 80s loop regions in the FKBP12, that have direct interaction to the FRB
domain, are not significantly different in 3D structure from that seen in the binary complexes.
These r.m.s. values were calculated by the rigid-body fitting on the main chain atoms in the FKBP12 using QUANTA. The overlay of FKBP12-FK506 to the ternary complex clearly con*rme~l the fact that FKBP12-FK506 complex can't bind FR~P as FK506's effector region does not extend enough. The protein-protein interactions by themselves between FKBP12 and FRB are not enough for the formation of a binary complex; rapall,y~ "~ is f~ nti ~l to mediate the interaction of the two proteins.

WO 97/1~659 PCT/US96/16953 FKBP12-rapamycin binding to FR~P
While the interactions of rapamycin with PRB are all hydrophobic, rapamycin-FKBP12 interactions employ five hydrogen bonds which are the same found in the binary complex of FKBP12-rapamycin, to govern this interaction. Rapamycin is ~ulloLulded by five conserved aromatic residues in FKBP12, which makes the binding pocket for the rapamycin a complete 'aromatic pocket' along with six aromatic residues in FRB domain. Comparing the sequence of these aromatic residues of FRB ~lomAin with other FKBP-rapamycin target proteins, these six aromatic residues are all conserved in RAFT (Sabatini et al, 1994), TOR1, and TOR2 (Stan, et al, 1994)--suggesting that these structural results will be applicable to other members of the PIK-related kinase family. It is expected that binding llomAin~ of these other proteins have a similar structure with FRB flom~in For the interaction between rapamycin and FRB domain, two major sites on FRB are considered crucial for rapamycin binding. Ser2035, whid~ is also conserved in other FKBP12-rapamycin target proteins, has dose contact with C27 and C51 of rapamycin (Table 2). The other site is Thr2098 which has a close contact with C50 of rapamycin. C50 of the rapamycin is at the end of C16 methoxy group, which has been a key target for substituted analogs. All of the hydrophobic interactions between rapamycin and FRB including Ser2035 and Thr2098 can be consifl~red as the main force contributing to complete ternary complex.

Mutational studies Ser2035 in FRB has been the major site for the site-directed mutation studies of FRAP
(Chen et al, 1995). Those studies revealed that the substitution of this residue to other residues larger than alanine abolish binding affinity toward FKBP12-rapamycin . The crystal structure of the ternary complex shows the direct effect of steric hindrance when this position is substituted by longer side chains. It has been suggested that this conserved serine site is a phosphorylation site, and phosphorylation would abrogate binding. By the binding of FKBP12-rapamycin, this serine site, which is open to the solvent when unbound, is protected from phosphorylation and this probably causes the inhibition of the downstream of the signaling pathway.
For rapamycin, C16 has been the main site for substitution in published structure-activity studies (Luengo et al, 1995). The studies of C16 analogs of rapamycin showed that the bulky group substitutions on this position have lower affinity for the FKBP12 binding and lower activity. However some analogs with dirr~l~ l.L stereochemistry or different groups showed retained activit,v and affinity to FKBP12. Such C-16 substituted analogs could be of therapeutic use.

Applications of the invention This invention encompasses crystalline compositions containing FRAP or a FRAP
~ hom(~log protein or portion thereof having a region characterized by structural coordinates of the FRB domain set forth in Appendix I, or by coordinates having a root mean square deviation th~re~lolll of less than about 1.5 A, preferably less than about 1 A, and even more preferably less than about 0.5 A, with respect to backbone atoms of amino acid residues listed there.
As practitioners in this art will appreciate, various computational analyses may be used to ~let~rmine the degree of cimilArity between the three dimensional structure of a given protein (or a portion or complex thereof) and FRAP or a FRAP homolog protein or portion (e.g. the FRB
domain) or complex thereof such as are described herein. Such analyses may be carried out with t~ommercially available software applications, such as the Molecular Similarity application of QUANTA (Mol~ r Simulations Inc., Waltham, MA) version 3.3, and as described in the ac~o~ ying User's Guide, Volume 3 pgs. 134 -135.
The Molecular SimilArity application permits cc,m~dlisons between different structures, different c~ llLc,Lmations of the same structure, and different parts of the same structure. The procedure used in Molecular SimilArity to compare structures is divided into four steps: (1) load the structures to be compared; (2) define the atom equivalences in these structures; (3) perform a fitting operation; and (4) analyze the results.
Each structure is identified by a name. One structure is i~1~nhfi.of1 as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures). Since atom equivalency within QUANTA is ll~fin~l by user input, for the purpose of this invention we define equivalent atoms as protein backbone atoms (N, Ca, C and O) for all conserved residues between the two structures being c~ a~d and con~ r only rigid fitting operations.
When a rigid fitting method is used, the working structure is translated and rotated to obtain an optimum fit with the target structure. The fitting operation uses a least squares fitting algorithm that com~ules the optimum translation and rotation to be applied to the moving structure, such that the root mean square difference of the fit over the specified pairs of equivalent atom is an absolute minimum. This number, given in angstroms, is reported by 25 QUANTA.
For the purpose of this invention, any set of structural coordinates of a FRAP or FRAP
homolog protein, portion of a FRAP or FRAP homolog protein or mnl~clllAr complex thereof that has a root mean square deviation of conserved residue backbone atoms (N, Coc, C, O) of less than 1.5A when superimposed--using backbone atoms--on the relevant structural 30 coordinates of a protein or complex of this invention, e.g. the coordinates listed in Appendix I, are considered i~l~nti~Al More preferably, the root mean square deviation is less than 1.0A.
Most preferably, the root mean square deviation is less than 0.5A.
The term "root mean square deviation" means the square root of the arithmetic mean of the squares of the deviations from the mean. It is a way to express the deviation or variation 35 from a trend or object. For purposes of this invention, the "root mean square deviation" defines the variation in the backbone of a protein from the backbone of a protein of this invention, such as the FRB of FRAP, as defined by the structural coordinates of Appendix I and described herein.

WO 97/15659 PCT/US96~169~i3 The term "least squares" refers to a method based on the principle that the best estimate of a value is that in which the sum of the squares of the deviations of observed values is a 11111 lill ILIll L
In order to use the structural coordinates generated for a crystalline substance of this 5 invention, e.g. the structural coordinates of the FRB of FRAP set forth in Appendix I, it is often ne~ PssAry or desirable to display them as, or convert them to, a three-~limPnsit)nAl shape, or to otherwise manipulate them. This is typically accomplished by the use of comlnercially available software such as a program which is capable of generating three-dimensional graphical representations of molecules or portions thereof from a set of structural coor linAtPs By way of illustration, a non-exclusive list of computer programs for viewing or otherwise manipulating protein structures include the following:

Midas (Univ. of California, San Francisco) X-Plor MidasPlus (Univ. of Cal., San Francisco) (Molecular Simulations, Inc.; Yale Univ.) MOIL (Ulliv~ Ly of Illinois) Spartan (Wavefunction, Inc.) Yummie (Yale Ulliv~l~iLy) Catalyst (Mol~clllAr SimlllAti- n~, Inc.) Sybyl (Tripos, Inc.) Molcadd (Tripos, Inc.) Insight/Discover (Biosym Technologies) VMD (Univ.of Illinois/Be- kmAn Institute) MacroModel (Columbia Ullivel:,ily) Sculpt (Interactive Simulations, Inc.) Quanta (Molecular SimlllAti-~ns, Inc.) Procheck (Brookhaven Nat'l Laboratory) Cerius (M~leclllAr Siml]lAtions, Inc.) DGEOM (QCPE) Alchemy (Tripos, Inc.) RE_VIEW (Brunel Univ~l~ily) LabVision (Tripos, Inc.) Modeller (Birbeck Col., Univ. of London) Rasmol (Glaxo Research and Development) Xmol (Minnesota Supt:lco~ Lillg Center) Ribbon (University of Alabama) Protein Expert (Cambridge S-iPntifi--) NAOMI (Oxford Univ~lsi~y) HyperChem (Hypercube) Explorer Eyechem (Silicon Graphics, Inc.) MD Display (University of Washington) Univision (Cray Research) PKB
Molscript (Uppsala University) (Nat'l Center for Biotech. Info., NIH) Chem-3D (Cambridge Scientific) ChemX (Chemical Design, Ltd.) Chain (Baylor College of Medicine) ~~AmPlPon (Oxford MoleclllAr, Inc.) O (Uppsala University) Iditis (Oxford Molecular, Inc.) GRASP (Columbia Univ~i~iLy) For storage, transfer and use with such programs of structural coordinates for a15 crystalline substance of this invention, a machine-readable storage medium is provided - comprising a data storage mAtPriAl encoded with machine readable data which, when using a machine progrAmm~-l with instructions for using said data, e.g. a computer loaded with one or more programs of the sort identified above, is capable of displaying a graphical three-rlimPn~ionAl l~r~sP, . I ,. I ion of any of the m(~ c~ s or m(~lPclllAr complexes described herein.
Machine-readable storage media comprising a data storage mA~riAl include cw,v~ iona computer hard drives, floppy disks, DAT tape, CD-ROM, and other magnetic, magneto-optical, optical, floptical and other media which may be adapted for use with a computer.
Even more ~le~ll~d is a machine-readable data storage m~ m that is capable of displaying a graphical three-dimensional f~res~.ldLion of a molecule or m~-leclllAr complex that is defined by the structural coordinates of a complex, FRB-containing protein component thereof, or portion thereof, comprising structural coordinates of an FRB domain such as the FRAP FRB coordinates set forth in our attached Appendix I + a root mean square deviation 10 from the conserved backbone atoms of the amino acids thereof of not more than 1.5 A. An illustrative embodiment of this aspect of the invention is a col.v~lllional 3.5" diskette, DAT
tape or hard drive encoded with a data set, preferably in PDB format, comprising the coordinates of our Appendix I. FIG. 3 illustrates a print-out of a graphical three-rlim~n~ nAl representation of such a complex.
In another embodiment, the machine-readable data storage m~lillm comprises a data storage m~t~rial encoded with a first set of machine readable data which com~lises the Fourier transform of the structural coordinates set forth in Appendix I (or again, a derivative thereof), and which, when using a machine programmed with instructions for using said data, can be combined with a second set of mArhin~ readable data comprising the X-ray diffraction pattern of a molecule or molecular complex to determine at least a portion of the structural coordinates corresponding to the second set of machine readable data.
FIG. 1 illustrates one version of these embodiments. The depicted system includes a computer A comprising a central processing unit ("CPU"), a working memory which may be, e.g., RAM (random-access memory) or "core" memory, mass storage memory (such as one or more disk drives or CD-ROM drives), one or more cathode-ray tube ("CRT") display terminals, one or more keyboards, one or more input lines (IP), and one or more output lines (OP), all of which are kllt:lcollllected by a conventional bidirectional system bus.
Input hardware ~, coupled to computer ~ by input lines, may be implemented in a variety of ways. Machine-readable data of this invention may be inputted via the use of a modem or modems connected by a telephone line or dedicated data line L. Alternatively or additionally, the input hardware may comprise CD-ROM drives or disk drives D. In conjunction with the CRT display terminal, a keyboard may also be used as an input device.
Output hardware, coupled to ~:olll~uLt:l A by output lines, may similarly be implemented by convenLional devices. By way of example, output hardware may include a CRT display tf~rminAl for displaying a graphical representation of a protein of this invention (or portion thereof) using a program such as QUANTA as described herein. Output hardware might also include a printer, so that hard copy output may be produced, or a disk drive, to store system output for later use.

WO 97/15659 PCTAUS96~16953In operation, the CPU coordinates the use of the various input and output devices, coordinates data ~CPssf~ from mass storage and accesses to and from working memory, and es the sequence of data processing steps. A number of programs may be used to process the machine-readable data of this invention. Examples of such programs are discussed 5 in reference to the co~ u~ n~l methods of drug discovery as described herein. Specific references to components of the hardware system of FIG. 1 are included as a~lo~l;ate throughout the following description of the data storage mf~ lm FIG. 2A shows a cross section of a magnetic data storage medium 100 which can beencoded with a machine-readable data that can be carried out by a system such as a system of 10 FIG. 1. Medium 100 can be a conventional floppy diskette or hard disk, having a suitable substrate 101, which may be convPntion~l, and a suitable coating 102, which may be convenlional~ on one or both sides, containing magnetic domains (not visible) whose polarity or orientation can be altered magnetically. Medium 100 may also have an opening (not shown) for receiving the spindle of a disk drive or other data storage device 24.
The magnetic domains of coating 102 of medium 100 are polari7~ 1 or oriented so as to encode in a manner which may be ~ullv~llLional, machine readable data such as that described herein, for execution by a system such as a system of FIG. 1.
FIG. 2B shows a cross section of an optically-readable data storage m~ m 110 which also can be encoded with such machine-readable data, or set of instructions, which can be carried out by a system such as a system of FIG. 1. Medium 110 can be a conventional compact disk read only memory (CD-ROM) or a rewritable medium such as a magnptQ-optical disk which is optically readable and magneto-optically writable. Medium 100 preferably has a suitable substrate 111, which may be conventional, and a suitable coating 112, which may be conventional, usually of one side of substrate 111.
In the case of CD-ROM, coating 112 is reflective and is impressed with a plurality of pits 113 to encode the machine-readable data. The arrangement of pits is read by reflecting laser light off the surface of coating 112. A protective coating 114, which preferably is substantially transparent, is provided on top of coating 112.
In the case of a magneto-optical disk, coating 112 has no pits 113, but has a plurality of magnetic ~ m~in~ whose polarity or orientation can be changed m~gnPtic~lly when heated above a certain temperature, as by a laser (not shown). The orientation of the rlom~ins can be read by measuring the polarization of laser light r~flP~t~ll from coating 112. The arrangement of the domains encodes the data as described above.

Use of Structure in Drug Discovery The availability of the three-dimensional structure of the ternary complex of FKBP12:rapamycin:FRB of FRAP makes structure-based drug discovery approaches possible.
Structure-based approaches include de Novo m~)lec~ r design, co~ uLeL-aided optimi7~tinn of , W O 97/15659 PCTAUS96/16953lead molecules, and computer-based s~lecti~ n of ~An~ Ate drug structures based on structural criteria.
Rapamycin mimetics may be developed from the bound conformation of rapamycin by design, by searching databases for rep1Acf~mf~nts of one or more structural segments of 5 rapamycin, or by en~Anr~mf~nt of existing ligand-protein interactions (i.e., by replacing a component moiety of a ligand with a substitute moiety capable of greater interaction with the target protein, whether through A~ ssihle protein contact points or by extrusion of otherwise sequestered waters). Knowledge of the bound conformation of a ligand can suggest avenues for conformational restriction and replA~ ~m.~nt of atoms and/or bonds of rapamycin. A less biased 10 approach involves c~ ulel al~,ol;Lhlns for seal.l~lg databases of three ~im~n.sional structures to identify replAc~ments for one or more portions of the ligand. By this method, one can generate compounds for which the bioactive conformation is heavily populated, i.e., compounds which are based on particularly biologically relevant c~ fc,llllation~s of the ligand.
AlgoLiLl~llls for this purpose are implemented in programs such as Cast-3D (Chemical Abstracts 15 Service), 3DB Unity (Tripos, Inc.), Quest-3D (Cambridge Crystallographic Data Center), and MACCS/ISIS-3D (Molecular Design Limited). These geometric searches can be allgm~nte-l by steric searching, in which the size and shape requirements of the binding site are used to weed out hits that have prohibitive ~lim.onsion~ Programs that may be used to synchronize the geometric and steric requirements in a search applied to the FRB of FRAP include CAVEAT (P.
20 Bartlett, University of California, Berkeley), HOOK (MSI), ALADDIN (Daylight Software) and DOCK (I.D. Kuntz, Uluvel:jily of California, San Francisco; see e.g.
http://www.cmpharm.ucsf.edu/kuntz-/kuntz.html and references cited therein). All of these searching protocols may be used in conjunction with existing corporate databases, the Cambridge Structural Database, or available chemical databases from ~ h~mic ~l suppliers.
Characterization of Compounds Compounds designed, selected and/or optimized by methods described above may be evaluated for binding activity with respect to proteins cullldillillg one or more FRB domains using various approaches, a nurnber of which are well known in the art. For instance, 30 compounds may be evaluated for activity as competitive inhibitors of the binding of a natural ligand for the FRB, e.g. FKBP12:rapamycin in the case of the FRAP FRB. Competitive inhibition may be d~rmin.o~l using any of the numerous available technologies known in the art.
Such compounds may be further evaluated for activity in inhibiting cellular or other biological events m.o~ te-1 by a pathway involving the interaction of interest using a suitable 35 cell-based assay or an animal model. Cell-based assays and animal models suitable for evaluating inhibitory actvity of a compound with respect to a wide variety of cellular and other biological events are known in the art. New assays and models are regularly developed and reported in the scientific literature.

CA 02229426 1998-03-ll W O 97/15659 PCT~US96/169~3For example, compounds which mimic the binding of ld~allLy~ill or FKBP12:rapamycin with respect to FRAP may be evaluated for biological activity in the mouse spelocyte mitogenesis assay or the high-flux yeast-based assay of Luengo et al, supra. A battery of in vivo models may be used to profile the breadth of the compound's immlmos~ xiv~ (or other) activity and compare the profile 5 to those of positive controls such as rapamycin itself. Comparisons may also be made to other Ll~ accepted immuno:,u~r~ iv~ compounds, e.g. cydophosphamide, and leflunomide. Initial in vivo screening models indude: Delayed type hypersensitivity testing, Allogeneic skin transplantation, and Popliteal lymph node hyperplasia. Compounds demonstrating optimal profiles in the above models are advanced into more sophisticated models designed to ~-onfirm immunosuppressive activity 10 in specific therapeutic areas including: Rheumatoid arthritis, Transplantation, Graft vs. host disease, and Asthma.
By way of further illustration, compounds may be evaluated in relevant conventional in vitro and in vivo assays for inhibition of the initiation, maintenance or spread of cancerous growth. See e.g., Ishii et al., J. Antibiot. XLII:1877-1878 (1989) (ir~ vifro evaluation of cytotoxic/antitumor activity); Sun et al, US Patent 5,206,249 (issued 27 April 1993)(in vitro evaluation of growth inhibitory activity on cultured leukernia cells); and Sun et al, supra (xenograft models using various human tumor cell lines xenografted into mice, as well as various transgenic animal models).
Single and multiple (e.g., 5 to 7 days) dose investigative toxicology studies are typically 20 performed in the efficacy test species using the intended route of administration for the efficacy study.
These investigative toxicology studies are performed to identify maximum tolerated dose, subjective bioavailability from the intrap~rit n~Al or oral routes of administration, and estimation of an initial safety margin. Initial bioavailability and pl~ArmAc~-kinetics (blood clearance) of the compounds may be determined, with standard cold or ra~ Active assay methods, to assist in defining appropriate dosing 25 regimens for the compounds in the animal models.

Pharmaceutical Compositions and Uses of rapamycin mimetics and other FRAP-binding compounds Compounds which bind to an FRB domain may be used as biological reagents in binding 30 assays as described herein for functional ~lA~xifi~Ation of members of the PIK-related kinase family, particularly newly discovered proteins, based on ligand specificity.
Moreover, compounds identified as described above can be used for their immunosuppressive or other phArmacologic activity in place of rapamycin.
A compound selected or identified in accordance with this invention can be formlllaf~l 35 into a pharmaceutical composition ~onldillillg a p~ArmAceutically acceptable carrier and/or - other excipient(s) using conventional mAf~ri~lx and means. Such a composition can be administered as an immlmoxu~pre:,dllL, for example, to an animal, either human or non-human.
Administration of such composition may be by any conventional route (parenteral, oral, inhAlafion, and the like) using a~l~liate formulations as are well known in this art. The _ compound can be employed in adll,i,cl.lle with cc,l,v~l.Lional excipients, i.e., phArmA~e1lti~Ally acceptable organic or inorganic carrier substances suitable for pdl~nl~dl administration.

Pharmaceutical applications By virtue of its capacity to mimic the interaction of rapamycin with FRAP, a compound i~7~ntifie~7 as described herein may be used in phArmA~elltirAl compositions and methods for treatment or ~l~vt:lllion of various ~7.i~eA~.os and disorders in a mammal in need thereof.
~rAmmAl~; indude rodents such as mice, rats and guinea pigs as well as dogs, cats, horses, cattle, sheep, non-human primates and humans.
The pr~r~lled method of sudh tr~Atm~nt or ~l~v~l-lion is by a-7mini~tering to a mAmmAl an effective amount of the compound to prevent, alleviate or cure said disease or disorder. Such effective amounts can be readily determined by evaluating the compounds of this invention in conventional assays well-known in the art, including assays described herein.

Therapeutic/Prophylactic Ad~"-~lisl~tion ~ PharmnretJticn1 Compositions The invention provides methods of treating, preventing and/or alleviating the ~ylll~Lwlls and/or severity of an untoward immune response or other disease or disorder referred to above by administration to a subject of a in an amount err~live therefor. The subject will be an animal, including but not limited to animals such as cows, pigs, ~hi(~k~n~, etc., and is preferably a mAmmAl, and most preferably hllmAn Various delivery systems are known and can be used to administer the compound, e.g., encapsulation in liposomes, microparticles, microcapsules, etc. One mode of delivery of interest is via pl71monAry Anmini~tration, as detailed more fully infra. Other methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, illLldv~llous, subcutaneous, intranasal, epidural and oral routes. The compound may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mllcosA~ etc.) and may be A~lmini~tered together with other biologically active agents. A~ il,isLldLion can be systemic or local. For treatment or prophylaxis of nasal, bronchial or pulmonary conditions, ~rer~l I ed routes of Anmini~tration are oral, nasal or via a bronchial aerosol or nebulizer.
In specific embodiments, it may thus be desirable to administer the compound locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, by injection, by means of a catheter, by means of a suppository, or by means of a skin patch or implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
~his invention also provides phArmAc~utical compositions. Such compositions comprise a therapeutically (or prophylA--ti~Ally) effective amount of the compound, and a phArmAceutically acceptable carrier or excipient. Such a carrier includes but is not limited to wo s7ns6~;s PC'r~US96~6~;3 saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The carrier and composition can be sterile. The formlllAtion should suit the mode of administration.
The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The composition can be a liquid solution, suspension, ~m~ n, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulAte~l as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as phArmAcel1*cal grades of mannitol, lactose, starch, mAgnf~ium ~l~dla~ sodium sAc~hArin~, cellulose, m~gn~ium carbonate, etc.In a specific embodiment, the composition is formlllflte-l in accordance with routine 10 procedures as a phArmAceutical composition adapted for illLldVt:lloUS A-lmini~tration to human beings. Typically, compositions for ill~ldvellous ~-lmini~tration are solutions in sterile isotonic aqueous buffer. Where nece~sa~y, the composition may also include a solubilizing agent and a local anesthe*c to ease pain at the side of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder 15 or water free cone~. .1. dlt~ in a hermetically sealed container such as an ampoule or sachette indicating the cluantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile phArmAc~llti~Al grade water or saline. Where the composition is A~1mini~tered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
Administration to an individual of an effective amount of the compound can also be accomplished topically by administering the compound(s) directly to the Aff~cte~l area of the skin of the individual. For this purpose, the compound is administered or applied in a composition including a phArmAt~ol~gically acceptable topical carrier, such as a gel, an ointment, a lotion, or a cream, which includes, without limitAtion, such carriers as water, 25 glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
Other topical carriers include liquid petroleum, is~,~roL,yl pAlmitAtP, polyethylene glycol, ethanol (95%), polyoxyethylene monolaurate (5%) in water, or sodium lauryl sulfate (5%) in water. Other mAt~riAl~ such as anti-oxidants, hllmf~ctAnt~, viscosity stabilizers, and similar agents may be added as necessary.
In addition, in certain instances, it is expected that the compound may be disposed within devices placed upon, in, or under the skin. Such devices include patches, implants, and injections which release the compound into the skin, by either passive or active release meC~Ani~m.~.

~ 35 ~rAtf~riAl~ and methods for producing the various formlllAtions are well known in the art [see e.g. US Patent Nos. 5,182,293 and 4,837,311 (tablets, capsules and other oral formulations as - well as intravenous formlllAtion~)].
The effective dose of the compound will typically be in the range of about 0.01 to about 50 mg/kgs, preferably about 0.1 to about 10 mg/kg of mAmmAliAn body weight, administered W O 97/15659 PCTAUS96/16953in single or multiple doses. Generally, the compound may be al1mini~t~red to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient.
The amount of the compound which will be effective in the tr~tm~nt or prevention of a particular disorder or c--n~ition will depend on the nature of the disorder or condition, and can 5 be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Effective doses may be extrapolated from dose-response curves derived from in vifro or animal model test systems.
The precise dosage level of the compound, as the active component(s), should be detf~rmin~r3 as in the case of all p~rmAceutical treatments, by the attending physician or other health care 10 provider and will depend upon well known factors, inrlll~ing route of administration, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; and the use (or not) of con.~o~;l,..,t therapies.
The invention also provides a ph~rm~t~elltirAl pack or kit comprising one or more containers filled with one or more of the ingredients of the ph~rm~reutical compositions of the 15 invention. Optionally associated with such container(s) can be a notice in the form prescribed by a ~;~ v~lnlllental agency regulating the manufacture, use or sale of p~Arm~c(~utical or biological products, which notice reflects a~rvvdl by the agency of manufacture, use or sale for human administration .

20 Pulmonary Adt~ ion In one embo~limf~nt of this invention, the compound is administered by pulmonaryadministration, e.g. via aerosolization. This route of administration may be particularly useful for treatment or prophylaxis of bronchial or p1l1mf~n~ry infection or tumors.
Pulmonary administration can be accomplished, for example, using any of various 25 delivery devices known in the art (see e.g., Newman, S.P., 1984, in Aerosols and the Lung, Clarke and Davia (eds.), Butterworths, London, England, pp. 197-224; PCT Publication No.
WO 92/16192 dated October 1, 1992; PCT Publication No. WO 91/08760 dated June 27, 1991; NTIS Patent Application 7-504-047 filed April 3, 1990 by Roosdorp and Crystal), induding but not limited to nebulizers, metered dose inhalers, and powder inhalers. Various 30 delivery devices are commercially available and can be employed, e.g., Ultravent nebulizer (Mallinckrodt, Inc., St. Louis, Missouri); Acorn II nebulizer (Marquest Medical Products, Englewood, Colorado), Ventolin metered dose inhaler (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, Massachusetts) or Turbohaler (Astra). Such devices typically entail the use of formulations suitable for dispensing 35 from such a device, in which a propellant material may be present.
Ultrasonic nebulizers tend to be more ~ffi~ nt than jet nebulizers in producing an aerosol of respirable size from a liquid (Smith and Spino, "Pll~rm~c kinetics of Drugs in Cystic Fibrosis," Consensus Conference, Clinical Outcomes for Evaluation of New CF Therapies, Rockville, Maryland, December 10-11, 1992, Cystic Fibrosis Foundation).

, WO 97/156~9 P ~ ~US96~16953 A neb~ er may be used to produce aerosol partides, or any of various physiologically acceptable inert gases may be used as an aerosolizing agent. Other components such as physiologically acceptable s1lrfActAnt~; (e.g., glycerides), excipients (e.g., lactose), carriers, and nt.c. may also be in~ 1e~1.
This invention is not to be limited in scope by the specific embodiments described herein.
Tn~lee~l, various mor~ifi~-Ations of the invention in addition to those described herein will become apparent to those skilled in the art from the ~re~,uillg description. Such modifications are intended to fall within the the scope of the appended claims.
Various patents, patent applirAtion.~ and publications are cited herein, the disclosures of which are in~ol~o~al~d by reference in their entireties.

Experimental Examples I. Protein Preparation cDNAs encoding human FKBP12 (Standaert et al, 1990) and the 12-kDa FRAP fragment~ ontAining the FRB domain (Chen e~ al, 1995) (FRAP12) were subdoned into pGEX-2T
(Pharmacia) for the expression of GST-FKBP12 and GST-FRAP12 fusion proteins in E.coli strain BL21. Typically, a 2-liter culture was grown to OD600~0.6 at 30 ~C and induced with 0.3 mM IPTG at room temperature for 6 hours. Pllrifi( Ation and thrombin cleavage of the fusion proteins were performed according to standard procedures (mAnllAl from Ph~rmAc-iA). After removal of free GST, the samples COl~dillil g FKBP12 or FRAP12 were concentrated to ~10 mL
in a 50 mL stir-cell ultraconc~nlldlor (Amicon) with a 3-kDa cutoff filter, and fractionated on a Sephacryl S-100 column (2.5 cm x 85 cm) equilibrated in 10 mM phosphate buffer (pH 7.4) containing 136 mM NaCl, 3 mM KCl, 1 mM DTT. Fractions col-ldi,~ing pure FKBP12 or FRAP12 (>95% purity judged by SDS-PAGE) were combined and concentrated to ~10 mg/mL
using a stir-cell ultr~ n~ aLol. The conc~llllal~d samples were stored in the same phosphate buffer at 4 ~C.

II. Cryst~11i7~tion & Structure Det~rmin~tion Cryst~ inn Recombinant human FKBP12 purified from E. coli was used at 10 mg/mL in 10 mM tris-HCl pH 8Ø Rapamycin was dissolved in methanol and mixed with FKBP12 in a 2:1 molar ratio. The mixture was lightly vortexed and stored overnight at 4~C to insure complete complex formAtinn. Purified 12-kDa FRB domain of FRAP at 10 mg/mL in 50 mM tris-HCl pH 8.0 was added to this mixture in a 1:1 (FKBP12-rapamycin complex:FRB domain) molar ratio. This mixture was also lightly vortexed and let sit overnight at 4~C to insure complete complex fnrm7~tion. Crystallization conditions were screened using the hanging drop method, and - rectangular rod-shaped crystals were obtained using: 20% PEG 8000, 10% MPD and 10 mM
tris-HCl at pH 8.5. For the hanging drop method, drops of 4~uL ~ il lg 2,uL of complex solution and 211L of reservoir solution were equilibrated against 0.5 mL of the reservoir solution.

Micro-seeding techniques were used to prepare additional crystals. The initial crystals were crushed and diluted to prepare a seed solution that was added to newly prepared drops.
After two weeks, a shower of tiny crystals was obtained. Macro-seeding techniques were then applied to get large crystals suitable for X-ray diffraction. A tiny but well-formed crystal was 5 picked and used as a cryst~lli7Ation seed. After two to three weeks, rectangular rod-shaped crystals with a maximum size of 0.3 x 0.2 x 0.1 mm3 were obtained, and these crystals were suitable for data coll~ctic n The Hg-derivative crystal was obtained by soaking the native crystal in 2 mM HgCk solution overnight. All of the cryst~lli7atic-n experiments were done at 4~C.

Data Collection All data sets were collected at room temperature on a San Diego multiwire area detector system mounted on a Rigaku RU-200 rotating anode X-ray source o~tldlillg at 50 kV and 150mA. The detector was positioned at a 20-value of -30~ with a 544 mm detector-crystal distance for the high resolution data and 12~ with a 506 mm detector-crystal distance for the low resolution data. The data collection was performed using an c~scan with an increment of 0.10~ for each frame and 40 second exposure time per frame. Crystals belong to the orthorhombic space group P212121 with unit-cell dimension of a=44.63, b=52.14, c=102.53 A
and one FKBP12-rapamycin-FRB complex in the asymmetric unit. Hg-d~livcllive crystal data 20 were collecte/l under the same con-litions. For the native data set, the measured intensity data were processed using SCALEPACK (Otwinski et al, 1992) giving 6920 unique reflections out of 43447 measured r~flection~ to 2.7 A resolution (98.5% data coverage) with RSym of 7.1%. For the Hg-derivative data set, the number of unique reflection was 6884 out of 42681 measured reflections to 2.7 A (98.0% data coverage), with RSym of 7.1%.

Structure det~rmin~tion The crystal structure of the ternary complex was solved using the molecular repl~ mf~nt (MR) method combined with the single isomorphous repl~c~mPnt with anomalous st ~ oring (SIRAS) method. Initial phases were obtained from the molecular repl~c~m~nt search using the 30 FKBP12-rapamycin complex structure as a search model. The cross rotation search revealed a dear peak at ~1=10.8~, ~2=70.0~,133=309.4~ with height/r.m.s. ratio of 12.9 and the translation search also showed a clear peak at x=0.000, y=0.230, z=0.417 with height/r.m.s.
ratio of 10.5. Rigid body r~fin~mPnt resulted in an R factor of 0.449 (10-2.7 A). All molecular repl~c~m~nt r~lc~ tions used the X-PLOR program (Brunger, 1990). However, the resulting 35 difference electron density map was noisy and hard to il~L~l~reL. In order to improve the map quality, an Hg d~livalive crystal was obtained. These data were co.l~ared with the native data to give an Rdiff of 12.7%. Two heavy atom sites were found from the difference Patterson map and were refined using the program PHASES (Furey et al,1990). One Hg is bound to Cys22 of FKBP12 with full occupancy - the same Hg site seen in the FKBP12-FK506 complex.

WO 97/15659 PCT~US96/169~;3 The other heavy atom site is in the middle of FRB rlnmAin where it is bound to Cys2085 of FRAP with an occupancy factor of 0.6. Both Pa~ o~ erl~lce~ heavy atom positions were v~ lA~(l in the Fo-Fc ~liLr~lel ce map using Fo of the heavy atom derivative and Fc from the molecular repl~c-om~nt solution. ~nnmAlous dispersion measurements were in~h~ l in this 5 data set and 16 cycles of a solvent flAtt~ning procedure were applied, resulting in a phasing power of 2.76 and mean figure of merit of 0.840. All of these calculations were performed using the program PHASES. The electron density map was ~Alc-llAte-l using the combined phase from the SIRAS and the mnleC~ r replacement solution, which clearly showed four helix bundle archiLe.:lule of FRB domain of FRAP.

Model Building and refinement The FKBP12-rapamycin part was well defined in the initial electron density map; only minor changes in the backbone of 30s loop and some side chains were enough to fit the model of FKBP12-rapamycin structure to this electron density map. For the FRB domain part, most of a 15 polyalanine chain could be traced for the helix regions in the initial map. After several cycles of the positional r~fin~m.ont using X-PLOR, loop regions could be traced and the amino acid sequence could be A~ignell The program CHA~ (Sack, 1988) was used for the model fitting and building the ternary complex. A total of 95 residues were built for the FRB domain of FRAP; three residues in the N-t~rminAl and two residues in the C-~rmin~l of FRB domain had 20 no electron density and were not i~ ]~ 1 Positional r~*n~m-ont was followed by ~im~ te-l annealing (slow cooling from 3000K to 300K in 25 K steps, 0.0005 ps per step and 50 total steps were used in the simulation at each temperature) and restrained B-factor r~finem~nt All rPfin~mf~nh were done using the X-PLOR package. Solvent molecules were assigned during the iL~laLiv~ positional and B-factor r~fin~m~nt procedure, if they appeared at the 3.5 c~ level of Fo-25 Fc map, showed good hydrogen bonding geometry and had a low B-factor (less than 50 A2).
The current structure includes 202 amino acids (107 for FKBP12 and 95 for FRB domain), one rapamycin, and 23 water molecules. The final R factor is 19.3% with an Rfree of 29.9%. The free R-factor is calculated with 10% of the data that were selected at the beginning of the analysis. Crystallographic statistics are sllmm~ri7erl in Table 1.
Quality of the coordinates The final coordinates have good geometry and r.m.s. deviations from the ideality are 0.008 A for bond lengths and 1.5~ for bond angles. ExAmine.l by the program PROCHECK
(Laskowski, 1993), the current 2.7 A resolution structure shows that the main-chain and side-35 chain geometrical parAmet~r~ are better than expected at this resolution with an overall G-factor of 0Ø Ramachandran plots of ~, ~r, angles showed that 86% of the nonglycine and - nonproline residues are in energetically most favored regions. The average temperature factors for total atoms and main-chain atoms are 17.0 and 14.7 ~2 respectively. The r.m.s. variation W O 97/15659 PCT~US96tl6953in the B-factor of bonded atoms is 2.5 ~2 The Luzzati plot (Luzzati, 1952) indicates that the average coordinate error of this complex structure is between 0.25 and 0.30 A.
Those structural coordinates are set forth in Protein Databank format in Appendix I, below. Such data may be transferred to any desired medium, and formatted as desired, for the practitioner's computer.
This invention encompasses those coordinates as well as any translation or rotation or the like thereof which mAinPins the internal coordinates, i.e., which mAintAins their intrinsic, intornAl relationship. Those skilled in the art will appreciate that the coordinates may be subjected to other transformations including, e.g. molecular me~ hAni~ ~ cAlcl11A*ons such as dynamic ~iml11Ation, mir~imi7A*~n~ etc. This invention further encompasses the use of coordinates of the FRB of FRAP, of the ternary complex, or of the corresponding region of FRAP homologs, and in particular, the coordinates set forth in Appendix I, in conducting such transformations (or more extensive transformAtit ns such as the generation of alternative conformations), as well as the products of such transformAtlt-n~ (i.e., d~L;vdLves of the coordinates).

Table 1 Crystallographic statistics of the ternary complex FKBP12--d~,alllycin-FRB domain of FR~P
Data rnll~rtinn statistics Data Set R~olllt;on No. of reflections Data R8ym(%)*
(A) Mea5ured Uni~ue CuV~L~y~(~) Native 2.1 43447 6920 98.5 7.1 HgCl2 2.7 42681 6884 98.0 7.1 Molecular repl~r-~n~nt results Rotation function ~1=10.82~ ~2=70.00~ ~3=309.35~ Height/r.m.s.=12.9 TrAnqlAt;~n function x=0.000 y=0.230 z=0.417 Height/r m s.=10 5 Heavy atom data statistics (SIRAS) Sites Rdiff(%)t Phasing power ~ figure-of-merit 2 12 7 2.76 0.84Q
~ statistics Resolution Reflections Number of R-factor Rfree R.M S deviation (A) (with ¦F ¦~8~)at~mS (96) (96) Bond lengths Bond angles (A) (~) 8-2 7 6206 1727 19.3 29 9 0.008 1 48 *RSym=~l I-<I> ¦/~ I, where I is the observed intensity and <I> is the a~erage intensity from multiple measurement.
tRdiff=~ ¦FPH_FP¦ /~FpH, where Fp and FpH are the amplitudes of native and derivative structure factors, respectively ~Phasing power=r.m s (FH/~), where FH is heavy-atom structure factor amplitude and ~ is residual lack of closure error WO 97/15659 PCT~US96~69~3 III. Assays Compounds which bind to the FRB of FRAP may be evaluated using mAt~nAl~ and methods useful for testing the biological or pharmA-Q1Ogical ac*vity of ldpall,ycin analogs. See e.g. Luengo et al, 1995. In addi*ion, the following animal models may be used for further 5 evalllAti- n of such compounds:
(a) DET ~YED TypT~HypET~sR~sIllv~Ty Mouse abdomens are painted with sensi*zing chPmi~ Al~ (sen~i*7Atic~n) such as dinillonourobenzene or oxazalone. Seven days later the ears of sensitized mice are painted (challenge) with a lower concentration of the compound. An*gen processing and prPCPntAhc n, 10 T lymphocyte ac*va*on, leukocyte infiltration, humoral me-liatc)r release, increased microvascular permeability, and plasma exudation all result from ~hAllPnge of sensitized mice and lead to edema forma*on. Edema presents as a two- to three- fold increase in ear thil-knP5s within twenty-four hours.
The test compounds or standards can be applied (topical or parenteral) at various times 15 before or after the sensitization or challenge phases. Increased ear thickness is ~l~v~nLed by several compounds in~ tling immuno~u~r~iv~ agents and steroids. This model is a primary model for contact rlPrmahh~
(b)AT.T.OGF.~T1TC SKTN TTt~SPT.~rEATION
An allogeneic skin transplant model is used to identify immlln(-~u~r~s~iv~ activity of 20 test compounds. In this model, donor mouse thoracic skin (Balb/c) is surgically grafted onto the thorax of recipient mice (C57bl/6). Host rejection of the graft is evidenced by erythema, drying out, and retraction of donor skin. The mean graft survival time is 10 to 11 days, with 80% of the grafts being rejected by 12 days. Active novel imml1no~u~lessive compounds, like existing immunos~ re~siv~ compounds, will prolong graft survival.
25 (c) POPT TTE~T T.YMPH NODl~ HYPERPr.~
This model directly assesses T lymphocyte proliferation in vivo. Spleen cells, obtained from Balb/c mice, are isolated and administered into the foot pads of C3H mice. Within four days, the popliteal lymph nodes can be removed from the recipient mice and weighed. Other hematological ac5~5~m~ntS inclllt1ing FACS scanning for T lymphocyte subpoplllation~ may also 30 be performed. Active compounds, like existing immunosuppressive compounds, will inhibit the increase in node mass.
(d)RT~F.U M ~TOID ATtTHRTllS
Several models are available for assessment of anti-arthritic activity, incln~ling adjuvant-induced, carageenan-in~lllce~1, and collagen-induced arthritis in rats and/or mice. Paw pads are 35 injecter1 with one of these agents. Paws increase in volume, and measurements are made between 20 and 30 days later. The ability of test compounds to prevent the induction of paw swelling is tested with daily treatment for 12 consecutive days following the injection of inducing agent. The ability for the test compounds to reverse the progression of the paw swelling is tested by a~minictration of the compound for 12 consecutive days beginning on the W O 97/156~9 PCTrUS96/16953 twelfth day following the injection of inducing agent. Paw swelling measurements are made by water displa~mPnt plethysmography. Histology is also an a~ ;ate endpoint for ~hese studies. The MRL/lpr-mouse model, described above, is required for the rheumatoid arthritis ir rli~ ation. This model is a spontaneous allloi~-.. J.. P model that develops rheumatoid arthritis resembling the human condition, ir~ ing the presence of cirClllAting rhel~mAt )i~l factor, pannus formAtiQn, and bone and cartilage erosion.
(e) SYST~ C LIJPUS ~ Tosus Systemic lupus erythematosus is another a~ e disease with several animal models.Several murine strains develop spontaneous SLE. One such strain is MRL/lpr-mice. These mice, over time (20 to 30 weeks) develop auto-antibodies against dsDNA, nudear antigens, and renal bAcPmPnt membrane. This leads to complement fixation and immlmP complex f~rmAtion.
Damage to the kidney becomes apparent with the onset of ~roleinL,lia. Many of the other physiologic, hPmAtc logic, and immunologic aberrations described below for the CGVHD model are present. Tmmlmo~u~lessiv~ compounds such as cyclosporin, cyclophosphamide, and lefllmomi~l~ can ~l~vent and reverse the course of disease in this model. L~ esLil,gly, these mice also develop pathologies akin to rheumatoid arthritis.
The murine chronic graft versus host disease model (CGVHD, described below) is a model of SLE that contains many of the clinical features of SLE. Activity in this model has been shown to be predictive of activity in the more l~lini~Ally relevant SLE models.
(f) ~rR ~NSP~ T~TION
Allograft transplantation (skin graft) assay is often used as an initial test ofimmunosu~ressive activity. While this model is useful as a screen, it may be supplemented with assays based on animal transplant models involving transplantation of internal organ (heart, liver, kidney, bone marrow) with use of "rlini~Ally acceptable" physiologic endpoints to assess graft survival. Efficacy of test compounds in only a very limited number of these rodent models is required. Following observation of activity in a rodent model, the test compounds are typically tested in further animal models (e.g., canine, porcine or non-human primate). Active compounds decrease acute and chronic rejection and prolong transplant survival.
(~) G~FT VS.HOST DISE~E
Chronic GVHD (CGVHD) can be used to model CD4+-dependent humoral immunity. It isinduced in BDF1 mice (which are progeny of DBA/2 male x C57BL/6 female matings) by Arlmini~tering to them isolated spleen:lymph node cells from DBA/2 mice. This results in: a) disregulation and stimulation of CD4+ T lymphocyte (Lyl+; murine marker) activity due to incompatibilities at MHC II nlolecl~lP~, and b) abnormal T-B lymphocyte cooperation. The resulting pathological state, in many ways, mimics systemic lupus erythematosus (SLE). Several measurable endpoints develop within 14 days; including, circl~lAting anti-host IgG and IgE
antibodies, altered T and B lymphocyte proliferation activity measured in vitro, complement utilization, hPmAgglll*nation, slow progressive wasting, dermal aberrations, splerlomegaly, lymphoid hyperplasia, and ~rol~i"u.ia. Only a few of these endpoints need to be measured.

=

WO g7/~5659 PC~,'US96/~6953 Active compounds are are those which limit T lymphocyte disregulation and abrogate changes in these variables. Many steroids (e.g., prednisolone), cyclosporine, FK-506, cyclophosphamide, and leflunomide are all active in this model and can be used as positive controls.
The acute GVHD model (AGVHD) is also produced in BDF1 mice. In this case, isolated 5 spleen:lymph node cells from C57BL/6 rnice are ad~ isL~led. This results in disregulation and stimlllAticn of CD8+ T lymphocytes due to incompatibilities in the MHC I mc-l~c~ s Elevated cytokine levels and donor clonal expansion occurs. Ultimately, donor cytotoxic T lymphocytes and NK cells rapidly reject host tissue and cause relatively rapid death of the recipient. The progression of AGVHD in this model is As~s~sse~l by measurement of hematologic abnorm~litif~s 10 (including T cell number and type), cytokine elevations (TNF, IL-1, IL-2, and/or IL-4), low body weight, hypo~globlllin~miA, circlllAting hematologic characteristics in~lirAtive of aplastic anemia (granulocytopenia, thrombocytopenia), eX vivo NK or CTL activity, and host survival.
Active compounds are those which abrogate changes in the variables, and prolong survival over 4 to 6 weeks.
15 (h) ~ ~T~l~
Asthma offers another oppo~ Ly for safe immunosu~ples~ive therapy. Atopic asthmatics have antibody mediated hypersensitivity and the often occurring late phase reaction is likenell to a DTH response. Asthma has only recently been defined as an inflAmmAtory disease (1992). Since then, several publications from prominent asthm~tologists demonstrate 20 the presence of activated CD4+ and CD8+ T lymphocytes in bronchoalveolar lavage fluid and blood of atopic asthmatics. The ratios of these cells changes in asthmatic conditions.
Furthermore, several of the T cell associated cytokines (IL-1, IL-2, IL~, IL-5, and TNF) are all implicated in dinical and experimental asthma. TnflAmmAtory events in asthma are now considered to be T lymphocyte driven. Initial clinical trials with inhaled cyclosporin suggest that 25 local immuno~ res~ion can ameliorate airway hyperreactivity - the underlying defect in asthma.
The guinea pig model of antigen-induced pulmonary aberrations is used as a model for asthma. These AnimAls are actively s~n~iti7e-1 to ovalbumin to generate high circulating titers of anti-ovalbumin antibody with serocollv~lbion to the IgE class, as is the case with atopic 30 asthmAti( s. Aerosol challenge of sensitized guinea pigs results in measurable eosinophil rich pulmonary infiltrates (a~loxilllately a 16-fold increase in eosinophils), pulmonary edema, and mucous plugging of the small airways; all ~lllminAting in the expression of the underlying defect in asthma- airway hyperreactivity (approximately a 3 to ~fold increase in reactivity). Acute bronchoconstriction is obviously present and points the afor~m~ntionf~ presence of the 35 pathophysiologic sequelae. Active compounds are those which lessen or abrogate such ~yllL~ JlllS.
- The above description is meant to illustrate, rather than limit the scope of the invention.
Given the ~re~;uillg description, numerous vAriAtions in the mA~riAls or methods employed in p~lfollllil-g the invention will be obvious to one skilled in the art. Any such obvious variation is W O 97/15659 PCT~US96/16953 to be cc ~ red within the scope of the invention. Full references to literature cited above (by reference to author and year) are provided below:

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Vezina, C., Kudelski, A. & Sehgal, S. N. J. Antibiot. 28, 721-726 (1975).
Zakian, V. A. Cell 82, 685-687 (1995) CA 02229426 l998-03-ll ~b'~ ;Y I

ATCM 1 C GLY 1 4.588 25.968 49.843 1.00 12.34 FKBP
ATCM 2 O G~Y 1 3.587 26.690 49.931 1.00 3.24 FKBP
ATCM 3 H~l G~Y 1 5.460 28.281 50.881 0.00 0.00 FKBP
AToM 4 HT2 GLY 1 5.463 28.482 49.221 0.00 0.00 FKBP
ATCM 5 N GLY 1 5.987 28.058 50.014 1.00 24.95 FKBP
ATCM 6 H~3 GLY 1 6.961 28.429 50.048 0.00 0.00 FKBP
ATCM 7 CA GLY 1 5.986 26.568 49.849 1.00 14.30 FKBP
10 ATCM 8 N V~L 2 4.539 24.648 49.684 1.00 9.85 FKBP
ATCM 9 H V~L 2 5.366 24.143 49.539 0.00 0.00 FKBP
ATCM 10 CA V~L 2 3.311 23.862 49.748 1.00 11.89 FKBP
ATCM 11 CB U~L 2 2.889 23.360 48.318 1.00 9.17 FKBP
ATCM 12 CGl U~L 2 4.114 23.006 47.492 1.00 14.93 FKBP
15 AToM 13 CG2 U~L 2 1.975 22.155 48.411 1.00 2.00 FKBP
ATCM 14 C U~L 2 3.549 22.668 50.692 1.00 15.67 FKBP
ATCM 15 O U~L 2 4.576 21.989 50.605 1.00 16.61 FKBP
ATCM 16 N GLN 3 2.643 22.482 51.646 1.00 17.91 FgBP
ATCM 17 H GLN 3 1.852 23.045 51.649 0.00 0.00 FKBP
20 AToM 18 CA GLN 3 2.789 21.445 52.664 1.00 20.42 FKBP
ATCM 19 CB GLW 3 2.600 22.065 54.056 1.00 26.51 EKBP
ATCM 20 CG GLN 3 2.416 21.064 55.181 1.00 34.77 FKBP
ATCM 21 CD GLN 3 3.718 20.451 55.660 1.00 41.28 FgBP
ATCM 22 OEl GLN 3 4.754 20.581 55.015 1.00 44.41 FKBP
25 AT~M 23 NE2 GLN 3 3.665 19.760 56.792 1.00 42.31 E~3P
AlaM 24 HE21 GLN 3 2.812 19.651 57.241 0.00 0.00 E~BP
ATOM 25 HE22 GrN 3 4.510 19.373 57.085 0.00 0.00 E~BP
A~OM 26 C GLN 3 1.817 20.280 52.454 1.00 17.06 EgBP
ATOM 27 O GLN 3 0.608 20.466 52.367 1.00 17.79 ~KBP
30 AT~M 28 N U~L 4 2.363 19.082 52.313 1.00 14.50 E~BP
ATaM 29 H U~L 4 3.336 19.008 52.381 0.00 0.00 FKBP
ATOM 30 CA U~L 4 1.540 17.890 52.127 1.00 13.12 FKBP
ATaM 31 CB U~L 4 2.054 17.030 50.930 1.00 10.68 ~K~P
AT~M 32 CGl U~L 4 0.924 16.172 50.364 1.00 7.51 FKBP
35 ATaM 33 CG2 U~L 4 2.630 17.930 49.842 1.00 9.85 FKBP
AT~M 34 C U~L 4 1.544 17.037 53.401 1.00 12.15 E~BP
AlaM 35 O U~L 4 2.600 16.705 53.947 1.00 15.65 EgBP
ATOM 36 N GLU 5 0.363 16.733 53.914 1.00 6.97 E~BP
ATaM 37 H GLU 5 -0.430 17.182 53.551 0.00 0.00 E~B~

CA 02229426 l998-03-ll WO 97/1~;659 PCT/US96/169~i3 AToM 38 CA GLU 50.27515.856 55.071 1.00 5.19 FKBP
ATCM 39 CB GLU 5-0.09616.664 56.308 1.00 8.81 F~3P
A~oM 40 CG GLU 50.62117.998 56.389 1.00 13.30 E~3P
AToM 41 CD GLU 50.34618.726 57.674 1.00 15.76 FKBP
ATCM 42 OE 1 GLU 51.18818.629 58.586 1.00 22.97 ~KBP
AT~M 43 OE 2 GLU 5-0.71019.385 57.778 1.00 22.20 EP~3P
AToM 44 C GLU 5-0.74314.752 54.848 1.00 3.46 FKBP
AToM 45 o GLU 5-1.93715.023 54.745 1.00 4.04 EKBP
AToM 46 N IHR 6-0.27113.511 54.805 1.00 2.00 ~KBP
10 AloM 47 H THR 60.66613.372 55.050 0.00 0.00 FKBP
ATCM 48 CA qHR 6-1.12512.365 54.508 1.00 5.26 EP~3P
ATCM 49 CF3 THR 6-0.33711.045 54.575 1.00 3.67 FKBP
ATCM 50 OGl qHR 60.88111.178 53.836 1.00 13.50 FKBP
AT~M 51 HGl THR 61.49310.508 54.158 0.00 0.00 E~3P
15 ATCM 52 CG2 THR 6-1.1329.919 53.972 1.00 2.01 FKBP
AloM 53 C T9R 6-2.35512.240 55.415 1.00 9.57 FKBP
A~oM 54 O THR 6-2.28112.454 56.629 1.00 15.36 E~3P
AloM 55 N lT~. 7-3.50912.099 54.772 1.00 8.03 E~3P
ATCM 56 H TT~ 7-3.50612.334 53.824 0.00 0.00 FKBP
20 ATCM 57 CA TT~ 7-4.75511.709 55.423 1.00 7.62 FKBP
AToM 58 C}3 Tl T~ 7 -5.965 12.465 54.799 1.00 5.96 FKBP
AI~M 59 CG2 TT.~. 7 -7.275 11.841 55.244 1.00 2.71 ~K~P
AI~M 60 CGl TT.T~ 7 -5.918 13.947 55.170 1.00 2.00 FgBP
Aq~M 61 CDl ILE 7-7.00814.764 54.527 1.00 2.01 F~BP
25 AI~M 62 C TT.F. 7-4.97910.199 55.249 1.00 11.96 ~K~P
AI~M 63 O TT.T~'. 7 -5.686 9.576 56.034 1.00 17.57 F~BP
ATOM 64 N ~ 8-4.4699.648 54.151 1.00 12.78 F~BP
AI~M 65 H SER 8-4.03910.240 53.499 0.00 0.00 E~BP
AI~M 66 CA SER 8-4.6298.226 53.842 1.00 12.24 F~BP
30 AqaM 67 CB SER 8-6.0797.930 53.450 1.00 6.63 FgBP
AI~M 68 OG SER 8-6.2366.581 53.064 1.00 12.33 FgBP
ATCM 69 HG SER 8-7.1796.384 53.022 0.00 0.00 F~BP
AI~M 70 C SER 8-3.6857.798 52.707 1.00 19.11 F~BP
AT~M 71 O SER 8-3.6078.454 51.664 1.00 17.14 FgBP
~ 35 AI~M 72 N PRO 9-2.8306.798 52.965 1.00 23.27 F~BP
AI~M 73 CD PRO 9-2.6656.076 54.238 1.00 22.82 ~K~P
AT~M 74 CA PRO 9-1.7066.548 52.055 1.00 25.68 F~BP
AI~M 75 CB PRO 9-0.7095.793 52.932 1.00 25.08 F~BP
AI~OM 76 CG PRO 9-1.5725.093 53.920 1.00 26.18 F~BP

CA 02229426 l998-03-ll W O 97/l5659 PCTAUS96/16953 ATCM 77 C P~O 9 -2.0565.766 50.778 1.00 28.63 ~ P
ATCM 78 O PRO 9 -3.0345.014 50.737 1.00 30.17 ~P
ATCM 79 N GhY 10 -1.2725.988 49.728 1.00 28.78 FKBP
ATCM 80 H GLY 10 -0.6026.696 49.796 0.00 0.00 FKBP
ATCM 81 CA GLY 10 -1.3735.168 48.531 1.00 32.81 E~3P
AToM 82 C GLY 10 -0.2414.154 48.412 1.00 34.72 FKBP
ATCM 83 O GLY 10 0.4793.916 49.386 1.00 37.49 FKBP
ATCM 84 N ASP 11 -0.0183.626 47.208 1.00 30.71 E~3P
ATCM 85 H ASP 11 -0.6643.846 46.504 0.00 0.00 FKBP
10 ATCM 86 CA ASP 11 0.9922.585 47.006 1.00 28.23 FKBP
ATCM 87 CB ASP 11 0.7671.862 45.675 1.00 23.26 ~'K~P
AToM 88 CG ASP 11 0.7132.804 44.493 1.00 21.83 FKBP
AloM 89 ODl ASP11 1.5913.686 44.377 1.00 13.66 FKBP
AToM 90 QD2 ASP11 -0.2042.635 43.659 1.00 23.38 FKBP
15 AToM 91 C ASP 11 2.4383.073 47.085 1.00 29.86 ~P
AToM 92 O ASP 11 3.3642.273 47.190 1.00 31.65 EKBP
ATCM 93 N GLY 12 2.6374 372 46.898 1.00 31.53 FKBP
ATCM 94 H GLY 12 1.8584.932 46.696 0.00 0.00 FKBP
ATCM 95 CA GLY 12 3.9584.948 47.081 1.00 34.79 FKBP
20 AToM 96 C GLY 12 4.9764.585 46.015 1.00 37.89 FKBP
ATCM 97 O GLY 12 6.1834.621 46.262 1.00 38.20 FgBP
ATCM 98 N ARG 13 4.4884.222 44.833 1.00 40.35 FKBP
AToM 99 H ARG 13 3.5723.918 44.840 0.00 0.00 FKBP
ATCM 100 C~ ARG 13 5.3574.030 43.667 1.00 43.98 FKBP
25 AlaM 101 CB A~G 13 5.7562.552 43.526 1.00 48.12 FKBP
A~OM 102 CG ARG 13 4.6241.555 43.724 1.00 56.08 FKBP
AlaM 103 CD ARG 13 5.1300.296 44.418 1.00 64.50 FKBP
ATOM 104 NE ARG 13 4.9630.361 45.870 1.00 70.55 FKBP
ATOM 105 HE A~G 13 5.5081.005 46.370 0.00 0.00 F~BP
30 ATOM 106 CZ ARG 13 4.154-0.435 46.567 1.00 73.54 FKBPATaM 107 NHl ARG13 4.023-0.266 47.877 1.00 74.82 E~BP
ATOM 108 HHll ARG 134.540 0.450 48.341 0.00 0.00 FKBP
A~OM 109 HHa2 ARG 133.414 -0.864 48.399 0.00 0.00 EKBP
AlaM 110 NH2 ARG13 3.490-1.415 45.961 1.00 75.14 FKBP
35 ATaM 111 HH21 ARG 133.595 -1.557 44.977 0.00 0.00 E~BP
AlaM 112 HH22 ARG 132.873 -2.001 46.485 0.00 0.00 EgBP
ATOM 113 C ARG 13 4.7204.537 42.369 1.00 40.88 E~3P
ATOM 114 O APG 13 5.4144.995 41.459 1.00 41.05 FgBP
AlaM 115 N IHR 14 3.3924.531 42.328 1.00 36.51 FKBP

CA 02229426 l998-03-ll AToM 116 H THR 14 2.944 3.906 42.915 0.00 0.00 E~3P
ATCM 117 CA THR 14 2.654 5.085 41.199 1.00 31.82 FKBP
ATCM 118 CB ~HR 14 1.296 4.362 41.010 1.00 34.22 FKBP
ATCM 119 OGl THR 14 1.477 2.945 41.172 1.00 31.38 FKBP
ATCM 120 HGl THR 14 0.659 2.484 40.952 0.00 0.00 FKBP
AloM 121 CG2 THR 14 0.722 4.651 39.621 1.00 29.70 F~3P
AloM 122 C THR 14 2.416 6.589 41.356 1.00 28.19 FgBP
ATCM 123 O IHR 14 1.373 7.023 41.846 1.00 25.30 ~K~P
ATCM 124 N PHE 15 3.430 7.364 41.000 1.00 27.12 E~3P
ATCM 125 H PHE 15 4.257 6.922 40.707 0.00 0 00 E~3P
ATCM 126 CA PHE 15 3.354 8.822 40.970 1.00 30.73 FKBP
ATCM 127 C~3 PHE 15 4.725 9.405 41.330 1.00 30.56 E~3P
AToM 128 CG PHE 15 5.202 9.018 42.701 1.00 31.81 E~3P
ATCM 129 CDl PHE 15 5.046 9.885 43.775 1.00 31.26 FKBP
ATCM 130 CD2 PHE 15 5.732 7.756 42.936 1.00 31.84 E~3P
ATCM 131 ~1 PHE 15 5.400 9.499 45 062 1.00 28.40 FKBP
ATCM 132 ~ PHE 15 6.089 7.363 44.218 1.00 31.05 F~3P
AToM 133 CZ EHE 15 5.919 8.237 45.283 1.00 31.16 FKBP
ATCM 134 C PHE 15 2.902 9.358 39.596 1.00 34.59 FgBP
AToM 135 O PHE 15 3.176 8.739 38.557 1.00 32.29 FKBP
AI~M 136 N ERO 16 2.232 10.53239.571 1.00 35.21 EgBP
AI~M 137 CD PRO 16 2.068 11.49340.671 1.00 32.43 E~BP
AI~IM 138 CA PRO 16 1.814 11.12238.296 1.00 36.14 E~BP
AI~M 139 CB PRO 16 0.852 12.24338.710 1.00 33.90 EgBP
AI~M 140 OG E'RO 16 0.905 12.31040.215 1.00 34.16 ~K~P
AI~M 141 C PRO 16 2.998 11.67237.512 1.00 38.59 EgBP
ATOM 142 O ERO 16 3.580 12.68337.895 1.00 40.62 EgBP
AlalM 143 N LYS 17 3.408 10.95836.467 1.00 44.97 kK~P
ATOM 144 H LYS 17 3.044 10.05436.366 0.00 0.00 I~P
AI~M 145 CA LYS 17 4.463 11.44135.572 1.00 49.95 EgBP
AI~M 146 CB LYS 17 4.856 10.35634.563 1.00 53.22 E~BP
AI~M 147 C'G LYS 17 5.973 9.427 35.030 1.00 61.47 FgBP
ATOM 148 CD LYS 17 5.425 8.075 35.497 1.00 69.15 EgBP
AI~IM 149 CE LYS 17 6.545 7.050 35.721 1.00 73.13 EgBP
AICIM 150 NZ LYS 17 6.050 5.706 36.174 1.00 72.77 FgBP
AI~M 151 HZl LYS 17 5.395 5.316 35.466 0.00 0.00 FgBP
AI~M 152 HZ2 LYS 17 5.550 5.803 37.081 0.00 0.00 EgBP
AICIM 153 HZ3 LYS 17 6.857 5.061 36.292 0.00 0.00 EgBP
ATOM 154 C LYS 17 4.031 12.70334.823 1.00 50.23 EgBP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 155 O LYS 17 2.88212.813 34.389 1.00 51.36 ~ P
ATCM 156 N ARG 18 4.93813.672 34.718 1.00 48.43 FKBP
AloM 157 H ARG 18 5.78213.553 35.190 0.00 0.00 FKBP
AToM 158 CA ARG 18 4.66614.908 33.986 1.00 46.13 EP~3P
ATCM 159 CB ARG 18 5.96815.671 33.732 1.00 47.22 FKBP
ATCM 160 CG ARG 18 5.75517.034 33.092 1.00 53.52 E~3P
AToM 161 CD ARG 18 7.03017.572 32.467 1.00 60.93 FKBP
AloM 162 NE ARG 18 8.00518.008 33.466 1.00 68.56 FKBP
AloM 163 HE ARG 18 8.69817.375 33.748 0.00 0.00 FKBP
10 ATCM 164 CZ AR~ 18 7.99519.201 34.054 1.00 71.82 FKBP
AToM 165 NHa ARG 18 8.95419.528 34.910 1.00 73.41 FKBP
Alo~ 166 HHll ARG 18 9.674 18.876 35.143 0.00 0.00 E~3P
AloM 167 HH12 ARG 18 8.923 20.425 35.358 0.00 0.00 FKBP
AloM 168 NH2 ARG 18 7.00020.052 33.826 1.00 74.07 E~?3P
15 AToM 169 HH21 ARG 18 6.256 19.798 33.207 0.00 0.00 FKBP
ATCM 170 HH22 ARG 18 6.994 20.950 34.267 0.00 0.00 ~x~P
AToM 171 C AR~ 18 3.96514.637 32.652 1.00 44.43 FKBP
AToM 172 O ARG 18 4.44013.832 31.844 1.00 44.85 FKBP
AloM 173 N GLY 19 2.77515.209 32.491 1.00 41.63 FKBP
20 ATCM 174 H GLY 19 2.43715.781 33.210 0.00 0.00 ~K~P
AloM 175 CA GLY 19 2.03715.058 31.246 1.00 36.64 EP~3P
AToM 176 C GLY 19 0.87814.072 31.281 1.00 33.71 FKBP
AloM 177 O GLY 19 0.24213.821 30.256 1.00 31.30 FKBP
AToM 178 N GLN 20 0.60313.509 32.454 1.00 31.51 FKBP
25 AloM 179 H GLN 20 1.27813.579 33.162 0.00 0.00 FKBP
AToM 180 CA GLN 20 -0.57112.655 32.647 1.00 27.89 FKBP
AloM 181 CB GLN 20 -0.29011.586 33.702 1.00 27.47 FKBP
ATCM 182 CG GLN 20 0.90710.723 33.416 1.00 29.05 E~3P
AToM 183 CD GLN 20 0.945 9.516 34.305 1.00 28.73 FKBP
30 ATaM 184 OEl GLN 20 1.852 9.355 35.112 1.00 29.95 FXBP
AlaM 185 NE2 GLN 20 -0.064 8.672 34.191 1.00 29.76 FKBP
ATaM 186 HE21 GLN 20 -0.781 8.854 33.542 0.00 0.00 E'KBP
ATOM 187 HE22 GLN 20 -0.025 7.895 34.776 0.00 0.00 FKBP
AT~M 188 C GLN 20 -1.78413.458 33.096 1.00 26.36 FKBP
35 ATaM 189 O GLN 20 -1.64114.558 33.652 1.00 23.69 FXBP
AlaM 190 N IHR 21 -2.95712.836 32.994 1.00 23.74 FKBP
AT~M 191 H THR 21 -2.99311.964 32.525 0.00 0.00 F'KBP
ATaM 192 CA THR 21 -4.18513.406 33.551 1.00 19.78 ~'K~P
AT~M 193 CB IHR 21 -5.39813.137 32.648 1.00 18.09 FKBP

, CA 02229426 l998-03-ll WO 97~15659 PCI-/US96~16953 ATCM 194 O~l THR 21 -5.103 13.576 31.319 1.00 25 65 FKBP
AToM 195 HGl THR 21 -4.667 12.831 30.862 0.00 0.00 ~ P
ATCM 196 CG2 IHR 21 -6.624 13.882 33.159 1.00 15.30 E~3P
ATCM 197 C IHR 21 -4.502 12.869 34.945 1.00 19.51 FKBP
5 ATCM 198 O IHR 21 -4.895 11.707 35.112 1.00 21.36 E~3P
ATCM 199 N CYS 22 -4.390 13.744 35.939 1.00 15.33 E~3P
ATCM 200 H CYS 22 -4.044 14.636 35.726 0.00 0.00 FKBP
ATCM 201 CA CYS 22 -4.794 13.421 37.302 1.00 7.92 E~3P
ATCM 202 C}3 CYS 22 -4.056 14.322 38.281 1.00 4.88 FKBP
10 ATCM 203 SG CYS 22 -2.300 14.464 37.959 1.00 9.58 FKBP
ATCM 204 C CYS 22 -6.301 13.589 37.492 1.00 7.02 FKBP
ATCM 205 O CYS 22 -6.840 14.676 37.284 1.00 8.66 FKBP
ATCM 206 N U~L 23 -6.991 12.485 37.760 1.00 4.33 FKBP
ATCM 207 H U~L 23 -6.547 11.617 37.634 0.00 0.00 FKBP
15 ATCM 208 CA V~L 23 -8.371 12.542 38.232 1.00 6.31 FKBP
ATCM 209 CF3 U~L 23 -9.180 11.314 37.743 1.00 3.87 FKBP
ATCM 210 CGl V~L 23 -10.658 11.483 38.043 1.00 2.00 E~3P
AToM 211 CG2 U~L 23 -8.972 11.121 36.264 1.00 5.84 FgBP
ATCM 212 C U~L 23 -8.353 12.579 39.770 1.00 11.82 FKBP
20 ATCM 213 O U~L 23 -7.678 11.765 40.416 1.00 17.38 E~3P
ATCM 214 N V~L 24 -8.946 13.622 40.342 1.00 10.13 FKBP
ATCM 215 H U~L 24 -9.395 14.274 39.762 0.00 0.00 EKBP
ATCM 216 CA V~L 24 -8.896 13.840 41.782 1.00 5.89 E~3P
ATCM 217 CB U~L 24 -7.806 14.883 42.170 1.00 3.59 FKBP
25 AToM 218 CGl U~L 24 -6.481 14.535 41.524 1.00 2.00 FKBP
AToM 219 CG2 U~L 24 -8.238 16.276 41.784 1.00 2.66 kK~P
ATCM 220 C U~L 24 -10.237 14.309 42.333 1.00 7.13 FKBP
AT~iM 221 O U~L 24 -11.078 14.804 41.583 1.00 8.15 E'KBP
A~iOM 222 N HIS 25 -10.481 14.041 43.617 1.00 8.15 EgBP
30 AIIOM 223 H HIS 25 -9.837 13.454 44.074 0.00 0.00 E~BP
A~iOM 224 CA HIS 25 -11.588 14.671 44.346 1.00 5.84 E~BP
ATIOM 225 CB HIS 25 -12.462 13.611 45.015 1.00 2.00 E~BP
ATCM 226 OG HIS 25 -13.789 13.412 44.351 1.00 2.00 E~BP
ATOM 227 CD2 HIS 25 -14.625 12.348 44.335 1.00 2.01 EKBP
35 AT~M 228 NDl HIS 25 -14.420 14.398 43.625 1.00 6.75 E~BP
AliOM 229 HDl HIS 25 -13.990 15.194 43.216 0.00 0.00 F~BP
- ATOM 230 CEl HIS 25 -15.591 13.959 43.204 1.00 2.00 E~BP
AT~M 231 NE2 HIS 25 -15.738 12.715 43.619 1.00 2.00 F~BP
ATCM 232 HE2 HIS 25 -16.532 12.146 43.449 0.00 0.00 E~BP

CA 02229426 l998-03-ll W O 97/156S9 PCT~US96/16953 ATCM 233 C HIS 25 -11.013 15.611 45.409 1.00 5.86 FKBP
AToM 234 O HIS 25 -10.085 15.233 46.125 1.00 8.08 EKBP
ATCM 235 N TYR 26 -11.456 16.867 45.414 1.00 2.00 ~K~P
ATCM 236 H TYR 26 -12.071 17.155 44.712 0.00 0.00 FKBP
5 ATCM 237 CA TYR 26 -10.956 17.840 46.389 1.00 2.00 FKBP
ATCM 238 CB TYR 26 -9.950 18.827 45.770 1.00 3.39 ~K~P
ATCM 239 CG TYR 26 -10.570 19.839 44.824 ~.00 8.68 FKBP
AToM 240 CDl TYR 26 -11.017 21.080 45.279 1.00 7.15 EKBP
ATCM 241 ~1 TYR 26 -11.725 21.939 44.434 1.00 11.31 FKBP
10 ATCM 242 CD2 TYR 26 -10.831 19.497 43.495 1.00 11.88 FKBP
ATCM 243 CE2 TYR 26 -11.536 20.342 42.651 1.00 8.71 FgBP
ATCM 244 CZ TYR 26 -11.982 21.551 43.122 1.00 9.36 FgBP
ATCM 245 CH TYR 26 -12.704 22.348 42.274 1.00 9.02 FKBP
ATCM 246 HH TYR 26 -12.792 21.935 41.411 0.00 0.00 FgBP
15 ATCM 247 C TYR 26 -12.057 18.638 47.045 1.00 2.60 FKBP
ATCM 248 O TYR 26 -13.162 18.746 46.515 1.00 2.96 ~K~P
ATCM 249 N THR 27 -11.778 19.056 48.276 1.00 8.98 E~3P
ATCM 250 H THR 27 -11.030 18.611 48.735 0.00 0.00 ~K~P
ATCM 251 CA IHR 27 -12.469 20.164 48.924 1.00 3.70 ~K~P
20 ATCM 252 CB IHR 27 -13.138 19.737 50.219 1.00 3.82 FKBP
ATCM 253 OGl THR 27 -13.987 18.606 49.972 1.00 5.37 FKBP
ATCM 254 HGl IHR 27 -13.409 17.851 49.785 0.00 0.00 FKBP
ATaM 255 CG2 THR 27 -13.957 20.891 50.779 1.00 2.73 E~BP
ATaM 256 C THR 27 -11.436 21.213 49.273 1.00 2.00 ~K~P
25 ATaM 257 O THR 27 -10.365 20.891 49.784 1.00 2.00 E~BP
ATCIM 258 N (~Y 28 -11.664 22.419 48.779 1.00 5.64 EgBP
ATCIM 259 H (~LY 28 -12.274 22.498 48.038 0.00 0.00 FE~BP
AT~IM 260 C~ GLY 28 -10.813 23.538 49.128 1.00 8.04 E~BP
AT{~M 261 C GLY 28 -11.438 24.437 50.175 1.00 8.15 E'KBP
30 ATOM 262 O ~LY 28 -12.646 24.729 50.131 1.00 9.73 EgBP
ATC~IM 263 N MET 29 -10.619 24.887 51.117 1.00 4.38 EgBP
ATCIM 264 H MEI 29 -9.683 24.601 51.122 0.00 0.00 ~K~P
ATCIM 265 CA ~ 29 -11.091 25.812 52.138 1.00 6.14 EgBP
ATCIM 266 CB MEI 29 -11.512 25.047 53.404 1.00 11.72 E~BP
35 ATC~IM 267 CG MEI 29 -10.445 24.128 53.999 1.00 14.88 E~BP
ATC~M 268 5D MEI 29 -11.065 22.500 54.510 1.00 7.90 E~BP
ATaM 269 CE MEr 29 -12.824 22.854 54.721 1.00 5.60 EgBP
ATC~M 270 C MEI 29 -10.033 26.845 52.477 1.00 6.50 E~BP
ATOM 271 O MEI 29 -8.847 26.630 52.242 1. O0 5.89 E~BP

CA 02229426 l998-03-ll WO 97~1S6S9 PCTnUS96/~6953 ATCM 272 N LEU 30-10.477 28.013 52.923 1.00 11.28 ~K~P
ATCM 273 ~ LEU 30-11.444 28.168 52.902 0.00 0.00 FKBP
ATCM 274 C~ LEU 30 -9.561 29.028 53.443 1.00 14.74 ~K~P
ATCM 275 CB LEU 30-10.281 30.379 53.572 1.00 12.99 FKBP
ATCM 276 CG LEU 30-10.887 30.967 52.292 1.00 10.36 FKBP
ATCM 277 CDl LEU 30-12.064 31.842 52.668 1.00 12.99 FKBP
ATCM 278 CD2 LEU 30 -9.848 31.761 51.510 1.00 3.34 FKBP
ATCM 279 C LEU 30 -9.042 28.573 54.805 1.00 14.12 FKBP
ATCM 280 O LEU 30 -9.664 27.732 55.453 1.00 16.16 FKBP
ATCM 281 N GLU 31 -7.944 29.169 55.262 1.00 14.66 FKBP
ATCM 282 H GLU 31 -7.506 29.828 54.682 0.00 0.00 FKBP
ATCM 283 CA GLU 31 -7.266 28.722 56.483 1.00 17.28 FKBP
ATCM 284 CB GLU 31 -6.294 29.799 56.962 1.00 14.61 FKBP
ATCM 285 CG GLU 31 -5.818 29.586 58.382 1.00 22.25 FKBP
ATCM 286 CD GLU 31 -4.510 30.284 58.698 1.00 26.77 FKBP
ATCM 287 OE 1 GLU 31 -4.245 31.362 58.107 1.00 21.74 FK~3P
ATo~ 288 OE 2 GLU 31 -3.774 29.762 59.576 1.00 23.08 FKBP
ATCM 289 C GLU 31 -8.187 28.313 57.642 1.00 18.96 FKBP
ATCM 290 O GLU 31 -8.008 27.258 58.262 1.00 18.93 FKBP
ATCM 291 N ASP 32 -9.238 29.090 57.855 1.00 17.34 FKBP
ATCM 292 H ASP 32 -9.405 29.814 57.223 0.00 0.00 FKBP
Al~IM 293 CA ASP 32-10.116 28.866 58.996 1.00 19.84 FKBPAI~M 294 CB ASP 32-10.894 30.142 59.308 1.00 27.98 FKBPAI~M 295 OG ASP 32-11.601 30.704 58.090 1.00 34.72 FKBPAI~IM 296 QDl ASP 32-12.727 30.254 57.801 1.00 32.49 FKBPAI~M 297 OD2 ASP 32-11.023 31.588 57.415 1.00 43.34 FKBPAq~lM 298 C ASP 32-11.096 27.713 58.816 1.00 18.08 FKBPAI~M 299 O ASP 32-11.986 27.541 59.638 1.00 17.85 FKBPAIOIM 300 N GLY 33-10.994 26.998 57.697 1.00 18.90 FE~3P
AI~IM 301 H GLY 33-10.204 27.111 57.137 0.00 0.00 F~BP
AI~M 302 CA GLY 33-11.909 25.896 57.417 1.00 14.65 FKBPAIOM 303 C GLY 33-13.146 26.270 56 616 1.00 10.95 F'KBP
AI~M 304 O GLY 33-14.020 25.437 56.370 1.00 11.28 F~BPAIOIM 305 N LYS 34-13.235 27.536 56.230 1.00 5.53 F'KBP
AIOM 306 H LYS 34-12.565 28.159 56.564 0.00 0.00 E~BP
AI~M 307 CA LYS 34-14.320 27.999 55.379 1.00 7.65 F ~ P
- A1~6M 308 CB LYS 34-14.270 29.521 55.255 1.00 15.91 F~BP
ATaM 309 CG LYS 34-15.468 30.131 54.554 1.00 23.47 F~BPAIOIM 310 CD LYS 34-15.360 31.646 54.513 1.00 34.71 F~BP

CA 02229426 l998-03-ll AToM 311 OE LYS 34 -15.213 32.245 55.918 1.00 38.38 FKBP
AToM 312 NZ LYS 34 -13.805 32.635 56.227 1.00 41.83 F~3P
ATCM 313 HZl LYS 34 -13.475 33.324 55.520 0.00 0.00 EKBP
AloM 314 HZ2 LYS 34 -13.196 31.792 56.185 0.00 0.00 FKBP
AToM 315 HZ3 LYS 34 -13.749 33.055 57.176 0.00 0.00 EP~3P
ATCM 316 C LYS 34 -14.222 27.369 53.991 1.00 7.56 E~3P
AloM 317 O LYS 34 -13.290 27.653 53.232 1.00 3.26 FKBP
AloM 318 N LYS 35 -15.067 26.371 53.757 1.00 8.73 FKBP
ATCM 319 H LYS 35 -15.554 26.012 54.530 0.00 0.00 FKBP
AloM 320 CA LYS 35 -15.178 25.719 52.459 1.00 8.15 FKBP
AToM 321 C3 LYS 35 -16.269 24.657 52.511 1.00 2.40 FKBP
ATCM 322 C~ LYS 35 -16.379 23.854 51.249 1.00 7.41 FKBP
AToM 323 CD LYS 35 -17.142 22.573 51.484 1.00 11.33 E~3P
AloM 324 OE LYS 35 -18.637 22.803 51.464 1.00 15.67 FKBP
AloM 325 NZ LYS 35 -19.352 21.501 51.304 1.00 20.77 FKBP
ATCM 326 HZl LYS 35 -19.180 20.892 52.129 0.00 0.00 FKBP
AloM 327 HZ2 LYS 35 -19.004 21.025 50.450 0.00 0.00 FKBP
AloM 328 HZ3 LYS 35 -20.373 21.681 51.212 0.00 0.00 FKBP
AloM 329 C LYS 35 -15.520 26.736 51.378 1.00 13.32 FKBP
ATCM 330 O LYS 35 -16.387 27.596 51.587 1.00 16.59 FKBP
AToM 331 N PHE 36 -14.796 26.690 50.257 1.00 12.19 FKBP
ATOM 332 H PHE 36 -13.981 26.149 50.278 0.00 0.00 FKBP
ATCM 333 CA PHE 36 -15.167 27.504 49.098 1.00 8.93 FKBP
ATCM 334 CB PHE 36 -14.077 28.541 48.753 1.00 4.86 FKBP
ATCM 335 CG PHE 36 -12.728 27.959 48.415 1.00 3.36 FKBP
AqOM 336 CDl PHE 36 -11.660 28.108 49.295 1.00 4.33 FKBP
ATOM 337 CD2 PHE 36 -12.470 27.442 47.151 1.00 7.57 ~K~P
ATOM 338 CEl PHE 36 -10.350 27.758 48.916 1.00 5.11 FKBP
ATCM 339 ~ EHE 36 -11.167 27.092 46.766 1.00 5.95 FKBP
AIOM 340 CZ PHE 36 -10.110 27.250 47.648 1.00 2.00 FKBP
AloM 341 C PHE 36 -15.553 26.696 47.861 1.00 11.24 FKBP
AloM 342 O PHE 36 -16.499 27.050 47.152 1.00 9.15 FKBP
AIOM 343 N ASP 37 -14.972 25.507 47.738 1.00 11.21 FKBP
ATC~M 344 H ASP 37 -14.365 25.202 48.445 0.00 0.00 FKBP
ATCEM 345 CA ASP 37 -15.201 24.672 46.568 1.00 8.81 FgBP
ATOM 346 CB ASP 37 -14.340 25.220 45.416 1.00 12.70 FKBP
AT{ ~M 347 CG ASP 37 -14.583 24.518 44.091 1.00 11.57 F~BP
ATOM 348 ODl ASP 37 -15.679 23.968 43.855 1.00 7.88 FgBP
AT~EM 349 OD2 ASP 37 -13.665 24.565 43.254 1.00 15.66 FKBP

CA 02229426 l998-03-ll WO 97/lS659 PCT/US96/16953 AToM 350 C ASP 37 -14.874 23.199 46.864 1.00 2.00 ~KEP
AToM 351 O ASP 37 -13.90S 22.904 47.545 1.00 2.01 FKBP
AToM 352 N ~K 38 -15.751 22.291 46.450 1.00 2.52 FKBP
ATCM 353 H ~K 38 -16.607 22.613 46.095 0.00 0.00 FKBP
5 ATCM 354 CA SER 38 -15.461 20.850 46.493 1.00 2.33 FKBP
AToM 355 CB SER 38 -15.954 20.223 47.800 1.00 12.19 E~3P
AToM 356 OG 5ER 38 -15.979 18.804 47.722 1.00 9.54 FKBP
AToM 357 HG SER 38 -15.613 18.490 48.571 0.00 0.00 FKBP
ATCM 358 C SER 38 -16.108 20.110 45.349 1.00 2.00 ~K~P
10 AToM 359 O 5ER 38 -17.313 20.210 45.168 1.00 2.31 FKBP
AToM 360 N SER 39 -15.339 19.252 44.684 1.00 2.00 FKBP
ATCM 361 H 5~K 39 -14.397 19.223 44.967 0.00 0.00 FKBP
AToM 362 CA 5ER 39 -15.840 18.414 43.584 1.00 3.72 FKBP
ATCM 363 CB S~R 39 -14.682 17.758 42.825 1.00 3.50 E~3P
15 AToM 364 OG 5ER 39 -13.861 16.976 43.683 1.00 3.28 FKBP
AToM 365 HG SER 39 -14.195 17.054 44.589 0.00 0.00 FKBP
AToM 366 C SER 39 -16.762 17.317 44.088 1.00 9.63 FKBP
ATCM 367 O ~K 39 -17.547 16.751 43.324 1.00 6.74 FKBP
ATCM 368 N ARG 40 -16.624 16.994 45.376 1.00 13.48 FKBP
20 AToM 369 H ARG 40 -16.027 17.536 45.944 0.00 0.00 FKBPATOM 370 CA ARG 40 -17.441 15.972 46.025 1.00 12.15 FKBP
AToM 371 CB ARG 40 -16.800 15.538 47.345 1.00 4.43 FKBP
ATOM 372 oG ARG 40 -15.385 15.003 47.220 1.00 2.00 FgBP
ATOM 373 CD ARG 40 -14.978 14.243 48.484 1.00 3.29 E~BP
25 ATaM 374 NE ARG 40 -13.546 13.940 48.561 1.00 4.66 E~BP
ATOM 375 HE ~RG 40 -12.924 14.683 48.660 0.00 0.00 E~BP
ATOM 376 CZ ARG 40 -13.031 12.714 48.497 1.00 2.00 FKBP
ATaM 377 NHl ARG 40 -11.727 12.527 48.631 1.00 2.00 E~BP
ATOM 378 HHll ARG 40 -11.112 13.308 48.782 0.00 0.00 E~BP
30 ATOM 379 HH12 ARG 40 -11.374 11.597 48.585 0.00 0.00 E~BPAT~OM 380 NH2 ARG 40 -13.812 11.673 48.262 1.00 2.00 ~x~P
ATOM 381 HH21 AR~ 40 -14.794 11.785 48.128 0.00 0.00 E~BP
ATaM 382 HH22 ARG 40 -13.417 10.752 48.214 0.00 0.00 FKBP
ATOM 383 C ARG 40 -18.883 16.433 46.270 1.00 17.11 E~BP
35 ATOM 384 O ARG 40 -19.798 15.612 46.350 1.00 17.06 EgBP
ATOM 385 N ASP 41 -19.085 17.746 46.370 1.00 20.79 E~BP
ATIOM 386 H A5P 41 -18.307 18.340 46.438 0.00 0.00 E~BP
ATOM 387 CA ASP 41 -20.435 18.315 46.454 1.00 26.68 E~BP
ATOM 388 CB ASP 41 -20.375 19.784 46.879 1.00 26.55 E~BP

W O 97/15659 PCT~US96/16953 AI~M 389 CG ASP 41 --19.64119.993 48.195 1.00 34.97 EgBP
AI~M 390 CDl ASP 41 -19.25119.001 48.852 1.00 38.14 ~x~P
AI~M 391 CD2 ASP 41 -19.42621.167 48.559 1.00 36.52 E~AI~M 392 C ASP 41 -21.187 18.206 45.124 1.00 30.48 l~BP
AI~M 393 O ASP 41 -22.416 18.085 45.106 1.00 31.53 FKBP
Al~ 394 N ARG 42 -20.447 18.307 44.018 1.00 31.99 FKBP
AI~IM 395 H AK~ 42 -19.519 18.595 44.120 0.00 0.00 E~BP
AI~M 396 CA ARG 42 -21.006 18.124 42.676 1.00 26.25 E~BP
AI~M 397 CB AP~ 42 -20.168 18.865 41.625 1.00 22.17 E~BP
10 AI~M 398 CG ARG 42 -19.815 20.302 41.976 1.00 26.16 F~P
AI~M 399 CD ARG 42 -18.697 20.840 41.089 1.00 29.95 E~BP
AI~M 400 NE ARG 42 --17.703 19.814 40.769 1.00 40.62 FKBP
AI~I 401 HE ARG 42 -17.911 18.869 40.922 0.00 0.00 EgBP
AI~M 402 CZ AR~ 42 -16.491 20.058 40.273 1.00 44.80 FKBP
15 AlaM 403 NHl A~ 42 -15.68419.045 39.978 1.00 43.55 F~3P
Aq~[ 404 HHLL AR~ 42 -16.00218.108 40.125 0.00 0.00 E~P
AI~IM 405 HH12 ARG 42 -14.77319.213 39.600 0.00 0.00 EgBP
AI~M 406 NH2 ARG 42 -16. D7021.306 40.089 1.00 47.04 l~BP
AI~M 407 HH21 ARG 42 -16.65522.080 40.328 0.00 0.00 E~KBP
20 AI~M 408 HH22 ARG 42 -15.15621.465 39.719 0.00 0.00 E~KBP
AI~M 409 C ~ 42 -21.051 16.642 42.320 1.00 25 62 E~BP
AI~M 410 O ARG 42 -21.679 16.252 41.338 1.00 29.04 FgBP
AI~M 411 N ASN 43 --20.302 15.832 43.064 1.00 20.94 FE~P
AI~M 412 H A~N 43 -19.786 16.217 43.793 0.00 0.00 l~BP
25 Al~ 413 CA ASN 43 -20.290 14.392 42.840 1.00 21.52 F~BP
Al~ 414 CB ASN 43 -21.724 13.852 42.869 1.00 23.52 ~BP
AI~M 415 C~ ASN 43 -21.808 12.455 43.431 1.00 28.90 FKBP
AI~M 416 CIDl ASN 43 -20.78911.802 43.662 1.00 28.67 E~P
AI~M 417 ND2 ASN 43 -23.02511.987 43.662 1.00 33.33 F~P
30 A~ 418 HD21 ASN 43 -23.78612.557 43.466 0.00 0.00 E~BPAIaM 419 HD22 ASN 43 -23.04111.094 44.043 0.00 0.00 E~BP
AI~M 420 C ASN 43 -19.628 14.078 41.498 1.00 20.93 ~ P
Al~ 421 O ASN 43 -20.087 13.228 40.740 1.00 21.51 l~BP
AI~M 422 N LYS 44 -18.475 14.696 41.275 1.00 20.83 FKBP
35 Al~ 423 H LYS 44 -18.152 15.288 41.984 0.00 0.00 E~BPAI~M 424 CA LYS 44 -17.874 14.757 39.947 1.00 19.75 E~BP
AI~M 425 CB LYS 44 --18.554 15.879 39.148 1.00 24.43 E~BP
AI~M 426 QG LYS 44 -18.478 15.755 37.638 1.00 23.61 ~PAI~I 427 CD LYS 44 -18.796 17.084 36.965 1.00 29.64 F~BP

-WO 97/15659 PCT~US96/16953 AToM 428 OE LYS 44 -20.212 17.565 37.282 1.00 34.29 ~K~P
ATCM 429 NZ LYS 44 -20.543 18.848 36.583 1.00 38.07 FKBP
AT~M 430 HZl LYS 44 -20.497 18.697 35.555 0.00 0.00 FKBP
AToM 431 HZ2 LYS 44- 19.853 19.580 36.854 0.00 0.00 FKBP
ATCM 432 HZ3 LYS 44-21.496 19.168 36.846 0.00 0.00 FKBPAToM 433 C LYS 44-16.361 15.014 40.049 1.00 17.91 FKBPATGM 434 o LYS 44-15.928 16.029 40.596 1.00 21.43 FKBPAToM 435 N PRO 45-15.545 14.014 39.695 1.00 16.30 FKBPAToM 436 CD PRO 45-15.909 12.612 39.438 1.00 17.34 E~3PATCM 437 CA PRO 45-14.093 14.182 39.830 1.00 17.48 FKBPAToM 438 CB PRO 45-13.539 12.779 39.557 1.00 14.90 FKBPAToM 439 CG PRO 45-14.679 11.871 39.886 1.00 19.40 EXBPATCM 440 C PRD 45-13.496 15.228 38.887 1.00 15.55 FKBPAToM 441 O ~RO 45-13.942 15.399 37.753 1.00 17.90 FKBPAToM 442 N EHE 46-12.501 15.942 39.389 1.00 11.92 FKBPAToM 443 H PHE 46-12.151 15.695 40.268 0.00 0.00 E~33P
ATCM 444 CA PHE 46- 11.825 16.989 38.637 1.00 10.26 EKBPAToM 445 CB EHE 46-11.346 18.068 39.615 1.00 7.26 EP~3P
AToM 446 CG EHE 46-10.549 19.165 38.980 1.00 2.00 E~3PAToM 447 CDl PHE 46 -9.192 19.284 39.246 1.00 2.00 FKBPATCM 448 ~D2 PHE 46-11.180 20.149 38.222 1.00 2.00 FKBPAToM 449 C 1 EHE 46 -8.472 20.369 38.779 1.00 2.30 ~K~PAI~M 450 OE2 PHE 46-10.475 21.243 37.749 1.00 2.00 EXBPAl~OM 451 CZ EHE 46 -9.117 21.357 38.030 1.00 5.96 ~'K13P
AICM 452 C PHE 46-10.644 16.371 37.898 1.00 10.45 E'KBP
A~OM 453 O EHE 46 -9.984 15.479 38.421 1.00 16.71 E'KBP
A~M 454 N LYS 47-10.421 16.782 36.655 1.00 9.72 E'KBP
AICM 455 H LYS 47-11.004 17.458 36.253 0.00 0.00 EXBPAI~M 456 CA LYS 47 -9.293 16.255 35.893 1.00 4.83 E'KBP
AI~M 457 CB LYS 47 -9.770 15.421 34.700 1.00 5.22 E'KBP
AI~M 458 C~ LYS 47-10.510 14.147 35.058 1.00 8.65 E'KBP
Al~OM 459 CD LYS 47-11.587 13.853 34.032 1.00 11.93 ~'K~P
A~OM 460 CE LYS 47-11.326 12.543 33.312 1.00 10.86 E'KBP
AI~IM 461 NZ LYS 47~11.608 11.397 34.216 1.00 15.06 E~BP
- 35 A~M 462 HZl LYS 47-12.594 11.462 34.542 0.00 0.00 E'KBP
A~OM 463 HZ2 LYS 47-10.981 11.442 35.042 0.00 0.00 E'KBP
AICM 464 HZ3 LYS 47-11.471 10.498 33.712 0.00 0.00 E'KBP
Al~M 465 C LYS 47 -8.435 17.389 35.395 1.00 2.00 E'KBP
AI~M 466 O LYS 47 -8.943 18.449 35.061 1.00 2.00 EgBP

CA 02229426 lsgs-03-ll ATCM 467 N PHE 48-7.125 17.205 35.472 1.00 2.00 E~3P
ATCM 468 H P~ 48-6.799 16.438 35.994 0.00 0.00 ~g~P
AToM 469 CA PHE 48-6.191 18.157 34.896 1.00 6.26 FgBP
ATCM 470 CB P ~ 48-5.964 19.323 35.875 1.00 2.45 FK~P
ATCM 471 CG PHE 48-4.948 19.036 36.942 1.00 4.20 FKBP
ATCM 472 CDl PHE 48-5.254 18.188 38.005 1.00 2.00 EP~3P
AToM 473 CD2 PHE 48-3.650 19.548 36.837 1.00 2.00 FKBP
AloM 474 CEl PHE 48-4.282 17.837 38.936 1.00 2.00 FKBP
ATCM 475 ~ PHE 48-2.664 19.200 37.769 1.00 2.59 FKBP
10 AloM 476 CZ PHE 48-2.983 18.340 38.817 1.00 2.53 FKBP
AToM 477 C PHE 48-4.866 17.469 34.538 1.00 10.81 FKBP
ATCM 478 O PHE 48-4.480 16.476 35.159 1.00 16.65 EP~3P
AToM 479 N MET 49-4.181 17.984 33.526 1.00 13.39 FKBP
AloM 480 H MET 49-4.543 18.774 33.084 0.00 0.00 FKBP
15 ATCM 481 CA MET 49-2.892 17.437 33.113 1.00 16.66 FKBP
AToM 482 CB MET 49-2.690 17.663 31.614 1.00 22.76 FKBP
ATCM 483 CG MET 49-1.538 16.885 31.016 1.00 32.61 FKBP
ATCM 484 SD MET 49-0.985 17.585 29.454 1.00 46.48 FKBP
ATCM 485 OE MET 49-0.812 16.105 28.435 1.00 45.16 FKBp 20 AToM 486 C MET 49-1.768 18.109 33.898 1.00 16.05 FKBP
ATCM 487 O MET 49-1.749 19.332 34.046 1.00 17.38 rK~P
AToM 488 N LEU 50-0.852 17.314 34.433 1.00 16.03 FKBP
AloM 489 H LEU 50-0.925 16.348 34.258 0.00 0.00 EP~3P
AI~IM 490 CALEU 50 0.16617.848 35.336 1.00 16.25 EgBP
25 ATOM 491 CB LEU 500.587 16.777 36.350 1.00 16.08 EPBP
ATOM 492 as LEU 501.737 17.151 37.290 1.00 15.77 EgBP
AIIOM 493 CDlLEU 50 1.18917.731 38.587 1.00 17.22 FKBP
ATaM 494 CD2 LEU50 2.591 15.92337.561 1.00 17.09 FKBP
Al~IM 495 C LEU 50 1.39818.380 34.606 1.00 18.27 FKBP
30 Al~IM 496 0 LEU 50 2.13017.629 33.962 1.00 17.62 ~K~P
A'IIOM 497 N GLY 51 1.65919.671 34.773 1.00 24.68 FKBP
Al~IM 498 H GLY 51 1.07120.196 35.347 0.00 0.00 ~K~P
AI~M 499 CA GLY 512.832 20.281 34.163 1.00 28.29 EgBP
ATCM 500 C GLY 512.511 21.451 33.246 1.00 30.06 EgBP
35 ATaM 501 O GLY 513.312 22.367 33.092 1.00 31.10 FKBP
AI~M 502 N LYS 521.283 21.482 32.739 1.00 31.85 FgBP
AI~IM 503 H LYS 52 0.65120.805 33.051 0.00 0.00 E~BP
ATaM 504 CA LYS 520.883 22.452 31.724 1.00 30.54 FKBP
ATaM 505 CB LYS 52-0.281 21.887 30.899 1.00 33.91 FgBP

CA 02229426 l998-03-ll WO 97/1~659 PCTAUS96;/169~3 ATCM 506 CG LYS 52 -0.110 20.427 30.479 1.00 38.74 ~K~P
ATCM 507 CD LYS 52 1.015 20.263 29.458 1.00 44.12 ~K~P
ATCM 508 OE LYS 52 1.708 18.913 29.584 1.00 44.68 FKBP
ATCM 509 NZ LYS 52 2.954 18.849 28.767 1.00 46.84 FKBP
ATCM 510 HZl LYS 52 3.632 19.546 29.134 0.00 0.00 E~3P
AToM 511 HZ2 LYS 52 2.732 19.066 27.773 0.00 0.00 FKBP
ATCM 512 HZ3 LYS 52 3.361 17.895 28.831 0.00 0.00 FKBP
AloM 513 C LYS 52 0.475 23.795 32.323 1.00 27.06 EP~3P
ATCM 514 O LYS 52 -0.349 24.498 31.741 1.00 30.79 FKBP
ATCM 515 N GLN 53 1.025 24.130 33.490 1.00 21.58 FKBP
ATCM 516 H GLN 53 1.847 23.671 33.747 0.00 0.00 FKBP
ATCM 517 CA GLN 53 0.572 25.282 34.279 1.00 18.83 EP~3P
ATCM 518 CB GLN 53 1.219 26.571 33.768 1.00 25.35 FKBP
AToM 519 CG GLN 53 2.599 26.848 34.333 1.00 34.50 FKBP
ATCM 520 CD GLW 53 3.585 25.737 34.025 1.00 42.12 FKBP
AToM 521 OE 1 GLN 53 3.854 25.432 32.865 1.00 46.61 FRBP
AloM 522 NE2 GLN 53 4.096 25.098 35.067 1.00 46.53 EK~BP
ATCM 523 HE21 GLN 53 3.837 25.352 35.970 0.00 0.00 FKBP
ATCM 524 HE22 GLN 53 4.723 24.391 34.821 0.00 0.00 FKBP
ATCM 525 C GLW 53 -0.950 25.457 34.313 1.00 15.57 E~3p ATCM 526 O GLN 53 -1.456 26.570 34.380 1.00 17.17 FKBP
ATCM 527 N GLU 54 -1.672 24.344 34.338 1.00 12.00 FKBP
AToM 528 H GLU 54 -1.188 23.505 34.304 0.00 0.00 FKBP
A~OM 529 CA GLU 54 -3.126 24.378 34.306 1.00 6.49 E'KBP
AI~M 530 CB GLU 54 -3.666 23.022 33.878 1.00 6.66 E~BP
AI~M 531 C~G GLU 54 -4.296 23.020 32.516 1.00 4.63 ~I~P
AI~M 532 CD GLU 54 -4.414 21.628 31.960 1.00 11.57 E~BPA~OM 533 OEl GLU 54 -3.543 21.242 31.157 1.00 18.19 E~BPAq~lM 534 OE2 ~T 54 -5.339 20.896 32.368 1.00 10.83 FKBPA~OM 535 C GLU 54 -3.741 24.762 35.642 1.00 5.69 E'KBP
Al~IM 536 O GLU 54 -4.873 25.238 35.696 1.00 4.44 E~BP
A~OM 537 N VAL 55 -3.035 24.444 36.722 1.00 4.70 E'KBP
AI~M 538 H U~l- 55 -2.142 24.084 36.580 0.00 0.00 E~BP
AI~IM 539 CA VAL 55 -3.513 24.731 38.071 1.00 6.95 ~P
AI~I 540 CB U~L 55 -3.774 23.446 38.849 1.00 3.43 E~BP
Al~IM 541 CGl U~ 55 -4.995 22.759 38.309 1.00 9.22 E~BP
AI~M 542 CG2 V~l 55 -2.573 22.538 38.761 1.00 2.21 E~BP
AI~IM 543 C U~ 55 -2.500 25.559 38.849 1.00 9.75 E ~ P
A~M 544 O VAI. 55 -1.369 25.737 38.408 1.00 9.34 E~BP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 545 N TT~ 56 -2.887 26.026 40.031 1.00 12.04 FKBP
AToM 546 H ILE 56 -3.799 25.844 40.322 0.00 0.00 FgBP
ATCM 547 CA TT~ 56 -1.964 26.785 40.869 1.00 10.94 FKBP
ATCM 548 CB TT~ 56 -2.674 27.36S 42.123 1.00 9.38 FK~P
5 AToM 549 CG2 ILE 56 -3.665 28.449 41.701 1.00 9.44 Q
AloM 550 CGl TT.~ 56 -3.377 26.263 42.920 1.00 4.02 FKBP
AloM 551 CDl TT.F. 56 -4.003 26.756 44.206 1.00 2.00 F~3P
AloM 552 C TT~ 56 -0.734 25.962 41.286 1.00 12.55 F~3P
AloM 553 O ILE 56 -0.759 24.729 41.270 1.00 15.13 FKBP
10 ATCM 554 N ARG 57 0.353 26.651 41.615 1.00 10.58 F~33P
AloM 555 H ARG 57 0.284 27.627 41.637 0.00 0.00 FKBP
AloM 556 CA ARG 57 1.648 26.013 41.850 1.00 12.39 FKBP
AloM 557 CB ARG 57 2.707 27.091 42.058 1.00 13.28 E~3P
ATCM 558 CG ARG 57 4.115 26.573 42.013 1.00 16.07 FKBP
15 ATCM 559 CD ARG 57 5.090 27.708 42.068 1.00 18.63 FKBP
AloM 560 NE ARG 57 6.447 27.196 42.189 1.00 29.56 FKBP
AloM 561 HE ARG 57 6.567 26.228 42.278 0.00 0.00 FKBP
ATCM 562 CZ ARG 57 7.535 27.957 42.208 1.00 29.74 FKBP
AloM 563 NHl ARG 57 8.728 27.390 42.332 1.00 34.84 FKBP
20 AToM 564 HHll ARG 57 8.794 26.398 42.443 0.00 0.00 FKBP
AloM 565 HH12 ARG 57 9.551 27.954 42.380 0.00 0.00 FP~3P
ATOM 566 NH2 ARG 57 7.430 29.277 42.124 1.00 24.22 F~BP
AlaM 567 HH21 A~G 57 6.534 29.712 42.038 0.00 0.00 FgBP
AT~M 568 HH22 ARG 57 8.258 29.836 42.149 0.00 0.00 F~BP
25 A~OM 569 C ARG 57 1.700 25.006 43.014 1.00 15.27 F~BP
ATOM 570 O AR!G 57 2.321 23.946 42.901 1.00 16.77 F~BP
A~OM 571 N GLY 58 1.084 25.349 44.142 1.00 13.48 F~BP
ATaM 572 H GLY 58 0.719 26.253 44.227 0.00 0.00 F~BP
ATCM 573 CA GLY 58 0.973 24.402 45.240 1.00 12.25 ~K~P
30 AlaM 574 C GLY 58 0.326 23.080 44.849 1.00 9.23 F~BP
AIOM 575 O GLY 58 0.633 22.043 45.438 1.00 8.04 F~BP
ATaM 576 N TRP 59 -0.567 23.124 43.856 1.00 6.52 F~BP
AlaM 577 H IRP 59 -0.838 24.004 43.525 0.00 0.00 F~BP
AloM 578 CA TRP 59 -1.177 21.927 43.269 1.00 2.00 F~BP
35 AT~M 579 CB TRP 59 -2.399 22.294 42.443 1.00 2.00 FP;BP
AIOM 580 CG IRP 59 -3.672 22.138 43.172 1.00 2.87 F~BP
ATOM 581 CD2 IRP 59 -4.707 21.189 42.889 1.00 4.49 F~BP
AIOM 582 CE2 TRP 59 -5.725 21.386 43.843 1.00 5.98 F'KBP
AIOM 583 OE3 IRP 59 -4.874 20.193 41.921 1.00 2.00 FgBP

CA 02229426 l998-03-ll WO 97/lS659 PCT/~JS96~695~
ATCM 584 CDl IRP 59 -4.093 22.857 44.252 1.00 2.00 FKBP
ATCM 585 NEl TRP 59 -5.327 22.413 44.659 1.00 4.48 FKBP
AToM 586 HEl qRP 59 -5.830 22.768 45.422 0.00 0.00 E~33P
ATCM 587 CZ2 TRP 59 -6.897 20.615 43.859 1.00 7.28 FKBP
ATCM 588 CZ3 IRP 59 -6.043 19.433 41.939 1.00 4.10 F~3P
ATCM 589 CH2 TRP 59 -7.033 19.648 42.900 1.00 2.01 FKBP
ATCM 590 C TRP 59 -0.215 21.196 42.365 1.00 3.20 E~3P
ATCM 591 O TRP 59 -0.186 19.969 42.345 1.00 9.79 FKBP
ATCM 592 N GLU 60 0.507 21.955 41.550 1.00 3.19 FKBP
10 ATCM 593 H GLU 60 0.323 22.919 41.539 0.00 0.00 E~3P
ATCM 594 CA GLU 60 1.484 21.388 40.636 1.00 5.73 EKBP
ATCM 595 CB GLU 60 2.142 22.502 39.819 1.00 10.18 ~K~P
ATCM 596 CG GLU 60 2.585 22.086 38.415 1.00 13.55 F~3P
- ATCM 597 CD GLU 60 1.463 22.147 37.398 1.00 16.71 FKBP
ATCM 598 OE 1 GLU 60 1.649 22.793 36.348 1.00 22.45 FKBP
AToM 599 OE2 GLU 60 0.393 21.551 37.640 1.00 19.83 ~'K~P
ATCM 600 C GLU 60 2.538 20.587 41.395 1.00 8.89 FKBP
ATCM 601 O GLU 60 2.703 19.395 41.150 1.00 14.67 FKBP
~ M 602 N GLU 61 3.116 21.189 42.428 1.00 11.93 FKBP
ATCM 603 H GLU 61 2.859 22.117 42.606 0.00 0.00 FKBP
ATCM 604 CA GLU 61 4.123 20.510 43.249 1.00 15.22 F~3P
ATCM 605 CB GLU 61 5.053 21.533 43.916 1.00 18.18 FKBP
Aq~M 606 CG GLU 61 5.177 22.868 43.171 1.00 28.20 F~BP
ATaM 607 CD GLU 61 6.615 23.314 42.926 1.00 31.43 F~BP
Aq~M 608 OE 1 GLU 61 7.478 23.101 43.807 1.00 35.07 F~BP
AqCM 609 OE2 GLU 61 6.865 23.933 41.867 1.00 34.62 F~BP
AT~M 610 C GLU 61 3.519 19.581 44.315 1.00 14.96 F~BP
Aq~M 611 O GLU 61 4.101 18.558 44.663 1.00 21.59 F'KBP
Aq~M 612 N GLY 62 2.355 19.938 44.840 1.00 16.29 F~BP
ATaM 613 H GLY 62 1.970 20.809 44.617 0.00 0.00 FKBP
AqCM 614 CA GLY 62 1.687 19.077 45.801 1.00 12.82 FKBP
Aq~M 615 C GLY 62 1.281 17.734 45.219 1.00 12.55 F~BP
Aq~M 616 O GLY 62 1.782 16.697 45.639 1.00 12.58 F~BP
Aq~M 617 N U~L 63 0.438 17.764 44.190 1.00 12.60 E~BP
Aq~M 618 H V~L 63 0.172 18.639 43.830 0.00 0.00 FKBP
ATaM 619 CA V~L 63 -0.092 16.550 43.570 1.00 12.62 FKBP
Aq~M 620 C~3 V~L 63 -1.164 16.899 42.511 1.00 7.73 FKBP
Aq~M 621 CGl U~L 63 -1.788 15.628 41.954 1.00 7.25 FKBP
Aq~M 622 CG2 V~L 63 -2.234 17.780 43.122 1.00 3.26 FKBP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 623 C V~L 63 0.99615.674 42.921 1.00 15.97 FKBP
ATCM 624 O V~L 63 0.92714.446 42.958 1.00 18.69 FKBP
AToM 625 N ALA 64 2.04816.305 42.416 1.00 15.67 FKBP
ATCM 626 H ALA 64 2.00917.279 42.315 0.00 0.00 FKB~
5 AloM 627 CA ALA 64 3.19615.570 41.905 1.00 14.59 FKBP
ATCM 628 CF3 ALA 64 4.20116.542 41.338 1.00 13.86 FKBP
ATCM 629 C ALA 64 3.85614.687 42.976 1.00 16.87 FKBP
ATCM 630 O ALA 64 4.54813.726 42.656 1.00 19.52 EKBP
AqoM 631 N GLN 65 3.65715.026 44.245 1.00 16.81 FKBP
10 ATCM 632 H GLN 65 3.16115.844 44.449 0.00 0.00 FKBP
ATCM 633 CA GLN 65 4.20214.233 45.353 1.00 14.57 FKBP
ATCM 634 CB GLN 65 4.35915.097 46.606 1.00 15.78 FKBP
ATCM 635 CG GLN 65 5.47316.118 46.542 1.00 27.03 FKBP
ATCM 636 CD GLN 65 5.52416.996 47.782 1.00 35.69 FKBP
15 ATCM 637 OEl GLN 65 5.54316.500 48.910 1.00 39.86 ~K~P
ATCM 638 NE2 GLN 65 5.51618.307 47.580 1.00 36.82 EP~3P
ATCM 639 HE21 GLN 65 5.428 18.638 46.667 0.00 0.00 ~K~P
AloM 640 HE22 GLN 65 5.596 18.845 48.387 0.00 0.00 EKBP
AToM 641 C GLN 65 3.32513.037 45.706 1.00 11.92 FKBP
20 ATCM 642 O GLN 65 3.69412.226 46.553 1.00 12.99 EKBP
ATCM 643 N MET 66 2.09413.034 45.210 1.00 8.83 FKBP
ATCM 644 H MET 66 1.87213.655 44.491 0.00 0.00 EKBP
Aq~M 645 CA MET 66 1.11912.044 45.646 1.00 9.40 E'KBP
ATaM 646 CB MET 66 -0.28612.651 45.616 1.00 5.56 E'KBP
25 AlaM 647 CG MET 66 -0.48713.766 46.628 1.00 3.07 FKBP
ATaM 648 SD MET 66 -2.08414.610 46.495 1.00 12.38 E~BP
ATaM 649 CE MET 66 -3.18613.301 46.911 1.00 12.15 E'KBP
ATaM 650 C MET 66 1.18610.788 44.774 1.00 13.38 EgBP
ATaM 651 O MET 66 1.70510.831 43.660 1.00 16.22 FKBP
30 Aq~M 652 N SER 67 0.832 9.643 45.346 1.00 13.44 FKBP
ATaM 653 H ~ 67 0.710 9.638 46.319 0.00 0.00 E'KBP
Aq~M 654 CA SER 67 0.727 8.409 44.565 1.00 11.42 ~K~P
Aq~M 655 CB ~ 67 1.649 7.317 45.134 1.00 7.60 FKBP
Aq~M 656 OG SER 67 1.250 6.897 46.427 1.00 7.91 E~BP
35 AI~M 657 HG SER 67 1.986 7.045 47.038 0.00 0.00 E'KBP
Aq~M 658 C SER 67 -0.721 7.926 44.518 1.00 12.45 E~BP
AT~M 659 O SER 67 -1.556 8.364 45.309 1.00 14.85 FKBP
ATaM 660 N V~L 68 -1.055 7.115 43.523 1.00 12.38 E'KBP
Aq~M 661 H V~L 68 -0.361 6.855 42.883 0.00 0.00 FKBP

CA 02229426 l998-03-ll WO 97/lS659 PCT/US96~69~3 ATCM 662 CA U~L 68 -2.457 6.756 43.314 1.00 10.06 ~'K~P
ATCM 663 CB U~L 68 -2.647 5.854 42.067 1.00 5.10 FKBP
ATCM 664 CGl U~L 68 -4.130 5.630 41.800 1.00 5.86 FKBP
ATCM 665 CG2 U~L 68 -2.010 6.489 40.874 1.00 2.65 FgBP
ATCM 666 C V~L 68 -3.080 6.069 44.532 1.00 9.51 FKBP
ATCM 667 o V~L 68 -2.603 5.033 44.999 1.00 13.72 FKBP
ATCM 668 N GLY 69 -4.190 6.630 44.992 1.00 7.92 FKBP
ATCM 669 H GLY 69 -4 587 7.362 44.469 0.00 0.00 FKBP
ATCM 670 CA GLY 69 -4.872 6.114 46.162 1.00 8.54 FKBP
10 ATCM 671 C GLY 69 -4.755 7.061 47.344 1.00 7.63 FgBP
ATCM 672 O GLY 69 -5.649 7.132 48.185 1.00 12.92 FKBP
ATCM 673 N GLN 70 -3.694 7.859 47.354 1.00 3.17 FKBP
ATCM 674 H GLN 70 -3.135 7.917 46 548 0.00 0.00 FKBP
ATCM 675 CA GLN 70 -3.357 8.660 48.515 1.00 2.00 FKBP
15 ATCM 676 CB GLN 70 -1.927 9.161 48.395 1.00 2 57 E~BP
ATCM 677 OG GLN 70 -1.483 10 064 49 524 1.00 10.26 FKBP
ATCM 678 CD GLN 70 -0.066 10.555 49.331 1.00 10.61 FKBP
ATCM 679 OEl GLN 70 0.673 10.028 48.505 1.00 18.69 FKBP
ATCM 680 NE2 GLN 70 0.310 11.586 50 067 1.00 11.45 FKBP
20 ATCM 681 HE21 GLN 70 -0.298 11.997 50.702 0.00 0.00 FKBP
ATCM 682 HE22 GLN 70 1.237 11.850 49.896 0.00 0.00 FKBP
ATCM 683 C GIN 70 -4.299 9.830 48 6711.00 2.00 FKBP
Al~IM 684 O GLN 70 -4.749 10.400 47.6911.00 3.88 F'KBP
AI~M 685 N ARG 71 -4.711 10.082 49.9041.00 5.36 F~BP
25 AlaM 686 H AR~ 71 -4.639 9.362 50.5430.00 0.00 FgBP
AI~M 687 CA ARG 71 -5.486 11.274 50.2461.00 5.53 F~3P
AI~M 688 CB AR~ 71 -6.753 10.873 50.9971.00 2.00 FgBP
AIOM 689 OG ARG 71 -7.697 12.010 51.2281.00 2.00 F~BP
AIOM 690 CD AP~G 71 -9.066 11.504 51.6391.00 3.25 EgBP
30 AIOIM 691 NE AR~ 71 -9.812 12.542 52.3471.00 8.85 FgB~
AIOM 692 HE ARG 71 -9.309 13.289 52.7350.00 0.00 K~P
AI~M 693 CZ AR~ 71-11.134 12.564 52.4751.00 18.29 F~BP
Al~IM 694N~Il ARG 71-11.708 13.525 53.1831.00 25.79 F~BP
AI~IM 695HHll AP~ 71-11.149 14.237 53.6090.00 0.00 FgBP
35 AIOIM 696HH12 ARL~ 71-12.702 13.542 53.2820.00 0.00 ~ P
AI~M 697NH2 ARG 71-11.888 11.640 51.8901.00 23.05 F~BP
~ AI~IM 698HH21 ARG 71-11.460 10.906 51.3610.00 0.00 F~BP
Al~lM 699 HH22 AR~ 71 -12.879 11.65452.011 0.00 0.00 F~BP
AI~M 700 C ARG 71 -4.650 12.208 51.1141.00 3.03 F~BP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 AToM 701 O AR~ 71 -4.006 11.764 52.060 1.00 4.39 FKBP
ATCM 702 N ALA 72 -4.628 13.489 50.774 1.00 2.46 ~X~P
ATCM 703 H ALA 72 -5.218 13.805 50.054 0.00 0.00 FKBP
AToM 704 CA ALA 72 -3.725 14.428 51.425 1.00 2.00 ~K~P
ATCM 705 CB AL~ 72 -2.456 14.557 50.636 1.00 2.00 EKBP
AToM 706 C ALA 72 -4.326 15.803 51.654 1.00 4.21 E~3P
AToM 707 O ALA 72 -5.376 16.145 51.119 1.00 10.57 ~K~P
ATCM 708 N LYS 73 -3.766 16.490 52.632 1.00 8.68 FKBP
ATCM 709 H LYS 73 -3.101 16.042 53.199 0.00 0.00 E~3P
ATCM 710 CA LYS 73 -4.121 17.861 52.917 1.00 4.13 FKBP
AToM 711 CB LYS 73 -4.387 18.018 54.410 1.00 6.40 FKBP
ATCM 712 CG LYS 73 -4.104 19.408 54.956 1.00 13.82 FKBP
AToM 713 CD LYS 73 -4.807 19.628 56.287 1.00 15.85 FKBP
ATCM 714 CE LYS 73 -4.136 20.729 57.086 1.00 18.32 FKBP
ATCM 715 NZ LYS 73 -5.033 21.240 58.148 1.00 22.33 E~3P
AToM 716 HZl LYS 73 -5.238 20.469 58.817 0.00 0.00 FKBP
ATCM 717 HZ2 LYS 73 -5.920 21.583 57.728 0.00 0.00 FKBP
ATCM 718 HZ3 LYS 73 -4.569 22.019 58.657 0.00 0.00 FKBP
ATCM 719 C LYS 73 -2.943 18.713 52.488 1.00 4.72 FKBP
ATCM 720 O LYS 73 -1.794 18.396 52.814 1.00 6.20 FKBP
ATCM 721 N T~T 74 -3.212 19.628 51.566 1.00 6.47 FKBP
ATCM 722 H LEU 74 -4 064 19.565 51.121 0.00 0.00 FKBP
ATCM 723 CA LEU 74 -2.218 20.582 51.082 1.00 8.06 FKBP
ATCM 724 CB LEU 74 -2.303 20.706 49.560 1.00 12.85 FKBP
ATCM 725 CG LEU 74 -1.440 19.791 48.695 1.00 11.86 FKBP
ATCM 726 CDl LEU 74 -1.789 18.330 48.947 1.00 11.50 E~3P
A~OM 727 CD2 LEU 74 -1.663 20.157 47.241 1.00 12.57 FKBP
AI~M 728 C LEU 74 -2.403 21.962 51.695 1.00 8.90 FXBP
AICM 729 0 LEU 74 -3.449 22.600 51.515 1.00 14.56 ~KI~P
AIIOM 730 N THR 75 -1.385 22.431 52.405 1.00 7.32 ~K~P
AI~M 731 H 1~ 75 -0.717 21.784 52.717 0.00 0.00 E~BP
Al~IM 732 CA T~ 75 -1.383 23.796 52.913 1.00 6.76 I~'K~P
A~OM 733 CB 1~3R 75 -0.905 23.830 54.397 1.00 6.87 E~BP
Al~IM 734 OGl THR 75 -1.957 23.327 55.227 1.00 2.01 EgBP
AIIOM 735 H~Gl TE~R 75 -2.720 23.90155.117 0.00 0.00 EgBP
AI~M 736 C!G2 THR 75 -0.556 25.23854.861 1.00 3.73 ~iXBP
AIIOM 737 C THR 75--O .513 24.654 52.000 1.00 6.27 E~BP
AI~M 738 0 THR 75 0.683 24.416 51.846 1.00 5.48 I~KI~P
A~OM 739 N II~E 76 -1.180 25.508 51.234 1.00 10.43 E'KBP

CA 02229426 l998-03-ll ATCM 740 H TT~76 -2.141 25.633 51.388 0.00 0.00 FKBP
ATCM 741 CA TT~76 -0.542 26.284 50.167 1.00 11.16 FKBP
AToM 742 CB TT.~76 -1.326 26.090 48.830 1.00 6.31 ~K~P
ATCM 743 CG2 TT~ 76-0.653 26.827 47.719 1.00 9.44 FKBP
ATCM 744 CGl TTE 76-1.388 24.601 48.459 1.00 5.62 FKBP
ATCM 745 CDl TT~ 76-2.630 24.205 47.691 1.00 2.00 FKBP
ATCM 746 C TT~ 76-0.454 27.788 50.522 1.00 12.21 FKBP
ATCM 747 O TT~. 76-1.476 28.460 50.752 1.00 13.89 FKBP
ATCM 748 N SER 770.768 28.287 50.692 1.00 10.50 FKBP
10 ATCM 749 H SER 771.535 27.692 50.566 0.00 0.00 E~3P
ATCM 750 CA SER 770.947 29.700 51.009 1.00 11.73 FKBP
AToM 751 CB SER 772.354 29.978 51.571 1.00 11.33 E~3P
AloM 752 OG ~K 773.405 29.669 50.667 1.00 18.57 E~3P
AToM 753 H~ 774.140 30.103 51.109 0.00 0.00 FKBP
15 AloM 754 C SER 770.681 30.566 49.790 1.00 12.45 E~3P
AToM 755 O SER 770.922 30.149 48.662 1.00 15.48 FKBP
ATCM 756 N PRO 780.151 31.778 49.998 1.00 14.32 FKBP
AloM 757 CD PRO 780.192 32.544 51.251 1.00 18.10 EK~P
AToM 758 CA PRO 78-0.362 32.607 48.906 1.00 14.95 FKBP
20 ATCM 759 C~3 PRO 78-0.594 33.957 49.573 1.00 15.74 FKBPATCM 760 CG PRO 780.309 33.944 50.759 1.00 15.85 FKBP
AToM 761 C PRO 780.574 32.728 47.710 1.00 15.21 FKBP
AIOM 762 O PRO 780.109 32.790 46.576 1.00 20.63 FKBP
A~OM 763 N ASP 791.882 32.698 47.956 1.00 13.60 E~BP
25 AI~M 764 H ASP 792.162 32.697 48.889 0.00 0.00 E'KBP
Al~IM 765 CA ASP 792.877 32.679 46.874 1.00 19.42 FKBP
AI~M 766 CB ASP 794.305 32.510 47.424 1.00 28.97 FKBP
A~OM 767 OG ASP 794.599 33.401 48.629 1.00 37.43 FKBP
AI~M 768 ODl ASP 795.657 33.195 49.270 1.00 39.71 E~BP
30 AI~M 769 C)D2 ASP 79 3.792 34.30648.939 1.00 45.91 ~K~P
Al~IM 770 C ASP 792.616 31.548 45.877 1.00 17.87 E~3P
A~OM 771 O ASP 792.547 31.777 44.676 1.00 20.31 EgBP
AI~M 772 N TYR 802.442 30.335 46.392 1.00 15.45 E~BP
AI~M 773 H TYR 802.347 30.254 47.356 0.00 0.00 E~BP
35 AI~IM 774 CA TYR 802.142 29.178 45.557 1.00 12.31 E~BP
Al~IM 775 CB TYR 802.611 27.897 46.234 1.00 10.17 E~BP
AI~M 776 C~ IIYR 804.082 27.626 46.070 1.00 9.13 E~BP
AI~IM 777 CDl TYR 805.022 28.600 46.373 1.00 5.08 E~BP
AI~M 778 CEl TYR 806.373 28.303 46.419 1.00 6.16 E~BP

, CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 AToM 779 CD2 IYR 80 4.536 26.347 45.781 1.00 12.62 FKBP
ATCM 780 ~ TYR 80 5.889 26.037 45.827 1.00 15.72 FKBP
AloM 781 CZ TYR 80 6.801 27.021 46.159 1.00 13.97 E~3P
AloM 782 OH TYR 80 8.124 26.683 46.343 1.00 19.55 FKBP
AloM 783 HH TYR 80 8.729 27.408 46.126 0.00 0.00 FKBP
ATCM 784 C TYR 80 0.657 29.033 45.227 1.00 9.68 FKBP
AloM 785 O TYR 80 0.194 27.936 44.907 1.00 9.28 FKBP
AToM 786 N ALA 81 -0.104 30.115 45.344 1.00 9.06 FKBP
AloM 787 H AL~ 81 0.347 31.010 45.423 0.00 0.00 FKBP
10 AToM 788 CA ALA 81 -1.536 30.071 45.028 1.00 8.94 FKBP
AI~M 789 CB ALA 81 -2.362 29.899 46.312 1.00 10.95 FKBP
ATCM 790 C ALA 81 -1.973 31.342 44.290 1.00 11.59 FXBP
AICM 791 O ALA 81 -1.507 31.630 43.192 1.00 14.63 FKBP
AToM 792 M TYR 82 -2.886 32.106 44.874 1.00 13.59 FKBP
15 AToM 793 H TYR 82 -3 142 32.049 45.838 0.00 0.00 FKBP
AloM 794 CA TYR 82 -3.462 33.239 44.147 1.00 15.87 FKBP
AToM 795 CB TYR 82 -4.982 33.249 44.324 1.00 15.49 FKBP
AloM 796 CG TYR 82 -5.676 32.084 43.658 1.00 19.64 FKBP
AToM 797 CDl TYR 82 -6.283 31.091 44.415 1.00 18.02 FKBP
20 ATCM 798 OE 1 TYR 82 -6.918 30.013 43.804 1.00 16.50 FKBP
ATCM 799 CD2 TYR 82 -5.724 31.975 42.262 1.00 19.36 FKBP
AToM 800 OE2 TYR 82 -6.357 30.904 41.648 1.00 12.44 FKBP
ATOM 801 CZ TYR 82 -6.946 29.930 42.425 1.00 12.60 F'KBP
ATC~M 802 CEI TYR 82 -7.546 28.871 41.800 1.00 12.06 FKBP
25 ATOM 803 HH TYR 82 -7.818 28.255 42.478 0.00 0.00 FKBP
ATOM 804 C TYR 82 -2.869 34.591 44.552 1.00 15.70 FKBP
ATOM 805 O TYR 82 -3.388 35.646 44.183 1.00 15.54 E~BP
AT~IM 806 N GLY 83 -1.763 34.539 45.288 1.00 17.13 F'KBP
ATaM 807 H GLY 83 -1.475 33.662 45.571 0.00 0.00 FKBP
30 AT~OM 808 CA GLY 83 -0.972 35.719 45.566 1.00 15.64 ~x~PATaM 809 C GLY 83 -1.681 36.878 46.233 1.00 20.32 FKBP
ATCIM 810 O GLY 83 -2.708 36.728 46.910 1.00 23.74 F~BP
ATC~M 811 N AIA 84 -1.099 38.055 46.055 1.00 19.06 FKBP
ATalM 812 H ALA 84 -0.306 38.078 45.480 0.00 0.00 F'KBP
35 ATOM 813 CA ALA 84 --1.639 39.270 46.628 1.00 15.70 FKBP
ATOM 814 CB Al~ 84 -0.640 40.394 46.455 1.00 19.93 FKBP
AT~OM 815 C AL~ 84 -2.965 39.637 45.982 1.00 13.85 FKBP
AT~OM 816 O ALA 84 ~3.823 40.230 46.618 1.00 14.46 E~BP
ATCIM 817 N THR 85 -3.131 39.247 44.726 1.00 17.88 FRBP

CA 02229426 l998-03-ll WO 97/15659 PCT~US96J16953 AToM 818 H ~ffR 85 -2.470 38.659 44.303 0.00 0.00 FKBP
AT~M 819 CA IHR 85 -4.308 39.623 43.934 1.00 24.03 F~3P
ATCM 820 OE THR 85 -4.036 39.482 42.419 1.00 21.29 FKBP
ATCM 821 OGl IHR 85 -3.482 38.185 42.150 1.00 28.80 FKBP
ATCM 822 HGl IHR 85 -4.132 37.483 42.316 0.00 0.00 E~3P
ATCM 823 CG2 IHR 85 -3.054 40.541 41.956 1.00 16.23 EKBP
ATCM 824 C IHR 85 -5.537 38.787 44.254 1.00 24.35 FKBP
AloM 825 O IHR 85 -6.660 39.189 43.954 1.00 27.70 FKBP
AToM 826 N GLY 86 -5.304 37.579 44.761 1.00 25.09 FKBP
ATCM 827 H GLY 86 -4.382 37.292 44.914 0.00 0.00 EP~3P
ATCM 828 CA GLY 86 -6.388 36.655 45.020 1.00 19.79 FKBP
AToM 829 C GLY 86 -7.151 36.310 43.759 1.00 21.57 FXBP
ATCM 830 O GLY 86 -6.589 36.200 42.659 1.00 18.32 E~3P
ATCM 831 N HIS 87 -8.454 36.149 43.930 1.00 21.72 FKBP
AIoM 832 H HIS 87 -8.780 36.318 44.827 0.00 0.00 F~3P
AToM 833 CA HIS 87 -9.355 35.858 42.828 1.00 24.25 FKBP
ATCM 834 CB HIS 87 -9.432 34.350 42.568 1.00 25.61 FKBP
AToM 835 CG HIS 87-10.134 33.994 41.292 1.00 29.60 FKBP
AToM 836 CD2 HIS 87-11.360 33.466 41.064 1.00 27.65 E~3P
ATCM 837 NDl HIS 87 -9.564 34.185 40.050 1.00 31.39 FKBP
AToM 838 HDl HIS 87 -8.690 34.592 39.843 0.00 0.00 F~3P
AToM 839 CEl HIS 87-10.405 33.783 39.115 1.00 32.76 FKBP
A~OM 840 NE2 HIS 87-11.503 33.347 39.703 1.00 30.12 FXBP
Al~OM 841 H HIS 87-12.329 33.167 39.202 0.00 0.00 EXBP
A~OM 842 C HIS 87-10.727 36.387 43.212 1.00 22.13 ~K~P
AI~OM 843 O HIS 87-11.356 35.891 44.152 1.00 27.18 FXBP
A~OM 844 N PRO 88-11.105 37.531 42.639 1.00 19.63 EXBP
A~OM 845 CD PRO 88-10.357 38.290 41.620 1.00 20.36 EXBP
AI~M 846 CA PRO 88-11.989 38.403 43.410 1.00 18.79 FXBP
A~OM 847 CB PRO 88-11.946 39.707 42.626 1.00 18.51 EgBP
AI~IM 848 OG PR~ 88-10.550 39.713 42.059 1.00 16.30 FXBP
AI~IM 849 C l~RO 88-13.399 37.848 43.580 1.00 18.22 FgBP
Al~ IM 850 O ~ 88 --13.974 37.286 42.650 1.00 21.77 EXBP
AI~M 851 N GLY 89-13.851 37.819 44.828 1.00 15.16 EX~3P
Aq~lM 852 H GLY 89-13.303 38.201 45.539 0.00 0.00 EXBP
AICM 853 CA GLY 89-15.160 37.271 45.120 1.00 12.28 FXBP
AI~M 854 C GLY 89--15.116 35.891 45.749 1.00 13.88 ~K~P
Aq~OM 855 O GLY 89-16.142 35.385 46.211 1.00 13.05 EXBP
AI~M 856 N Tl ~ 90-13.932 35.289 45.812 1.00 12.11 EgBP

CA 02229426 l998-03-ll AToM 857 H TT~ 90-13.164 35.742 45.410 0.00 0.00 FKBP
AloM 858 CA TT.F. 90-13.831 33.928 46.328 1.00 17.75 FK~P
ATCM 859 C}3 TT~go -13.950 32.875 45.177 1.00 23.54 E~3P
AToM 860 CG2 TT .F. 90 -13.063 33.252 44.007 1.00 24.28 FKBP
ATCM 861 CGl TT~ 90-13.590 31.478 45.688 1.00 28.28 FKBP
ATCM 862 CDl ILE 90-14.036 30.361 44.764 1.00 34.25 FKBP
AToM 863 C TT~ 90-12.577 33.670 47.150 1.00 14.47 FXBP
AloM 864 o TT~ 90-12.663 33.134 48.247 1.00 15.69 FKBP
AToM 865 N ILE 91-11.416 34.013 46.600 1.00 12.99 ~x~P
ATCM 866 H TT.~. 91-11.413 34.380 45.696 0.00 0.00 E~3P
ATCM 867 CA TT~ 91-10.150 33.915 47.328 1.00 9.92 FgBP
ATCM 868 CB ILE 91-9.091 33.085 46.559 1.00 6.38 ~ P
ATCM 869 C~2 TT~ 91-7.873 32.881 47.428 1.00 2.00 E~3P
AToM 870 CGl TT~ 91-9.681 31.762 46.041 1.00 4.55 FKBP
AloM 871 CDl TT.~ 91-10.163 30.821 47.084 1.00 3.68 FKBP
ATCM 872 C TT,~ 91-9.584 35.324 47.520 1.00 15.34 FKBP
AloM 873 O TT~ 91-9.285 36.025 46.539 1.00 13.98 EKBP
ATCM 874 N PRO 92-9.520 35.797 48.781 1.00 17.29 FKBP
AToM 875 CD PRO 92-9.964 35.110 50.011 1.00 14.17 FKBP
20 ATCM 876 CA PRO 92-9.007 37.143 49.062 1.00 12.40 FKBPATCM 877 CB PRO 92-9.421 37.381 50.514 1.00 10.67 FKBP
ATCM 878 OG PRO 92-9.477 36.019 51.107 1.00 11.96 FKBP
ATCM 879 C PRO 92-7.492 37.264 48.855 1.00 14.30 EKBP
ATCM 880 O PRO 92-6.815 36.290 48.516 1.00 17.48 FKBP
25 ATCM 881 N PRO 93-6.966 38.493 48.923 1.00 15.65 FKBPAToM 882 CD PRO 93-7.700 39.762 48.785 1.00 18.15 FKBP
ATCM 883 CA PRO 93-5.518 38.704 48.833 1.00 16.50 FKBP
ATCM884 CB PRO93 -5.380 40.217 48.941 1.00 17.10 FKBP
AI~IM885 OGPRO93 -6.629 40.717 48.308 1.00 22.16 E~BP
30 A~OM886 CPRO93 -4,743 37,999 49.933 1.00 16.97 ~KBPAl~IM887 O~)93 -5.160 37.971 51.090 1.00 20.11 EXBP
A~M888NHIS94-3.609 37.424 49.563 1.00 15.46~
A~M889H~S94-3.476 37.286 48.598 0.00 0.00FgBP
A~M890CA~S94-2.701 36.830 50.538 1.00 14.40FKBP
35 AI~M891 CB E~S 94-2.366 37.855 51.608 1.00 12.10 FKBP
A~M892OGHIS94-1.762 39.103 51.061 1.00 15.95FXBP
AI~IM893CD2HIS94-2.313 40.308 50.781 1.00 16.10 E~BP
A~OM894NDlHIS94-0.455 39.165 50.621 1.00 16.58EgBP
AI~M895HDlHIS94 0.241 38.484 50.761 0.00 0.00 FKBP

-CA 02229426 l998-03-ll ATCM 896 ~1 HIS 94 -O.230 40.351 50.086 1.00 20.16 FKBP
ATCM 897 N HIS 94 -1.342 41.063 50.171 1.00 21.63 FKBP
ATCM 898 HE2 HIS 94 -1.470 41.979 49.833 0.00 0.00 ~K~P
ATCM 899 C HIS 94 -3.176 35.531 51.202 1.00 13.30 FKBP
5ATCM 900 O HIS 94 -2.380 34.843 51.836 1.00 16.61 FKBP
AToM 901 M ALA 95 -4.403 35.112 50.915 1.00 6.56 FKBP
AToM 902 H AL~ 95 -4,911 35.568 50.215 0.00 0.00 EKBP
ATCM 903 CA ALA 95 -4.982 33.954 51.S76 1.00 7.81 FKBP
ATCM 904 CB ALA 95 -6.365 33.676 51.026 1.00 2.72 E~3P
10ATCM 905 C ALA 95 -4.132 32.683 51.516 1.00 10.01 FKBPATCM 906 O A~ 95 -3.691 32.260 50.456 1.00 10.42 FRBP
ATCM 907 N IHR 96 -3.801 32.165 52.691 1.00 12.98 FKBP
ATCM 908 H IHR 96 -3.847 32.758 53.468 0.00 0.00 FKBP
ATCM 909 CA IHR 96 -3.319 30.797 52.831 1.00 12.92 FgBP
15ATCM 910 CB IHR 96 -2.740 30.568 54.254 1.00 9.93 F~3PATCM 911 O~l THR 96 -1.655 31.480 54.472 1.00 11.98 FKBP
ATCM 912 HGl THR 96 -1.236 31.644 53.620 0.00 0.00 E~3P
AloM 913 CG2 IHR 96 -2.240 29.139 54.430 1.00 3.68 E~3P
ATCM 914 C THR 96 -4.501 29.852 52.600 1.00 14.35 FKBP
20ATCM 915 O THR 96 -5.569 30.025 53.212 1.00 14.86 FKBPATCM 916 N LEU 97 -4.349 28.937 51.642 1.00 8.43 E~33PAloM 917 H LEU 97 -3.495 28.902 51.157 0.00 0.00 FKBP
ATCIM 918 CA LEU 97 -5.406 27.976 51.332 1.00 3.80 E~BP
A~OM 919 CB LEU 97 -5.672 27.930 49.826 1.00 3.61 E~BP
25ATOM 920 C!G LEU 97 -5.948 29.193 49.011 1.00 6.56 E~BPAI~M 921 CDl LEU 97 -5.831 28.841 47.534 1.00 2.62 EgBP
ATIOM 922 CD2 ~EU 97 -7.326 29.758 49.318 1 00 6.52 E~BP
ATOM 923 C LEU 97 -5.083 26.557 51.814 1.00 5.71 E~BP
ATIOM 924 O LEU 97 -3.926 26.123 51.815 1.00 7.74 E~BP
30ATIOM 925 N U~L 98 -6.121 25.814 52.167 1.00 2.33 E~BPAI~IM 926 H V~L 98 --7.012 26.221 52.183 0.00 0.00 E~BP
A1~2!I 927 CA VAL 98 -5.968 24.407 52.476 1.00 3.09 E~BPAI~M 928 CB VAL 98 -6.461 24.079 53.900 1.00 4.96 E~BP
A~OM 929 CGl V~L 98 -6.144 22.638 54.230 1.00 2.00 E~BP
35AI~M 930 CG2 UAL 98 -5.824 25.011 54.917 1.00 2.00 E~BPATaM 931 C V~L 98 -6.801 23.602 51.491 1.00 7.78 E~BP
AI~M 932 O V~L 98 -8.012 23.836 51.346 1.00 8.13 E~BP
ATaM 933 N E3E 99 -6.166 22.622 50.853 1.00 7.58 E~BP
ATaM 934 H PHE 99 -5.202 22.540 50.970 0.00 0.00 E ~ P

W O 97/15659 PCT~US96/16953 AI~M 935 CA PHE99 -6.87721.677 49.996 1.00 6.62 l~BP
AI~M 936 CB PHE99 -6.30321.728 48.578 1.00 2.00 ~BP
AI~M 937 CG PHE99 -6.82422.873 47.763 1.00 4.66 FE~3P
AI~M 938 CDl PHE99 -6.11524.070 47.687 1.00 4.09 E~BP
Al~a!I 939 CD2PHE 99 -8.069 22.78747.138 1 00 2.68 E~KBP
Aq~M 940 CEl PHE99 -6.63825.166 47.008 1.00 2.00 ~ ~p AI~M 941 (~ PHE99 -8.59823.874 46.462 1.00 2.00 FKBP
AI~M 942 CZ PHE99 -7.87925.068 46.399 1.00 2.00 F~KBP
AI~M 943 C PHE99 -6.84920.239 50.519 1.00 5.20 FE~BP
10 AI~M 944 O PHE99 -5.79619.718 50.860 1.00 5.24 ~BP
AI~M 945 N ASP100 -8 01419.613 50.627 1.00 3.90 FKBP
AI~M 946 H ASP100 -8.83420.147 50.593 0.00 0.00 FKBP
AI~M 947 CA ASP100 -8.07018.167 50.830 1.00 7.59 FKBP
AI~M 948 CB ASP100 -9.20517.817 51.804 1.00 6.95 FE~BP
15 AlaM 949 C~G ASP100 -9.42416.310 51.966 1.00 7.89 FKBP
AI~M 950 ODl ASP 100 -8.56415.494 51.568 1.00 14.35 FE~BP
AI~M 951 OD2 ASP100-10.48015.937 52.511 1.00 12.55 E~KBP
Al~ 952 C ASP100 -8.28017.463 49.482 1.00 9.31 F~KBP
AI~M 953 O ASP100 -9.37917.490 48.934 1.00 10.21 FKBP
20 AI~M 954 N VAL101 -7.23216.832 48.954 1.00 9.09 E~BP
AI~M 955 H ~ 101 -6.41616.741 49.499 0.00 0 00 ~BP
AI~M 956 CA V~l. 101 -7.306 16.20247.633 1.00 11.24 FKBP
AI~M 957 CB VAII 101 -6.417 16.95646.557 1.00 7.24 FKBP
AI~M 958 C~Gl VAL101 -6.12218.380 47.014 1.00 5.62 FKBP
25 AI~M 959 C~G2 V~L101 -5.11816.208 46.278 1.00 3.42 FKBP
AI~M 960 C VAI, 101 -6.957 14.71147.652 1.00 12.17 FKBP
AI~M 961 O VAL101 -5.96214.296 48.251 1.00 12.83 F~BP
AI~M 962 N ~LU102 -7.79613.913 47.001 1.00 11.69 FKBP
AI~M 963 H (~LU 102 -8.591 14.30746.611 0.00 0.00 FKBP
30 ATCM 964 CA GLU 102 -7.52712.490 46.813 1.00 14.51 FKBP
ATCM 965 CB GLU 102 -8.69711.660 47.356 1.00 12.86 FgBP
ATCM 966 CG GLU 102 -8.56210.171 47.074 1.00 18.32 FKBP
ATCM 967 CD GLU 102 -9.681 9.340 47.666 1.00 20.79 FKBP
ATCM 968 OEl GLU 102-10.840 9.811 47.715 1.00 26.66 FKBP
35 ATCM 969 OE2 GLU 102 -9.402 8.187 48 052 1.00 23.60 FKBP
AToM 970 C GLU 102-7.266 12.132 45.336 1.00 13.17 FKBP
ATCM 971 O GLU 102-8.100 12.392 44.465 1.00 15.41 FKBP
ATCM 972 N LEU 103-6.147 11.465 45.079 1.00 9.34 FKBP
ATCM 973 H LEU 103-5.600 11.178 45.846 0.00 0.00 ~K~P

-CA 02229426 l998-03-ll WO 97/15659 PC~US96~6953 ATCM974 CA LEU 103-5.76311.096 43.722 1.00 13.72 FKBP
ATCM975 CB LEU 103-4.22611.024 43.593 1.00 6.09 E~3P
AloM976 CG LEU 103-3.64310.842 42.180 1.00 4.19 FKBP
ATCM977 CDl LEU 103-4.30911.807 41.220 1.00 8.95 FKBP
5 ATCM978 CD2 LEU 103-2.14911.088 42.180 1.00 3.73 FKBP
AToM979 C LEU 103-6.4049.767 43.302 1.00 15.75 FKBP
AT~M980 O LEU 103-5.8388.698 43.511 1.00 16.07 ~K~P
AToM 981 N LEU 104-7.5799.856 42.685 1.00 18.31 FKBP
ATCM982 H LEU 104-7.91510.758 42.502 0.00 0.00 FKBP
10 ATCM983 CA LEU 104-8.3428.680 42.257 1.00 16.33 E~3P
ATCM984 CB LEU 104-9.6649.120 41.633 1.00 14.17 FKBP
ATCM985 CG LEU 104-10.54710.017 42.500 1.00 14.18 FXBP
ATCM986 CDl LEU 104-11.83810.345 41.772 1.00 13.42 FP~3P
ATCM987 CD2 LEU 104-10.8439.307 43.804 1.00 14.17 FKBP
15 ATCM988 C LEU 104-7.5947.786 41.266 1.00 18.03 FKBP
ATCM989 O LEU 104-7.3906.599 41.516 1.00 18.22 FKBP
ATCM990 N LYS 105-7.1968.360 40.134 1.00 20.74 FKBP
ATCM991 ~ LYS 105-7.3439.323 40.023 0.00 0.00 FKBP
ATCM992 CA LYS 105-6.5107.603 39.086 1.00 20.67 F~3P
20 ATCM993 CB LYS 105-7.5296.806 38.263 1.00 24.07 FKBP
AToM994 CG LYS 105-8.7657.605 37.853 1.00 27.58 FKBP
ATCM995 CD LYS 105-9.7336.771 37.027 1.00 30.34 FKBP
A~OM996 OE LYS 105-10.9947.557 36.684 1.00 34.49 FgBP
AI~IM 997 NZ LYS105-11.853 7.826 37.876 1.00 35.90 FXBP
25 AlaM998 H2;1 LYS 105-11.3178.378 38.576 0.00 0.00 EKBP
Al~iM 999 HZ2 LYS105-12.151 6.928 38.306 0.00 0.00 FXBP
AI~M1000 ~;3 LYS 105-12.6908.371 37.584 0.00 0.00 EXBP
AI~OM 1001 C LYS105 -5.692 8.497 38.154 1.00 19.89 EXBP
Al~IM 1002 0 LYS105 -5.948 9.696 38.038 1.00 21.43 F~BP
30 AI~M1003 N LEU 106-4.6647.927 37.545 1.00 22.51 Fl~BP
AI~M1004 H LEU 106-4.3927.031 37.820 0.00 0.00 E~BP
A~M1005 CA LEU 106-4.0158.575 36.411 1.00 24.63 EXBP
AIIOM 1006 CB LEU106 -2.500 8.385 36.469 1.00 20.64 E~BP
AI~IM 1007 OG LEU106 -1.709 9.334 37.369 1.00 25.07 FXBP
35 AI~IM 1008 CDl LEU106 -2.201 10.77137.213 1.00 26.33 E~BP
AI~M1009 CD2 LEU 106-1.8538.891 38.791 1.00 25.85 F~BP
AI~M1010 C LEU 106-4.5448.044 35.076 1.00 27.28 F'KBP
AI~M1011 0 LEU 106-4.9696.887 34.978 1.00 30.28 E~BP
Al~M1012 N GLU 107-4.6608.946 34.108 1.00 28.70 F~BP

, CA 02229426 l998-03-ll W O 97/15659 PCTrUS96/169S3 ATCM 1013 H GLU107-4.585 9.896 34.325 0.00 0.00 FKBP
ATCM 1014 CA GLU 107 -4.910 8.585 32.718 1.00 28.85 ~gB~
ATCM 1015 CB GLU 107 -6.410 8.650 32.415 1.00 24.83 EKBP
AToM 1016 CG GLU 107 -7.125 9.812 33.068 1.00 28.14 FKBP
ATCM 1017 CD GLU 107 -8.428 10.140 32.379 1.00 33.36 E~3P
ATCM 1018 OEl GLU 107 -9.439 9.461 32.672 1.00 26.99 FKBP
ATCM 1019 OE2 GLU 107 -8.433 11.070 31.534 1.00 36.01 ~K~P
ATCM 1020 C GLU107-4.122 9.520 31.789 1.00 32.85 FKBP
ATCM 1021 O GLU107-2.875 9.520 31.888 1.00 37.58 FKBP
10 AToM 1022 OT GLU 107 -4.739 10.301 31.034 1.00 39.52 EKBP
ATCM 1023 Ol RAPX 108-7.715 26.73939.504 1.00 6.16 RAPX
AloM 1024 Cl RAPX 108-6.816 26.01440.365 1.00 5.94 RAPX
ATCM 1025 02 RAFX 108-5.659 25.86339.953 1.00 4.69 RAPX
AloM 1026 C2 RAPX 108-7.234 25.47241.742 1.00 2.10 RAPX
15 ATCM 1027 C3 RAPX 108-6.748 24.03841.963 1.00 2.00 RAPX
ATCM 1028 C4 RAPX 108-7.531 22.96841.204 1.00 2.86 RAEX
ATCM 1029 C5 RAPX 108-9.027 23.08541.430 1.00 2.00 RAFX
ATCM 1030 C6 RAEX 108-9.492 24.48541.139 1.00 2.08 RAPX
ATCM 1031 N7 RAPX 108 -8.68525.389 41.9851.00 3.45 RAEX
20 ATCM 1032 C8 RAPX 108-9.287 26.22342.852 1.00 2.80 RAPX
ATCM 1033 03 RAP~ 108-8.653 27.06643.484 1.00 4.16 RAEX
ATCM 1034 C9 RAEX 108-10.645 26.30943.120 1.00 3.33 RAPX
ATCM 1035 04 RAPX 108-11.026 25.60744.055 1.00 2.89 RAPX
AI~IM 1036 C10 RAE~ 108-11.647 27.18942.361 1.00 7.35 R~E?X
25 ATOM 1037 Cll RAl~X108-11.102 28.62342.177 1.00 5.50 R ~
A~OM 1038 C12 RA~X 108-12.102 29.45341.362 1.00 2.25 R ~ X
AI~M 1039 C13 RAE~ 108-12.661 28.75540.117 1.00 3.81 R;~E?X
AI~M 1040 C14 RA~X 108-12.744 27.22540.197 1.00 5.55 R;~PX
AI~M 1041 05 RAE~ 108-11.749 26.67541.029 1.00 5.80 RAPX
30 ATOM 1042 06 RAl~X108-12.815 27.19543.206 1.00 7.04 RA~X
A~OM 1043 C43 RA~X 108-10.856 29.28743.527 1.00 10.83 RAPX
AI~M 1044 C15 RAE~X108-12.476 26.55838.844 1.00 6.36 R;~E?X
AI~M 1045 C16 RAE~ 108-13.491 26.68837.700 1.00 7.22 RAE~
ATOM 1046 07 RAE!X108-14.764 26.28838.070 1.00 6.77 RAPX
35 A~EM 1047 C50 RAE~ 108-15.819 26.94637.457 1.00 2.69 R ~ X
ATOM 1048 C17 RAl~X108-13.020 25.79436.553 1.00 7.17 R ~ X
A~OM 1049 C44 R ~ X108-12.882 24.30436.817 1.00 5.39 RAPX
A~OM 1050 C18 R ~ X108-12.702 26.34435.400 1.00 12.19 R~PX
A~OM 1051 Cl9 RAE~X108-12.183 25.69434.165 1.00 14.38 R ~ X

CA 02229426 l998-03-ll W O 97/15659 PCT~US96~69~3 Al~ 1052 C20 R~ 108-12.264 26.351 33.003 1.00 13.32 RAPX
ATCM 1053 C21 F~ 108-11.719 25.829 31.760 1.00 10.57 RAPX
Al~ 1054 C22 F~ 108-10.967 26.472 30.890 1.00 7.17 RAPX
Al~ 1055 ~23 F~ 108-10.527 25.696 29.671 1.00 3.85 RAPg ATCM 1056 C45 RW ~ 108-11.166 26.303 28.459 1.00 2.00 R~PX
ATCM 1057 C24 R~i~X 108 -9.009 25.760 29.546 1.00 5.00 R~iE~
ATCM 1058 C25 R~X 108 -8.217 25.354 30.783 1.00 6.28 F~
AIX~ 1059 C46 RUi~ 108 -8.066 23.836 30.825 1.00 4.71 F~
Al~ 1060 C26 R~ 108 -6.853 26.023 30.751 1.00 9.09 F~
ATCM 1061 08 R~ 108 -5.913 25.475 30.185 1.00 17.77 R~
AI~M 1062 C27 R~ 108 -6.684 27.414 31.356 1.00 14.08 RAPX
AlY~ 1063 O9 F~ 108 -5.514 27.884 30.789 1.00 14.20 F~
AI~M 1064 C51 R~ 108 -5.711 28.919 29.903 1.00 21.98 RAPX
AI~X~ 1065 C28 F~ 108 -6.426 27.335 32.858 1.00 13.28 R~i~
Al~ 1066 O10 RW ~X 108 -5.394 26.369 33.097 1.00 17.10 RAPX
Al~ 1067 C29 R~X 108 -7.657 26.973 33.703 1.00 7.79 RAPX
ATCM 1068 C47 F~ 108 -8.663 28.083 33.806 1.00 2.00 RAPX
Al~ 1069 C30 R~X 108 -7.814 25.804 34.281 1.00 5.36 RAPX
AI~M 1070 C31 F~X 108 -8.914 25.353 35.171 1.00 5.26 RAPX
Al~ 1071 C48 R~ 108 -9.109 23.870 34.864 1.00 3.40 F~
AI~IM 1072 C32 R;~ 108 -8.560 25.557 36.644 1.00 8.61 R~XAI~M 1073 Oll RAEX 108 -8.235 24.591 37.334 1.00 12.38 R~
Al~IM 1074 C33 R~X 108 -8.639 26.961 37.262 1.00 6.28 R~
AI~M 1075 C34 RAl~X108 -7.455 27.273 38.205 1.00 7.20 R~
AI~M 1076 C35 RA~X 108 -7.353 28.808 38.512 1.00 4.56 RA~X
Al~IM 1077 C49 RAl~X 108 -8.736 29.425 38.657 1.00 2.00 R~XAI~IM 1078 C36 RAl~X 108 -6.618 29.542 37.393 1.00 6.95 R;~PX
AI~IM 1079 C37 R~X 108 -5.242 29.057 36.926 1.00 11.47 R~X
AI~IM 1080 C38 RAl~X 108 -4.839 29.836 35.667 1.00 9.55 R~XAI~M 1081 C39 RA~X 108 -3.488 29.508 35.015 1.00 14.00 R~X
AI~IM 1082 012 R~ 108 -3.117 30.527 34.126 1.00 21.91 R~
Al~!I 1083 C52 RAl~X 108 -4.002 31.014 33.140 1.00 21.11 R~X
AI~M 1084 C40 R~ 108 -2.354 29.491 36.072 1.00 15.37 RAl~X
AI~IM 1085 013 R~ 108 -1.167 28.920 35.507 1.00 6.26 R~XAIOM 1086 C41 RAE~ 108 -2.766 28.682 37.309 1.00 13.80 R;~PX
AI~M 1087 C42 R~X 108 -4.078 29.130 37.914 1.00 9.01 R~
- Al~IM 1088 H6 RAE~X 108 -12.593 27.124 44.143 0.00 0.00 RA~X
AI~M 1089 H10 R~X 108 -4.969 26.537 33.948 0.00 0.00 R~X
AI~M1090 H13 RAl~X 108 -0.427 29.516 35.649 0.00 0.00 R~X

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 1091 CB ARG 2018-17.032 35.522 6.831 1.00 40.78 FRAP
ATCM 1092 CG AR~ 2018-18.205 36.058 7.690 1.00 39.26 FRAP
AloM 1093 CD ARG 2018-18.451 35.201 8.947 1.00 39.90 FRAP
AloM 1094 NE AR~ 2018-17.238 35.062 9.755 1.00 40.36 FRAP
5 AloM 1095 HE AR~ 2018-16.986 35.810 10.336 0.00 0.00 FRAP
ATCM 1096 CZ ARG 2018-16.466 33.977 9.783 1.00 36.06 FRAP
ATCM 1097 NHl AR~ 2018-15.238 34.057 10.282 1.00 33.73 FRAP
ATCM 1098 HHll ARG 2018 -14.887 34.922 10.634 0.00 0.00 FRAP
AloM 1099 HH12 ARG 2018 -14.676 33.233 10.320 0.00 0.00 FRAP
10 ATCM 1100 NH2 AR~ 2018 -16.931 32.806 9.364 1.00 32.42 FRAPAToM 1101 HH21 ARG 2018 -17.868 32.729 9.020 0.00 0 00 FRAP
AToM 1102 HH22 ARG 2018 -16.342 31.999 9.380 0.00 0.00 FRAP
AToM 1103 C AR~ 2018-14.580 34.887 6.780 1.00 38.22 FRAP
AloM 1104 O ARG 2018-13.857 35.228 5.840 1.00 36.64 FRAP
15 AloM 1105 HTl ARG 2018-15.235 37.392 6.027 0.00 0.00 FRAP
AICM 1106 HT2 AR~ 2018-14.365 37.551 7.457 0.00 0.00 FRAP
ATCM 1107 N ARG 2018-15.291 37.286 7.064 1.00 42.10 FRAP
AloM 1108 HT3 AR~ 2018-16.030 37.925 7.426 0.00 0.00 FRAP
ATCM 1109 CA AR~ 2018-15.622 35.859 7.359 1.00 39.30 FRAP
20 ATCM 1110 N UAL 2019 -14.474 33.705 7.388 1.00 36.94 FRAP
ATCM 1111 H UAL 2019 -15.146 33.399 8.027 0.00 0.00 FRAP
AI~M 1112 CA VAL 2019 -13.432 32.725 7.052 1.00 30.21 F~AP
ATOM 1113 CB U~L 2019 -12.157 32.939 7.942 1.00 32.18 FRAP
AI~M 1114 OGl U~L 2019 -12.536 32.966 9.417 1.00 26.50 FRAP
25 AI~M 1115 OG2 U;~L 2019 -11.107 31.853 7.679 1.00 32.10 FR~P
AI~M 1116 C U~L 2019 -13.973 31.314 7.273 1.00 24.65 FRAP
AI~M 1117 O U~L 2019 --14.934 31.123 8.016 1.00 24.40 FRAP
ATOM 1118 N Al~ 2020 -13.355 30.329 6.635 1.00 22.00 FRAP
A~OM 1119 H Al~ 2020 -12.627 30.546 6.016 0.00 0.00 FRAP
30 AI~M 1120 CA AL;Z~ 2020 -13.693 28.930 6.883 1.00 22.59 F~AP
Al~IM 1121 CB AL~ 2020 -13.356 28.087 5.664 1.00 21.75 FRAP
AI~M 1122 C ACA 2020 -13.000 28.354 8.125 1.00 22.82 FRAP
ATOM 1123 O AIA 2020 -11.764 28.295 8.199 1.00 19.38 F~AP
A1~3M 1124 N 1~ 2021 -13.805 27.988 9.118 1.00 20.69 FRAP
35 A~OM 1125 H IIE 2021 -14.741 28.270 9.101 0.00 0.00 FRAP
AI~M 1126 CA ~ 2021 -13.312 27.233 10.266 1.00 18.46 E~RAP
Al~IM 1127 CB ILE 2021 -12.730 28.173 11.358 1.00 22.76 l~RAP
AI~M 1128 OG2 TT ~ 2021 -13.769 29.208 11.775 1.00 25.54 F~AP
AI~M 1129 CGl rrF 2021 -12.249 27.351 12.562 1.00 25.06 FRAP

CA 02229426 l998-03-ll WO 97/15659 PC'r~US96~69~3 AToM 1130 CDl TTF~' 2021 -11.140 28.005 13 366 1 00 25.45 FRAP
ATCM 1131 C TTT~ 2021 -14.413 26.367 10.876 1.00 15.19 FRAP
ATCM 1132 O TTE 2021 -15.580 26.750 10.885 1.00 15.20 FRAP
ATCM 1133 N LEU 2022 -14.051 25.164 11.303 1.00 12.39 FRAP
AToM 1134 H LE~T 2022 -13.191 24.841 10.981 0.00 0.00 FRAP
AToM 1135 CA LEU 2022 -14.967 24.324 12.072 1.00 10.94 FRAP
AToM 1136 CB TEIT 2022 -14.339 22.958 12.314 1.00 4.40 FRAP
ATCM 1137 CG T.~T 2022 -14.001 22.196 11.041 1.00 3.20 FRAP
ATCM 1138 CDl LEU 2022 -13.224 20.961 11.400 1.00 2.00 FRAP
AToM 1139 CD2 LEU 2022 -15.279 21.845 10.295 1.00 2.00 FRAP
ATCM 1140 C LEU 2022 -15.347 24.946 13.414 1.00 11.66 FRAP
AToM 1141 O LEU 2022 -14.489 25.468 14.134 1.00 11.57 FRAP
ATCM 1142 M TRP 2023 -16.628 24.838 13.766 1.00 11.70 FRAP
ATCM 1143 H TRP 2023 -17.279 24.666 13.058 0.00 0.00 FRAP
ATCM 1144 CA TRP 2023 -17.128 25.262 15.079 1.00 13.42 FRAP
ATCM 1145 CB TRP 2023 -18.624 24.943 15.192 1.00 6.83 FRAP
ATCM 1146 CG TRP 2023 -19.499 25.971 14.562 1.00 2.00 FRAP
ATCM 1147 CD2 TRP 2023 -20.927 26.075 14.671 1.00 2.00 FRAP
AT3M 1148 ~F~ IRP 2023 -21.309 27.257 14.015 1.00 2.00 FRAP
ATCM 1149 CE3 TRP 2023 -21.917 25.288 15.267 1.00 2.00 FRAP
AT3M 1150 CDl TRP 2023 -19.093 27.063 13.854 1.00 2.00 FRAP
AT~M 1151 MEl TRP 2023 -20.169 27.839 13.525 1.00 2.00 FRAP
ATIOM 1152 HEl TRP 2023 -20.112 28.705 13.064 0.00 0.00 FRAP
AT~M 1153 CZ2 IRP 2023 -22.640 27.672 13.937 1.00 2.00 FR~P
25 ATaM 1154 CZ3 TRP 2023 -23.241 25.706 15.188 1.00 2.00 FRAP
AT~M 1155 CH2 IRP 2023 -23.585 26.881 14.528 1.00 2.00 FR~P
ATaM 1156 C TRP 2023 -16.359 24.603 16.230 1.00 14.99 FRAP
ATIOM 1157 O TRP 2023 -16.174 25.189 17.292 1.00 20.57 FRAP
ATaM 1158 N HIS 2024 -15.921 23.373 15.999 1.00 17.48 FRAP
30 AT~M 1159 H HIS 2024 -16.377 22.943 15.254 0.00 0.00 FRAP
ATOM 1160 CA HIS 2024 -14.969 22.689 16.871 1.00 19.39 FR~P
ATaM 1161 CB HIS 2024 -14.560 21.346 16.234 1.00 25.50 FRAP
ATaM 1162 CG HIS 2024 -15.693 20.627 15.555 1.00 33.39 FRAP
ATaM 1163 CD2 HIS 2024 -16.181 20.726 14.293 1.00 33.72 FRAP
35 AT~M 1164 NDl HIS 2024 -16.571 19.807 16.233 1.00 41.22 FRAP
AT~M 1165 HDl HIS 2024 -16.490 19.465 17.152 0.00 0.00 FRAP
- AT~M 1166 CEl HIS 2024 -17.559 19.450 15.429 1.00 38.35 FRAP
AT~M 1167 ME2 HIS 2024 -17.347 19.999 14.248 1.00 38.10 FRAP
ATOM 1168 HE2 HIS 2024 -17.975 19.937 13.490 0.00 0.00 FRAP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/169S3 AToM 1169 C HIS 2024-13.728 23.558 17.158 1.00 19.84 ERAP
ATCM 1170 O HIS 2024-13.541 24.012 18.280 1.00 22.62 FRAP
ATCM 1171 N GLU 2025-12.963 23.906 16.127 1.00 20.21 FRAP
AToM 1172 H GLU 2025 -13.279 23.712 15.223 0.00 0.00 FR~P
ATCM 1173 CA GLU 2025 -11.732 24.686 16.318 1.00 20.43 FRAP
AToM 1174 CB GLU 2025 -10.969 24.846 14.994 1.00 27.02 FRAP
ATCM 1175 CG GLU 2025 -10.961 23.614 14.089 1.00 41.60 FRAP
ATCM 1176 CD GLU 2025 -10.550 23.937 12.652 1.00 47.27 FRAP
ATCM 1177 OEl GLU 2025 -9.330 23.903 12.369 1.00 54.42 FRAP
10 ATCM 1178 OE2 GLU 2025 -11.440 24.219 11.810 1.00 37.45 FR~P
ATCM 1179 C GLU 2025 -12.037 26.074 16.875 1.00 17.30 FRAP
ATCM 1180 O G~U 2025 -11.268 26.641 17.651 1.00 15.80 FRAP
ATCM 1181 N MET 2026-13.159 26.625 16.444 1.00 15.93 FRAP
AToM 1182 H MET 2026 -13.715 26.119 15.820 0.00 0.00 FRAP
15 ATCM 1183 CA MET 2026 -13.552 27.971 16.816 1.00 18.01 FRAP
ATCM 1184 CB MET 2026 -14.806 28.354 16.021 1.00 21.46 FRAP
ATCM 1185 CG MET 2026 -15.619 29.490 16.603 1.00 28.72 ERAP
ATCM 1186 SD MET 2026 -16.931 30.032 15.505 1.00 34.40 FRAP
AToM 1187 OE MET 2026 -15.938 30.642 14.095 1.00 36.70 FRAP
20 AToM 1188 C MET 2026 -13.805 28.060 18.325 1.00 18.72 FRAP
ATCM 1189 O MET 2026 -13.257 28.927 19.012 1.00 18.88 FRAP
ATCM 1190 N IRP 2027-14.553 27.092 18.845 1.00 18.28 FRAP
ATCM 1191 H TRP 2027 -14.929 26.414 18.243 0.00 0.00 E~P
AT~M 1192 CA TRP 2027 -14.890 27.047 20.263 1.00 16.52 E~P
25 ATaM 1193 CB TRP 2027 -16.087 26.129 20.481 1.00 14.68 E~AP
ATOM 1194 OG TRP2027 -17.381 26.861 20.453 1.00 16.26 E~AP
ATaM 1195 CD2 T~P 2027 -17.870 27.760 21.450 1.00 16.49 FRAP
ATaM 1196 OE2 TRP 2027 -19.120 28.239 21.003 1.00 15.26 E~P
AT~M 1197 OE3 TRP 2027 -17.373 28.214 22.681 1.00 18.70 E~AP
30 ATaM 1198 CDl TRP 2027 -18.322 26.831 19.466 1.00 16.17 FRAP
ATaM 1199 NFl TRP 2027 -19.370 27.656 19.789 1.00 13.89 FRAP
AT~M 1200 HEl IRP 2027 -20.150 27.816 19.215 0.00 0.00 ERAP
AT~M 1201 CZ2 TRP 2027 -19.886 29.142 21.745 1.00 17.88 FRAP
ATaM 1202 CZ3 T~P 2027 -18.133 29.114 23.421 1.00 17.25 FRAP
35 AT~M 1203 CH2 TRP 2027 -19.376 29.565 22.950 1.00 21.47 FRAP
ATaM 1204 C TRP2027 -13.736 26.609 21.159 1.00 15.61 FRAP
ATaM 1205 O TRP 2027 -13.561 27.129 22.254 1.00 18.72 E~AP
AT~M 1206 N HIS 2028 -12.906 25.702 20.665 1.00 11.04 FRAP
AT~M 1207 H HIS 2028 -13.152 25.290 19.807 0.00 0.00 E~AP

AI~M 1208 CA HIS 2028-11.735 25.275 21.412 1.00 10 15 ERAP
AI~M 1209 CB HIS 2028--10.920 24.28220.604 1.00 9.23 FR~P
AI~M 1210 CG HIS 2028-9.821 23.642 21.389 1.00 10.39 F~RAP
Al~M 1211 CD2 HIS 2028-9.786 22.484 22.091 1.00 8.51 E'RAP
AI~M 1212 NDl HIS 2028-8.575 24.215 21.529 1.00 13.26 FE~AP
AI~M 1213 HDl HIS 2028-8.284 25.084 21.180 0.00 0.00 FR~P
AI~M 1214 OEl HIS 2028-7.814 23.433 22.276 1.00 15.69 FR~P
AI~M 1215 N E:~S 2028-8.527 22.377 22.629 1.00 18.29 ERAP
AI~M 1216 HE2 HIS 2028-8.221 21.579 23.119 0.00 0.00 l~RAP
10 AI~M 1217 C HIS 2028--10.827 26.42421.805 1.00 10.27 FR~P
Al~ 1218 O XCS 2028-10.401 26.519 22.941 1.00 10.19 FR~P
AI~M 1219 N GLU 2029-10.360 27.167 20.817 1.00 19.72 FR~P
AlaM 1220 H (~LU 2029--10.688 27.01719.900 0.00 0.00 ~RAP
AI~M 1221 CA (~LU 2029-9.433 28.257 21.093 1.00 27.56 F~RAP
15 AI~M 1222 CB t~LU 2029-8.601 28.592 19.843 1.00 34.06 FR~PAI~M 1223 aG (~LU 2029-9.401 28.822 18.565 1.00 44.39 F~RAP
AI~M 1224 CD t~U 2029-8.554 28.678 17.307 1.00 50.63 FRAP
AI~M 1225 OEl (~LU 2029-8.624 29.570 16.429 1.00 54.55 ~RAP
Al~q 1226 OE2 (~LU 2029-7.828 27.664 17.191 1.00 51.32 ~RAP
20 AI~IM 1227 C (~LU 2029-10.133 29.508 21.642 1.00 27.45 E~RAP
AlaM 1228 O GLU 2029-9.533 30.277 22.392 1.00 29.68 FR~P
AI~M 1229 N GLY 2030-11.433 29.634 21.380 1.00 25.66 FE~AP
AI~Z!I 1230 H (~Y 2030 --11.84329.093 20.670 0.00 0.00 l~RAP
AI~I 1231 CA ~LY 2030-12.214 30.696 21.997 1.00 21.35 F~AP
25 AI~M 1232 C ~LY 2030-12.307 30.538 23.504 1.00 16.02 FR~PAI~M 1233 O ~LY 2030-11.837 31.390 24.257 1.00 17.01 ~RAP
AI~I 1234 N LEU 2031-12.767 29.368 23.932 1.00 11.25 FR~P
Al~l 1235 H LEU 2031-13.130 28.749 23.264 0.00 0.00 FRAP
AI~M 1236 CA ~EU 2031-12.805 29.012 25.341 1.00 6.54 FR~P
30 AI~M 1237 CB LEU 2031-13.382 27.612 25.511 1.00 2.00 ERAP
AI~M 1238 C!G LEU 2031-14.869 27.475 25.192 1.00 2.25 E~RAP
AI~M 1239 CDl LEU 2031-15.347 26.079 25.568 1.00 2.00 ~RAP
Al~l!l 1240 CD2 IEU 2031 -15.65628.530 25.936 1.00 2.00 FR~P
AlOi!¢ 1241 C ~EU 2031-11.441 29.088 26.024 1.00 10.09 FRAP
35 AI~M 1242 O T.T;~ 2031--11.337 29.53827.168 1.00 16.95 FRAP
AI~M 1243 M GLU 2032-10.386 28.657 25.348 1.00 8.34 E'RAP
AI~M 1244 H (3~U 2032-10.522 28.216 24.483 0.00 0.00 E~RAP
AI~M 1245 CA C~U 2032-9.068 28.756 25.957 1.00 12.37 FRZ~P
AI~M 1246 CB C~LU 2032-8.028 27.986 25.146 1.00 16.26 FRAP

CA 02229426 l998-03-ll W O 97/15659 PCTrUS96/16953 ATCM 1247 CG GLU 2032 -6.692 27.831 25.861 1.00 23.62 FRAP
AToM 1248 CD GLU 2032 -5.792 26.772 25.235 1.00 30.03 FRAP
ATCM 1249 OEl GLU 2032 -4.617 27.092 24.948 1.00 31.98 FRAP
ATCM 1250 OE2 GLU 2032 -6.241 25.611 25.078 1.00 32.01 FRAP
ATCM 1251 C GLU 2032 -8.629 30.210 26.154 1.00 12.81 FRAP
ATCM 1252 O GLU 2032 -8.263 30.588 27.261 1.00 21.81 FRAP
ATCM 1253 N GLU 2033 -8.837 31.053 25.147 1.00 11.47 FRAP
ATCM 1254 H GLU 2033 -9.243 30.710 24.323 0.00 0.00 FRAP
ATCM 1255 CA GLU 2033 -8.462 32.473 25.225 1.00 12.69 FRAP
10 ATCM 1256 CB GLU 2033 -8.631 33.140 23.854 1.00 19.44 FRAP
AloM 1257 CG GLU 2033 -7.834 34.437 23.650 1.00 30.82 FRAP
ATCM 1258 CD GLU 2033 -8.155 35.152 22.319 1.00 42.12 FRAP
ATCM 1259 QEl GLU 2033 -7.793 36.346 22.186 1.00 44.44 FRAP
AloM 1260 OE2 GLU 2033 -8.759 34.530 21.408 1.00 39.63 FRAP
15 AToM 1261 C GLU 2033 -9.308 33.226 26.254 1.00 10.31 FRAP
ATCM 1262 O GLU 2033 -8.808 34.068 26.994 1.00 6.92 FRAP
ATCM 1263 N ALA 2034 -10.600 32.933 26.275 1.00 6.18 FRAP
ATCM 1264 H ALA 2034 -10.945 32.334 25.587 0.00 0.00 FRAP
AToM 1265 CA ALA 2034 -11.509 33.572 27.205 1.00 2.76 FRAP
20 ATCM 1266 CB AL~ 2034 -12.920 33.101 26.943 1.00 2.50 FRAP
ATCM 1267 C ALA 2034 -11.101 33.257 28.641 1.00 6.07 ERAP
AIOM 1268 O ALA 2034 -10.907 34.157 29.453 1.00 11.33 E~Ap A~OM 1269 N ~ 2035 -10.811 31.988 28.903 1.00 8.47 E~AP
ATaM 1270 H ~ 2035 -10.871 31.330 28.175 0.00 0.00 FRAP
25 A~OM 1271 CA ~K 2035 -10.482 31.543 30.250 1.00 4.56 FRAP
A~OM 1272 CB SER 2035 -10.357 30.016 30.294 1.00 2.00 E~AP
AT~M 1273 OG SER 2035 -9.012 29.595 30.200 1.00 7.26 E~AP
AlaM 1274 HG ~K 2035 -8.700 29.696 29.288 0.00 0.00 E~AP
A~OM 1275 C SER 2035 -9.201 32.193 30.749 1.00 5.40 ERAP
30 A~OM 1276 O SER 2035 -9.171 32.734 31.846 1.00 11.51 FRAP
AT~M 1277 N AR~ 2036 -8.195 32.265 29.886 1.00 3.96 E~AP
A~OM 1278 H AR~ 2036 -8.314 31.862 28.998 0.00 0.00 E~AP
AT~M 1279 CA ARG 2036 -6.934 32.909 30.233 1.00 6.68 FRAP
ATCM 1280 CB AR~ 2036 -5.959 32.792 29.065 1.00 7.24 E~AP
35 ATaM 1281 O~ ARG 2036 -4.695 33.631 29.210 1.00 17.54 ERAP
A~M 1282 CD ARG 2036 -4.229 34.185 27.860 1.00 17.93 FRAP
A~OM 1283 NE AR~ 2036 -3.637 35.515 27.997 1.00 18.57 FRAP
A~OM 1284 HE AR~ 2036 -2.897 35.626 28.628 0.00 0.O0 E~AP
ATaM 1285 CZ AR~ 2036 -4.0S5 36.595 27.344 1.00 20.32 ERAP

CA 02229426 l998-03-ll WO 97/15659 PCT/US96~169~3 AToM 1286 N ~ ARG 2036-3.456 37.762 27.540 1.00 24.32 FRAP
ATCM 1287 HHll ARG 2036 -2.689 37.827 28.180 0.00 0.00 FRAP
ATCM 1288 HH12 AR~ 2036 -3.766 38.572 27.045 0.00 0.00 FRAP
AToM 1289 NH2 ARG 2036-5.080 36.518 26.505 1.00 20.76 FRAP
5 ATCM 1290 HH21 AR~ 2036 -5.564 35.653 26.375 0.00 0.00 FRAP
ATCM 1291 HH22 ARG 2036 -5.391 37.341 26.030 0.00 0.00 FRAP
ATCM 1292 C AR~ 2036 -7.110 34.382 30.624 1.00 9.31 FRAP
ATCM 1293 O ARG 2036 -6.463 34.872 31.548 1.00 12.91 FRAP
AToM 1294 N LEU 2037 -8.041 35.057 29.964 1.00 10.78 FRAP
10 ATCM 1295 H LEU 2037 -8.541 34.590 29.261 0.00 0.00 FRAP
ATCM 1296 CA LEU 2037 -8.309 36.466 30.214 1.00 8.83 FRAP
AToM 1297 CB T.T~T 2037 -9.163 37.034 29.084 1.00 9.75 FRAP
ATCM 1298 CG LEU 2037 -8.302 37.375 27.873 1.00 8.95 FRAP
ATCM 1299 CDl LEU 2037 -9.130 37.388 26.613 1.00 11.32 FRAP
15 ATCM 1300 CD2 LEU 2037 -7.624 38.713 28.110 1.00 7.83 FRAP
ATCM 1301 C LE~T 2037 -9.004 36.692 31.543 1.00 12.66 FRAP
ATCM 1302 O LEU 2037 -8.626 37.583 32.295 1.00 17.85 FRAP
ATCM 1303 N TYR 2038 -10.020 35.886 31.832 1.00 11.90 FRAP
ATCM 1304 H TYR 2038-10.327 35.266 31.130 0.00 0.00 FRAP
20 ATaM 1305 CA TYR 2038-10.693 35.930 33.132 1.00 11.68 FRAP
AT~M 1306 CB TYR 2038 -12.006 35.138 33.071 1.00 9.29 FRAP
AT~M 1307 CG TYR 2038 -12.761 35.090 34.375 1.00 12.17 FRAP
ATaM 1308 CDl TYR 2038 -12.942 36.239 35.143 1.00 10.58 FRAP
ATOM 1309 OEl TYR 2038 -13.555 36.181 36.391 1.00 17.63 FRAP
25 ATOM 1310 CD2 TYR 2038 -13.230 33.880 34.884 1.00 17.46 FR~P
ATaM 1311 ~ TYR 2038 -13.850 33.810 36.131 1.00 17.47 ERAP
ATaM 1312 CZ TYR 2038-14.006 34.962 36.880 1.00 18.99 FRAP
ATOM 1313 OH TYR 2038-14.596 34.893 38.123 1.00 22.39 FRAP
ATaM 1314 HH TYR 2038-15.321 34.267 38.078 0.00 0.00 FRAP
30 ATaM 1315 C TYR 2038-9.811 35.403 34.277 1.00 13.86 FRAP
ATaM 1316 O TYR 2038-9.408 36.164 35.158 1.00 17.65 FR~P
ATaM 1317 N PHE 2039 -9.481 34.113 34.235 1.00 13.85 FRAP
ATaM 1318 H PHE 2039 -9.764 33.595 33.452 0.00 0.00 FR~P
ATOM 1319 C~ PHE 2039 -8.717 33.455 35.299 1.00 10.83 FRAP
35 ATOM 1320 CB PHE 2039 -8.665 31.950 35.054 1.00 2.58 FRAP
ATaM 1321 CG PHE 2039-9.988 31.281 35.235 1.00 6.64 FRAP
ATaM 1322 CDl PHE 2039 -10.540 31.147 36.510 1.00 4.84 FRAP
ATaM 1323 CD2 PHE 2039 -10.745 30.902 34.131 1.00 2.79 FRAP
ATaM 1324 CEl PHE 2039 -11.828 30.656 36.680 1.00 5.26 FRAP

CA 02229426 l998-03-ll AToM 1325 CE2 EHE 2039 -12.039 30.408 34.292 1.00 2.18 FRAP
ATGM 1326 CZ PHE 2039 -12.581 30.287 35.563 1.00 4.94 FRAP
ATCM 1327 C EHE 2039 -7.306 33.980 35.460 1.00 14.37 FRAP
AToM 1328 O EHE 2039 -6.861 34.248 36.579 1.00 15.23 FR~P
5 ATCM 1329 N GLY 2040 -6.619 34.155 34.336 1.00 17.70 FRAP
ATCM 1330 H GLY 2040 -7.060 34.013 33.471 0.00 0.00 FRAP
ATCM 1331 CA GLY2040 -5.221 34.544 34.369 1.00 19.07 FR~P
ATCM 1332 C GLY2040 -4.954 36.026 34.561 1.00 19.43 FRAP
ATCM 1333 O GLY2040 -3.957 36.384 35.180 1.00 24.65 FRAP
10 ATCM 1334 N GLU2041 -5.815 36.881 34.012 1.00 17.18 FRAP
AToM 1335 ~ GLU 2041 -6.555 36.502 33.494 0.00 0.00 FRAP
AToM 1336 CA GLU 2041 -5.590 38.328 34.019 1.00 16.74 FRAP
ATCM 1337 C~3 GLU 2041 -5.476 38.867 32.589 1.00 21.26 FRAP
AToM 1338 CG GLU 2041 -5.030 37.856 31.544 1.00 34.57 FRAP
15 ATCM 1339 CD GLU 2041 -3.792 38.302 30.785 1.00 39.88 FRAP
ATCM 1340 OEl GLU 2041 -3.772 39.459 30.303 1.00 41.61 FRAP
ATCM 1341 OE2 GLU 2041 -2.844 37.489 30.664 1.00 43.16 FRAP
ATCM 1342 C GLU 2041 -6.689 39.108 34.733 1.00 16.00 FRAP
ATCM 1343 O GLU 2041 -6.754 40.330 34.629 1.00 16.19 FRAP
20 AToM 1344 N AR~ 2042 -7.626 38.392 35.340 1.00 16.54 FRAP
ATCM 1345 H AR~2042 -7.540 37.419 35.364 0.00 0.00 FRAP
ATCM 1346 CA ARG2042 -8.785 39.011 35.974 1.00 17.30 FRAP
AI~M 1347 C~3 ARG 2042 -8.389 39.691 37.283 1.00 21.74 FRAP
AlaM 1348 CG ~RG2042 -8.704 38.869 38.515 1.00 29.43 FRAP
25 A~OM 1349 CD ARG2042 -7.650 37.815 38.736 1.00 31.60 FRAP
A~OM 1350 NE ARG2042 -6.318 38.396 38.627 1.00 34.93 FRAP
AI~M 1351 HE ~R~2042 -6.148 39.074 37.940 0.00 0.00 F~AP
A~OM 1352 CZ ARG2042 -5.273 38.026 39.358 1.00 41.93 FRAP
A~OM 1353 NHl ARG 2042 -4.097 38.606 39.146 1.00 43.89 FRAP
30 ATOM 1354 HHll ARG 2042 -4.011 39.312 38.444 0.00 0.00 F~AP
A~OM 1355 HH12 ARG 2042 -3.309 38.359 39.710 0.00 0.00 FR~P
A~OM 1356 NH2 ~R~ 2042-5.398 37.089 40.296 1.00 42.95 FRAP
AlaM 1357 HH21 ARG 2042 -6.289 36.673 40.485 0.00 0.00 FRAP
AlaM 1358 HH22 ~RG 2042 -4.609 36.857 40.865 0.00 0.00 FRAP
35 A~OM 1359 C ARG 2042 -9.485 40.015 35.074 1.00 15.46 FRAPAT~M 1360 O ARG 2042-10.031 41.009 35.550 1.00 17.81 FRAP
A~OM 1361 N ASN 2043 -9.560 39.689 33.789 1.00 13.57 FRAP
A~OM 1362 H ASN 2043 -9.152 38.845 33.525 0.00 0.00 F~P
AlaM 1363 CA ASN 2043-10.219 40.545 32.805 1.00 12.63 FRAP

CA 02229426 l998-03-ll ATCM 1364 CB A ~ 2043 -9.322 40.702 31.567 1.00 9.40 FRAPATCM 1365 CG ASN 2043 -9.673 41.928 30.734 1.00 13.89 FRAP
ATCM 1366 ODl ASN 2043 -10.778 42.457 30.805 1.00 13.79 FRAP
ATCM 1367 ND2 ASN 2043 -8.725 42.382 29.941 1.00 19.98 FRAP
5 AT~M 1368 HD21 ASN 2043 -7.861 41.929 29.933 0.00 0.00 FRAP
ATCM 1369 HD22 ASN 2043 -8.951 43.171 29.415 0.00 0.00 FRAP
AToM 1370 C ASN 2043 -11.589 39.985 32.399 1.00 11.08 FRAP
AToM 1371 O ASN 2043 -11.704 39.254 31.410 1.00 15.73 FRAP
ATCM 1372 N V~L 2044 -12.622 40.329 33.164 1.00 7.83 FRAP
10 AT~M 1373 H U~L 2044 -12.407 40.817 33.986 0.00 0.00 FRAP
AToM 1374 CA V~L 2044 -13.996 39.930 32.841 1.00 8.89 FRAP
ATCM 1375 CB U~L 2044 -14.942 40.079 34.049 1.00 4.93 FRAP
ATCM 1376 CGl U~L 2044 -16.254 39.343 33.783 1.00 2.00 FRAP
ATCM 1377 CG2 U~L 2044 -14.280 39.541 35.300 1.00 6.55 FRAP
15 ATCM 1378 C V~L 2044 -14.599 40.724 31.680 1.00 12.31 FRAP
AToM 1379 O U~L2044 -15.607 40.328 31.111 1.00 16.97 FRAP
ATCM 1380 N LYS2045 -14.013 41.873 31.366 1.00 15.26 FRAP
ATCM 1381 H LYS2045 -13.326 42.230 31.961 0.00 0.00 FRAP
ATCM 1382 CA LYS 2045 -14.387 42.614 30.158 1.00 18.66 FRAP
20 ATCM 1383 CB LYS 2045 -13.791 44.027 30.205 1.00 20.39 FRAP
ATCM 1384 CG LYS 2045 -13.868 44.787 28.894 1.00 27.87 FRAP
ATCM 1385 CD LYS 2045 -12.848 45.913 28.846 1.00 36.04 FRAP
ATCM 1386 OE LYS 2045 -13.013 46.763 27.592 1.00 39.79 FR~P
AToM 1387 NZ LYS 2045 -12.203 48.015 27.646 1.00 42.34 FRAP
25 ATCM 1388 HZl LYS 2045 -11.19447.773 27.696 0.00 0.00 FRAP
ATCM 1389 HZ2 LYS 2045 -12.47748.555 28.491 0.00 0.00 FRAP
ATCM 1390 HZ3 LYS 2045 --12.387 48.579 26.791 0.00 0.00 FRAP
ATOM 1391 C LYS 2045 -13.912 41.880 28.890 1.00 15.74 E~RAP
AI~M 1392 O LYS 2045 -14.697 41.616 27.982 1.00 15.10 F~RAP
30 AI~M 1393 N GLY 2046 -12.640 41.493 28.885 1.00 13.71 E'RAP
ATOM 1394 H GLY 2046 -12.091 41.759 29.647 0.00 0.00 FRAP
AT~IM 1395 CA GLY 2046 -12.063 40.767 27.768 1.00 11.16 ~RAP
AI~M 1396 C GLY 2046 -12.716 39.427 27.486 1.00 11.68 FRAP
AI~M 1397 O GLY 2046 -13.079 39.138 26.350 1.00 12.25 FRAP
35 AT~M 1398 N MEI 2047 -12.944 38.632 28.522 1.00 14.02 FR~P
AI~M 1399 H MEI 2047 -12.639 38.911 29.412 0.00 0.00 FRAP
AI~IM 1400 CA MEI 2047 -13.555 37.327 28.317 1.00 12.90 FR~P
A~IM 1401 CB MEI 2047 -13.571 36.520 29.625 1.00 9.26 FRAP
AT~IM 1402 O~ MEI 2047 -14.762 36.725 30.521 1.00 6.02 E~RAP

CA 02229426 l998-03-ll AT3M 1403 SD MET 2047 -15.175 35.189 31.335 1.00 6.46 FRAP
AToM 1404 OE MET 2047 -16.865 35.461 31.714 1.00 4.80 ~RAP
ATCM 1405 C MET 2047 -14 954 37.413 27.691 1.00 14.99 FRAP
AToM 1406 O MET 2047 -15.275 36.624 26.816 1.00 20.34 ER~P
ATCM 1407 N FHE 2048 -15.710 38.465 28.001 1.00 13.61 FRAP
ATCM 1408 H PHE 2048 -15.410 39.078 28.703 0.00 0.00 FRAP
ATCM 1409 CA PHE 2048 -16.992 38.707 27.324 1.00 12.00 F2AP
ATCM 1410 C}3 PHE 2048 -17.754 39.849 28.012 1.00 15.37 FRAP
ATCM 1411 CG PHE 2048 -18.356 39.479 29.357 1.00 19.64 FRAP
10 ATCN 1412 CDl PHE 2048 -18.849 38.201 29.600 1.00 20.36 FRAP
ATCM 1413 CD2 PHE 2048 -18.506 40.442 30.352 1.00 17.04 FRAP
AToM 1414 OE 1 PHE 2048 -19.481 37.901 30.806 1.00 12.14 ERAP
AloM 1415 OE2 PHE 2048 -19.137 40.138 31.552 1.00 7.86 FRAP
ATCM 1416 CZ PHE 2048 -19.623 38.875 31.774 1.00 2.66 FRAP
15 ATCM 1417 C PHE 2048 -16.785 39.054 25.839 1.00 11.47 FRAP
ATCM 1418 O PHE 2048 -17.540 38.619 24.968 1.00 9.57 FRAP
AT~M 1419 N GLU 2049 -15.754 39.843 25.558 1.00 10.97 ERAP
AToM 1420 H GLU 2049 -15.274 40.244 26.315 0.00 0.00 FRAP
AToM 1421 CA GLU 2049 -15.368 40.161 24.189 1.00 12.08 FRAP
20 ATCM 1422 CB GLU 2049 -14.144 41.090 24.187 1.00 18.49 FRAP
ATCM 1423 CG GLU 2049 -14.432 42.512 24.700 1.00 28.61 FRAP
ATCM 1424 CD GLU 2049 -13.244 43.464 24.566 1.00 32.92 FRAP
ATaM 1425 CEl GLU 2049 -13.006 44.240 25.521 1.00 34.23 FRAP
ATOM 1426 OE2 GLU 2049 -12.598 43.492 23.489 1.00 32.94 FRAP
25 ATaM 1427 C GLU 2049 -15.072 38.890 23.387 1.00 10.88 FRAP
ATaM 1428 0 GLU 2049 -15.771 38.579 22.427 1.00 12.08 FRAP
ATOM 1429 N V~L 2050 -14.120 38.096 23.862 1.00 10.17 FRAP
ATOM 1430 H V~L 2050 -13.667 38.388 24.675 0.00 0.00 FRAP
ATOM 1431 CA U~L 2050 -13.800 36.807 23.247 1.00 10.01 FRAP
30 AIOM 1432 CB V~L 2050 -12.318 36.446 23.457 1.00 6.62 FRAPAIOM 1433 OGl V~L 2050 -11.942 36.639 24.901 1.00 11.08 FRAP
A~aM 1434 OG2 V~L 2050 -12.039 35.006 22.995 1.00 11.04 FRAP
AToM 1435 C U~L 2050 -14.693 35.680 23.781 1.00 14.92 FRAP
ATaM 1436 0 U~L 2050 -14.244 34.799 24.529 1.00 20.63 FRAP
35 ATOM 1437 N LEU 2051 -15.981 35.775 23.454 1.00 12.19 FRAP
ATOM 1438 H LEU 2051 -16.263 36.655 23.111 0.00 0.00 FRAP
ATaM 1439 CA LEU 2051 -16.971 34.764 23.816 1.00 9.54 FRAP
ATOM 1440 CB LEU 2051 -17.122 34.686 25.336 1.00 8.37 FRAP
ATIOM 1441 OG LEU 2051 -17.216 33.329 26.046 1.00 8.86 FRAP

CA 02229426 l998-03-ll WO 97/1~;6~;g PC7~/US96~6953 AToM 1442 CDl LEU 2051 -16.110 32.395 25.592 1.00 5.79 FRAP
AToM 1443 CD2 LEU 2051 -17.118 33.550 27.538 1.00 2.00 FRAP
ATCM 1444 C 1EU 2051 -18.310 35.117 23.188 1.00 10.79 FRAP
ATCM 1445 O LEU 2051 -19.052 34.237 22.752 1.00 14.03 FRAP
ATCM 1446 N GLU 2052 -18.562 36.413 23.042 1.00 11.63 FRAP
ATCM 1447 H GLU 2052 -17.932 37.078 23.408 0.00 0.00 FRAP
ATCM 1448 CA GLU 2052 -19.837 36.897 22.525 1.00 13.53 FRAP
ATCM 1449 C~3 GLU 2052 -19.980 38.399 22.792 1.00 18.53 FRAP
AToM 1450 CG GLU 2052 -21.396 38.835 23.103 1.00 29.17 FRAP
10 ATCM 1451 CD GLU 2052 -21.530 40.343 23.220 1.00 34.41 FRAP
AT~M 1452 OEl GLU 2052 -22.567 40.884 22.772 1.00 39.61 FRAP
ATCM 1453 OE2 GLU 2052 -20.605 40.987 23.766 1.00 36.83 FRAP
ATCM 1454 C GLU 2052 -20.059 36.587 21.044 1.00 9.88 FRAP
ATCM 1455 O GLU 2052 -21.045 35.948 20.693 1.00 11.10 FRAP
15 ATCM 1456 N PRO 2053 -19.085 36.922 20.175 1.00 9.83 FRAP
ATCM 1457 CD PRO 2053 -18.104 38.004 20.386 1.00 7.70 FRAP
ATCM 1458 CA PRD 2053 -18.978 36.374 18.814 1.00 9.97 FRAP
ATCM 1459 CB PRO 2053 -17.537 36.674 18.444 1.00 12.18 FRAP
AToM 1460 CG PRO 2053 -17.265 37.981 19.139 1.00 11.41 FRAP
20 ATCM 1461 C PRO 2053 -19.301 34.882 18.639 1.00 11.69 FRAP
ATCM 1462 O PRO 2053 -20.157 34.520 17.837 1.00 15.54 FRAP
AToM 1463 N LEU 2054 -18.588 34.021 19.362 1.00 12.26 FRAP
AI~IM 1464 H LEU 2054 --17.894 34.386 19.944 0.00 0.00 F~AP
Al~IM 1465 CA LEU 2054 -18.813 32.574 19.304 1.00 7.01 FRAP
25 AI~IM 1466 CB LEU 2054 -17.897 31.859 20.296 1.00 2.00 FRAP
Al~M 1467 CG LEU 2054 --16.431 32.303 20.307 1.00 2.00 FRAP
AI~M 1468 CDl ~EU 2054 -15.60331.503 21.299 1.00 2.00 ERAP
Aq~M 1469 CD2 LEU 2054 -15.87332.146 18.921 1.00 12.00 FRAP
AI~M 1470 C LEU 2054 --20.267 32.247 19.621 1.00 6.82 FRAP
30 A~M 1471 O LEU 2054 --20.928 31.510 18.895 1.00 7.84 FRAP
AI~M 1472 N ~ S 2055 -20.805 32.908 20.632 1.00 4.28 FI~AP
Al~IM 1473 H HIS 2055 --20.241 33.532 21.142 0.00 0.00 FRAP
AI~M 1474 CA HIS 2055 -22.205 32.716 20.965 1.00 5.58 FE?AP
AI~M 1475 CB HIS 2055 --22.533 33.366 22.310 1.00 5.95 F~ P
35 AI~IM 1476 C.'G ~ S 2055 -22.23732.495 23.491 1.00 2.00 FRAP
AI~IM 1477 CD2 ~ S 2055 --21.13632.399 24.270 1.00 2.00 FRAP
AI~M 1478 NDl HIS 2055 -23.11831.542 23.952 1.00 2.00 FRAP
AI~IM 1479 HDl HIS 2055 --24.02531.364 23.581 0.00 0.00 FRAP
AI~M 1480 CF1 HCS 2055 -22.56930.891 24.960 1.00 2.00 FRAP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 1481 NE2 HIS 2055 -21.362 31.384 25.166 1.00 3.10 FRAPATCM 1482 HE2 HIS 2055 -20.608 30.877 25.532 0.00 0.00 FRAP
AToM 1483 C HIS 2055 -23.118 33.276 19.884 1 00 8.31 FRAP
AToM 1484 O HIS 2055 -24.215 32.765 19.667 1.00 14.91 FRAP
AToM 1485 N ALA 2056 -22.644 34.290 19.170 1.00 10.33 FRAP
AToM 1486 H ALA 2056 -21.767 34.651 19.397 0.00 0.00 FRAP
AloM 1487 CA ALA 2056 -23.442 34.935 18.130 1.00 10.51 FRAP
ATCM 1488 CB A~A 2056 -22.729 36.161 17.619 1.00 9.92 FRAP
AToM 1489 C ALA 2056 -23.731 33.985 16.974 1.00 14.24 FRAP
10 AToM 1490 O A~A 2056 -24.885 33.829 16.556 1.00 17.21 FRAP
ATCM 1491 N MET 2057 -22.680 33.340 16.476 1.00 11 79 FRAP
ATCM 1492 H MET 2057 -21 792 33.596 16.814 0.00 0.00 FRAP
ATCM 1493 CA MET 2057 -22.810 32.294 15.469 1.00 15.13 FRAP
AToM 1494 CB MET 2057 -21.452 31.642 15.231 1.00 17.94 FRAP
15 AloM 1495 CG MET 2057 -20.692 32.266 14.087 1.00 27.92 FRAP
ATCM 1496 SD MET 2057 -18.979 31.767 14.037 1.00 39.79 FRAP
AToM 1497 OE MET 2057 -18.164 33.353 14.482 1.00 41.99 FRAP
ATCM 1498 C MET 2057 -23.842 31.222 15.834 1.00 17.76 FRAP
ATCM 1499 O MET 2057 -24.808 31.000 15.100 1.00 16.63 FRAP
20 AToM 1500 N MET 2058 -23.679 30.615 17.005 1.00 20.22 FRAP
ATCM 1501 H MET 2058 -22.898 30.870 17.543 0.00 0.00 FRAP
ATCM 1502 CA MET 2058 -24.617 29.603 17.489 1.00 21.71 FRAP
AloM 1503 CB MET 2058 -24.359 29.323 18.969 1.00 20.36 FRAP
ATOM 1504 CG MET 2058 -22.991 28.760 19.256 1.00 15.47 FRAP
25 ATaM 1505 SD MET 2058 -22.714 27.281 18.302 1.00 20.16 FRAP
ATOM 1506 OE MET 2058 -23.353 26.049 19.380 1.00 12.03 F~P
AT~M 1507 C MET 2058 -26.074 30.032 17.295 1.00 25.10 F~AP
ATOM 1508 O MET 2058 -26.865 29.330 16.659 1 00 28.18 F~AP
ATaM 1509 N GLU 2059 -26.375 31.246 17.742 1.00 25.58 F~P
30 AT~M 1510 H GLU 2059 -25.654 31.794 18.125 0.00 0.00 FRAP
AT~M 1511 CA GLU 2059 -27.725 31.798 17.694 1.00 26.53 F~P
ATaM 1512 CB GLU 2059 -27.759 33.099 18.504 1.00 26.67 FRAP
ATOM 1513 OG GLU 2059 -29.007 33.941 18.330 1.00 28.36 F~P
ATOM 1514 CD GLU 2Q59 -28 701 35.344 17.828 1.00 34.40 F~AP
35 ATOM 1515 OEl GLU 2059 -27.515 35.648 17.560 1.00 37.80 F~P
AT~M 1516 OE2 GLU 2059 -29.653 36.146 17.699 1.00 36.Q2 F~AP
ATOM 1517 C GLU 2059 -28.224 32.039 16.261 1.00 24.75 F~P
AT~M 1518 O GLU 2059 -29.425 32.148 16.022 1.00 24.66 F~AP
AT~M 1519 N ARG 2060 -27.303 32.057 15.307 1.00 23.58 F~AP

CA 02229426 l998-03-ll WO 97/~5659 PCT~US96~169~;3 AToM ~520 H ARG 2060 -26.365 31.985 15.562 0.00 0.00 FRAP
ATCM 1521 CA ARG 2060 -27.660 32.296 13.914 1.00 27.89 FRAP
~ 1522 CB ~RG 2060 -26.547 33.091 13.224 1.00 31.68 FRAP
ATCM 1523 CG ARG 2060 -26.338 34.497 13.808 1.00 33.63 FRAP
ATCM 1524 CD ARG 2060 -27.275 35.527 13.173 1.00 36.15 FRAP
ATCM 1525 NE ARG 2060 -28.381 35.927 14.046 1.00 35.55 FRAP
ATCM 1526 HE AR~ 2060 -28.189 36.558 14.770 0.00 0.00 FRAP
A~CM 1527 CZ ARG 2060 -29.635 35.492 13.924 1.00 37.00 FRAP
AToM 1528 NHl ARG 2060 -30.590 35.982 14.704 1.00 38.84 FRAP
10 ATCM 1529 HHll ARG 2060 -30.376 36.677 15.389 0.00 0.00 FRAP
A~CM 1530 HHa2 ARG 2060 -31.526 35.646 14.601 0.00 0.00 FRAP
ATCM 1531 NH2 ARG 2060 -29.933 34.533 13.057 1.00 33.57 FRAP
AToM 1532 HH21 ARG 2060 -29.220 34.125 12.486 0.00 0.00 FRAP
ATCM 1533 HH22 AR~ 2060 -30.874 34.210 12.967 0.00 0.00 FRAP
15 AToM 1534 C ARG 2060 -27.992 31.021 13.117 1.00 26.90 FRAP
ATCM 1535 O ARG 2060 -28.925 31.013 12.317 1.00 26.30 FRAP
ATCM 1536 N GLY 2061 -27.246 29.945 13.351 1.00 27.44 FRAP
A~CM 1537 H GLY 2061 -26.500 30.030 13.976 0.00 0.00 FRAP
ATCM 1538CA GLY 2061 -27.597 28.66212.758 1.0023.84 FRAP
20 Aq~M 1539 C GLY 2061 -26.442 27.75112.361 1.0025.08 FRAP
AI~M 1540 0 GLY 2061 -25.500 28.19811.690 1.0029.79 FR~P
ATOM 1541 N PRO 2062 -26.516 26.44812.695 1.0021.10 FR~p A~M 1542CD PRO 2062 -27.590 25.83613.489 1.0018.97 ERAP
AI~IM 1543CA PRO 2062 -25.740 25.43311.976 1.0019.45 FR~P
25 Aq~M 1544CB PRO 2062 --26.204 24.110 12.585 1.00 14.25 FR~P
Al~IM 1545CG PRO 2062 -27.072 24.46713.734 1.0014.98 FR~P
AI~M 1546 C PRO 2062 -26.051 25.46310.487 1.0021.95 E~RAP
ATOM 1547 0 PRO 2062 -27.208 25.34910.085 1.0026.38 E~RAP
AI~IM 1548 N GLN 2063 -25.048 25.7299.670 1.0021.33 E~RAP
30 AI~IM 1549 H GIN 2063 -24.240 26.06510.056 0.000.00 E~RAP
AI~M 1550CA GLN 2063 -25.258 25.6688.224 1.0022.88 E~RAP
AI~M 1551CB GLN 2063 -24.384 26.7007.510 1.0025.75 FR~P
Aq~M 1552C~G Gl~ 2063 -25.131 27.9227.002 1.0030.23 FR~P
AI~M 1553CD GLN 2063 -24.186 29.0356.545 1.0037.47 ~RAP
35 A~M 1554OEl Gl~ 2063 --23.139 28.776 5.945 1.00 42.91 FRAP
AI~IM 1555NE2 GLN 2063 -24.556 30.2806.822 1.0034.40 ~RAP
- AI~M 1556HE21 G~ 2063 -25.396 30.4887.270 0.000.00 ~RAP
AICM 1557HE22 G~ 2063 -23.899 30.9176.484 0.000.00 ERAP
A~OM 1558 C (~LN 2063 -24.930 24.2787.701 1.0019.53 ~RAP

CA 02229426 l998-03-ll W O 97tl5659 PCT~US96/16953 ATCM 1559 O GLN 2063 -25.781 23.568 7.181 1.00 22.10 FRAP
ATCM 1560 N IHR 2064 -23.685 23.880 7.897 1.00 16.77 FRAP
ATCM 1561 H IHR 2064 -23.114 24.477 8.406 0.00 0.00 FRAPAloM 1562 CA IH~ 2064-23.220 22.593 7.423 1.00 17.61 FRAP
AloM 1563 CB THR 2064-21.689 22.551 7.414 1.00 18.02 FRAP
ATCM 1564 OGl IHR 2064 -21.213 22.465 8.763 1.00 16.37 FRAP
ATCM 1565 H~l IHR 2064 -21.145 21.529 8.956 0.00 0.00 FRAP
AToM 1566 CG2 IHR 2064 -21.128 23.812 6.763 1.00 19.18 FRAP
AloM 1567 C THR 2064-23.743 21.471 8.322 1.00 17.50 FRAP
10 AloM 1568 O IHR 2064-24.272 21.725 9.402 1.00 19.82 FRAP
AToM 1569 N LEU 2065-23.481 20.231 7.922 1.00 17.20 FRAP
AToM 1570 H LEU 2065-23.146 20.079 7.018 0.00 0-~~ FRAP
AloM 1571 CA LEU 2065-23.813 19.063 8.731 1.00 13.79 FRAP
AloM 1572 CB T.T~T 2065 -23.667 17.808 7.879 1.00 17.73 FRAP
15 AloM 1573 C~ LEU 2065-24.909 16.954 7.614 1.00 18.83 FRAP
ATCM 1574 CDl LEU 2065 -26.158 17.819 7.466 1.00 19.10 FRAP
ATCM 1575 CD2 TT~t 2065 -24.658 16.129 6.365 1.00 14.71 FRAP
ATCM 1576 C LEU 2065-22.940 18.949 9.988 1.00 13.22 FRAP
ATCM 1577 O LEU 2065-23.445 18.670 11.070 1.00 12.57 FRAP
20 AToM 1578 N LYS 2066 -21.649 19.264 9.848 1.00 9.29 FRAP
ATCM 1579 H LYS 2066 -21.297 19.271 8.935 0.00 0.00 FRAP
ATCM 1580 CA LYS 2066 -20.707 19.308 10.976 1.00 8.13 FRAP
ATOM 1581 CB LYS 2066 -19.297 19.636 10.475 1.00 2.00 FRAP
ATOM 1582 OG LYS 2066 -18.442 18.438 10.157 1.00 2.00 FRAP
25 A~OM 1583 CD LYS 2066 -17.028 18.870 9.846 1.00 2.00 FRAP
ATOM 1584 CE LYS 2066 -16.122 17.672 9.553 1.00 9.62 FRAP
A~OM 1585 NZ LYS 2066 -16.549 16.861 8.378 1.00 5.28 FRAP
ATOM 1586 HZl LYS 2066-16.491 17.449 7.520 0.00 0.00 FRAP
ATOM 1587 HZ2 LYS 2066-17.527 16.533 8.514 0.00 0.00 FRAP
30 A~OM 1588 HZ3 LYS 2066-15.912 16.043 8.283 0.00 0.00 FRAP
ATOM 1589 C LYS 2066 -21.072 20.317 12.070 1.00 11.53 FRAP
AT~M 1590 O LYS 2066 -20.704 20.148 13.226 1.00 16.33 FR~P
A~OM 1591 N GLU 2067-21.548 21.479 11.646 1.00 14.92 FRAP
ATOM 1592 H GLU 2067-21.556 21.672 10.692 0.00 0.00 FRAP
35 A~OM 1593 CA GLU 2067-21.998 22.508 12.569 1.00 15.78 FRAP
AT~M 1594 CB GLU 2067-22.143 23.842 11.835 1.00 22.50 FRAP
A~OM 1595 CG GLU 2067-20.877 24.292 11.105 1.00 25.09 FR~P
ATOM 1596 CD GLU 2067-21.032 25.619 10.365 1.00 25.97 FRAP
A~OM 1597 OEl GLU 2067 -22.161 26.174 10.309 1.00 16.81 FRAP

CA 02229426 l998-03-ll WO 97/15659 PCTAUS96~169~3 AToM 1598 OE 2 GLU 2067 -20.002 26.108 9.844 1.00 26.65 FRAP
AT~M 1599 C GLU 2067-23.336 22.108 13.173 1.00 19.42 FRAP
ATCM 1600 O GLU 2067-23.693 22.562 14.260 1.00 22.50 FRAP
ATCM 1601 N THR 2068-24.096 21.300 12.435 1.00 19.36 FRAP
AToM 1602 H THR 2068-23.847 21.150 11.501 0.00 0.00 FRAP
ATCM 1603 CA IHR 2068-25.345 20.731 12.940 1.00 18.73 FRAP
AToM 1604 CB IHR 2068-26.140 20.025 11.809 1.00 14.88 FRAP
AToM 1605 OGl IHR 2068 -26.656 21.013 10.912 1.00 16.48 FRAP
ATCM 1606 HGl IHR 2068 -25.961 21.423 10.376 0.00 0.00 FRAP
10 AToM 1607 CG2 IHR 2068 -27.317 19.239 12.370 1.00 13.69 FRAP
ATCM 1608 C THR 2068-25.120 19.751 14.100 1.00 20.11 FRAP
AToM 1609 O THR 2068-25.625 19.971 15.204 1.00 24.18 FRAP
AToM 1610 N ~K 2069-24.303 18.724 13.879 1.00 15.42 FRAP
AToM 1611 H ~K 2069-23.872 18.626 13.000 0.00 0.00 FRAP
15 ATCM 1612 CA 5ER 2069-24.066 17.701 14.898 1.00 11.92 FRAP
AloM 1613 CB SER 2069-23.234 16.555 14.315 1.00 3.97 FRAP
ATCM 1614 OG SER 2069-21.951 16.993 13.917 1.00 2.00 FRAP
AToM 1615 H~ SER 2069-21.427 16.200 13.756 0.00 0.00 FRAP
AToM 1616 C SER 2069-23.404 18.243 16.180 1.00 14.81 FRAP
20 AToM 1617 O SER 2069-23.865 17.962 17.295 1.00 17.69 FRAP
AToM1618 N PHE 2070 -22.371 19.070 16.018 1.00 12.68 FRAP
A~M1619H PHE 2070 -21.960 19.083 15.126 0.00 0.00 ~P
A~M1620CA PHE 2070 -21.786 19.831 17.132 1.00 6.20 F~P
A~M1621 CB PHE 2070 -20.732 20.811 16.607 1.00 5.44 F~P
25A~M1622OG PHE 2070 -20.154 21.726 17.656 1.00 2.00 ~P
A~M1623CDl PHE 2070 -18.861 21.521 18.130 1.00 2.00 F~P
A~M1624CD2PHE2070 -20.857 22.848 18.092 1.00 2.00 F~P
A~M1625OEl PHE 2070 -18.272 22.419 19.016 1.00 2.00 F~P
A~M1626~ PHE 2070 -20.283 23.748 18.980 1.00 2.00 ~P
30A~M1627CZ PHE 2070 -18.985 23.534 19.441 1.00 2.00 ~AP
A~M1628CP~2070 -22.856 20.601 17.888 1.00 2.60 F~P
A~M1629O PHE 2070 -22.752 20.790 19.082 1.00 7.27 FRAP
A~M1630 N ~ 2071 -23.836 21.135 17.182 1.00 2.01 F~P
A~M1631H~2071 -23.831 21.076 16.202 0.00 0.00 F~P
35A~M1632CA~2071 -24.876 21.880 17.851 1.00 2.00 F~P
A~M1633 CB ~ 2071 -25.689 22.675 16.841 1.00 7.02 ~P
A~M1634~2071 -26.604 23.677 17.501 1.00 8.30 F~P
A~OM1635~1~2071 -27.805 23.463 17.602 1.00 11.66 F~P
A~M1636~2~2071 -26.035 24.766 17.987 1.00 12.66 ~P

CA 02229426 l998-03-ll ATCM 1637 HD21 ASN 2071 -25.081 24.904 17.878 0.00 0.00 FRAPAloM 1638 HD22 ASN 2071 -26.665 25.370 18.419 0.00 0.00 FRAPATCM 1639 C ASN 2071 -25.784 20.959 18.646 1.00 4.16 FRAP
ATCM 1640 O ASN 2071 -26.258 21.328 19.711 1.00 10.87 FRAP
ATCM 1641 N GLN 2072 -25.998 19.747 18.143 1.00 8.02 FRAP
AToM 1642 H GLN 2072 -25.642 19.564 17.247 0.00 0.00 FRAP
AT~M 1643 CA GLN 2072 -26.801 18.741 18.845 1.00 8.00 FR~P
ATCM 1644 CB GLN 2072 -27.061 17.554 17.934 1.00 2.00 FRAP
ATCM 1645 C~ GLN 2072 -28.010 17.884 16.798 1.00 6.79 FRAP
10 AToM 1646 CD GLN 2072 -27.941 16.881 15.665 1.00 8.96 FRAP
AToM 1647 OEl GLN 2072 -27.006 16.088 15.570 1.00 4.92 FRAP
ATCM 1648 NE2 GLN 2072 -28.940 16.908 14.798 1.00 6.99 FRAP
ATCM 1649 HE21 GLN 2072 -29.659 17.557 14.919 0.00 0.00 FRAP
ATCM 1650 HE22 GLN 2072 -28.875 16.258 14.072 0.00 0.00 FRAP
15 AToM 1651 C GLN 2072 -26.101 18.262 20.103 1.00 12.51 FRAP
AloM 1652 O GLN 2072 -26.693 18.224 21.178 1.00 19.60 FRAP
ATCM 1653 N Al~ 2073 -24.795 18.054 19.978 1.00 14.16 FRAP
ATCM 1654 H ALA 2073 -24.426 18.142 19.081 0.00 0.00 FRAP
AloM 1655 CA ALA 2073 -23.940 17.625 21.077 1.00 14.24 FRAP
20 AToM 1656 CB AL~ 2073 -22.583 17.223 20.518 1.00 15.34 FRAP
AloM 1657 C ALA 2073 -23.756 18.666 22.196 1.00 15.13 FRAP
ATCM 1658 O ALA 2073 -24.013 18.383 23.369 1.00 18.26 FRAP
AT~M 1659 N TYR 2074 -23.228 19.834 21.832 1.00 12.69 FRAP
ATaM 1660 H TYR 2074 -23.091 19.988 20.874 0.00 0.00 F~AP
25 ATaM 1661 CA TYR 2074 -22.791 20.842 22.796 1.00 8.11 ERAP
ATaM 1662 CB TYR 2074 -21.330 21.206 22.547 1.00 3.13 F~AP
ATaM 1663 CG TYR 2074 -20.444 20.034 22.216 1.00 8.31 F~AP
ATaM 1664 CDl TYR 2074 -19.990 19.839 20.918 1.00 10.92 F~AP
ATOM 1665 OE 1 TYR 2074 -19.160 18.772 20.591 1.00 12.41 F~AP
30 AT~M 1666 CD2 TYR 2074 -20.045 19.124 23.197 1.00 11.16 F~AP
ATaM 1667 OE2 TYR 2074 -19.205 18.050 22.882 1.00 12.75 F~AP
ATaM 1668 CZ TYR 2074 -18.771 17.886 21.569 1.00 12.54 FRAP
ATaM 1669 OH TYR 2074 -17.960 16.836 21.215 1.00 21.64 FRAP
ATaM 1670 HH TYR 2074 -17.868 16.773 20.266 0.00 0.00 F~AP
35 AT~M 1671 C TYR 2074 -23.618 22.128 22.804 1.00 8.66 FRAP
ATaM 1672 O TYR 2074 -23.291 23.074 23.509 1.00 9.77 FRAP
ATaM 1673 N GLY 2075 -24.714 22.153 22.063 1.00 10.37 F~AP
ATaM 1674 H GLY 2075 -24.997 21.355 21.565 0.00 0.00 F~AP
AT~M 1675 CA GLY 2075 -25.478 23.380 21.946 1.00 12.34 FRAP

CA 02229426 l998-03-ll WO 97/lS659 PCT/US96/~6953 ATCM 1676 C GLY 2075 -26.130 23.796 23.246 1.00 17.07 ~ P
AToM 1677 O GLY 2075 -26.010 24.946 23.660 1.00 24.52 FRAP
AToM 1678 N AR~ 2076 -26.770 22.843 23.921 1.00 19.49 FRAP
ATCM 1679 H ARG 2076 -26.782 21.950 23.516 0.00 0.00 ~ P
ATCM 1680 CA AR~ 2076 -27.476 23.089 25.187 1.00 16.21 FRAP
AICM 1681 C~3 AR~ 2076 -28.162 21.794 25.651 1.00 17.61 FRAP
ATCM 1682 CG ARG 2076 -28.703 21.826 27.072 1.00 25.98 FRAP
ATCM 1683 CD ARG 2076 -29.913 20.929 27.228 1.00 33.40 FRAP
ATCM 1684 NE ~R~ 2076 -31.135 21.578 26.754 1.00 44.19 FRAP
10 ATCM 1685 HE ARG 2076 -31.060 22.233 26.029 0.00 0.00 FRAP
ATCM 1686 CZ AR~ 2076 -32.351 21.341 27.241 1.00 50.69 FRAP
ATCM 1687 NHl AR~ 2076 -33.396 22.014 26.769 1.00 53.46 FRAP
ATCM 1688 HHll ARG 2076 -33.274 22.698 26.051 0.00 0.00 FRAP
ATCM 1689 HHa2 AR~ 2076 -34.308 21.839 27.144 0.00 0.00 FRAP
15 ATCM 1690 NH2 ARG 2076 -32.532 20.415 28.180 1.00 51.70 FRAPATCM 1691 HH21 AR~ 2076 -31.750 19.895 28.525 0.00 0.00 FRAP
ATCM 1692 HH22 AR~ 2076 -33.446 20.249 28.551 0.00 0.00 FRAP
AloM 1693 C ARG 2076 -26.574 23.640 26.305 1.00 11.79 FRAP
ATCM 1694 O AR~ 2076 -26.861 24.680 26.885 1.00 11.52 FRAP
20 ATCM 1695 N ASP 2077 -25.490 22.936 26.604 1.00 8.15 FgAP
ATCM 1696 H ASP 2077 -25.346 22.086 26.144 0.00 0.00 FRAP
ATCM 1697 CA ASP 2077 -24.526 23.394 27.594 1.00 6.48 FRAP
AI~IM 1698 CB ASP 2077 -23.332 22.448 27.637 1.00 5.61 FRAP
Al~lM 1699 (~G ~SP 2077 -23.615 21.196 28.425 1.00 10.00 FRAP
25 AI~M 1700 ODl ASP 2077 -24.72621.096 28.999 1.00 9.97 FRAP
AI~M 1701 OD2 l~SP 2077 -22.724 20.317 28.479 1.00 12.06 FRAP
AI~IM 1702 C ASP 2077 -24.035 24.809 27.331 1.00 8.55 FRAP
A~OM 1703 O ASP 2077 -24 126 25.669 28.201 1.00 13.05 F~AP
AI~M 1704 N LEU 2078 -23.544 25.058 26.123 1.00 6.49 FRAP
30 Al~IM 1705 H IEU 2078 -23.477 24.330 25.469 0.00 0.00 F:RAP
AI~IM 1706 CA LEU 2078 -23.064 26.386 25.752 1.00 4.74 Fg~P
A~OM 1707 CB LEU 2078 -22.495 26.364 24.333 1.00 3.18 FRAP
AI~M 1708 CG 1~!3U 2078 -21.161 25.653 24.084 1.00 2.91 F~AP
AI~M 1709 CDl LEU 2078 -20.928 25.574 22.593 1.00 2.37 F:RAP
35 AI~M 1710 CD2 LEU 2078 -20.010 26.387 24.764 1.00 2.00 FRAP
AI~M 1711 C LEIJ 2078 -24.146 27.466 25.862 1.00 4.72 F:RAP
A~OM 1712 O LEU 2078 -23.847 28.626 26.118 1.00 2.64 FRAP
AI~IM 1713 N MEI 2079 -25.401 27.091 25.651 1.00 7.76 FRAP
AI~M 1714 H MEI 2079 -25.579 26.181 25.326 0.00 0.00 F~AP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 1715 CA MET 2079 -26.507 28.022 25.850 1.00 14.65 FRAP
AToM 1716 CB MET 2079 -27.803 27.434 25.295 1.00 18.67 FRAP
ATCM 1717 CG MET 2079 -28.999 28.367 25.363 1.00 25.96 FRAP
ATCM 1718 SD MET 2079 -29.718 28.677 23.724 1.00 40.57 FRAP
AToM 1719 OE MET 2079 -30.358 27.004 23.294 1.00 36.64 FRAP
ATCM 1720 C MET 2079 -26.686 28.344 27.330 1.00 17.59 FRAP
ATCM 1721 O MET 2079 -26.714 29.505 27.716 1.00 21.68 FRAP
ATCM 1722 N GLU 2080 -26.769 27.308 28.158 1.00 18.54 FRAP
AToM 1723 H GLU 2080 -26.733 26.408 27.770 0.00 0.00 FRAP
10 ATCM 1724 CA GLU 2080 -26.928 27.477 29.599 1.00 18.17 FRAP
ATCM 1725 CB GLU 2080 -27.006 26.111 30.286 1.00 24.46 FRAP
~TCM 1726 CG GLU 2080 -27.581 26.144 31.708 1.00 33.04 FRAP
ATCM 1727 CD GLU 2080 -27.199 24.914 32.530 1.00 37.28 FRAP
ATCM 1728 CEl GLU 2080 -26.827 25.080 33.714 1.00 39.48 FRAP
15 AToM 1729 ~ GLU 2080 -27.253 23.783 31.991 1.00 40.40 FRAP
ATCM 1730 C GLU 2080 -25.773 28.284 30.191 1.00 16.44 FRAP
ATCM 1731 O GLU 2080 -25.995 29.230 30.940 1.00 17.68 FRAP
AToM 1732 N ALA 2081 -24.555 27.981 29.756 1.00 15.30 FRAP
ATCM 1733 H ALA 2081 -24.449 27.180 29.211 0.00 0.00 FRAP
20 ATCM 1734 CA ALA 2081 -23.375 28.743 30.149 1.00 12.75 FRAP
ATCM 1735 CB ALA 2081 -22.163 28.263 29.373 1.00 8.47 FRAP
ATCM 1736 C ALA 2081 -23.591 30.233 29.912 1.00 14.17 FRAP
ATCM 1737 O AL~ 2081 -23.284 31.057 30.767 1.00 17.02 FRAP
ATOM 1738 N GLN 2082 -24.253 30.560 28.809 1.00 16.91 FRAP
25 ATIOM 1739 H GLN 2082 -24.566 29.833 28.233 0.00 0.00 FRAP
ATOM 1740 CA GLN 2082 -24.557 31.948 28.477 1.00 18.00 FRAP
ATOM 1741 CB GLN 2082 -25.085 32.032 27.048 1.00 22.74 FRAP
AT~M 1742 CG GLN 2082 -25.879 33.280 26.739 1.00 26.79 FRAP
ATaM 1743 CD GLN 2082 -26.176 33.408 25.268 1.00 31.68 ER~P
30 ATOM 1744 OEl GLN 2082 -25.360 33.930 24.509 1.00 29.64 FRAP
AlaM 1745 ~ GLN 2082 -27.299 32.846 24.838 1.00 31.52 FRAP
ATOM 1746 HE21 GLN 2082 -27.890 32.386 25.460 0.00 0.00 FRAP
ATOM 1747 HE22 GLN 2082 -27.467 32.967 23.886 0.00 0.00 FRAP
ATOM 1748 C GLN 2082 -25.558 32.584 29.439 1.00 17.54 FRAP
35 ATOM 1749 0 GLN 2082 -25.442 33.759 29.768 1.00 19.50 FRAP
AT~M 1750 N GLU 2083 -26.551 31.819 29.875 1.00 18.34 FRAP
A~OM 1751 H GLU 2083 -26.603 30.892 29.552 0.00 0.00 FRAP
ATaM 1752 CA GLU 2083 -27.523 32.342 30.826 1.00 19.36 FRAP
AlaM 1753 CB GLU 2083 -28.680 31.362 31.021 1.00 26.08 FRAP

CA 02229426 l998-03-ll WO 97/lS659 P ~ AUS96~16953 ATCM 1754 OG GLU 2083 -29.802 31.897 31.915 1.00 40 13 FRAPAToM 1755 CD GLU 2083 -30.388 33.226 31.428 1.00 46.90 FRAPAToM 1756 OEl GLU 2083 -30.392 34.207 32.209 1.00 48.07 FRAPAqoM 1757 OE2 GLU 2083 -30.878 33.280 30.279 1.00 52.86 FRAP5 . ATCM 1758 C t3UU 2083 -26.863 32.651 32.166 1.00 13.37 FRAPAqoM 1759 O GLU 2083 -27.102 33.701 32.747 1.00 17.15 FRAPATCM 1760 N qRP 2084 -25.915 31.817 32.563 1.00 6.62 FRAP
AqoM 1761 H IRP 2084 -25.769 30.992 32.047 0.00 0.00 FRAP
AToM 1762 C~ IRP 2084 -25.139 32.069 33.761 1.00 3.33 FRAP
10 ATCM 1763 C~3 TRP 2084 -24.190 30.914 34.037 1.00 5.07 FRAP
ATCM 1764 CG IRP 2084 -24.879 29.734 34.575 1.00 6.00 FRAP
ATCM 1765 CD2 qRP 2084 -25.606 29.664 35.801 1.00 10.76 FRAP
AloM 1766 CE2 TRP 2084 -26.292 28.433 35.807 1.00 14.65 FRAP
AT3M 1767 t~ TRP 2084 -25.765 30.533 36.887 1.00 9.81 FRAP
15 AToM 1768 CDl TRP 2084 -25.110 28.564 33.924 1.00 10.88 FRAP
ATCM 1769 NEl TRP 2084 -25.972 27.781 34.646 1.00 17.13 FRAP
ATCM 1770 HEl TRP 2084 -26.397 26.972 34.309 0.00 0.00 FRAP
AToM 1771 CZ2 TRP 2084 -27.129 28.050 36.853 1.00 14.61 FRAP
ATCM 1772 CZ3 TRP 2084 -26.597 30.156 37.923 1.00 11.54 FRAP
ZO AToM 1773 CH2 IRP 2084 -27.272 28.924 37.899 1.00 16.36 FRAP
AT~M 1774 C TRP 2084 -24.348 33.355 33.677 1.00 4.82 FRAP
ATOM 1775 O TRP 2084 -24.240 34.076 34.665 1.00 10.80 FRAP
AI~M 1776 N CYS 2085 -23.760 33.625 32.514 1.00 7.15 FRAP
Aq~OM 1777 H CYS 2085 -23.725 32.895 31.856 0.00 0.00 FRAP
25 ATOM 1778 CA CYS 2085 -23.062 34.894 32.274 1.00 7.94 FRAP
AqlOM 1779 CB CYS 2085 -22.329 34.868 30.935 1.00 2.21 FRAP
Aq~M 1780 SG CYS 2085 -20.748 34.024 30.993 l.O0 14.42 FRAP
Aq~ 1781 C CYS 2085 -24.030 36.070 32.284 1.00 11.28 FRAP
AqlOM 1782 O CYS 2085 -23.718 37.138 32.813 1.00 13.68 FRAP
30 ATOM 1783 N ARG 2086 -25.214 35.864 31.718 1.00 10.58 FRAP
AIIOM 1784 H AR~ 2086 -25.382 35.014 31.259 0.00 0.00 FRAP
Aq~M 1785 CA ARG 2086 -26.250 36.878 31.749 1.00 11.82 FRAP
AqlOM 1786 CB ARG 2086 -27.476 36.405 30.970 1.00 16.71 FRAP
Aq~M 1787 OG ARG 2086 -27.279 36.429 29.458 1.00 22.27 FRAP
35 Aq~M 1788 CD ARG 2086 -28.160 35.398 28.768 1.00 36.61 FRAP
Aq~M 1789 NE ARG 2086 -29.300 35.986 28.060 1.00 45.02 FRAP
AT~M 1790 HE ARG 2086 -29.553 36.906 28.280 0.00 0.00 FRAP
AqlOM 1791 CZ ARG 2086 -30.003 35.357 27.118 1.00 49.39 FRAP
Aq~M 1792 NHl ARG 2086 -31.021 35.971 26.523 1.00 48.26 FRAP

-W O 97/15659 PCT~US96/16953 AI~M 1793H~Ll AR~ 2086 -31.246 36.916 26.762 0.00 0.00 FRAP
Aq~M 1794HH12 AP~: 2086 --31.538 35.49925.809 0.00 0.00 AICM 1795NH2 ARG 2086 -29.673 34.120 26.747 1.00 49.75 FRAPAl~l!I 1796 HH21 AR~ 2086 -28.91333.645 27.190 0.00 0.00 ERAPAI~M 1797 HH22 AR~ 2086 -30.218 33.649 26.053 0.00 0.00 FR~P
Aq~M 1798 C AR~ 2086 -26.618 37.180 33.193 1.00 11.93 FR;~P
AI~M 1799 O ARG 2086 -26.536 38.325 33.629 1.00 14.05 ~RAP
AI~M 1800 N LYS 2087 -26.792 36.120 33.976 1.00 14.39 E~
A'raM 1801 H LYS 2087 -26.697 35.240 33.583 0.00 0.00 FR~P
10 AI~M 1802 CA I,YS 2087 -27.104 36.240 35.401 1.00 11.99 FR~PAI~IM 1803 CB LYS 2087 -27.217 34.858 36.040 1.00 12.74 FRAP
AICM 1804 aG LYS 2087 -28.510 34.139 35.778 1.00 13.98 FR~P
AI~M 1805 CD LYS 2087 -28.412 32.700 36.270 1.00 17.19 E~RAP
Al~ 1806 OE LYS 2087 -29.760 31.998 36.220 1.00 26.67 FRAP
15 AI~M 1807 NZ LYS 2087 -29.640 30.517 36.341 1.00 33.46 FR~PAI~M 1808 HZl LYS 2087 -29.184 30.284 37.245 0.00 0.00 FR~P
AI~M 1809 HZ2 LYS 2087 -29.051 30.158 35.561 0.00 0.00 ~RAP
AI~M 1810 HZ3 LYS 2087 -30.581 30.076 36.301 0.00 0.00 FR~P
AI~M 1811 C LYS 2087 -26.038 37.041 36.144 1.00 9.73 FR~P
20 AI~M 1812 O LYS 2087 -26.356 37.859 37.000 1.00 12.76 E~RAP
Aq~M 1813 N TYR 2088 -24.771 36.803 35.821 1.00 7.02 E~RAP
AI~IM 1814 H TYR 2088 -24.578 36.057 35.209 0.00 0.00 FRAP
AI~M 1815 CA TYR 2088 -23.693 37.592 36.407 1.00 12.48 FRAP
ATCM 1816 CB TYR 2088 -22.327 37.135 35.892 1.00 9.00 FRAP
25 ATCM 1817 CG TYR 2088 -21.194 38.013 36.386 1.00 11.53 FRAP
AToM 1818 CDl TYR 2088 -20.780 37.953 37.712 1.00 13.53 FRAP
AloM 1819 OE 1 TYR 2088 -19.817 38.822 38.205 1.00 13.24 FRAP
AToM 1820 CD2 TYR 2088 -20.603 38.967 35.553 1.00 9.73 FRAP
AloM 1821 OE2 TYR 2088 -19.631 39.835 36.032 1.00 8.20 FRAP
30 AToM 1822 CZ TYR 2088 -19.248 39.758 37.364 1.00 14.19 FRAP
AToM 1823 OH TYR 2088 -18.308 40.621 37.881 1.00 21.06 FRAP
ATCM 1824 HH TYR 2088 -17.982 41.148 37.148 0.00 0.00 FRAP
AT~M 1825 C TYR 2088 -23.872 39.079 36.109 1.00 15.40 FRAP
ATCM 1826 O TYR 2088 -23.750 39.921 37.000 1.00 21.76 FRAP
35 AToM 1827 N MET 2089 -24.238 39.383 34.870 1.00 14.77 FRAP
ATCM 1828 H MET 2089 -24.371 38.652 34.223 0.00 0.00 FRAP
ATCM 1829 CA MET 2089 -24.442 40.757 34.446 1.00 13.39 FRAP
ATCM 1830 CB ~ET 2089 -24.813 40.789 32.962 1.00 11.91 FRAP
ATCM 1831 CG MET 2089 -23.637 40.488 32.049 1.00 11.63 FRAP

, CA 02229426 l998-03-ll W<~ 97~65g PCTJ~JS96J16953 ATCM 1832 SD MET 2089 -24.124 40.080 30.365 1.00 13.84 FRAP
ATCM 1833 OE MET 2089 -22.620 39.331 29.759 1.00 2.00 FRAP
AT~M 1834 C MET 2089 -25.500 41.475 35.272 1.00 11.34 FRAP
ATCM 1835 O MET 2089 -25.392 42.669 35.511 1.00 16.85 FRAP
ATCM 1836 N LYS 2090 -26.475 40.728 35.775 1.00 13.58 FRAP
ATCM 1837 H LYS 2090 -26.475 39.771 35.559 0.00 0.00 FRAP
ATCM 1838 CA LYS 2090 -27.591 41.322 36.506 1.00 17.01 FRAP
ATCM 1839 CB LYS 2090 -28.886 40.552 36.209 1.00 17.48 FRAP
AToM 1840 CG LYS 2090 -29.218 39.436 37.207 1.00 30.54 FRAP
ATCM 1841 CD LYS 2090 -30.240 39.892 38.254 1.00 39.03 FRAP
AToM 1842 OE LYS 2090 -30.140 39.078 39.545 1.00 40.52 FRAP
AT~M 1843 NZ LYS 2090 -30.477 39.893 40.756 1.00 38.43 FRAP
AToM 1844 HZl LYS 2090 -31.451 40.248 40.672 0.00 0.00 FRAP
ATCM 1845 HZ2 LYS 2090 -29.826 40.700 40.829 0.00 0.00 FRAP
AToM 1846 HZ3 LYS 2090 -30.396 39.308 41.612 0.00 0.00 FRAP
ATCM 1847 C LYS 2090 -27.371 41.420 38.023 1.00 18.18 FRAP
ATCM 1848 O LYS 2090 -28.022 42.230 38.695 1.00 16.27 FRAP
ATCM 1849 N SER 2091 -26.466 40.597 38.554 1.00 18.19 FRAP
AToM 1850 H SER 2091 -25.955 40.047 37.923 0.00 0.00 FRAP
ATCM 1851 CA ~K 2091 -26.302 40.464 40.008 1.00 16.08 FRAP
AToM 1852 CB ~ 2091 -26.662 39.051 40.465 1.00 15.61 FRAP
ATCM 1853 OG ~K 2091 -25.722 38.108 39.982 1.00 18.00 FRAP
AToM 1854 HG SER 2091 -26.010 37.832 39.096 0.00 0.00 FRAP
ATCM 1855 C ~ 2091 -24.917 40.794 40.537 1.00 14.61 FRAP
ATOM 1856 O SER 2091 -24.761 41.071 41.724 1.00 16.95 FRAP
ATOM 1857 N GLY 2092 -23.903 40.637 39.691 1.00 10.93 FRAP
ATOM 1858 H GLY 2092 -24.107 40.356 38.784 0.00 0.00 FRAP
ATOM 1859 CA GLY 2092 -22.536 40.883 40.117 1.00 12.47 FRAP
ATOM 1860 C GLY 2092 -22.009 39.837 41.083 1.00 13.42 FRAP
A~OM 1861 O GLY 2092 -20.913 39.974 41.622 1.00 11.96 FRAP
ATaM 1862 N ASN 2093 -22.701 38.704 41.127 1.00 14.42 FR~P
AT~M 1863 H ASN 2093 -23.481 38.626 40.514 0.00 0.00 FRAP
ATOM 1864 CA ASN 2093 -22.465 37.664 42.114 1.00 15.72 FRAP
ATOM 1865 CB ASN 2093 -23.572 36.626 42.021 1.00 15.84 FRAP
ATaM 1866 CG ASN 2093 -23.884 35.977 43.353 1.00 16.87 FRAP
ATaM 1867 ODl ASN 2093 -25.031 35.976 43.798 1.00 23.23 FRAP
- ATOM 1868 ND2 ASN 2093 -22.879 35.381 43.975 1.00 9.23 FRAP
ATOM 1869 HD21 ASN 2093 -21.955 35.362 43.700 0.00 0.00 FRAP
ATOM 1870 HD22 ASN 2093 -23.187 35.027 44.822 0.00 0.00 FRAP

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 1871 C ASN 2093 -21.112 36.959 42.015 1.00 20.92 FRAP
ATCM 1872 O ASN 2093 -20.599 36.466 43.015 1.00 28.74 FRAP
AToM 1873 N VAL 2094 -20.653 36.711 40.797 1.00 18.46 FRAP
AToM 1874 H UAL 2094 -21.105 37.113 40.045 0.00 0.00 FRAP
AToM 1875 CA U~L 2094 -19.386 36.003 40.528 1.00 19.15 FRAP
AToM 1876 CB UAL 2094 -18.134 36.636 41.223 1.00 17.65 FRAP
AToM 1877 CGl V~L 2094 -17.885 36.035 42.612 1.00 19.24 FRAP
ATCM 1878 CG2 U~L 2094 -16.911 36.422 40.333 1.00 22.37 FRAP
ATCM 1879 C UAL 2094 -19.390 34.508 40.807 1.00 17.55 FRAP
10 AToM 1880 O UAL 2094 -18.534 33.779 40.311 1.00 20.43 FRAP
AloM 1881 N LYS 2095 -20.415 34.016 41.485 1.00 16.99 FRAP
AToM 1882 H LYS 2095 -20.859 34.593 42.164 0.00 0.00 FRAP
ATCM 1883 CA LYS 2095 -20.615 32.570 41.511 1.00 19.09 FRAP
ATCM 1884 CB LYS 2095 -21.166 32.125 42.869 1.00 24.46 FRAP
15 AloM 1885 CG LYS 2095 -20.193 31.221 43.633 1.00 33.72 FRAP
AT~M 1886 CD LYS 2095 -18.736 31.682 43.507 1.00 32.25 FRAP
AToM 1887 CE LYS 2095 -17.771 30.625 44.033 1.00 37.61 FRAP
AToM 1888 NZ LYS 2095 -17.512 29.527 43.054 1.00 34.92 FRAP
AToM 1889 HZl LYS 2095 -17.131 29.930 42.177 0.00 0.00 FRAP
20 AToM 1890 HZ2 LYS 2095 -18.395 29.025 42.842 0.00 0.00 FRAP
AqoM 1891 HZ3 LYS 2095 -16.816 28.873 43.458 0.00 0.00 FRAP
AT~M 1892 C LYS 2095 -21.515 32.087 40.378 1.00 16.91 FRAP
AToM 1893 O LYS 2095 -21.621 30.893 40.110 1.00 15.63 FRAP
AloM 1894 N ASP 2096 -22.168 33.029 39.710 1.00 14.55 FRAP
25 ATCM 1895 H ASP 2096 -22.269 33.893 40.141 0.00 0.00 FRAPAloM 1896 CA ASP 2096 -22.850 32.737 38.459 1.00 11.12 FRAP
ATCM 1897 CB ASP 2096 -23.799 33.868 38.099 1.00 12.16 FRAP
AToM 1898 CG ASP 2096 -24.973 33.956 39.042 1.00 14.76 FRAP
AloM 1899 ODl ASP 2096 -25.630 32.925 39.259 1.00 18.49 FRAP
30 AToM 1900 OD2 ASP 2096 -25.238 35.055 39.567 1.00 24.14 FRAP
AToM 1901 C ASP 2096 -21.837 32.538 37.339 1.00 10.59 FRAP
AT~M 1902 O ASP 2096 -21.903 31.563 36.590 1.00 13.81 FRAP
AT~M 1903 N LEU 2097 -20.816 33.386 37.326 1.00 7.24 FRAP
AqOM 1904 H LEU 2097 -20.814 34.129 37.956 0.00 0.00 FRAP
35 ATOM 1905 CA LEU 2097 -19.723 33.244 36.383 1.00 7.03 FRAPATOM 1906 CB LEU 2097 -18.701 34.357 36.591 1.00 2.85 FRAP
AIOM 1907 OG LEU 2097 -18.252 35.073 35.317 1.00 7.43 FRAP
AIOM 1908 CDl LEU 2097 -19.451 35.345 34.428 1.00 2.68 FRAP
A~aM 1909 CD2 LEU 2097 -17.543 36.371 35.661 1.00 6.68 FRAP

CA 02229426 l998-03-ll ATCM 1910 C LEU 2097 -19.056 31.873 36.504 1.00 12.75 FRAP
ATCM 1911 O LEU 2097 -18.854 31.190 35.499 1.00 17.71 FRAP
ATCM 1912 N THR 2098 -18.847 31.410 37.735 1.00 13.89 FRAP
ATCM 1913 H IHR 2098 -19.017 31.985 38.512 0.00 0.00 FRAP
AToM 1914 CA ~HR 2098 -18.266 30.082 37.954 1.00 14.50 FRAP
AloM 1915 CB ~HR 2098 -17.866 29.853 39.429 1.00 18.86 FRAP
ATCM 1916 OGl IHR 2098 -18.952 30.231 40.288 1.00 27.76 FRAP
AToM 1917 HGl THR 2098 -19.663 29.576 40.325 0.00 0.00 FRAP
AToM 1918 CG2 IHR 2098 -16.624 30.666 39.781 1.00 14.88 FRAP
10 ATCM 1919 C IHR 2098 -19.187 28.940 37.521 1.00 14.65 FRAP
AT~M 1920 O IHR 2098 -18.733 27.967 36.924 1.00 20.42 FRAP
ATCM 1921 N GLN 2099 -20.486 29.070 37.772 1.00 13.41 FRAP
ATCM 1922 H GLN 2099 -20.807 29.834 38.297 0.00 0.00 FRAP
AToM 1923 CA GLN 2099 -21.443 28.076 37.293 1.00 10.97 FRAP
15 ATCM 1924 C~3 GLN 2099 -22.843 28.371 37.838 1.00 19.13 FRAP
ATCM 1925 CG GLN 2099 -23.423 27.264 38.720 1.00 26.63 FRAP
AToM 1926 CD GLN 2099 -23.315 25.887 38.084 1.00 33.37 FRAP
AloM 1927 OEl GLN 2099 -22.604 25.017 38.580 1.00 35.83 FRAP
ATCM 1928 NE2 GLN 2099 -23.989 25.697 36.959 1.00 38.47 FRAP
20 AToM 1929 HE21 GLN 2099 -24.521 26.407 36.558 0.00 0.00 FRAP
AToM1930HE22GLN2099 -23.848 24.808 36.587 0.00 0.00 FRAP
A~M1931CGLN2099 -21.478 28.072 35.768 1.00 9.33 ~P
A~M1932OGLN2099 -21.842 27.085 35.147 1.00 13.05 ~P
A~M1933NA~2100 -21.146 29.211 35.178 1.00 9.52 ~P
25A~M1934HA~2100 -21.074 30.018 35.723 0.00 0.00 ~P
A~M1935CAA~2100 -21.016 29.323 33.738 1.00 3.77 ~P
A~M1936CBA~2100 -20.953 30.796 33.348 1.00 2.00 ~P
A~M1937CA~2100 -19.760 28.586 33.277 1.00 2.86 ~P
A~M1938OA~2100 -19.823 27.736 32.394 1.00 2.63 ~P
30A~M1939N~P2101 -18.659 28.801 33.988 1.00 2.00 ~P
A~M1940H~P2101 -18.717 29.421 34.743 0.00 0.00 ~P
A~M1941CA~P2101 -17.367 28.222 33.627 1.00 3.21 ~P
A~M1942CF3~P2101 -16.263 29.010 34.300 1.00 3.18 ~P
A~M1943CG~P2101 -15.704 30.029 33.420 1.00 4.37 ~P
35A~M1944CD2~P2101 -15.003 29.798 32.198 1.00 5.80 F~P
A~M1945CE2~P2101 -14.676 31.057 31.662 1.00 7.80 ~P
A~M1946CE3~P2101 -14.625 28.646 31.500 1.00 5.41 ~P
A~M1947CDl~P2101 -15.775 31.378 33.581 1.00 5.99 ~P
A~M1948~1~P2101 -15.158 32.008 32.525 1.00 13.05 ~P

CA 02229426 l998-03-ll AToM 1949 HEl TRP 2101 -15.113 32.979 32.395 0.00 0.00 FRAP
AToM 1950 CZ2 IRP 2101 -13.993 31.197 30.456 1.00 6.76 FRAP
ATo~ 1951 CZ3 TRP 2101 -13.951 28.786 30.301 1.00 3.13 FRAP
ATCM 1952 CH2 TRP 2101 -13.644 30.052 29.791 1.00 6.31 FRAP
5 AToM 1953 C TRP 2101 -17.206 26.736 33.960 1.00 8.69 FRAP
AToM 1954 O IRP 2101 -16.274 26.065 33.501 1.00 10.67 FRAP
AToM 1955 N ASP 2102 -18.091 26.240 34.807 1.00 8.35 FRAP
AToM 1956 H ASP 2102 -18.571 26.864 35.388 0.00 0.00 FRAP
AToM 1957 CA ASP 2102 -18.235 24.815 35.005 1.00 9.05 FRAP
10 ATCM 1958 CB ASP 2102 -19.277 24.564 36.099 1.00 13.12 FRAP
AToM 1959 CG ASP 2102 -19.127 23.207 36.759 1.00 16.43 FRAP
A~oM 1960 oDl ASP 2102 -20.084 22.779 37.436 1.00 23.14 FRAP
AToM 1961 OD2 ASP 2102 -18.048 22.585 36.637 1.00 18.55 FRAP
AToM 1962 C ASP 2102 -18.688 24.180 33.686 1.00 10.27 FRAP
15 AToM 1963 O ASP 2102 -18.144 23.158 33.248 1.00 11.33 FRAP
ATCM 1964 N TT~T 2103 -19.646 24.828 33.029 1.00 8.01 FRAP
ATCM 1965 H T.T~T 2103 -19.988 25.662 33.421 0.00 0.00 FRAP
AT~M 1966 CA LEU 2103 -20.230 24.302 31.794 1.00 7.80 FRAP
AToM 1967 CB LEU 2103 -21.589 24.951 31.537 1.00 2.00 FRAP
20 AToM 1968 CG LEU 2103 -22.694 24.551 32.512 1.00 2.00 FRAP
AloM 1969 CDl LEU 2103 -23.659 25.697 32.675 1.00 2.04 FRAP
AToM 1970 CD2 LEU 2103 -23.417 23.318 32.012 1.00 2.00 FRAP
ATCM 1971 C LEU 2103 -19.314 24.486 30.577 1.00 7.45 FRAP
AloM 1972 O LEU 2103 -19.177 23.580 29.756 1.00 5.72 FRAP
25 ATCM 1973 N TYR 2104 -18.594 25.602 30.530 1.00 6.39 FRAP
AloM 1974 H TYR 2104 -18.814 26.319 31.162 0.00 0.00 FRAP
AToM 1975 CA TYR 2104 -17.605 25.821 29.482 1.00 7.03 FRAP
AT~M 1976 CB TYR 2104 -16.987 27.215 29.602 1.00 7.14 FRAP
AToM 1977 CG TYR 2104 -17.865 28.342 29.108 1.00 4.21 FRAP
30 ATOM 1978 CDl TYR 2104 -18.003 29.508 29.852 1.00 7.88 FRAP
ATOM 1979 OE 1 TYR 2104 -18.772 30.564 29.400 1.00 5.53 FRAP
AT~OM 1980 CD2 T~R 2104 -18.535 28.256 27.888 1.00 2.00 FRAP
ATOM 1981 CE2 TYR 2104 -19.316 29.308 27.423 1.00 3.76 FRAP
ATOM 1982 CZ TYR 2104 -19.419 30.462 28.187 1.00 8.86 FRAP
35 ATOM 1983 OH TYR 2104 -20.122 31.548 27.727 1.00 12.11 FRAP
ATOM 1984 HH TYR 2104 -20.693 31.333 27.011 0.00 0.00 FRAP
AT~OM 1985 C T~R 2104 -16.506 24.771 29.555 1.00 9.25 FRAP
ATOM 1986 O T~R 2104 -16.102 24.216 28.536 1.00 12.91 FRAP
A~OM 1987 N TYR 2105 -16.054 24.475 30.771 1.00 12.79 FR~P

CA 02229426 l998-03-ll AToM 1988 H TYR 2105 -16.371 25.002 31.536 0.00 0.00 FRAP
ATCM 1989 CA TYR 2105 -15.030 23.452 30.996 1.00 10.70 FRAP
ATCM 1990 CF3 TYR 2105 -14.680 23.376 32.481 1.00 7.06 FRAP
AToM 1991 CG TYR 2105 -13.496 22.488 32.765 1.00 4.50 FRAP
AT~M 1992 CDl TYR 2105 -12.288 22.693 32.111 1.00 8.17 FRAP
AToM 1993 CEl TYR 2105 -11.184 21.892 32.360 1.00 12.33 FRAP
ATCM 1994 CD2 TYR 2105 -13.579 21.446 33.684 1.00 6.11 FRAP
AloM 1995 CE2 TYR 2105 -12.472 20.629 33.946 1.00 12.32 FRAP
AToM 1996 CZ TYR 2105 -11.276 20.866 33.279 1.00 15.17 FRAP
10 AqoM 1997 QH TYR 2105 -10.155 20.113 33.542 1.00 21.26 FRAP
AToM 1998 HH TYR 2105 -9.397 20.447 33.059 0.00 0.00 FRAP
ATCM 1999 C TYR 2105 -15.479 22.070 30.515 1.00 10.02 FRAP
ATCM 2000 O TYR 2105 -14.702 21.307 29.942 1.00 11.77 FRAP
AloM 2001 N HIS 2106-16.746 21.759 30.737 1.00 9.87 FRAP
15 ATCM 2002 H HI~2106 -17.288 22.402 31.250 0.00 0.00 FRAP
ATCM 2003 CA HIS2106 -17.298 20.488 30.314 1.00 11.64 FRAP
ATCM 2004 CB HIS2106 -18.705 20.326 30.881 1.00 15.15 FRAP
ATCM 2005 CG HIS2106 -19.294 18.971 30.664 1.00 24.44 FRAP
ATCM 2006 CD2 HIS 2106 -20.529 18.588 30.259 1.00 25.83 FRAP
20 ATCM 2007 NDl HIS 2106 -18.578 17.808 30.865 1.00 28.70 FRAP
ATOM 2008 HDl HIS2106 -17.628 17.736 31.114 0.00 0.00 FR~P
ATCIM 2009 OEl HIS2106 -19.346 16.767 30.595 1.00 28.91 E'RAP
ATOM 2010 NE2 HIS2106 -20.535 17.214 30.226 1.00 31.03 FR~P
ATaM 2011 HE2 HIS2106 --21.295 16.644 29.972 0.00 0.00 E~RAP
25 ATIOM 2012 C HIS2106 -17.315 20.332 28.787 1.00 14.72 E~RAP
ATIOM 2013 O HIS2106 -16.928 19.284 28.273 1.00 17.34 FRAP
ATCIM 2014 N VAL2107 -17.768 21.355 28.062 1.00 13.33 FR~P
ATOM 2015 H V~I,2107 -18.077 22.171 28.519 0.00 0.00 FRAP
ATCIM 2016 CA VAL2107 -17.797 21.281 26.599 1.00 10.31 ERAP
30 ATCIM 2017 C}3 V~L2107 -18.640 22.425 25.963 1.00 9.70 E~RAP
ATIOM 2018 CGl V~L 2107 -20.08222.296 26.372 1.00 11.91 ~RAP
ATaM 2019 OG2 ~L 2107 -18.116 23.780 26.371 1.00 15.79 FRAP
ATOM 2020 C VAL2107 -16.384 21.294 26.009 1.00 10.92 FRAP
ATCIM 2021 O U~L2107 -16.047 20.456 25.172 1.00 11.27 FRAP
35 ATOM 2022 N PHE2108 -15.518 22.127 26.576 1.00 9.62 FRAP
ATCIM 2023 H PHE2108 -15.849 22.771 27.234 0.00 0.00 FRAP
ATCIM 2024 CA PHE2108 -14.109 22.164 26.187 1.00 8.05 FR~P
ATIOM 2025 CB PHE2108 -13.371 23.223 27.007 1.00 4.20 FR~P
ATCM 2026 CG PHE2108 -11.923 23.366 26.651 1.00 2.00 FR~P

W O 97/15659 PCTrUS96/16953 AI~M 2027 CDl E~HE 2108-11.519 24.292 25.702 1.00 4.15 E'RAP
AlaM 2028 CD2 PHE 2108-10.961 22.606 27.295 1.00 3.42 FR~P
AI~M 2029 CEl PHE 2108-10.170 24.461 25.396 1.00 8.79 FR~P
AI~M 2030 CE2 ~HE 2108--9.613 22.760 27.000 1.00 9.05 ~RAP
AI~M 2031 CZ l~!HE 2108 -9.214 23.69226.045 1.00 12.56 E~RAP
Al~ 2032 C PHE 2108--13.423 20.81026.364 1.00 9.13 FR~P
AI~M 2033 O l~HE 2108-12.685 20.368 25.493 1.00 10.33 E~RAP
AI~M 2034 N AR~; 2109-13.609 20.198 27.528 1.00 11.74 E~
AI~IM 2035 H ARG 2109-14.125 20.671 28.212 0.00 0.00 FR;~P
10 Alal!I 2036 CA ARG2109 -13.001 18.905 27.832 1.00 12.27 FR~P
AI~M 2037 CB ARG 2109-13.358 18.476 29.256 1.00 18.36 FR;~P
AI~M 2038 C!G ARG 2109-12.193 18.477 30.239 1.00 32.13 F~RAP
AI~M 2039 CD AR~ 2109-11.939 17.082 30.819 1.00 43.37 E~RAP
AI~M 2040 NE ARC~ 2109-13.169 16.442 31.297 1.00 53.59 l~RAP
15 AI~M 2041 HE ARG 2109-13.738 16.951 31.910 0.00 0.00 ~RAP
AI~M 2042 CZ ARG 2109-13.573 15.218 30.956 1.00 54.76 FRAP
AI~M 2043 NHl AR~ 2109--14.732 14.75431.413 1.00 54.90 l~RAP
AI~M 2044 HHll ARG 2109-15.288 15.321 32.021 0.00 0.00 ~RAP
AI~M 2045 E3H12 AR~2109 -15.033 13.832 31.173 0.00 0.00 E~RAP
20 AI~M 2046NH2 ARG 2109-12.812 14.444 30.188 1.00 53.94 E'RAP
Al~l 2047 HH21 AR(~ 2109--11.931 14.77629.851 0.00 0.00 E~RAP
AI~M 2048 HH22 AR~ 2109-13.130 13.529 29.944 0.00 0.00 FR;~P
AI~M 2049 C ARG 2109-13.454 17.829 26.849 1.00 11.58 E~RAP
AI~M 2050 O ARG 2109-12.682 16.939 26.509 1.00 11.33 FR;~P
25 AI~M 2051 N AR~ 2110-14.710 17.911 26.412 1.00 10.43 FR~PAI~M 2052 H AR~ 2110-15.280 18.632 26.748 0.00 0.00 FR~P
AI~M 2053 CA AR~ 2110-15.260 16.952 25.455 1.00 10.64 FR~P
AI~M 2054 CB AR~ 2110-16.795 16.947 25.499 1.00 12.47 FRAP
A~M 2055 CG AR~ 2110-17.418 16.320 26.743 1.00 19.35 ~RAP
30 AI~M 2056 CD ARG 2110-17.423 14.786 26.714 1.00 31.28 FR~PAI~M 2057 NE ARG 2110-16.091 14.194 26.900 1.00 41.95 FRAP
AI~IM 2058 HE AR~; 2110--15.389 14.43226.260 0.00 0.00 ERAP
AI~IM 2059 CZ ARG 2110-15.762 13.332 27.865 1.00 41.41 E~RAP
AI~M 2060NHl ARG 2110-14.534 12.815 27.899 1.00 36.39 FR~P
35 AI~M 2061HHll ARG 2110-13.866 13.068 27.201 0.00 0.00 E~RAP
Al~l!I 2062 HH12 ARG 2110 -14.28212.171 28.621 0.00 0.00 FRAP
AI~IM 2063NH2 AR~ 2110-16.633 13.017 28.820 1.00 36.79 FR;~P
AI~M 2064HH21 ARG 2110-17.547 13.422 28.830 0.00 0.00 E~RAP
AI~M 2065HH22 AR~ 2110-16.368 12.373 29.538 0.00 0.00 E~RAP

CA 02229426 l998-03-ll WO 97/156~;9 PCT/U596~1695:~
AloM 2066 C A ~ 2110 -14 810 17.200 24.014 1.00 12.51 FRAP
AToM 2067 O ARG 2110 -14.818 16.280 23.209 1.00 15.19 FRAP
ATCM 2068 N TT~2111 -14.494 18.447 23.670 1.00 14.35 FRAP
AToM 2069 H ILE2111 -14.598 19.149 24.342 0.00 0.00 FRAP
5 ~ M 2070 CA TT~2111 -14.033 18.769 22.314 1.00 18.50 FRAP
AToM 2071 CF3 IT~2111 -14.644 20.117 21.784 1.00 14.09 FRAP
ATCM 2072 CG2 ILE 2111 -16.148 20.108 21.982 1.00 19.97 FRAP
AToM 2073 CGl TT~ 2111 -14.044 21.333 22.500 1.00 13.58 FRAP
AloM 2074 CDl TT~ 2111 -14.821 22.615 22.301 1.00 2.00 FRAP
10 AToM 2075 C TT~2111 -12.510 18.791 22.163 1.00 22.21 FRAP
AToM 2076 o TT~2111 -11.963 19.586 21.395 1.00 27.42 FRAP
ATCM 2077 N SER2112 -11.840 17.887 22.870 1.00 27.11 FRAP
ATCM 2078 H SER 2~1~ -12.312 17.230 23.418 0.00 0.00 FRAP
AToM 2079 CA SER 2112 -10.410 17.634 22.673 1.00 32.50 FRAP
15 ATCM 2080 CB SER 2117 -9.590 18.179 23 852 1.00 31.61 FRAP
ATCM 2081 OG SER 2112 -9 589 19.601 23.899 1.00 28.34 FRAP
ATCM 2082 H~ SER 2112 -9.617 19.750 24.846 0.00 0.00 FRAP
AT~M 2083 C SER 2112 -10.155 16.126 22.525 1.00 35.63 FRAP
ATCM 2084 O SER 2112 -10.552 15.361 23.432 1.00 36.42 FRAP
20 AToM 2085 OT SER 2112 -9.613 15.712 21.474 1.00 41.38 FRAP
ATOM 2086 OH2 WATR 301 -13.963 32.282 39.005 1.00 20.07 WATR
A~OM 2087 Hl WATR 301 -14.436 33.059 39.326 0.00 20.00 WATR
AT~M 2088 H2 WATR 301 -13.909 31.701 39.771 0.00 20.00 WATR
ATOM 2089 QH2 WATR 302 -0.900 21.657 34.783 1.00 23.80 WATR
25 AT~M 2090 Hl WATR 302 -1.021 21.041 35.510 0.00 20.00 WATR
ATOM 2091 H2 WATR 302 -1.478 21.246 34.123 0.00 20.00 WATR
AT~M 2092 OH2 WATR 303 -6.938 34.185 40.131 1.00 41.17 WATR
AT,OM 2093 H~ WATR 303 -6.199 34.542 39.638 0.00 20.00 WATR
ATOM 2094 H2 WATR 303 -6.527 33.918 40.941 0.00 20.00 WATR
30 ATaM 2095 OH2 WATR 304 -10.919 15.222 48.819 1.00 28.06 WATR
ATaM 2096 H~ WATR 304 -10.331 15.994 48.864 0.00 20.00 WATR
ATOM 2097 H2 WATR 304 -10.602 14.763 48.037 0.00 20.00 WATR
ATOM 2098 CH2 WATR 305 -21.400 35.769 26.707 1.00 26.77 WATR
ATOM 2099 Hl WATR 305 -21.139 35.329 27.513 0.00 20.00 WATR
35 AT~M 2100 H2 WATR 305 -22.356 35.778 26.710 0.00 20.00 WATR
AT,OM 2101 OH2 WATR 306 0.813 27.087 37.460 1.00 15.38 WATR
ATOM 2102 H~ WATR 306 0.278 27.451 36.742 0.00 20.00 WATR
AT~M 2103 H2 WATR 306 0.156 26.516 37.895 0.00 20.00 WATR
A~OM 2104 oH2 WATR 307 -30.428 31.660 28.013 1.00 46.41 WATR

CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ATCM 2105 Hl WATR 307-30.299 30.737 27.805 0.00 20.00 WATR
ATCM 2106 H2 WATR 307-30.248 31.722 28.946 0.00 20.00 ~RAToM 2107 OH2 WATR 308-4.519 32.837 47.558 1.00 15.92 WAIR
ATCM 2108 Hl WATR 308-4.435 32.964 48.515 0.00 20.00 WATR
AToM 2109 H2 WATR 308-4.287 31.920 47.465 0.00 20.00 WATR
AToM 2110 OH2 WATR 309-18.089 22.614 12.803 1.00 25.97 WAIR
ATCM 2111 Hi WATR 309-17.511 23.005 12.138 0.00 20.00 WATR
ATCM 2112 H2 WATR 309-18.955 22.733 12.394 0.00 20.00 WAIR
AToM 2113 OH2 WATR 310-22.152 21.619 36.180 1.00 41.59 WATR
10 ATCM 2114 Hl WATR 310-22.437 22.341 36.738 0.00 20.00 WATR
AToM 2115 H2 WATR 310-22.872 21.464 35.569 0.00 20.00 WATR
AloM 2116 OH2 WATR 311 -6.459 3.543 52.877 1.00 32.94 WATR
AToM 2117 Hl WATR 311 -6.280 2.752 52.368 0.00 20.00 WAIR
AToM 2118 H2 WATR 311 -5.832 4.191 52.543 0.00 20.00 WATR
15 ATCM 2119 OH2 WATR 312 -5.993 11.471 28.804 1.00 18.59 ~TR
ATCM 2120 Hl WATR 312 -6.909 11.725 28.881 0.00 20.00 WATR
AToM 2121 H2 WATR 312 -5.782 11.031 29.653 0.00 20.00 WATR
AToM 2122 OH2 WATR 313-0.619 20.784 55.049 1.00 19.50 WATR
AToM 2123 Hl WATR 313 -0.854 20.074 55.637 0.00 20.00 WATR
20 ATCM 2124 H2 WATR 313 -1.113 21.551 55.388 0.00 20.00 WATR
ATCM 2125 OH2 WATR 314 -5.598 26.321 58.876 1.00 36.20 WATR
ATCM 2126 Hl WATR 314 -6.497 26.108 58.602 0.00 20.00 WATR
ATCM 2127 H2 WATR 314 -5.118 25.491 58.861 0.00 20.00 WATR
ATCM 2128 OH2 WATR 315 -3.023 33.604 37.769 1.00 26.43 WATR
25 ATCM 2129 Hl WATR 315-2.394 34.283 37.516 0.00 20.00 WATR
ATCM 2130 H2 WATR 315-3.855 33.984 37.469 0.00 20.00 WATR
ATCM 2131 OH2 WATR 316 -25.006 29.561 22.950 1.00 41.75 W~TR
AloM 2132 Hl WATR 316 -24.532 29.047 23.605 0.00 20.00 WATR
ATOM 2133 H2 WATR 316 -25.677 28.934 22.652 0.00 20.00 WATR
30 ATOM 2134 OH2 WATR 317 -23.638 29.893 10.609 1.00 16.55 WATR
AT~M 2135 Hl WATR 317 -23.016 29.169 10.621 0.00 20.00 WATR
ATOM 2136 H2 WAT'R 317-24.395 29.529 11.101 0.00 20.00 WAT'R
ATOM 2137 OH2 WATR 318-7.744 6.880 50.272 1.00 20.83 WATR
ATIOM 2138 Hl WAT'R 318-7.080 6.901 49.564 0.00 20.00 WATR
35 ATOM 2139 H2 WATR 318-7.480 6.116 50.785 0.00 20.00 WA~R
A~OM 2140 OH2 WAT'R 319 -2.748 2.703 46.777 1.00 31.05 WA~R
ATOM 2141 Hi WAT'R 319-3.202 3.462 46.395 0.00 20.00 WATR
ATOM 2142 H2 WAT'R 319-3.353 2.352 47.432 0.00 20.00 WATR
A~OM 2143 OH2 WATR 320-19.295 42.654 40.303 1.00 39.42 WATR

WO 97/lS6S9 PCI'JUS96~695:~
AIOM 2144 Hl WATR320 -19.042 41.825 39.876 0.00 20.00 WATR
AIOM 2145 H2 ~TR320 -18.638 43.269 39.991 0.00 20.00 WATR
AI~M 2146 ClH2 WATR 321 0.583 32.369 55.901 1.00 39.29 W~TR
AI~M 2147 Hl ~TR321 -0.191 32.008 55.428 0.00 20.00 WATR
AI~M 2148 H2 ~R321 1.272 31.719 55.776 0.00 20.00 WATR
A~M 2149 OH2 WArR322 -16.781 17.874 51.246 1.00 33.48 WATR
AI~M 2150 Hl WATR322 -17.172 18.545 50.688 0.00 20.00 WATR
AI~M 2151 H2 ~TR322 -15.838 18.064 51.228 0.00 20.00 WATR
A~M 2152 OH2 WATR323 --19.829 12.916 46.549 1.00 26.46 ~TR10 AI~M 2153 Hl WArR323 --19.808 13.873 46.697 0.00 20.00 WATR
ATaM 2154 H2 WAIR323 --19.224 12.538 47.193 0.00 20.00 WATR

Note: FKBP sequence is SEQ ID NO: 1 FRAP sequence is SEQ ID NO: 2 CA 02229426 l998-03-ll W O 97/15659 PCT~US96/16953 ~U~ LISTING

(1) GENERAL INFORMATION:

(i) APPLICANT: CORNELL RESEARCH FOUNDATION, INC.

(ii) TITLE OF INVENTION: cRysTAr~rlTNr~ FP~AP COMPLEX

(iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: ARIAD Pharmaceuticals, Inc.
(B) STREET: 26 Landsdowne Street (C) CITY: Cam~ridge (D) STATE: MA
(E) COUNTRY: USA
(F) ZIP: 02139-4234 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: PatentIn Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE: HEREWITH
(C) CLASSIFICATION:

3U (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 60/005,808 (B) FILING DATE: 23-OCT-1995 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 60/006,069 (B) FILING DATE: 24-OCT-1995 CA 02229426 l998-03-ll (viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: BERSTEIN, David L.
(B) REGISTRATION NUMBER: 31,235 (C) REFERENCE/DOC ~ T NUMBER: ARIAD 35OA-PCT

(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 617-494-0400 (B) TELEFAX: 617-494-0208 (2) INFORMATION FOR SEQ ID NO:l:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 107 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:

Gly Val Gln Val Glu Thr Ile Ser Pro Gly Asp Gly Arg Thr Phe Pro Lys Arg Gly Gln Thr Cys Val Val His Tyr Thr Gly Met Leu Glu Asp Gly Lys Lys Phe Asp Ser Ser Arg Asp Arg Asn Lys Pro Phe Lys Phe Met Leu Gly Lys Gln Glu Val Ile Arg Gly Trp Glu Glu Gly Val Ala Gln Met Ser Val Gly Gln Arg Ala Lys Leu Thr Ile Ser Pro Asp Tyr Ala Tyr Gly Ala Thr Gly His Pro Gly Ile Ile Pro Pro His Ala Thr W O 97/15659 PCT~US96/16953 Leu Val Phe Asp Val Glu Leu Leu Lys Leu Glu (2~ INFORMATION FOR SEQ ID NO:2:

(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID No:2:
Glu Leu Ile Arg Val Ala Ile Leu Trp His Glu Met Trp His Glu Gly Leu Glu Glu Ala Ser Arg Leu Tyr Phe Gly Glu Arg Asn Val Lys Gly Met Phe Glu Val Leu Glu Pro Leu His Ala Met Met Glu Arg Gly Pro Gln Thr Leu Lys Glu Thr Ser Phe Asn Gln Ala Tyr Gly Arg Asp Leu Met Glu Ala Gln Glu Trp Cys Arg Lys Tyr Met Lys Ser Gly Asn Val Lys Asp Leu Thr Gln Ala Trp Asp Leu Tyr Tyr His Val Phe Arg Arg Ile Ser Lys Gln

Claims (10)

Claims

1. A crystalline composition comprising a complex formed by a first protein containing an FRB domain, a second protein containing an FKBP domain and a ligand capable of forming a ternary complex with the first and second proteins.

2. A composition of claim 1 in which the complex is characterized by the coordinates of Appendix I, or by coordinates having a root mean square deviation therefrom, with respect to conserved backbone atoms of the listed amino acids, of not more than 1.5 .ANG..

3. A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex comprising a protein containing an FRB domain.

4. A machine-readable data storage medium of claim 3 in which the machine readable data includes data corresponding to the coordinates for the FRB domain set forth in Appendix I, or coordinates having a root mean square deviation therefrom, with respect to conserved protein backbone atoms, of not more than 1.5 .ANG..

5. A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which, when combined with a second set of machine-readable data, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the coordinates corresponding to the second set of machine-readable data, wherein: said first set of data comprises a Fourier transform of at least a portion of the coordinates of the FRB domain set forth in Appendix I
and said second set of data comprises an X-ray diffraction pattern of a molecule or molecular complex.

6. A method for displaying a three dimensional representation of a composition of claims 1 or 2 which comprises:
(a) providing a machine capable of reading data stored on a machine-readable storage medium of any of claims 3-5, programmed with instructions for using said data to display a graphical three-dimensional representation of a protein or protein:ligand complex or portion thereof defined by said data, and loaded with a machine-readable storage medium of any of claims 3-5; and, (b) permitting the machine to read said data and display the three-dimensional representation.

7. A method for determining the three-dimensional structure of a protein containing an FRB
domain, or a complex of such protein with a ligand therefor, which comprises (a) obtaining x-ray diffraction data for crystals of the protein or complex, (b) providing three-dimensional structural coordinates for a composition of claims 1 or 2, and (c) determining the three-dimensional structure of the protein or complex by analyzing the x-ray diffraction data with reference to the previous structural coordinates using molecular replacement techniques.

8. A method for determining the three dimensional structure of a protein containing an an FRB domain or co-complex of said protein with a ligand therefor, which method comprises:
(a) providing structural coordinates for a composition of claims 1 or 2, and (b) determining the three-dimensional structure of the FRB domain-containing protein or complex by homology modeling with reference to the previous structural coordinates.

9. A method for selecting a compound capable of binding to an FRB domain which comprises:
(a) providing coordinates defining the three dimensional structure of the FRB
domain;
(b) characterizing points associated with that three dimensional structure with respect to the favorability of interactions with one or more selected functional groups;
(c) providing a database of one or more candidate compounds; and (d) identifying from the database those compounds having structures which best fit the points of favorable interaction with the three dimensional structure.

10. A method of claim 9 which further comprises testing a compound so identified for its ability to:
(a) bind to FRAP, with or without FKBP12, (b) inhibit the binding of rapamycin or FKBP12:rapamycin to FRAP, and/or (c) trigger a biological function mediated by rapamycin.