CASPASE-8 CRYSTALS, MODELS AND METHODS

Abstract: A caspase-8/inhibitor complex has been crytallized, and the three dimensional x-ray crystal structure of a recombinant human caspase-8 has been solved at atomic resolution (1.2 ANGSTROM ), and substrate binding pocket has been identified. The x-ray crystal structure is useful for solving the structure of other molecules or molecular complexes, and designing modulators of caspase-8 activity.

Description: CASPASE-8 CRYSTALS, MODELS AND METHODS Background of the Invention The caspases are a family of related cysteine proteases that play important intracellular roles in inflammation and apoptosis. Members of this protease family, which currently number more than a dozen, share various features in common, but are structurally unrelated to the papain superfa ily of cysteine proteases. They all employ a conserved cysteine residue as the nucleophile for attack on peptide bonds, and the sites of cleavage all show aspartate in the PI position of the peptide substrates. The caspase catalytic domain has a mass of roughly 30 kDa and comprises two polypeptide chains, a 17-20 kDa N-terminal ( -subunit) fragment which contains the active site cysteine, and a 10-12 kDa C-teπninal (β-subunit) which contributes to the formation of the active site. These chains arise by internal cleavage of a single- chain zymogen precursor, and are tightly associated in an αβ heterodimer. Proteolytic processing which gives rise to these component polypeptides is either autocatalytic, or is mediated by other caspases or enzymes of similar specificity (e.g. granzyme B). The αβ dimeric protein associates further to form a α 2 β 2 heterotetramer that appears to be required for catalytic activity. Three- dimensional structures of enzyme/ligand complexes have been reported for both caspase-1 (interleukin converting enzyme; ICE) (Walker et al., Cell 78:343-352 (1994); Wilson et al., Nature 370:270-275 (1994)) and caspase-3 (CPP32, apopain, Yama) (Rotonda et al., Nat. Struct. Biol. 3 :619-625 (1996); Mittl et al., J . Biol. Chem. 272:6539-6547 (1997)) from 2.3 to 2.5 A resolution. As with all proteolytic enzymes, the caspases exist as inactive precursors, or proenzymes. The length of the N-terminal prodomains of the caspases varies considerably depending on how activation is regulated. Our interest has been focused on those caspases which are involved in apoptosis, principally caspase-8 and one of its natural substrates, caspase-3. The catalytic regions of caspase-3 and caspase-8 correspond closely with regard to length, placement of the active site cysteine, and pattern of processing required for activation. The remarkable distinction between the two is in the greater length of the N-terminal prodomain in caspase-8, a region that contains two death-effector domains (DED). Immunoprecipitation experiments of activated death-initiation signaling complexes (DISC) show that procaspase-8 is a component of the activated receptor complexes. Because of sequence homology between the DED's of procaspase-8 and the death domains (DD) of FADD and TRADD, the death domain proteins associated with TNF and Fas receptors (Medema et al.. EMBO J. 16:2794-2804 (1997)), the DED's are thought to result in association or recruitment of procaspase-8 to the activated receptors. Therefore, as a component of activated DISC, procaspase-8 is positioned in the direct line of signal transduction induced by a variety of effectors such as TNF-α. Activation of the Fas or TNF receptors with Fas ligand or TNF-α results in the autocatalytic activation of procaspase-8. Activated caspase-8 is then thought to activate other downstream caspases like caspase-3 which have prosegments that are shorter and whose intracellular concentrations are not high enough to support their autocatalytic processing and activation. Thus, caspase-8 has been designated as an "upstream" caspase and it is believed to sit at the apex of the Fas or TNF mediated apoptotic cascade. Its likely role is to serve as the prime mover for activation of downstream caspases such as caspase-3, the "executioners" of apoptosis, whose function is to destroy critical cellular proteins in programmed cell death. Because of its initiating role in Fas or TNF mediated apoptosis, caspase-8 is a likely target in blockade of the undesirable cell death that occurs in a variety of diseases. Drugs that will inhibit this activity selectively could well find important therapeutic application, and one avenue toward drug design is via a well defined three dimensional structure of an enzyme/inhibitor complex. Summary of the Invention Structural knowledge of a protein provides a means of investigating the mechanism of action of the protein in the body. It is an object of this invention to provide information on the three-dimensional structure of caspase-8, and further to enable rational drug design of small molecules that specifically inhibit or otherwise affect the activity of caspase-8 or caspase-8 mutants with altered catalytic activity. For example, computer models can predict binding of caspase proteins to various receptor molecules. Upon discovering that such binding in fact takes place, knowledge of the protein structure then allows chemists to design and synthesize chemical entities that mimic the functional binding of caspase-8 to its receptor, in what has become known as rational drug design. A caspase-8/inhibitor complex has been crystallized, and the three dimensional x-ray crystal structure of a recombinant human caspase-8 has been solved at atomic resolution (1.2 A). A substrate binding pocket has been identified, and structure coordinates are set forth in Figure 10. The invention thus provides a molecule or molecular complex that includes least a portion of a caspase-8 or caspase-8-like substrate binding pocket. The substrate binding pocket includes backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Trp 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. The positions of these backbone atoms within the molecule or molecular complex are preferably represented by the structure coordinates according to Fig. 10, essentially without any root mean square deviation. The substrate binding pocket can be further defined by a set of points having a root mean square deviation from the nonhydrogen side chain atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Trp 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. Alternatively, the substrate binding pocket can be defined as including backbone atoms characterized by interatomic distances having a root-mean- square deviation from the interatomic distances characterizing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Trp 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; or as including backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids as represented by structure coordinates according to Fig. 10 situated within a sphere having a radius of about 10 A and centered on the coordinates representing the alpha carbon atom of residue 360, of less than about 2.0 A. Also provided is a molecule or molecular complex that is structurally homologous to a caspase-8 molecule or molecular complex. The high quality of the caspase-8 x-ray crystal structure serves as an important basis for evaluating detailed interactions between ligands and the enzyme subsites and for development of inhibitors with optimized binding properties. Accordingly, in one aspect the present invention relates to the three- dimensional structure of caspase-8, as determined by X-ray crystallography and represented by the structure coordinates shown in Figure 10. The invention further relates to models of caspase-8 and a computer readable form having stored thereon a model of caspase-8. Also included are methods of using the three-dimensional structure and models of caspase-8. For example, the structure coordinates of caspase-8 can be used to solve the crystal structures of caspase-8 homologues and other crystal forms of caspase-8, mutants and co-complexes of caspase-8 or structurally related proteins. The structure coordinates can also serve as the starting point for modeling the structure of other members of the caspase family of proteins, or other structurally related proteins. Use of the structure coordinates of caspase-8 in "rational drug design" is also contemplated. Specifically, the invention provides a scalable three dimensional configuration of points that includes selected points derived from the structure coordinates according to Fig. 10 representing the backbone atoms of a plurality of caspase-8 amino acids defining at least a portion of a caspase-8 substrate binding pocket and having a root mean square deviation of less than about 2.0 A from said structure coordinates. Preferably, the caspase-8 substrate binding pocket comprises amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Trp 420, and the scalable three dimensional configuration of points include selected points derived from the structure coordinates according to Fig. 10 representing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Trp 420. More preferably, the selected points represent at least 50 contiguous backbone atoms of caspase-8 and having a root mean square deviation of less than about 2.0 A from said structure coordinates. The invention further includes a scalable three dimensional configuration of points that includes selected points derived from the structure coordinates of at least a portion of a molecule or a molecular complex that is structurally homologous to a caspase-8 molecule or molecular complex as represented by the structure coordinates according to Fig. 10, wherein the selected points have a root mean square deviation of less than about 2.0 A from the structure coordinates of said structurally homologous molecule or molecular complex. Advantageously, the scalable three-dimensional configuration of points of claim 8 displayed as a physical model, a computer- displayed image, a holographic image, or a stereodiagram. The invention also provides 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 any molecule or molecular complex of the invention, or portion thereof. The invention further provides a computer-assisted method for obtaining structural information about a molecule or a molecular complex of unknown structure. The method utilizes the technique of molecular replacement, and includes: crystallizing the molecule or molecular complex; generating an x-ray diffraction pattern from the crystallized molecule or molecular complex; and applying at least a portion of the structure coordinates set forth in Fig. 10 to the x-ray diffraction pattern to generate a three-dimensional electron density map of at least a portion of the molecule or molecular complex whose structure is unknown. Also provided is a computer-assisted method for homology modeling a caspase-8 homolog. The amino acid sequence of the caspase-8 homolog is aligned with the -unino acid sequence of caspase-8 (SEQ ID NO:l) to yield an amino acid alignment, then used to incorporate the sequence of the caspase-8 homolog into a model of caspase-8 derived from the structure coordinates set forth in Fig. 10 to yield a preliminary model of the caspase-8 homolog. The preliminary model is subjected to energy --------imization to yield an energy minimized model, and regions of the energy minimized model where stereochemistry restraints are violated are remodeled to yield a final model of the caspase-8 homolog. A method for solving a crystal structure of a crystal of a caspase-8 molecule or molecular complex is also provided, wherein the crystal is characterized by the trigonal space group P3i21 and having unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120° . The method includes generating an x-ray diffraction pattern from the crystal, collecting diffraction data, and analyzing the data to generate the structure coordinates for the caspase-8 molecule or molecular complex. The invention further provides computer-assisted methods for identifying a modulator of caspase-8 activity. In one embodiment, the method involves: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates of a chemical entity; and determining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket,- wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. In another embodiment, the method involves: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates for a chemical entity; evaluating the potential binding interactions between the chemical entity and substrate binding pocket of the molecule or molecular complex; structurally modifying the chemical entity to yield a set of structure coordinates for a modified chemical entity; and deter-nining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. The set of structure coordinates for the chemical entity can be obtained from a chemical fragment library, and either of the methods can be performed a multiplicity of times to screen a library of chemical entities. The invention also provides for de novo design a modulator of caspase-8 activity. The method involves: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; computationally building a chemical entity represented by set of structure coordinates; and detei-mining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. The methods optionally include assaying the potential modulator to determine whether it modulates caspase-8 activity. A modulator of caspase-8 activity identified using a method of the invention is preferably an inhibitor of caspase-8 activity. Preferably, deter-r-ining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket involves performing a fitting operation between the chemical entity and the substrate binding pocket, followed by computationally analyzing the results of the fitting operation to quantify the association between the chemical entity and the substrate binding pocket. Also provided by the invention is a method for making a modulator of caspase-8 activity that involves chemically or enzymatically synthesizing a chemical entity to yield a modulator of caspase-8 activity, wherein the chemical entity has been designed or identified during a computer-assisted process as described herein. It should be understood that the invention further encompasses a modulator of caspase-8 activity identified or designed according to any embodiment of the methods of the invention, as well as a composition that includes such modulator of caspase-8 activity. A pharmaceutical composition that includes a modulator of caspase-8 activity as identified or designed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is also included in the invention. The invention further provides a method for treating a patient having an injury or disease that is accompanied by or associated with abnormal caspase-8 activity. The method involves administering to the patient an effective amount of a pharmaceutical composition comprising a modulator of caspase-8 activity identified or designed according to the method of any of claims 21, 22 or 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The composition can be used to Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, cancer, spinal cord injury, cardiovascular disease and neurological disease. In another aspect the invention relates to caspase-8 in crystallized form and to a method of preparing caspase-8 crystals. Preferred crystals of caspase-8 are of sufficient quality to determine the three dimensional structure of the protein by X-ray diffraction methods are provided. Obtaining such crystals is in fact very much an unexpected result. It is well known in the protein crystallographic art that obtaining crystals of quality sufficient for determining the structure of caspase-8 has not been achievable until the present application. Accordingly, the invention provides a method for crystallizing a caspase- 8 molecule that involves growing a crystal by hanging and sitting drop vapor diffusion from a precipitant solution. The precipitant solution includes about 2 to about 5 mg/ml purified caspase-8, a buffer and a salt, and is buffered to a pH of about 7 to about 8. A caspase- 8/ligand complex can be grown by including a ligand, such as a modulator of caspase-8 activity, in the precipitant solution. The modulator is preferably an inhibitor of caspase-8 activity, more preferably it is a peptide or a peptidomimetic compound and is covalently bound to caspase-8. Crystallized caspase-8, and crystallized caspase-8/ligand complex are also included in the invention. A composition comprising crystalline caspase-8 or crystalline caspase-8 complexed with a small molecule ligand is also provided. Brief Description of the Drawings Figure 1 shows the amino acid sequences of caspase-8 (SEQ ID NO:l), caspase-3 (SEQ ID NO:2) and caspase-1 (SEQ ID NO:3) with spatially aligned α helix and β-sheet secondary structural elements indicated. Alignment of the ends and loop (L) regions of the subunits is not implied. The first 12 residues of pi 8 (the α-subunit of caspase-8) and first 4 residues of pi 1 (the β-subunit if caspase-8) are disordered. Vertical arrows indicate cleavage sites as follows: D210>l-S211 at the beginning and D3754S376 at the end of the α-subunit in caspase-8. The cleavage site D384-1-L385 produces the β-subunit in caspase-8. Figure 2 is a schematic diagram with labeling of the heterodimer with the pi 8 subunit shown in light shades and the pi 1 subunit shown in dark shades, β- strands are arrows; α-helices, coils. The N and C termini of the subunits are labeled. The Ac-IETD-H (SEQ ID NO:4) inhibitor is shown as a ball and stick model. Figure 3 is a backbone drawing of the superimposed structures of caspase-8 shown in light shades, caspase-3 medium shades and caspase-1 in dark shades. The dyad related caspase-8 dimer is shown as a white cord. Strands of the protein surrounding the substrate-binding pocket and the approximate location of the binding subsites are indicated. Orientation is similar to that of Figure 2. Figure 4 presents a table of hydrogen bond contacts between heterodimers along the dimer-dimer interface. The asterisk denotes the symmetry-related molecule. Figure 5 shows the molecular surface of (A) caspase-8 and (B) caspase-3 generated by GRASP (Nicholls et al., J. Appl. Crvst. 24:946-950 (1991)) and viewed down the two-fold axis. The surface is seen approximately parallel to the 2-fold axis. The central cavities are outlined in black. The tetrapeptide inhibitors and dithiane-diol molecules are shown as stick models. (C) Close-up of the electron-density of the dithiane-diol molecule located in the central cavity of caspase-8. Figure 6 shows a schematic of the hydrogen bonding scheme in the Ac- IETD-caspase-8 complex. The ligand is covalently linked to the active site nucleophilic Cys-360 through a thiohemiacetal bond. The hydrogen bonds are represented by dashed lines. Figure 7 is shows the following: (A) Electron density of the substrate binding pocket using Amber parameters (Weiner et al., J. Comp. Chem. 7:230- 252 (1986)) for electrostatic surface of the protein. (B) Electron density of the catalytic triad region. Figure 8 presents a summary of data collection and processing parameters. Figure 9 presents refinement statistics for the Ac-IETD-caspase-8 complex. Figure 10 lists the atomic structure coordinates for the Ac-IETD-caspase- 8 complex as derived by X-ray diffraction from a crystal of that complex. The following abbreviations are used in Figure 10: "Atom type" refers to the element whose coordinates are measured. The first letter in the column defines the element. "X, Y, Z" crystallographically define the atomic position of the element measured. "B" is a thermal factor that measures movement of the atom around its atomic center. "Occ" is an occupancy factor that refers to the fraction of the molecules in which each atom occupies the position specified by the coordinates. A value of "1 " indicates that each atom has the same conformation, i.e., the same position, in all molecules of the crystal. Detailed Description of the Invention The following abbreviations are used throughout the application: A = Ala = Alanine T = Thr = Threonine N = Nal = Valine C = Cys = Cysteine L = Leu = Leucine Y = Tyr = Tyrosine I = He = Isoleucine Ν = Asn = Asparagine P = Pro = Proline Q = Gin = Glutamine F = Phe = Phenylalanine D = Asp = Aspartic Acid W = Trp = Tryptophan E = Glu = Glutamic Acid M = Met = Methionine K = Lys = Lysine G = Gly = Glycine R = Arg = Arginine S = Ser = Serine H = His = Histidine The caspase-8 structure described herein is the third caspase to be solved crystallographically, and can be compared to those of caspase-1, an enzyme associated with inflammation, and caspase-3, the downstream executioner of apoptosis. Fig. 1 shows structurally aligned secondary structure elements for these three proteins, and Fig. 3 shows their superimposed tertiary structures. The high resolution of the caspase-8 structure has also helped to clarify some issues regarding the enzyme mechanism and binding of substrate. In the present caspase literature, numbering of --mino acids is often based upon their positions in the proenzymes, and since the proenzymes differ dramatically in the lengths of their prosegments, this leads to differences in numbering of residues in the catalytic domains. In our comparisons of structurally equivalent amino acids in the three caspases, we will follow this convention of numbering residues according to their position in the corresponding proenzymes. The two subunits of caspase-8 will be referred to as the pi 8 and pi 1 subunits The numbering convention used herein is shown in Fig. 1 and also in the following schematic representations of the α- and β- subunits of procaspases 8, 3, and 1 (Cohen, Biochem. J. 326:1-16 (1997)): Procaspase-8: α-subunit β- subunit Prosegment with Death Domains IS 211 pi 8 D 374 L 385 pn D 479 Procaspase-3: 4S 29 pl7 D 175 S 176 pl2 H 277 Procaspase-1: Prosegment with CARD Domains — 4-S 104 — p20 D 297 A 317 - plO~-N 404 The active site cysteine of caspase-8 is at position 360 and the following residues are believed to be involved in substrate binding or otherwise contribute to the activity of the enzyme: R258, D259, R260, N261, H317, Q358, Y365, V410, S411,Y412, R413, P415, W420. It should be understood that unless otherwise indicated, the term "caspase-8" as used herein is intended to include wild-type caspase-8, preferably human wild-type caspase-8, as well as caspase-8 isoforms, caspase-8 mutants and caspase-8 fusion proteins (e.g. Histidine-tagged caspase-8). A "mutant" caspase-8 is a polypeptide whose amino acid sequence differs from the wild-type caspase-8 sequence given in Fig. 1 (SEQ ID NO:l) by deletion, insertion or preferably replacement of one or more selected amino acids. An example of a caspase-8 mutant is the caspase-8 mutant C360A, wherein the cysteine at position 360 in SEQ ID NO:l is replace with an alanine. Crystalline form(s) and method of making One embodiment of the invention provides a caspase-8 crystal (crystalline caspase-8). Optionally, the crystal additionally comprises a low molecular weight compound associated with caspase-8. Preferably, the low molecular weight compound is an inhibitor, such as an irreversible inhibitor, of caspase-8 activity, yielding a caspase-8/inhibitor complex. It should be understood that the words "complex," "molecular complex," and "co-complex" are used herein interchangeably to refer to a covalent or noncovalent complex of caspase-8 and a small molecule ligand, such as a substrate, substrate analog, modulator, inhibitor and the like. Protease inhibition is readily deteπninable by assays known to the field; a representative assay is described herein in Example 4. The inhibitor is preferably a peptide or a peptidomimetic compound. A "peptidomimetic" compound is a compound that functionally and/or structurally mimics a peptide, but that lacks one or more of the peptide bonds that characterize the peptide. Peptidomimetic compounds therefore not typically do not serve as substrate for proteases and are likely to be active in vivo for a longer period of time as compared to the analogous peptides. Unless otherwise specified, the term "peptide" when used herein in the context of an inhibitor peptide or inhibitor molecule includes peptides and peptidomimetic compounds. An irreversible cysteine protease inhibitor is typically, although not necessarily, characterized by a functional group capable of reacting with the thiol group of the active site caspase-8 cysteine (C360) resulting in a covalent bond. Thus, in a preferred embodiment, the crystal includes a low molecular weight compound is covalently bound to the active site cysteine (C360) of caspase-8. Usually this functional group is located at the Pi amino acid of a peptide inhibitor. The amino acid residues of a caspase-8 substrate are designated Pi, P 2 , etc., for those extending towards the N-teπrunus from the scissile bond of the substrate. Likewise, the residues designated Pi', P 2 ', etc., extend toward the C-terminus from the scissile bond of the substrate. A particularly preferred irreversible inhibitor is a derivative of the tetrapeptide Ile- Glu-Thr-Asp, for example Ac-Ile-Glu-Thr-Asp-H (also referred to herein as Ac- IETD-H) (SEQ ID NO:4). The amino acids in SEQ ID NO:4 are referred to, from left to right, as substrate P 4 to Pi amino acids (i.e., starting from the N- terminal He, thus He being P 4 , Glu being P 3 , Thr being P 2 and Asp being Pi. The crystallization process typically begins with the isolation and purification of caspase-8. Caspase-8 is "isolated" if it has been removed from its natural environment, produced using recombinant techniques, or chemically or enzymatically synthesized. "Purified" caspase-8 is essentially free from any other biomolecules and associated cellular products or other impurities. Preferably, purified recombinant caspase-8 is used for crystallization. If needed or desired, the enzyme is deactivated, for example, by adding a suitable low molecular weight compound to form a complex of caspase-8 and the low molecular weight compound. The enzyme or enzyme complex is then crystallized from a solution using a suitable precipitating agent and, preferably, by a vapor diffusion technique. The crystallization buffer is prepared by mixing a caspase-8 complex solution with a "reservoir buffer", preferably in a 1 : 1 ratio, such that the crystallization buffer has a lower concentration of the precipitating agent necessary for crystal formation than the reservoir buffer. To form crystals, the concentration of the precipitating agent in the crystallization buffer is increased by allowing the concentration of the precipitating agent to balance through diffusion between the crystallization buffer and the reservoir buffer. In the crystallization buffer, caspase-8 has a concentration or about 2 to about 5 mg/ml. Diffusion occurs along a vapor gradient through a "hanging drop" or a "sitting drop". For example, in the "sitting drop" method, a 1 :1 mixture of the crystallization buffer containing the protein is placed in a micro-bridge that is placed in a larger pool of reservoir buffer. The micro-bridge prevents the protein from being diluted into the reservoir buffer. The crystals are typically stable for three to four weeks, if kept at 4° C in a buffer of 1.4M sodium citrate, 0.1M HEPES, pH 7.9. Formation of caspase-8 crystals depends upon the following parameters: pH, presence of salts, presence of additives, temperature, protein concentration, and precipitating agent. The pH of the crystallization buffer is preferably about pH 7.0 to about pH 8.0. The concentration/type of buffer is relatively unimportant, and can be varied considerably. Suitable buffers included HEPES, MES, Tris, citrate, acetate and phosphate. Some useful salts and additives include chlorides, sulfates and some low molecular weight organic solvents, such as ethanol. Suitable precipitating agents include water miscible organic solvents, like a polyethylene glycol that has a molecular weight between about 100 and about 20,000, preferably between about 2,000 and about 8,000; and salts, such as ammonium sulfate, chloride, citrate or tartrate. Prior to crystallization, caspase-8 may be equilibrated with a low molecular weight compound as described above. The low molecular compound may bind, covalently or noncovalently, and may stabilize caspase-8. Preferably the low molecular weight compound inhibits caspase-8 activity. A particularly preferred crystal comprises caspase-8 belonging to the trigonal space group P3ι21 with unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120°, preferably having one (pl8/pl 1) heterodimer and one inhibitor molecule in the asymmetric unit. The invention further includes caspase-8 complexes that are characterized by having the same space group and cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120°. X-ray crystallographic analysis Applicants have solved the three-dimensional structure of a caspase- 8/inhibitor complex using high resolution x-ray crystallography. Preferably, the crystallized enzyme or enzyme/ligand complex has the trigonal space group P3 1 21. The unit cell of the crystal preferably has the dimensions of a = b = 62.4 A± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120°. The crystallized enzyme or enzyme/ligand complex is preferably a heterotetramer, with one (pl8/pl 1) heterodimer (or, in the case of the co-complex, one heterodimer and one inhibitor molecule) in the asymmetric unit. Each of the constituent amino acids of caspase-8 is defined by a set of structure coordinates as set forth in Fig. 10. The term "structure coordinates" refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of x-rays by the atoms (scattering centers) of a caspase-8 complex in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are then used to establish the positions of the individual atoms of the caspase-8 protein or protein/ligand complex. Slight variations in structure coordinates can be generated by mathematically manipulating the caspase-8 or caspase-8/ligand structure coordinates. For example, the structure coordinates set forth in Fig. 10 could be manipulated by crystallographic permutations of the structure coordinates, fractionalization of the structure coordinates, integer additions or subtractions to sets of the structure coordinates, inversion of the structure coordinates or any combination of the above. Alternatively, modifications in the crystal structure due to mutations, additions, substitutions, and/or deletions of amino acids, or other changes in any of the components that make up the crystal, could also yield variations in structure coordinates. Such slight variations in the individual coordinates will have little effect on overall shape. If such variations are within an acceptable standard error as compared to the original coordinates, the resulting three-dimensional shape is considered to be structurally equivalent. Structural equivalence is described in more detail below. It should be noted that slight variations in individual structure coordinates of the caspase-8 or caspase- 8/ligand complex, as defined above, would not be expected to significantly alter the nature of ligands that could associate with the substrate binding pocket. Thus, for example, a ligand that bound to the substrate binding pocket of caspase-8 would also be expected to bind to another substrate binding pocket whose structure coordinates define a shape that falls within the acceptable error. Substrate binding pocket, active site, and other structural features Applicants' invention has provided, for the first time, detailed information about the shape and structure of the substrate binding pocket of caspase-8. Binding pockets are of significant utility in fields such as drug discovery. The association of natural ligands or substrates with the binding pockets of their corresponding receptors or enzymes is the basis of many biological mechanisms of action. Similarly, many drugs exert their biological effects through association with the binding pockets of receptors and enzymes. Such associations may occur with all or any parts of the binding pocket. An understanding of such associations helps lead to the design of drugs having more favorable associations with their target, and thus improved biological effects. Therefore, this information is valuable in designing potential inhibitors of caspase-8-like binding pockets, as discussed in more detail below. The term "binding pocket," as used herein, refers to a region of a molecule or molecular complex, that, as a result of its shape, favorably associates with another chemical entity or compound. The substrate binding pocket of caspase-8 preferably comprises those amino acids whose backbone atoms are situated within about 3.5 A, more preferably within about 5.0 A, most preferably within about 7.0 A, of one or more constituent atoms of a bound substrate or inhibitor, as deteπnined from the structure coordinates in Fig. 10. Preferably, the substrate binding pocket of caspase-8 includes amino Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415, and Tφ 420. It will be readily apparent to those of skill in the art that the numbering of amino acids in other isoforms of caspase-8 may be different than that of human caspase-8. Alternatively, the substrate binding pocket is defined as including those -unino acids whose backbone atoms are situated within a sphere centered on the coordinates representing the alpha carbon atom of residue 360, the sphere having a radius of about 10 A, preferably having a radius of about 15 A. Another way of defining the substrate binding pocket of caspase-8 is in terms of pairwise interatomic distances. Thus, the substrate binding pocket of caspase-8 includes the amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Ser 411, Tyr 412, and Arg 413; more preferably Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415, and Tφ 420, wherein the constituent atoms are positioned in space according pairwise interatomic distances readily determinable from the structure coordinates listed in Fig. 10. The substrate binding pocket of caspase-8 is capable of binding a tetrapeptide (^-termmus-P4-P3-P2-Pl-C-terminus), such that Arg 413, Arg 260, Gin 358, and His 317 comprise the S 1 binding site; Nal 410, Tyr 412 and Tyr 365 comprise the S2 binding site; Arg 413, Arg 258, Pro 415 and Asn 261 comprise the S3 binding site; and Tφ 420 and Tyr 412 comprise the S4 site. The amino acid constituents of a caspase-8 substrate binding pocket as defined herein, as well as selected constituent atoms thereof, are positioned in three dimensions in accordance with the structure coordinates listed in Fig. 10. In one aspect, the structure coordinates of the substrate binding pocket of caspase-8 includes structure coordinates of all atoms in the constituent amino acids as thus identified; in another aspect, the structure coordinates of the substrate binding pocket of caspase-8 includes the structure coordinates of just the backbone atoms of the constituent atoms. The term "caspase-8-like binding pocket" refers to a portion of a molecule or molecular complex whose shape is sufficiently similar to at least a portion of the substrate binding pocket of caspase-8 as to be expected to bind a common ligand. A structurally equivalent binding pocket is defined by a root mean square deviation from the structure coordinates of the backbone atoms of the amino acids that make up the substrate binding pocket of caspase-8 (as set forth in Fig. 1) of at most about 2.0 A, preferably at most about 1.5 A. How this calculation is obtained is described below. The term "associating with" refers to a condition of proximity between a chemical entity or compound, such as a ligand or substrate, or portions thereof, and a caspase-8 molecule or portions thereof. The association may be non- covalent, wherein the juxtaposition is energetically favored by hydrogen bonding, van der Waals forces, or electrostatic interactions, or it may be covalent. Accordingly, the invention thus provides molecules or molecular complexes comprising an caspase-8 substrate binding pocket or caspase-8-like substrate binding pocket, as defined by the sets of structure coordinates described above. The asymmetric unit of caspase-8 contains the pl8/pl 1 heterodimer (Fig. 2). The overall topology is similar to that of caspase-1 and caspase-3, with the pi 8 and pi 1 subunits folded into a compact cylinder of approximately 28 A x 37A x 48A in size. The protein has a typical of an α/β folding motif with a central 6-strand β-sheet with five parallel strands (βl, residues 231-241; β2, 278- 285; β3, 308-316; β4, 351-358; β5, 397-404) and one antiparallel strand (β6, residues 462-467). These structural elements are defined for caspase-8 in Fig. 1. The antiparallel strand lies on the edge of the sheet, peφendicular and adjacent to the crystallographic 2-fold axis. Also identified in Fig. 1 are the six α-helices (αl', residues 244-250, within a large loop 1; αl, residues 261-276; α2, 289- 302; α3, 332-341; α4, 419-435; and α5, 438-452), three on one side of the main β-sheet and two on the other side. There is a turn of helix (αl ', residues 244- 250) that is part of loop 1 that occurs along the binding pocket region of the pl8 subunit. There is also a two-stranded antiparallel sheet made up of contributions from loop 3 (residues 317-320) and loop 4 (residues 408-415) at the top of the main β-sheet that forms the base of the pocket. In the heteroteframer, the first segment (residues 385-396) of the pi 1 subunits and the last segment (residues 363-374) of the pi 8 extend from the compact structure in an antiparallel fashion and interact across the crystallographic two-fold with the other heterodimer. There are many differences observed among caspase-1, caspase-3 and caspase-8 in the loop regions near the active site; these are indicated structurally in Fig. 3 and in terms of amino acid sequence in Fig. 1. When compared to caspase-3, caspase-8 has an insertion of seven residues, designated as loop 1, between β-strand 1 and α-helix. In comparison with caspase-1, this loop is even bigger (10 residues) and this larger sized loop in caspase-8 is clearly seen in the structural overlay. This insertion includes a helical segment, αl', which has not been observed in either caspase-1 or caspase-3. In caspase-1, loop 3 is six residues longer than in caspases-3 and 8, again, clearly evident in Fig. 3. Loop 4 is identical in length in all 3 caspases, and this is seen in the coincidence of fold in this region. Loop 5 is intermediate in length between caspases 3 and 8. All three caspases can adopt different conformations and these differences have an important bearing on the specificity of the S 4 pocket. Two pi 8/pl 1 heterodimers form a tetramer around a crystallographic 2- fold axis (Fig. 3). This extends the 6 strands of the β-sheet per dimer to twelve strands with the two-fold axis peφendicular to the middle of the β-sheet. Besides the extended β-sheet there are other interactions around the 2-fold axis, which influence the substrate-binding region. Residues Lys-367 through Asp-374 of one heterodimer extend into the 2-fold related molecule to form interactions with residues Thr-390 through Asp-395. Crystal structures of caspase-1 in two crystal forms and caspase-3 in two crystal forms show similar tetrameric interactions to that found in caspase-8. The structural and mutagenic studies indicate that this tetramer and the dimer/dimer interface are necessary for biological activity. The formation of the heterotetramer probably modifies the neighboring tertiary structure resulting in the activation of the catalytic and substrate binding site. The approximate area of the solvent accessible interface between the two dimers is 2100 A 2 in caspase- 8. Both hydrophobic and hydrophilic interactions are important in forming a strong dimer-dimer interface. This interface contains twenty-three hydrogen bonds (or twelve per dimer) with main chain and side chain atoms involved (Fig. 5). A deep cavity of 17 x 15 x 11 A 3 is present on the crystallographic 2-fold axis (Figure 5A). This cavity is larger than those are in caspase-3 (Figure 5B) and caspase-1 (17 x 7 x 11 A 3 and 9 x 5 x 11 A 3 , respectively) (Mittl et al., J. Biol. Chem. 272:6539-6547 (1997)). There is a clearly identifiable oxidized dithiothreitol molecule (l,2-dithiane-4,5-diol) (Figure 5C) and its symmetric- related pair in this cavity. These dithiane-diol molecules are separated by ~ 13 A and are approximately 19 A from the P P 4 substrate binding pocket. Another dithiane-diol molecule is located elsewhere on the surface of the protein. Examination of other data sets indicate that these dithiane-diol molecules are not always present in crystals of caspase-8, but depend on the concentration of dithiothreitol and age of crystals. It is possible that ligand binding in the central cavity could effect that catalytic activity of the enzyme and further work is planned to study effects of ligand binding in the cavity. Fig. 6 is a schematic of the hydrogen bonding of the inhibitor, acetyl-Ile- Glu-Thr- Asp-aldehyde, to caspase-8. Fig. 7 A shows the electrostatic surface of the protein and the quality of the electron density map for the inhibitor bound in caspase-8. The inhibitor binds in an extended conformation and with the aldehyde forming a thiohemiacetal bond to Sγ of Cys-360 (Fig. 7B). In caspase- 8, the main chain of the inhibitor, like in many other proteases, is antiparallel with respect to residues lining the binding pocket (411-413). Pi -P residues form a β-sheet type hydrogen-bonding network. The active site cysteine (Cys-360) resides on a long C-terrninal segment of pi 8 (Fig. 1) which interacts with the N- terminal portion of the pi 1 unit in the 2-fold related heterodimer (Fig. 2). The acetyl end of the inhibitor is situated near loop 4. The carboxyl group of the Pi Asp forms salt bridges with Arg-413 and Arg-260 and hydrogen bonds to Gln-358 in a pattern similar to that found in caspase-1 and caspase-3. All these residues are conserved. The Pi α-carbonyl rotates and rehybπdizes (sp to sp ) to become a hydroxyl and form a hydrogen bond with the imidazole group of His-317 (Fig. 7B). Mittl et al. (J. Biol. Chem. 272:6539-6547 (1997) suggested that the CED3/ICE-like proteases have a catalytic Cys/His dyad rather than the classical (Cys/His/Asn) triad as seen in papain and most other cysteine proteases. Wilson et al. (Nature 370:270-275 (1994)) have also proposed the Cys/His catalytic dyad for caspase-1, but they indicated the possible involvement of a putative third component, the backbone carbonyl oxygen of Pro- 177, that could affect the basicity of the histidine imidazole. In fact, Rotonda et al. (Nat. Struct. Biol. 3:619-625 (1996)) later invoked the existence of the same carbonyl oxygen in caspase-3, this time from the spatially equivalent Thr-62 in an interaction with the catalytic imidazole ring. No one has provided evidence that this backbone carbonyl oxygen might play a role as the third member of a catalytic triad. Based upon our high-resolution structure of caspase-8, a clear interaction exists between the carbonyl oxygen of Arg-258, equivalent to Pro- 177 in caspase-1 and Thr-62 in caspase-3, and the N ε of His-317. We would infer, therefore, that irrespective of the nature of the -imino acid at this position, the carbonyl oxygen could serve as a member of a catalytic triad in the caspases. The tetrahedral nature of the thiohemiacetal C is clearly evident in the 1.2 A resolution map. This is the same conformation as was modeled for the aldehyde inhibitor models of caspase-1 and caspase-3 (Rotonda et al., Nat. Struct. Biol. 3:619-625 (1996)), but different from those modeled for the methyl ketone inhibitors in which the carbonyl oxygen extends into the "oxyanion" pocket. There was some uncertainty regarding the different inteφretation of the conformation in this region because the other caspase structures were determined with ~ 2.5 A resolution data. Our data at high resolution clearly establishes the interaction between the thiohemiacetal OH group and N δ of His-317. In the case of the caspase-3/Ac-DNAD-fluoromethyl ketone structure (M et al., J. Biol. Chem. 272:6539-6547)), the carbonyl oxygen points directly into the presumptive "oxyanion hole" to form a hydrogen bond with a peptide ΝH group in a highly conserved region of these enzymes (a Gly residue in caspases 8, 3, and 1; residues 350, 122, and 238, respectively, Fig. 1). We would agree with earlier inteφretations that the thiohemiacetal can, and in this case does, bind in a non-transition state conformation. The Cγ of the Thr side chain at P 2 lies in a hydrophobic pocket formed by the side chains of Nal-410 and Tyr-412 (Tyr-204 and Tφ-206 in caspase-3). The Oγ is surrounded by water molecules, one of which forms a bridge to O η of Tyr- 365. The Glu at P 3 sits in a cleft defined by Arg-413, Arg-258, Pro-415, and Asn-261. All interactions with these residues are mediated through solvent molecules with the exception of that to Arg-413. The residue forms salt bridges to both P 3 Glu and Pi Asp side chains. Besides these salt bridges, Arg-413 is a crucial residue foπning hydrogen-bonding interactions between its main chain atoms and the peptide inhibitors main chain. In caspase-8, the preference for Glu in the S 3 pocket is enhanced by the proximity of Arg-258 and Asn-261. For example, Arg-258 is homologous to Thr-62 and Asn-258 to Ser-65 in caspase-3. Comparing the specificities of the different caspases suggests that the size and nature of the S 4 pocket is especially important in selectivity (Thornberry et al., J. Biol. Chem. 272:17907-17911 (1997)). Caspase-3 prefers an Asp in P 4 while caspase-1 and caspase-8 prefer hydrophobic groups. In caspase-8, the acetyl hydrogen bonds through a water bridge to the carboxyl of the P 3 Glu. The S 4 pocket differs from that of caspase-3 with the hydrogen bond participants moving away to accommodate a nonpolar residue. The faces of the aromatic groups, Tφ-420 and Tyr-412 form a hydrophobic S 4 pocket. It is fairly open and additional functional groups might be substituted onto the side group. Three-dimensional configurations The structure coordinates listed in Fig. 10 for the caspase-8/substrate complex or a portion thereof, such as its substrate binding pocket, define a unique configuration of points in space. Those of skill in the art understand that a set of structure coordinates for protein or an protein/ligand complex, or a portion thereof, define a relative set of points that, in turn, define a configuration in three dimensions. A similar or identical configuration can be defined by an entirely different set of coordinates, provided the distances and angles between coordinates remain essentially the same. The present invention thus includes the three-dimensional configuration of points derived from the structure coordinates of at least a portion of a caspase- 8 molecule or molecular complex, as shown in Fig. 10, as well as structurally equivalent configurations, as described below. Preferably, the three-dimensional configuration includes points derived from structure coordinates representing the locations of a plurality of the amino acids defining the caspase-8 substrate binding pocket. In one embodiment, the three-dimensional configuration includes points derived from structure coordinates representing the locations the backbone atoms of a plurality of amino acids defining the caspase-8 substrate binding pocket, preferably Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Nal 410, Ser 411, Tyr 412, Arg 413, Pro 415, and Tφ 420; in another embodiment, the three-dimensional configuration includes points derived from structure coordinates representing the locations of the side chain and the backbone atoms (other than hydrogens) of a plurality of the amino acids defining the caspase-8 substrate binding pocket. In yet another embodiment, the three-dimensional configuration includes points derived from structure coordinates representing the locations the backbone atoms of at least 50 ainino acids that are contiguous in the amino acid sequence of human caspase-8 (SEQ ID NO:l). In still another embodiment, the three-dimensional configuration includes points derived from structure coordinates representing the locations the side chain atoms and the backbone atoms of at least 50 amino acids that are contiguous in the amino acid sequence of caspase-8 (SEQ ID NO:l). Likewise, the invention also includes the three-dimensional configuration of points derived from structure coordinates of molecules or molecular complexes that are structurally homologous to caspase-8, as well as structurally equivalent configurations. Structurally homologous molecules or molecular complexes are defined below. Advantageously, structurally homologous molecules can be identified using the structure coordinates of the caspase- 8/ligand complex (Fig. 10) according to a method of the invention. The configurations of points in space derived from structure coordinates according to the invention can be visualized as, for example, a holographic image, a stereodiagram, a model or a computer-displayed image, and the invention thus includes such images, diagrams or models. Structurally equivalent crystal structures Various computational analyses can be used to determine whether a molecule or the binding pocket portion thereof is "structurally equivalent," defined in terms of its three-dimensional structure, to all or part of caspase-8 or its substrate binding pocket. Such analyses may be carried out in current software applications, such as the Molecular Similarity application of QUANTA (Molecular Simulations Inc., San Diego, CA) version 4.1, and as described in the accompanying User's Guide. The Molecular Similarity application permits comparisons between different structures, different conformations 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 identified as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures). Since atom equivalency within QUANTA is defined by user input, for the puφose of this invention equivalent atoms are defined as protein backbone atoms (N, Cα, C, and O) for all conserved residues between the two structures being compared. For this puφose, conserved residues are defined as a set of atoms with the same interatomic connectivity . Only rigid fitting operations are considered. 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 an algorithm that computes 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 QUANTA. For the puφose of this invention, any molecule or molecular complex or binding pocket thereof, or any portion thereof, that has a root mean square deviation of conserved residue backbone atoms (N, Cα, C, O) of less than about 2.0 A, preferably less than about 1.5 A, when superimposed on the relevant backbone atoms described by the reference structure coordinates listed in Fig. 10, is considered "structurally equivalent" to the reference molecule. That is to say, the crystal structures of those portions of the two molecules are substantially identical, within acceptable error. Particularly preferred structurally equivalent molecules or molecular complexes are those that are defined by the entire set of structure coordinates in Fig. 10, ± a root mean square deviation from the conserved backbone atoms of those amino acids of not more than about 2.0 A. More preferably, the root mean square deviation is less than about 1.5 A, most preferably less than about 1.0 A. 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 from a trend or object. For puφoses of this invention, the "root mean square deviation" defines the variation in the backbone of a protein from the backbone of caspase-8 or a portion thereof, such as its substrate binding pocket, as defined by the structure coordinates of caspase-8 described herein. Computers and machine readable storage media Transformation of the structure coordinates for all or a portion of caspase-8 or the caspase-8/ligand complex or one its substrate binding pocket, for structurally homologous molecules as defined below, or for the structural equivalents of any of these molecules or molecular complexes as defined above, into three-dimensional graphical representations of the molecule or complex can be conveniently achieved through the use of computer-assisted methods utilizing commercially-available software. The invention thus further provides a machine-readable 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 any of the molecule or molecular complexes of this invention that have been described above. In a preferred embodiment, the machine-readable data storage medium comprises a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex comprising all or any parts of the caspase-8 substrate binding pocket or an caspase-8-like binding pocket, as defined above. In another preferred embodiment, the machine-readable data storage medium is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex defined by the structure coordinates of all of the amino acids in Fig. 10, ± a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 A, preferably of not more than about 1.5 A In an alternative embodiment, the machine-readable data storage medium comprises a data storage material encoded with a first set of machine readable data which comprises the Fourier transform of the structure coordinates set forth in Fig. 10, and which, when using a machine programmed with instructions for using said data, can be combined with a second set of machine readable data comprising the x-ray diffraction pattern of a molecule or molecular complex to deteπnine at least a portion of the structure coordinates corresponding to the second set of machine readable data. The invention further includes, and computer-assisted methods of the invention advantageously utilize, a system that includes a computer 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 teπninals, one or more keyboards, one or more input lines, and one or more output lines, all of which are interconnected by a conventional bidirectional system bus. Machine-readable data of the invention may be inputted in a variety of ways, for example via the use of one or more modems connected by a telephone line or dedicated data line. Alternatively or additionally, the input hardware may comprise CD-ROM drives or disk drives. In conjunction with the display terminal, the keyboard may also be used as an input device. Output hardware may include a CRT display terminal for displaying a graphical representation of a caspase-8 molecule, or a portion thereof such as a substrate binding pocket, using a program such as QUANTA as described herein. Output hardware can also include a printer, so that hard copy output may be produced, or a disk drive, to store system output for later use. In operation, the CPU coordinates the use of the various input and output devices, coordinates data accesses from mass storage and accesses to and from working memory, and determines the sequence of data processing steps. A number of programs may be used to process the machine-readable data of this invention. Such programs are discussed in reference to the computational methods of drug discovery as described herein. Specific references to components of the hardware system are included as appropriate throughout the following description of the data storage medium. The machine-readable data storage medium encoded with machine- readable data or set of instructions can be, for example, a magnetic data storage medium, an optically-readable data storage medium, or magneto-optical data storage medium. Examples of a magnetic data storage medium include a conventional floppy diskette or hard disk, having a suitable substrate and coating on one or both sides containing magnetic domains whose polarity or orientation can be altered magnetically. The magnetic medium optionally contains a opening for receiving the spindle of a disk drive or other data storage device. The magnetic domains of the medium coating are polarized or oriented so as to encode machine readable data such as that described herein, for execution by the system. Examples of an optically-readable data storage medium encoded with machine-readable data or set of instructions include a conventional compact disk read only memory (CD-ROM) or a rewritable medium such as a magneto-optical disk which is optically readable and magneto-optically writable. The optically- readable medium typically contains a suitable substrate and a coating on at least one side of the substrate. In the case of CD-ROM, as is well known, the coating is reflective and is impressed with a plurality of pits to encode the machine- readable data or instructions. The arrangement of pits is read by reflecting laser light off the surface of the coating. A protective coating, which preferably is substantially transparent, is provided on top of the reflective coating. In the case of a magneto-optical disk, as is also well known, the coating has no pits but has a plurality of magnetic domains whose polarity or orientation can be changed magnetically when heated above a certain temperature, as by a laser. The orientation of the domains can be read by measuring the polarization of laser light reflected from coating. The arrangement of the domains encodes the data as described above. Structurally homologous molecules, molecular complexes, and crystal structures The structure coordinates set forth in Fig. 10 can be used to aid in obtaining structural information about another crystallized molecule or molecular complex. A "molecular complex" means a protein in covalent or non- covalent association with a chemical entity or compound. The method of the invention allows deteπnination of at least a portion of the three-dimensional structure of molecules or molecular complexes which contain one or more structural features that are similar to structural features of caspase-8. These molecules are referred to herein as "structurally homologous" to caspase-8. Similar structural features can include, for example, regions of amino acid identity, conserved active site or binding site motifs, and similarly arranged secondary structural elements (e.g., α helices and β sheets). Optionally, structural homology is determined by aligning the residues of the two amino acid sequences to optimize the number of identical amino acids along the lengths of their sequences; gaps in either or both sequences are permitted in making the alignment in order to optimize the number of identical amino acids, although the amino acids in each sequence must nonetheless remain in their proper order. Preferably, two amino acid sequences are compared using the Blastp program, version 2.0.9, of the BLAST 2 search algorithm, as described by Tatusova et al., FEMS Microbiol. Lett. 174:247-250 (1999)), and available at htφ://www.ncbi.n--m.r_i-n.gov/gorf-^12.html. Preferably, the default values for all BLAST 2 search parameters are used, including matrix = BLOSUM62; open gap penalty = 11, extension gap penalty = 1, gap x_dropoff = 50, expect = 10, wordsize = 3, and filter on. In the comparison of two amino acid sequences using the BLAST search algorithm, structural similarity is referred to as "identity." Preferably, a structurally homologous molecule is a protein that has an amino acid sequence sharing at least 65% identity with the amino acid sequence of caspase-8 (SEQ ID NO:l). More preferably, a protein that is structurally homologous to caspase-8 includes at least one contiguous stretch of at least 50 amino acids that shares at least 80% amino acid sequence identity with the analogous portion of caspase-8. Methods for generating structural information about the structurally homologous molecule or molecular complex are well-known and include, for example, molecular replacement techniques. Therefore, in another embodiment this invention provides a method of utilizing molecular replacement to obtain structural information about a molecule or molecular complex whose structure is unknown comprising the steps of: (a) crystallizing the molecule or molecular complex of unknown structure; (b) generating an x-ray diffraction pattern from said crystallized molecule or molecular complex; and (c) applying at least a portion of the structure coordinates set forth in Fig. 10 to the x-ray diffraction pattern to generate a three-dimensional electron density map of the molecule or molecular complex whose structure is unknown. By using molecular replacement, all or part of the structure coordinates of caspase-8 or the caspase-8/ligand complex as provided by this invention (and set forth in Fig. 10) can be used to determine the structure of a crystallized molecule or molecular complex whose structure is unknown more quickly and efficiently than attempting to determine such information ab initio. Molecular replacement provides an accurate estimation of the phases for an unknown structure. Phases are a factor in equations used to solve crystal structures that cannot be deteπnined directly. Obtaining accurate values for the phases, by methods other than molecular replacement, is a time-consuming process that involves iterative cycles of approximations and refinements and greatly hinders the solution of crystal structures. However, when the crystal structure of a protein containing at least a structurally homologous portion has been solved, the phases from the known structure provide a satisfactory estimate of the phases for the unknown structure. Thus, this method involves generating a preliminary model of a molecule or molecular complex whose structure coordinates are unknown, by orienting and positioning the relevant portion of caspase-8 or the caspase-8/ligand complex according to Fig. 10 within the unit cell of the crystal of the unknown molecule or molecular complex so as best to account for the observed x-ray diffraction pattern of the crystal of the molecule or molecular complex whose structure is unknown. Phases can then be calculated from this model and combined with the observed x-ray diffraction pattern amplitudes to generate an electron density map of the structure whose coordinates are unknown. This, in turn, can be subjected to any well-known model building and structure refinement techniques to provide a final, accurate structure of the unknown crystallized molecule or molecular complex (E. Lattman, "Use of the Rotation and Translation Functions," in Meth. Enzvmol.. 115, pp. 55-77 (1985); M.G. Rossman, ed., "The Molecular Replacement Method," Int. Sci. Rev. Ser.. No. 13, Gordon & Breach, New York (1972)). Structural information about a portion of any crystallized molecule or molecular complex that is sufficiently structurally homologous to a portion of caspase-8 can be resolved by this method. In addition to a molecule that shares one or more structural features with caspase-8 as described above, a molecule that has similar bioactivity, such as the same catalytic activity, subsfrate specificity or ligand binding activity as caspase-8, may also be sufficiently structurally homologous to caspase-8 to permit use of the structure coordinates of caspase-8 to solve its crystal structure. In a preferred embodiment, the method of molecular replacement is utilized to obtain structural information about a molecule or molecular complex, wherein the molecule or molecular complex comprises at least one caspase-8 subunit or homolog. A "subunit" of caspase-8 is a caspase-8 molecule that has been truncated at the N-terminus or the C-teπriinus, or both. In the context of the present invention, a "homolog" of caspase-8 is a protein that contains one or more amino acid substitutions, deletions, additions, or rearrangements with respect to the amino acid sequence of caspase-8, but that, when folded into its native conformation, exhibits or is reasonably expected to exhibit at least a portion of the tertiary (three-dimensional) structure of caspase-8. For example, structurally homologous molecules can contain deletions or additions of one or more contiguous or noncontiguous amino acids, such as a loop or a domain. A preferred caspase-8 homolog comprises an amino acid other than the native arginine 258, as it has been discovered that the backbone carbonyl of Arg 258 helps form the active site of caspase-8, not the arginine side chain. Structurally homologous molecules also include "modified" caspase-8 molecules that have been chemically or enzymatically derivatized at one or more constituent amino acid, including side chain modifications, backbone modifications, and N- and C- terminal modifications including acetylation, hydroxylation, methylation, amidation, and the attachment of carbohydrate or lipid moieties, cofactors, and the like. A heavy atom derivative of caspase-8 is also included as a caspase-8 homolog. The term "heavy atom derivative" refers to derivatives of caspase-8 produced by chemically modifying a crystal of caspase-8. In practice, a crystal is soaked in a solution containing heavy metal atom salts, or organometallic compounds, e.g., lead chloride, gold thiomalate, thiomersal or uranyl acetate, which can diffuse through the crystal and bind to the surface of the protein. The location(s) of the bound heavy metal atom(s) can be determined by x-ray diffraction analysis of the soaked crystal. This information, in turn, is used to generate the phase information used to construct three-dimensional structure of the protein (T.L. Blundell and N.L. Johnson, Protein Crystallography. Academic Press (1976)). Because it is expected that caspase-8 can crystallize in more than one crystal form, the structure coordinates of caspase-8 as provided by this invention are particularly useful in solving the structure of other crystal forms of caspase-8 or caspase-8/subsfrate complexes. The structure coordinates of caspase-8 as provided by this invention are particularly useful in solving the structure of caspase-8 mutants. Mutants may be prepared, for example, by expression of caspase-8 cDNA previously altered in its coding sequence by oligonucleotide-directed mutagenesis. The structure coordinates of caspase-8 in Fig. 10 are also particularly useful to solve the structure of crystals of caspase-8, caspase-8 mutants or caspase-8 homologs co-complexed with a variety of chemical entities. This approach enables the determination of the optimal sites for interaction between chemical entities, including candidate caspase-8 inhibitors and caspase-8. Potential sites for modification within the various binding site of the molecule can also be identified. This information provides an additional tool for deterrmning the most efficient binding interactions, for example, increased hydrophobic interactions, between caspase-8 and a chemical entity. For example, high resolution x-ray diffraction data collected from crystals exposed to different types of solvent allows the determination of where each type of solvent molecule resides. Small molecules that bind tightly to those sites can then be designed and synthesized and assayed for their caspase-8 inhibition activity. All of the complexes referred to above may be studied using well-known x-ray diffraction techniques and may be refined versus 1.5-3.0 A resolution x-ray data to an R value of about 0.20 or less using computer software, such as X- PLOR (Yale University, ©1992, distributed by Molecular Simulations, Inc.; see, e.g., Blundell & Johnson, supra; Meth. Enzvmol.. Vol. 114 & 115, H.W. Wyckoff et al., eds., Academic Press (1985)). This information may thus be used to optimize known caspase-8 inhibitors, and more importantly, to design new caspase-8 inhibitors. The invention also includes the unique three-dimensional configuration defined by a set of points defined by the structure coordinates for a molecule or molecular complex structurally homologous to caspase-8 as determined using the method of the present invention, structurally equivalent configurations, and magnetic storage media comprising such set of structure coordinates. Further, the invention includes structurally homologous molecules as identified using the method of the invention. Homology modeling Using homology modeling, a computer model of a caspase-8 homolog can be built or refined without crystallizing the homolog. First, a preliminary model of the caspase-8 homolog is created by sequence alignment with caspase- 8, secondary structure prediction, the screening of structural libraries, or any combination of those techniques. Computational software may be used to carry out the sequence alignments and the secondary structure predictions. Structural incoherences, e.g., structural fragments around insertions and deletions, can be modeled by screening a structural library for peptides of the desired length and with a suitable conformation. For prediction of the side chain conformation, a side chain rotamer library may be employed. Where the caspase-8 homolog has been crystallized, the final homology model can be used to solve the crystal structure of the homolog by molecular replacement, as described above. Next, the preliminary model is subjected to energy minimization to yield an energy rninimized model. The energy minimized model may contain regions where stereochemistry restraints are violated, in which case such regions are remodeled to obtain a final homology model. The homology model is positioned according to the results of molecular replacement, and subjected to further refinement comprising molecular dynamics calculations. Rational drug design Computational techniques can be used to screen, identify, select and design chemical entities capable of associating with caspase-8 or structurally homologous molecules. Knowledge of the structure coordinates for caspase-8 permits the design and/or identification of synthetic compounds and or other molecules which have a shape complementary to the conformation of the caspase-8 substrate binding site. In particular, computational techniques can be used to identify or design chemical entities, such as inhibitors, agonists and antagonists, that associate with a caspase-8 substrate binding pocket or a caspase-8 -like substrate binding pocket. Inhibitors may bind to all or a portion of the active site of caspase-8, and can be competitive, non-competitive, or uncompetitive inhibitors; or interfere with dimerization by binding at the interface between the two monomers. Once identified and screened for biological activity, these inhibitors may be used therapeutically or prophylactically to block caspase-8 activity and, thus, inhibit cell death. Structure-activity data for analogs of ligands bind to caspase-8 or caspase-8 -like binding pockets can also be obtained computationally. The term "chemical entity," as used herein, refers to chemical compounds, complexes of two or more chemical compounds, and fragments of such compounds or complexes. Chemical entities that are determined to associate with caspase-8 are potential drug candidates. Data stored in a machine-readable storage medium that is capable of displaying a graphical three-dimensional representation of the structure of caspase-8 or a structurally homologous molecule, as identified herein, or portions thereof may thus be advantageously used for drug discovery. The structure coordinates of the chemical entity are used to generate a three- dimensional image that can be computationally fit to the three-dimensional image of caspase-8 or a structurally homologous molecule. The three- dimensional molecular structure encoded by the data in the magnetic storage medium can then be computationally evaluated for its ability to associate with chemical entities. When the molecular structures encoded by the data is displayed in a graphical three-dimensional representation on a computer screen, the protein structure can also be visually inspected for potential association with chemical entities. One embodiment of the method of drug design involves evaluating the potential association of a known chemical entity with caspase-8 or a structurally homologous molecule, particularly with a caspase-8 subsfrate binding pocket or caspase-8 -like substrate binding pocket. The method of drug design thus includes computationally evaluating the potential of a selected chemical entity to associate with any of the molecules or molecular complexes set forth above. This method comprises the steps of: (a) employing computational means to perform a fitting operation between the selected chemical entity and the substrate binding pocket of the molecule or molecular complex; and (b) analyzing the results of said fitting operation to quantify the association between the chemical entity and the subsfrate binding pocket. In another embodiment, the method of drug design involves computer- assisted design of chemical entities that associate with caspase-8, its homologs, or portions thereof. Chemical entities can be designed in a step-wise fashion, one fragment at a time, or may be designed as a whole or "de novo." To be a viable drug candidate, the chemical entity identified or designed according to the method must be capable of structurally associating with at least part of a caspase-8 or caspase-8 -like binding pockets, and must be able, sterically and energetically, to assume a conformation that allows it to associate with the caspase-8 or caspase-8 -like binding pocket. Non-covalent molecular interactions important in this association include hydrogen bonding, van der Waals interactions, hydrophobic interactions, and electrostatic interactions. Conformational considerations include the overall three-dimensional structure and orientation of the chemical entity in relation to the binding pocket, and the spacing between various functional groups of an entity that directly interact with the caspase-8 -like binding pocket or homologs thereof. Optionally, the potential binding of a chemical entity to a caspase-8 substrate binding pocket or a caspase-8-like substrate binding pocket is analyzed using computer modeling techniques prior to the actual synthesis and testing of the chemical entity. If these computational experiments suggest insufficient interaction and association between it and the caspase-8 substrate binding pocket or caspase-8-like binding pocket, testing of the entity is obviated. However, if computer modeling indicates a strong interaction, the molecule may then be synthesized and tested for its ability to bind to a caspase-8 subsfrate binding pocket or caspase-8-like subsfrate binding pocket. Binding assays to determine if a compound actually binds to and inhibits the activity of caspase-8 can also be performed and are well known in the art; see, for example, Example IN herein. One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with a caspase-8 or caspase-8- like binding pocket. This process may begin by visual inspection of, for example, a caspase-8 or caspase-8-like binding pocket on the computer screen based on the caspase-8 structure coordinates in Fig. 10 or other coordinates which define a similar shape generated from the machine-readable storage medium. Selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within the binding pocket. Docking may be accomplished using software such as QUANTA and SYBYL, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARMM and AMBER. Specialized computer programs may also assist in the process of selecting fragments or chemical entities. Examples include GRID (P.J. Goodford, J. Med. Chem. 28:849-857 (1985); available from Oxford University, Oxford, UK); MCSS (A. Miranker et al., Proteins: Struct. Funct. Gen..l 1 :29-34 (1991); available from Molecular Simulations, San Diego, CA); AUTODOCK (D.S. Goodsell et al., Proteins: Struct. Funct. Genet. 8:195-202 (1990); available from Scripps Research Institute, La JoUa, CA); and DOCK (I.D. Kuntz et al., Mol. Biol. 161 :269-288 (1982); available from University of California, San Francisco, CA) Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound or complex. Assembly may be preceded by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of caspase-8. This would be followed by manual model building using software such as QUANTA or SYBYL (Tripos Associates, St. Louis, MO). Useful programs to aid one of skill in the art in connecting the individual chemical entities or fragments include, without limitation, CAVEAT (P.A. Bartlett et al., in Molecular Recognition in Chemical and Biological Problems." Special Publ, Royal Chem. Soc, 78:182-196 (1989); G. Lauri et al., J, Comput. Aided Mol. Des. 8:51-66 (1994); available from the University of California, Berkeley, CA); 3D database systems such as ISIS (available from MDL Information Systems, San Leandro, CA; reviewed in Y.C. Martin, J. Med. Chem. 35:2145-2154 (1992)); and HOOK (M.B. Eisen et al., Proteins: Struc. Funct.. Genet. 19:199-221 (1994); available from Molecular Simulations, San Diego, CA). Caspase-8 inhibitors may be designed "de novo" using either an empty binding site or optionally including some portion(s) of a known inhibitor(s). There are many de novo ligand design methods including, without limitation, LUDI (H.-J. Bohm, J. Comp. Aid. Molec. Design. 6:61-78 (1992); available from Molecular Simulations Inc., San Diego, CA); LEGEND (Y. Nishibata et al., Tetrahedron, 47:8985 (1991); available from Molecular Simulations Inc., San Diego, CA); LeapFrog (available from Tripos Associates, St. Louis, MO); and SPROUT (N. Gillet et al., J. Comput. Aided Mol. Design 7:127-153 (1993); available from the University of Leeds, UK). Once a compound has been designed or selected by the above methods, the efficiency with which that entity may bind to a caspase-8 substrate binding pocket or caspase-8-like substrate binding pocket may be tested and optimized by computational evaluation. For example, an effective inhibitor must preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient inhibitors should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole; more preferably, not greater than 7 kcal/mole. Caspase-8 inhibitors may interact with the binding pocket in more than one conformation that is similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free entity and the average energy of the conformations observed when the inhibitor binds to the protein. An entity designed or selected as binding to a caspase-8 substrate binding pocket or caspase-8-like binding pocket may be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target enzyme and with the surrounding water molecules. Such non-complementary electrostatic interactions include repulsive charge-charge, dipole-dipole, and charge-dipole interactions. Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interactions. Examples of programs designed for such uses include: Gaussian 94, revision C (M.J. Frisch, Gaussian, Inc., Pittsburgh, PA ©1995); AMBER, version 4.1 (P.A. Kollman, University of California at San Francisco, ©1995); QUANTA CHARMM (Molecular Simulations, Inc., San Diego, CA ©1995); Insight II/Discover (Molecular Simulations, Inc., San Diego, CA ©1995); DelPhi (Molecular Simulations, Inc., San Diego, CA ©1995); and AMSOL (Quantum Chemistry Program Exchange, Indiana University). These programs may be implemented, for instance, using a Silicon Graphics workstation such as an Indigo 2 with "IMPACT" graphics. Other hardware systems and software packages will be known to those skilled in the art. Another approach encompassed by this invention is the computational screening of small molecule databases for chemical entities or compounds that can bind in whole, or in part, to a caspase-8 or caspase-8-like substrate binding pocket. In this screening, the quality of fit of such entities to the binding site may be judged either by shape complementarity or by estimated interaction energy (E.C. Meng et al., J. Comp. Chem.13:505-524 (1992)). This invention also enables the development of chemical entities that can isomerize to short-lived reaction intermediates in the chemical reaction of a substrate or other compound that binds to or with caspase-8. Time-dependent analysis of structural changes in caspase-8 during its interaction with other molecules is carried out. The reaction intermediates of caspase-8 can also be deduced from the reaction product in co-complex with caspase-8. Such information is useful to design improved analogs of known caspase-8 inhibitors or to design novel classes of inhibitors based on the reaction intermediates of the caspase-8 and inhibitor co-complex. This provides a novel route for designing caspase-8 inhibitors with both high specificity and stability. Yet another approach to rational drug design involves probing the caspase-8 crystal of the invention with molecules comprising a variety of different functional groups to determine optimal sites for interaction between candidate caspase-8 inhibitors and the protein. For example, high resolution x- ray diffraction data collected from crystals soaked in or co-crystallized with other molecules allows the determination of where each type of solvent molecule sticks. Molecules that bind tightly to those sites can then be further modified and synthesized and tested for their heφes protease inhibitor activity [J. Travis, Science. 262:1374 (1993)1. In a related approach, iterative drug design is used to identify inhibitors of caspase-8 activity. Iterative drug design is a method for optimizing associations between a protein and a compound by determining and evaluating the three-dimensional structures of successive sets of protein/compound complexes. In iterative drug design, crystals of a series of protein/compound complexes are obtained and then the three-dimensional structures of each complex is solved. Such an approach provides insight into the association between the proteins and compounds of each complex. This is accomplished by selecting compounds with inhibitory activity, obtaining crystals of this new protein/compound complex, solving the three dimensional structure of the complex, and comparing the associations between the new protein/compound complex and previously solved protein/compound complexes. By observing how changes in the compound affected the protein/compound associations, these associations may be optimized. Ligands and inhibitors Included in the invention are compounds that modulate, and preferably inhibit, the activity of caspase-8 or homologs thereof by associating directly with the binding site, for example as identified in the method of rational drug design above. Therapeutic uses of such compounds are also envisioned. In one embodiment, an inhibitor compound is a peptide or a peptidomimetic compound, preferably one that comprises at least three amino acids. In a particularly preferred embodiment, an inhibitor of caspase-8 activity is a peptide or a peptidomimetic compound comprising at least four amino acids, wherein the -unino acid at the P4 position is a hydrophobic amino acid. More preferably, the amino acids at the P3 and/or PI positions of the peptide or peptidomimetic inhibitor are negatively charged amino acids. Positions PI, P2, P3 and P4 preferably associate with caspase-8 binding sites SI, S2, S3 and S4, respectively. Peptide and peptidomimetic inhibitors are optionally derivatized at one or both ofthe N- and C-tei-mini. For example, the inhibitor can be derivatized with an acetyl group on the N-terminus and/or an aldehyde, fluoromethylketone, or the like on the C-terminus. Pharmaceutical compositions Pharmaceutical compositions of this invention comprise an inhibitor of caspase-8 activity identified according to the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The term "pharmaceutically acceptable carrier" refers to a carrier(s) that is "acceptable" in the sense of being compatible with the other ingredients of a composition and not deleterious to the recipient thereof. Optionally, the pH of the formulation is adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. Methods of making and using such pharmaceutical compositions are also included in the invention. The pharmaceutical compositions of the invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. Oral administration or administration by injection is preferred. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intrasynovial, intrasternal, infrathecal, intralesional, and intracranial injection or infusion techniques. Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of a caspase-8 inhibitor are expected to be useful for the prevention and treatment of diseases associated with abnormal caspase-8 activity, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, cancer, spinal cord injury, cardiovascular and neurological diseases. Typically, the pharmaceutical compositions of this invention will be a<--ministered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such aclministration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound. EXAMPLES The present invention is illustrated by the following examples. It is to be understood that the particular examples, materials, amounts, and procedures are to be inteφreted broadly in accordance with the scope and spirit of the invention as set forth herein. Example 1; Gene Construction and Protein Expression The gene for the procaspase-8 construct was cloned into the BamHI and Hindlll sites of vector pQE30 (Qiagen) and transformed into Ml 5 (pREP4) cells (Qiagen) for propagation and expression in E. coli, using standard protocols. Cell cultures were grown in LB broth with 100 μg/ml ampicillin and 25 μg/ml kanamycin. At A 55 o = 0.7 to 0.8, expression was induced by addition of IPTG to 1 mM. Cells were harvested after 30 minutes, resuspended in 10 mM Tris, pH 8.0, 1 mM EDTA and frozen at -70 degrees C. The presence of inclusion bodies was determined by light microscopy. Cells were disrupted by sonication and the inclusion bodies were separated from soluble proteins and cell debris by low speed centrifugation (Sorvall SS34; 3000 rpm, 30 minutes). Example 2: Refolding Protocol E. coli inclusion bodies harboring the procaspase-8 were resuspended in 10 mM Tris buffer, pH 8.0, containing ImM EDTA, washed in the same buffer, and finally collected by centrifugation at 1074 x g. The inclusion bodies were then dissolved in 6M guanidinium chloride, 0.1 M Tris, pH 8.0, containing 5 mM DTT, and insoluble material was removed by centrifugation. The solution of procaspase-8 in 6M guanidinium chloride (2-3 mg protein/ml) was treated with an equal volume of glacial acetic acid, followed by dialysis against 50% acetic acid. This solution was added rapidly to nine volumes of water to produce a clear solution of protein in 5% acetic acid. The pH was brought rapidly to 8.0 by addition of this solution to nine volumes of 1.0 M Tris buffer, pH 8, containing 5 mM DTT. This resulted in a clear solution of procaspase-8 at neutral pH. SDS-PAGE showed a single band corresponding to a mass of 33 kDa. The solution of protein was concentrated by ultrafiltration in an Amicon stirred cell concentrator. This concentration step led to autocatalytic processing of all of the 33 kDa procaspase-8 to the pi 8 and pi 1 species that are characteristic of the activated caspase. Sequence and mass spectrometric analysis of the activated caspase-8 established that the pi 8 subunit begins at Ser- 211 and extends on to Asp-374, while the pi 1 subunit starts at Leu-285 and continues on to the C-terrninal Asp-479 (Fig. 1). Example 3: Analytical Methods Protein quantitation was afforded by -imino acid analysis employing a Beckman Model 6300 ion-exchange instrument. Protein sequencing was performed using a Perkin Elmer/ Applied Biosystems Procise™ Sequencer. The masses of major procaspase processing fragments and intermediates were determined with electrospray ionization on a Micromass Quattro II MS and MALDI ionization on a Perseptive Biosystems Voyager Elite time-of-flight MS. Sodium dodecyl sulfate polyacrylamide gel elecfrophoresis (SDS-PAGE) was carried out using Novex 16 % Tris-glycine or 10% NuPage Bis-Tris (with MES inning buffer) precast mini-gels and a Novex Xcell II mini-cell apparatus. Example 4: Assay of caspase-8 Enzyme activity of caspase-8 preparations was monitored using the chromogenic subsfrates Ac-DEVD-pNA (SEQ ID NO:5) or Ac-IETD-pNA (SEQ ID NO:6) (California Peptide Research, Inc.). Kinetic release of para- nitroaniline (pNA) was followed spectrophotometrically at 405 nm in reactions maintained at pH 7.50 and 37 degrees C. The autocatalytically processed caspase-8 preparations (Example 2) readily cleaved the chromogenic caspase-8 (Ac-IETD-pNA) (SEQ ID NO:5) or caspase-3 (Ac-DEVD-pNA) (SEQ ID NO: 6) subsfrates, but exhibited no measurable activity toward the caspase-1 (ICE) substrate Ac-YVAD-AMC (SEQ ID NO:7). For the optimal subsfrate, Ac- IETD-pNA (SEQ ID NO:6), Km = 66 ± 5 μM, Vmax = 8.43 ± 0.18 μmol/min/mg. Example 5: Preparation of the Caspase-8/Ligand Complex To a volume of 2.5 ml of a 8.4 mg/ml solution of caspase-8 (0.7 μmol) in 20 mM Tris, 100 mM DTT, pH 8.0 was added 140 μl of a 10 mM stock solution of the peptide inhibitor Ac-IETD-H (SEQ ID NO:4) in DMSO (1.4 μmol, 2 fold molar excess). Ac-IETD-aldehyde (SEQ ID NO:4) is a substrate mimic which covalently modifies the active-site Cys360 (IC 50 = 50 nM). The solution was stirred on ice for 30 minutes. Example 6: Crystallization and Data Collection The caspase-8 :Ac-IETD complex was crystallized by hanging and sitting drop vapor diffusion according to the method of McPherson (in Preparation and Analysis of Protein Crystals, McPherson, A., ed., pp. 94-97, Kreiger Publishing Co., Malabar, FL (1989)). Drops (3 μl) of protein-inhibitor solution (8.4 mg/ml in 20 mM Tris, pH 8.0, 100 mM DTT) were mixed with an equal volume of reservoir buffer (1.4M sodium cifrate, 0.1M HEPES, pH 8.0) and incubated at 4°C. The average size of the crystals was 0.20 x 0.30 x 0.40 mm. The crystals were mounted in nylon loops and frozen directly in the nitrogen stream just prior to measurement of the data. In the first data set, X-ray diffraction data were measured using a rotating anode Cu Ka source (50 kV, 100 mA) equipped with a Bruker Dual Hi-Star area detector system. A 100% complete data set to 2.07 A was used to solve and refine the structure during the early rebuilding stages. The second data set was measured at the Advanced Photon Source (Argonne National Laboratory, Argonne, IL) IMCA-CAT beamline ID- 17 using a wavelength of 1.03 A and a Bruker Mosaic CCD area detector system. Data collection and processing for both crystals were carried out using SMART and SAINT software (SMART software reference manual and SAINT software reference manual; Bruker Analytical X-ray Systems, Madison, WI (1998)). The data collection statistics are given in Fig. 8. Example 7: Structure Solution and Refinement The structure was solved by molecular replacement using the program AMoRe in the CCP4 program suite (Collaborative Computational Project No. 4 , "The CCP4 Suite: programs for protein crystallography," Acta Crvstallogr. D 50:760-763 (1994); Nazava, Acta Crvstallogr. A 50:157-163 (1994)) using the diffraction data (Data set I) from the Bruker Dual Hi-Star system. A truncated pi 0/p20 poly-alanine search model based on the caspase-3 (1 CP3 in the Brookhaven Data Bank) structure (Mittl et al., J. Biol. Chem. 272:6539-6547 (1997)) was used. A peak was found in the cross-rotation function with the rotation angles α=8.18, β=62.21 and γ=l 50.08 (peak height = 7σ), in the resolution range 8 - 4.0 A with an integration radius of 25 A. The two- dimensional translation function, calculated with the search model rotated according to the above angles in the resolution 8 - 3 A, yielded a solution for the translation a = 0.2479, b = 0.5195, and c = 0.1947 (correlation coefficient = 19.8%, R F = 0.519). Initial refinement was carried out with data set I and PROFFT (Finzel, J. Appl. Crvstallogr. 20:53-55 (1987)). The high-resolution refinement was carried out using the synchrotron radiation data set II. The structure was refined by alternating rounds of restrained least squares using SHELXL97 (Sheldrick et al., Methods Enzvmol. 277:319-343 (1997)) with manual interventions on the graphic terminal (CHAIN; Sack et al.. J. Mol. Graphics 6:224-225 (1998) and EORE (Finzel, Acta Crvstallogr. D 51:450-457 (1995)). The R F converged at 0.147 for all the data greater than 2σ F between 10- 1.2 A resolution. 340 water molecules, the inhibitor and two dithiane-diol molecules were included in the final model. Hydrogen parameters for the non- solvent atoms were included in the model but not refined. The root mean square deviations for bond lengths and angles are 0.024 A and 2.14°, respectively. Not all of the residues could be assigned because the electron density was too weak. In the pi 8 and pi 1 di ers, twelve and four N-terminal residues, respectively, could not be located due to disorder. Final refinement and PROCHECK (Laskowski et al., J. Appl. Crvstallogr. 26:283-291 (1993)) statistics are included in Fig. 9. The atomic coordinates and structure factors of the caspase-8 :Ac-IΕTD- aldehyde complex (accession code 1 QTN) were deposited in the RCSB Protein Data Bank (PDB ® ) located at Rutgers University (http://www.csb.org/pdb/) on 28 June 1999 ("hold" status) and are scheduled to be publicly released 15 September 2000. The complete disclosures of all patents, patent applications including provisional patent applications, and publications, and electronically available material (e.g., GenBank amino acid and nucleotide sequence submissions; RCSB and Brookhaven Protein Data Bank atomic coordinate submissions) cited herein are incoφorated by reference. The foregoing detailed description and examples have been provided for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described; many variations will be apparent to one skilled in the art and are intended to be included within the invention defined by the claims. WHAT IS CLAIMED IS: 1. A molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket, the substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 2. The molecule or molecular complex of claim 1 wherein the subsfrate binding pocket is further defined by a set of points having a root mean square deviation from the nonhydrogen side chain atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 3. The molecule or molecular complex of claim 1 that is structurally homologous to a caspase-8 molecule or molecular complex. 4. The molecule or molecular complex of claim 1 wherein the substrate binding pocket comprises backbone atoms defined by a set of points representing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10. 5. A molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket, the subsfrate binding pocket comprising backbone atoms characterized by interatomic distances having a root-mean-square deviation from the interatomic distances characterizing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 6. A molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket, the subsfrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 --mino acids as represented by structure coordinates according to Fig. 10 situated within a sphere having a radius of about 10 A and centered on the coordinates representing the alpha carbon atom of residue 360, of less than about 2.0 A. 7. A scalable three dimensional configuration of points comprising selected points derived from the structure coordinates according to Fig. 10 representing the backbone atoms of a plurality of caspase-8 amino acids defining at least a portion of a caspase-8 substrate binding pocket and having a root mean square deviation of less than about 2.0 A from said structure coordinates. 8. The scalable three dimensional configuration of points wherein the caspase-8 substrate binding pocket comprises amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420. 9. The scalable three dimensional configuration of points of claim 8 wherein the selected points are defined by the structure coordinates according to Fig. 10 representing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420. 10 The scalable three dimensional configuration of points of claim 10 further comprising selected points derived from the structure coordinates according to Fig. 10 representing at least 50 contiguous backbone atoms of caspase-8 and having a root mean square deviation of less than about 2.0 A from said structure coordinates. 11. The scalable three-dimensional configuration of points of claim 8 displayed as a physical model, a computer-displayed image, a holographic image, or a stereodiagram. 12. A scalable three dimensional configuration of points comprising selected points derived from the structure coordinates of at least a portion of a molecule or a molecular complex that is structurally homologous to a caspase-8 molecule or molecular complex as represented by the structure coordinates according to Fig. 10, wherein the selected points have a root mean square deviation of less than about 2.0 A from the structure coordinates of said structurally homologous molecule or molecular complex. 13. The scalable three-dimensional configuration of points of claim 12 displayed as a physical model, a computer-displayed image, a holographic image, or a stereodiagram. 14. 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 (i) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; (ii) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms and nonhydrogen side chain atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Ser 411, Tyr 412 and Arg 413, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; (iii) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms characterized by interatomic distances having a root-mean-square deviation from the interatomic distances characterizing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; (iv) a molecule or molecular complex that is structurally homologous to a molecule or molecular complex comprising at least a portion of a caspase-8- like subsfrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; or (v) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids as represented by structure coordinates according to Fig. 10 situated within a sphere having a radius of about 10 A and centered on the coordinates representing the alpha carbon atom of residue 360, of less than about 2.0 A. 15. A machine-readable data storage medium comprising a data storage material encoded with structure coordinates as shown in Fig. 10 representing at least the backbone atoms of at least a portion of caspase-8 molecule comprising a caspase-8 substrate binding pocket. 16. The machine-readable data storage medium of claim 15 wherein the data storage material is encoded with structure coordinates as shown in Fig. 10 representing at least the backbone atoms of at least amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420. 17. A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which, when combined with a second set of machine readable data, using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the structure coordinates corresponding to the second set of machine readable data, wherein said first set of data comprises a Fourier transform of at least a portion of the structural coordinates for caspase-8 according to Fig. 10; and said second set of data comprises an x-ray diffraction pattern of a molecule or molecular complex of unknown structure. 18. A computer-assisted method for obtaining structural information about a molecule or a molecular complex of unknown structure using the technique of molecular replacement, the method comprising: crystallizing the molecule or molecular complex; generating an x-ray diffraction pattern from the crystallized molecule or molecular complex; applying at least a portion of the structure coordinates set forth in Fig. 10 to the x-ray diffraction pattern to generate a three-dimensional electron density map of at least a portion of the molecule or molecular complex whose structure is unknown. 19. The method of claim 18 wherein the molecule or molecular complex of unknown structure is structurally homologous to a caspase-8 molecule or molecular complex. 20. A computer-assisted method for homology modeling a caspase-8 homolog comprising: aligning the amino acid sequence of the caspase-8 homolog with the amino acid sequence of caspase-8 (SEQ ID NO:l) to yield an amino acid alignment; utilizing the amino acid alignment to incoφorate the sequence of the caspase-8 homolog into a model of caspase-8 derived from the structure coordinates set forth in Fig. 10 to yield a preliminary model of the caspase-8 homolog; subjecting the preliminary model to energy rninimization to yield an energy minimized model; remodeling regions of the energy minimized model where stereochemistry restraints are violated to yield a final model of the caspase-8 homolog. 21. A computer-assisted method for identifying a modulator of caspase-8 activity comprising: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates of a chemical entity; and determining whether the chemical entity is expected to bind to the molecule or molecular complex at the subsfrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. 22. A computer-assisted method for designing a modulator of caspase-8 activity comprising: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates for a chemical entity; evaluating the potential binding interactions between the chemical entity and substrate binding pocket of the molecule or molecular complex; structurally modifying the chemical entity to yield a set of structure coordinates for a modified chemical entity; and determining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. 23. The method of claims 22 wherein the set of structure coordinates for the chemical entity is obtained from a chemical fragment library. 24. The method of claim 21 or 22 performed a multiplicity of times to screen a library of chemical entities. 25. A computer-assisted method for designing a modulator of caspase-8 activity de novo comprising: supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; computationally building a chemical entity represented by set of structure coordinates; and detennining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. 26. The method of any of claims 21, 22 or 25 wherein the modulator is an inhibitor of caspase-8 activity. 27. The method of any of claims 21, 22 or 25 further comprising supplying or synthesizing the potential modulator, then assaying the potential modulator to determine whether it modulates caspase-8 activity. 28. The method of any of claims 21, 22 or 25 wherein the substrate binding pocket is defined by a scalable set of points in three dimensions having a root mean square deviation from the backbone atoms of caspase-8 -imino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 29. The method of claim 28 wherein the substrate binding pocket is further defined by a scalable set of points in three dimensions having a root mean square deviation from the nonhydrogen side chain atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 30. The method of claim 28 wherein the subsfrate binding pocket is defined by a scalable set of points in three dimensions representing the backbone atoms of caspase-8 -imino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10. 31. The method of any of claims 21 , 22 or 25 wherein the substrate binding pocket is defined by a scalable set of points in three dimensions characterized by pairwise distances having a root-mean-square deviation from the interatomic distances characterizing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 32. The method of any of claims 21 , 22, or 25 wherein the subsfrate binding pocket is defined by a scalable set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids as represented by structure coordinates according to Fig. 10 situated within a sphere having a radius of about 10 A and centered on the coordinates representing the alpha carbon atom of residue 360, of less than about 2.0 A. 33. The method of any of claims 21 , 22 or 25 wherein the dete-mi-oing step comprises performing a fitting operation between the chemical entity and the substrate binding pocket, followed by computationally analyzing the results of the fitting operation to quantify the association between the chemical entity and the substrate binding pocket. 34. The method of any of claims 21, 22 or 25 further comprising chemically or enzymatically synthesizing the chemical entity to yield a modulator of caspase-8 activity. 35. The method of claim 34 wherein the modulator of caspase-8 activity is an inhibitor of caspase-8 activity. 36. A method for making a modulator of caspase-8 activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield a modulator of caspase-8 activity, the chemical entity having been identified during a computer-assisted process comprising supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates of a chemical entity; and deteπnining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase- 8 activity. 37. A method for making a modulator of caspase-8 activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield a modulator of caspase-8 activity, the chemical entity having been designed during a computer-assisted process comprising supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; supplying the computer modeling application with a set of structure coordinates for a chemical entity; evaluating the potential binding interactions between the chemical entity and substrate binding pocket of the molecule or molecular complex; structurally modifying the chemical entity to yield a set of structure coordinates for a modified chemical entity; and determining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. 38. A method for making a modulator of caspase-8 activity, the method comprising chemically or enzymatically synthesizing a chemical entity to yield a modulator of caspase-8 activity, the chemical entity having been designed during a computer-assisted process comprising supplying a computer modeling application with a set of structure coordinates of a molecule or molecular complex, the molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket; computationally building a chemical entity represented by set of structure coordinates; and determining whether the chemical entity is expected to bind to the molecule or molecular complex at the substrate binding pocket, wherein binding to the molecule or molecular complex is indicative of potential modulation of caspase-8 activity. 39. A modulator of caspase-8 activity identified or designed according to the method of any of claims 21, 22, 25, 36, 37 or 38. 40. A composition comprising a modulator of caspase-8 activity identified or designed according to the method of any of claims 21 , 22, 25, 36, 37 or 38. 41. A pharmaceutical composition comprising a modulator of caspase-8 activity identified or designed according to the method of any of 21, 22, 25, 36, 37 or 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 42. A method for treating patient having an injury or disease that is accompanied by or associated with abnormal caspase-8 activity, the method comprising ad---ιinistering to the patient an effective amount of a pharmaceutical composition comprising a modulator of caspase-8 activity identified or designed according to the method of any of claims 21 , 22 or 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 43. The method of claim 42 wherein the injury or disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, cancer, spinal cord injury, cardiovascular disease and neurological disease. 44. A method for crystallizing a caspase-8 molecule comprising growing a crystal by hanging and sitting drop vapor diffusion from a precipitant solution buffered to a pH of about 7 to about 8, the precipitant solution comprising about 2 to about 5 mg/ml purified caspase-8, a buffer and a salt. 45. A method for crystallizing a caspase-8/modulator complex comprising growing a crystal by hanging and sitting drop vapor diffusion from a precipitant solution buffered to a pH of about 7 to about 8, the precipitant solution comprising about 2 to about 5 mg/ml purified caspase-8, a modulator of caspase- 8 activity, a buffer and a salt. 46. The method of claim 45 wherein the modulator is an inhibitor of caspase-8 activity. 47. The method of claim 45 wherein the inhibitor is a peptide or a peptidomimetic compound. 48. The method of claim 45 wherein the inhibitor is Acetyl-Ile-Glu-Thr-Asp-H. 49. The method of claim 45 wherein the inhibitor is covalently bound to caspase-8. 50. The method of claim 45 wherein the salt comprises at least one anion selected from the group consisting of sulfate, chloride, citrate and tartrate. 51. The method of claim 45 wherein the precipitant solution further comprises polyethylene glycol having a molecular weight of about 2000 to about 8000. 52. Crystalline caspase-8. 53. Crystalline caspase-8 complexed with a small molecule ligand. 54. Crystalline caspase-8 of claim 53 wherein the small molecule ligand is a peptide or a peptidomimetic compound that binds to the subsfrate binding pocket. 55. Crystalline caspase-8 of claim 53 wherein the small molecule ligand is Acetyl-Ile-Glu-Thr-Asp-H. 56. Crystalline caspase-8 characterized by the trigonal space group P3ι21. 57. Crystalline caspase-8 of claim 56 further characterized by having unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120°. 58. Crystalline caspase-8 complexed with Acetyl-Ile-Glu-Thr-Asp-H characterized by the trigonal space group P3ι21 and having unit cell dimensions of a = b = 62.4A ± 3.0 A, c = 129.4A ± 3.0 A, α = 90°, β = 90°, γ = 120° with one (pi 8/pl 1) heterodimer and one inhibitor molecule in the asymmetric unit. 59. Crystalline caspase-8 or crystalline caspase-8 complexed with a small molecule ligand wherein the amino acid sequence of the caspase-8 is represented in Fig. 1. 60. A composition comprismg crystalline caspase-8 or crystalline caspase-8 complexed with a small molecule ligand. 61. A method for solving a crystal structure of a crystal of a caspase-8 molecule or molecular complex characterized by the trigonal space group P3ι21 and having unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90 ° , β = 90 ° , γ = 120 ° , the method comprising: generating an x-ray diffraction pattern from the crystal, collecting diffraction data, and analyzing the data to generate the structure coordinates for the caspase-8 molecule or molecular complex. 62. The method of claims 61 wherein the -imino acid sequence of the caspase-8 is represented in Fig. 1.

Claims: AMENDED CLAIMS [received by the International Bureau on 1 December 2000 (01.12.00) ; original claims 1-7, 8-11, 13-62 replaced by amended claims 1-7, 8-11, 13-62 new claims 63-66 added; remaining claims unchanged (4 pages)] 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A. 6. A molecule or molecular complex comprising at least a portion of a caspase-8 or caspase-8-like substrate binding pocket, the substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids as represented by structure coordinates according to Fig. 10 situated within a sphere having a radius of about 10 A and centered on the coordinates representing the alpha carbon atom of residue 360, of less than about 2.0 A. 7. A scalable three dimensional corj-Qguration of points comprising selected points derived from the structure coordinates according to Fig. 10 representing the backbone atoms of a plurality of caspase-8 amino acids defining at least a portion of a ca--pa--e-8 substrate binding pocket and having a root mean square deviation of less than about 2.0 A from said structure coordinates. 8. The scalable three dimensional configuration of points of claim 7 wherein the caspase-8 substrate binding pocket comprises amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr412, Arg 413, Pro 415 and Tφ 420. 9. Tbe scalable three dimensional configuration of points of claim 7 wherein the selected points are defined by the structure coordinates according to Fig. 1 representing the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and Tφ 420. 10. The scalable three dimensional configuration of points of claim 7 further comprising selected points derived from the structure coordinates according to Fig. 10 representing at least 50 contiguous backbone atoms of caspase-8 and having a root mean square deviation of less than about 2.0 A from said structure coordinates. 11. The scalable three-dimensional configuration of points of claim 7 displayed as a physical model, a computer-displayed image, a holographic image, or a stereodiagram. 12. A S(-al-ώle t--_ree dimensioι-- --orjfiguration of points comprising selected points derived from the structure coordinates of at least a portion of a molecule or a molecular complex that is structurally homologous to a caspase-8 molecule or molecular complex as represented by the structure coordinates according to Fig. 10, wherein the selected points have a root mean square deviation of less than about 2.0 A from the structure coordinates of said structurally homologous molecule or molecular complex. 13. The scalable t-r-ree-dimensional configuration of points of claim 12 displayed as a physical model, a computer-displayed image, a holographic image, or a stereodiagram- 14. A ------ud-ine-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 (i) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the caspase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms of caspase-8 amino acids Arg 258, Asp 259, Arg 260, Asn 261, His 317, Gin 358, Tyr 365, Val 410, Ser 411, Tyr 412, Arg 413, Pro 415 and T 420, as represented by structure coordinates according to Fig. 10, of less than about 2.0 A; (ii) a molecule or molecular complex comprising at least a portion of a caspase-8-like substrate binding pocket, the c--spase-8-like substrate binding pocket comprising backbone atoms defined by a set of points having a root mean square deviation from the backbone atoms and nonhydrogen side chain atoms of 57. Crystalline caspase-8 of claim 56 further characterized by having unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ = 120°. 58. Crystalline caspase-8 complexed with Acetyl-πe-Glu-Thr-Asp-H characterized by the trigonal space group P3- . 21 and having unit cell dimensions of a = b - 62.4A ± 3.0 A, c = 129.4A ± 3.0 A, α = 90°, β - 90°, γ = 120° with one (pl8/pl 1) heterodimer and one inhibitor molecule in the asymmetric unit. 59. Cry-rtal-ine c--spase-8 or c-y-rtalline caspase-8 complexed with a small molecule ligand wherein the amino acid sequence of the caspase-8 is represented in Fig. 1. 60. A composition comprising crystalline caspase-8 or crystalline caspase-8 complexed with a small molecule ligand. 61. A method for solving a crystal structure of a crystal of a caspase-8 molecule or molecular complex characterized by the trigonal space group P3ι21 and having unit cell dimensions of a = b = 62.4 A ± 3.0 A, c = 129.4 A ± 3.0 A, α = 90°, β = 90°, γ - 120°, the method comprising: generating an x-ray diffraction pattern from the crystal, collecting diffraction data, and analyzing the data to generate the structure coordinates for the caspase-8 molecule or molecular complex. 62. The method of claims 61 wherein the amino acid sequence of the caspase-8 is represented in Fig. 1. 63. A method for preparing caspase-8 comprising: expressing recombinant procaspase-8 in E. coli to yield inclusion bodies comprising ρrocasρase-8; contacting the inclusion bodies with a chaotropic agent and a reducing agent to yield a mixture comprising reduced procaspase-8; acidifying the mixture; and concentrating the ---uxture so as to cause autocatalytic processing of the procaspase-8 to activated caspase-8 comprising and β subunits. 64. The method of claim 63 wherein the chaotropic agent is gu--n--di-αium chloride. 65. The method of claim 63 wherein the reducing agent is dithiothreitol. 66. The method of claim 63 wherein the mixture is acidified with glacial acetic acid.

Inventors: WATENPAUGH KEITH D, WATT WILLIAM, WATENPAUGH, KEITH, D., WATT, WILLIAM
Applicants: UPJOHN CO, WATENPAUGH KEITH D, WATT WILLIAM, PHARMACIA & UPJOHN COMPANY, WATENPAUGH, KEITH, D., WATT, WILLIAM
Application year: 2000
Main classification: C12N9
IPC codes: A61K38, A61K45, A61P9, A61P25, A61P35, A61P43, C07K5, C12N9, C12N15