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Document Page 411 design of inhibitors. The structure of ICE has been solved by x-ray crystallography to 2.6 Å in complex with an acetyl-Tyr-Val-Asp-H tetra-peptide [50]. Figure 8a illustrates the tertiary structure of the heterodimer with a dimension of about 45 Å × 35 Å × 25 Å. The molecule itself is oligomeric and contains two subunits, p20 (residues 120–297) and p10 (317–404) of relative molecular weight 20 kDa and 10 kDa, respectively. The two subunits form an intimately connected heterodimer. The core of ICE is a six-stranded β sheet containing 5 parallel strands and one antiparallel strand. The core is bounded by six alpha helices that lie parallel to the beta sheets. Physiologically ICE occurs as a (p20) 2(p10) 2 tetramer. The molecule is a cysteine protease, which has a unique preference among the mammalian proteases for cleaving bonds. It has only one known with aspartic acid adjacent and N-terminal to the P 1 scissile bond. It has only one known physiological substrate, proIL-1β, which it cleaves to active IL-1β. The struc- Figure 8 (a) Stereo diagrams of the heterodimer structure of Interleukin-1 Converting Enzyme (ICE). (b) The tetrapeptide inhibitor (Asp-Ala-Val-Tyr) covalently bound to Cys285 in the active site. Tetrapeptied shown in black, p20 subunit in dark gray, and p10 subunit in light gray. Produced by Molscript [106]. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_411.html (1 of 2) [4/5/2004 5:46:08 PM]
Document Page 412 ture is unlike other cysteine proteases such as papain and appears to have only one known possible homologue, CED-3 protein [54]. The crystal structure with the tetrapeptide (acetyl-Tyr-Val-Ala-Asp-H) substrate in the binding pocket (Figure 8b), coupled with the results obtained by the mutational experiments, has provided a detailed understanding of the enzyme mechanism and substrate bonding of the molecule. Structural analysis has pinpointed a catalytic diad of residues Cys285 and His237 responsible for the catalytic activity of the molecule: Cys285 acts as an active-site nucleophile while the imidazole ring of His237 participates in destabilizing the cysteine Oγ hydrogen. Although both of above these residues are contained in the p20 subunit, the p10 subunit is essential for the maintenance of a binding pocket (and thus the specificity of the molecule), providing binding sites S2 to S4 (residues 338–341) and jointly contributing, with subunit p20, the S1 (Arg179–Arg341) site. The uniqueness and substrate specificity of ICE make it an ideal target for small molecules to block the production of mature, active IL-1β. Since the substrate peptide sequence is known (Tyr-Val-Ala-Asp), it has been a starting point to develop peptidomimetics to inhibit ICE. IV. Therapeutic Strategies A. Manipulating the IL-1 System Since IL-1 is an important mediator of human disease processes, modulating its activity or completely inhibiting its synthesis may be of therapeutic benefit. Blake and Henderson [7] reviewed and portrayed a general strategy to interfere with the cytokine at any one of the following stages: induction or initiation of gene expression–transcription, RNA processing and translation in IL-1 production, folding, release and secretion of extracellular protein, IL-1 in circulation, IL-1 binding to its cell surface receptors, signal transduction and resulting activities (Figure 9). All of the above approaches hold promise for the future. The wealth of structural information on IL-1 combined with extensive site-directed mutagenesis studies on the molecules have helped to build up a picture of the regions involved in biological function. A schematic representation of the present-day efforts to design efficient antagonists of IL-1 its shown in Figure 10. B. Site-Directed Mutants Extensive mutagenesis studies have provided information related to the structural integrity, receptor binding region, and residues that are important for IL-1 function. Site-directed mutagenesis (SDM) can create a single-site mutant and its receptor binding and bioactivity values can be calculated. The results http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_412.html [4/5/2004 5:46:10 PM]
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