The structures of caspases-1,-3,-7 and-8 reveal the basis for substrate and inhibitor selectivity

Background: Peptide inhibitors of caspases have helped define the role of t hese cysteine proteases in biology. Structural and biochemical characteriza tion of the caspase enzymes may contribute to the development of new drugs for the treatment of caspase-mediated inflammation and apoptosis. Results: The crystal structure of the previously unpublished caspase-7 (Csp 7; 2.35 Angstrom) bound to the reversible tetrapeptide aldehyde inhibitor a cetyl-Asp-Glu-Val-Asp-CHO is compared with crystal structures of caspases-1 (2.3 Angstrom), -3 (2.2 Angstrom),and -8 (2.65 Angstrom) bound to the same inhibitor. Csp7 is a close homolog of caspase-3 (Csp3), and these two casp ases possess some quarternary structural characteristics that support their unique role among the caspase family. However, although Csp3 and Csp7 are quite similar overall, they were found to have a significantly different su bstitution pattern of amino acids in and around the S4-binding site. Conclusions: These structures span all three caspase subgroups, and provide a basis for inferring substrate and inhibitor binding, as well as selectiv ity for the entire caspase family. This information will influence the desi gn of selective caspase inhibitors to further elucidate the role of caspase s in biology and hopefully lead to the design of therapeutic agents to trea t caspase-mediated diseases, such as rheumatoid arthritis, certain neurogen erative diseases and stroke.