Homology modeling of nematode Caenorhabditis elegans CED3 protein-inhibitor complex

CED3 protein, the product of a gene necessary for programmed cell death in the nematode Caenorhabditis elegans, is related to a highly specific cystei ne protease family i.e., caspases. A tertiary-structural model has keen con structed of a complex of the CED3 protein with tetrapeptide-aldehyde inhibi tor, Ac-DEVD-CHO. The conformation of CED3 protein active site and the gene ral binding features of inhibitor residues are similar to those observed in other caspases. The loop segment (Phe380-Pro387) binds with the P4 Asp in a different fashion compared to caspase-3. The comparative modeling of acti ve sites from caspase-3 and CED3 protein indicated that although these enzy mes require Asp at the position P4, variation could occur in the binding of this residue at the S4 subsite. This model allowed the definition of subst rate specificity of CED3 protein from the structural standpoint and provide d insight in designing of mutants for structure-function studies of this cl assical caspase homologue. (C) 2001 Academic Press.