Prediction of the tertiary structure and substrate binding site of caspase-8

The caspases represent a family of sulfhydryl proteases that play important regulatory roles in the cell. The tertiary structure of the protease domain of caspase-8, also called FLICE, has been predicted by a segment match modeling procedure. First, the atomic coordinates of the catalytic domain of caspase-3, also called CPP32, a member of the family that is closely related to caspase-8, were determined based upon the crystal structure of human caspase-1 (interleukin converting enzyme). Then, the caspase-3 structure was used as a template for modeling the protease domain of caspase-8. The resulting structure shows the expected level of similarity with the conformations of caspases-1 and -3 for which crystal structures have been determined. Moreover, the subsite contacts between caspase-8 and the covalently linked inhibitor, Ac-DEVD-aldehyde, are only slightly different from those seen in the caspase-3 enzyme/inhibitor complex. The model of caspase-8 can serve as a reference for subsite analysis relative to design of enzyme inhibitors that may find therapeutic application.