title: Prediction of the tertiary structure and substrate binding site of caspase-8.
abstract: 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.
authors.affiliation: Pharmacia & Upjohn, Kalamazoo, MI 49007-4940, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Chou
authors.forename: D
authors.initials: D
authors.lastname: Jones
authors.forename: R L
authors.initials: RL
authors.lastname: Heinrikson
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020170:Caspase 1; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1