title: Mechanism of zinc-mediated inhibition of caspase-9.
abstract: Zinc-mediated inhibition is implicated in global caspase regulation, with relief of zinc-mediated inhibition central to both small-molecule and natively induced caspase activation. As an initiator, caspase-9 regulates the upstream stages of the apoptotic caspase cascade, making it a critical control point. Here we identify two distinct zinc-binding sites on caspase-9. The first site, composed of H237, C239, and C287, includes the active site dyad and is primarily responsible for zinc-mediated inhibition. The second binding site at C272 is distal from the active site. Given the amino-acid conservation in both regions, these sites appear to be present across the caspase family underscoring the importance of zinc-mediated regulation of this class of enzymes.
authors.affiliation: Department of Chemistry, University of Massachusetts Amherst, Amherst, Massachusetts 01003, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Huber
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Hardy
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D053453:Caspase 9 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D015032:Zinc / Q000378:metabolism*
chemical_list: D053453:Caspase 9; D015032:Zinc