title: Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation.
abstract: Caspase-6 is a cysteine protease implicated in neuronal survival and apoptosis. Deregulation of caspase-6 activity was linked to several neurodegenerative disorders including Alzheimer's and Huntington's Diseases. Several recent studies on the structure of caspase-6 feature the caspase-6 zymogen, mature apo-caspase-6 as well as the Ac-VEID-CHO peptide complex. All structures share the same typical dimeric caspase conformation. However, mature apo-caspase-6 crystallized at low pH revealed a novel, non-canonical inactive caspase conformation speculated to represent a latent state of the enzyme suitable for the design of allosteric inhibitors. In this treatise we present the structure of caspase-6 in the non-canonical inactive enzyme conformation bound to the irreversible inhibitor Z-VAD-FMK. The complex features a unique peptide binding mode not observed previously.
authors.affiliation: BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.
authors.forename: Ilka
authors.initials: I
authors.lastname: Müller
authors.forename: Marieke B A C
authors.initials: MB
authors.lastname: Lamers
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ritchie
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Alex
authors.initials: A
authors.lastname: Kiselyov
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D053178:Caspase 6 / Q000737:chemistry / Q000378:metabolism; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053178:Caspase 6