Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation |
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Authors: | Müller Ilka Lamers Marieke B A C Ritchie Alison J Dominguez Celia Munoz-Sanjuan Ignacio Kiselyov Alex |
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Institution: | BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK. |
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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. |
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Keywords: | Apoptosis Huntington’s Disease Human caspase-6 Irreversible inhibitor binding Structure-based drug design |
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