Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation.

Ilka Müller, Marieke B A C Lamers, Alison J Ritchie, Celia Dominguez, Ignacio Munoz-Sanjuan, Alex Kiselyov

BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.

Bioorganic & medicinal chemistry letters 2011 Sep 15

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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. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Ilka Müller, Marieke B A C Lamers, Alison J Ritchie, Celia Dominguez, Ignacio Munoz-Sanjuan, Alex Kiselyov. Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation. Bioorganic & medicinal chemistry letters. 2011 Sep 15;21(18):5244-7