Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10594009 | Bioorganic & Medicinal Chemistry Letters | 2011 | 4 Pages |
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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Authors
Ilka Müller, Marieke B.A.C. Lamers, Alison J. Ritchie, Celia Dominguez, Ignacio Munoz-Sanjuan, Alex Kiselyov,