1f9e
From Proteopedia
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| , resolution 2.9Å | |||||||
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CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO
Contents |
Overview
Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor.
Disease
Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[601763], Breast cancer, protection against OMIM:[601763], Hepatocellular carcinoma, somatic OMIM:[601763], Lung cancer, protection against OMIM:[601763]
About this Structure
1F9E is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex., Blanchard H, Donepudi M, Tschopp M, Kodandapani L, Wu JC, Grutter MG, J Mol Biol. 2000 Sep 8;302(1):9-16. PMID:10964557
Page seeded by OCA on Thu Mar 20 11:06:12 2008
