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  • Caspase-8 specificity probed at the subsite S4: crystal structure of the caspase-ZDEVD-cho complex.

    Author(s)
    Blanchard, H
    Donepudi, M
    Tschopp, M
    Kodandapani, L
    Wu, JC
    Grutter, MG
    Griffith University Author(s)
    Blanchard, Helen
    Year published
    2000
    Metadata
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    Abstract
    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 P1 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 P4 substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde ...
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    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 P1 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 P4 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 S4. Kinetic data reveal that Z-DEVD (Ki 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (Ki 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 S4. We propose that the subsite S3 must be considered as an important specificity-determining factor.
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    Journal Title
    Journal of Molecular Biology
    Volume
    302
    Issue
    1
    DOI
    https://doi.org/10.1006/jmbi.2000.4041
    Subject
    Medicinal and Biomolecular Chemistry
    Biochemistry and Cell Biology
    Microbiology
    Publication URI
    http://hdl.handle.net/10072/58197
    Collection
    • Journal articles

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