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dc.contributor.authorBlanchard, H
dc.contributor.authorDonepudi, M
dc.contributor.authorTschopp, M
dc.contributor.authorKodandapani, L
dc.contributor.authorWu, JC
dc.contributor.authorGrutter, MG
dc.date.accessioned2006-06-15
dc.date.accessioned2014-04-10T05:12:57Z
dc.date.accessioned2017-03-02T00:11:58Z
dc.date.available2017-03-02T00:11:58Z
dc.date.issued2000
dc.date.modified2014-04-10T05:12:57Z
dc.identifier.issn0022-2836
dc.identifier.doi10.1006/jmbi.2000.4041
dc.identifier.urihttp://hdl.handle.net/10072/58197
dc.description.abstractCaspase-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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.publisher.placeUniversity of Zurich
dc.relation.ispartofpagefrom9
dc.relation.ispartofpageto16
dc.relation.ispartofissue1
dc.relation.ispartofjournalJournal of Molecular Biology
dc.relation.ispartofvolume302
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3107
dc.titleCaspase-8 specificity probed at the subsite S4: crystal structure of the caspase-ZDEVD-cho complex.
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codec1x
gro.facultyInstitute for Glycomics
gro.date.issued2000
gro.hasfulltextNo Full Text
gro.griffith.authorBlanchard, Helen


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