1F9E

CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO

Summary for 1F9E

• Entry DOI: 10.2210/pdb1f9e/pdb
• Related: 1CP3 1PAU 1QDU 1QTN
• Related PRD ID: PRD_000331
• Descriptor: Caspase-8 subunit p18, Caspase-8 subunit p10, (PHQ)DEVD, ... (4 entities in total)
• Functional Keywords: cysteine protease, caspase-8, flice, mch5, mach, apoptosis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q14790
• Total number of polymer chains: 18
• Total formula weight: 169822.13

Authors

Blanchard, H.,Donepudi, M.,Tschopp, M.,Kodandapani, L.,Wu, J.C.,Grutter, M.G. (deposition date: 2000-07-10, release date: 2001-07-10, Last modification date: 2024-10-30)

Primary citation

Blanchard, H.,Donepudi, M.,Tschopp, M.,Kodandapani, L.,Wu, J.C.,Grutter, M.G.
Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex.
J.Mol.Biol., 302:9-16, 2000

PubMed 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 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.

PubMed: 10964557
DOI: 10.1006/jmbi.2000.4041

Experimental method

X-RAY DIFFRACTION (2.9 Å)