1F9E

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

1F9E の概要

• エントリーDOI: 10.2210/pdb1f9e/pdb
• 関連するPDBエントリー: 1CP3 1PAU 1QDU 1QTN
• 関連するBIRD辞書のPRD_ID: PRD_000331
• 分子名称: Caspase-8 subunit p18, Caspase-8 subunit p10, (PHQ)DEVD, ... (4 entities in total)
• 機能のキーワード: cysteine protease, caspase-8, flice, mch5, mach, apoptosis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: Q14790
• タンパク質・核酸の鎖数: 18
• 化学式量合計: 169822.13

構造登録者

Blanchard, H.,Donepudi, M.,Tschopp, M.,Kodandapani, L.,Wu, J.C.,Grutter, M.G. (登録日: 2000-07-10, 公開日: 2001-07-10, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.9 Å)