2QL5

Crystal Structure of caspase-7 with inhibitor AC-DMQD-CHO

2QL5 の概要

• エントリーDOI: 10.2210/pdb2ql5/pdb
• 関連するPDBエントリー: 2QL7 2QL9 2QLB 2QLF 2QLJ
• 関連するBIRD辞書のPRD_ID: PRD_000431
• 分子名称: Caspase-7, inhibitor, peptide, ... (6 entities in total)
• 機能のキーワード: cysteine protease, apoptosis, thiol protease, zymogen, 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: P55210 P55210
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 63593.69

構造登録者

Agniswamy, J.,Fang, B.,Weber, I. (登録日: 2007-07-12, 公開日: 2007-08-28, 最終更新日: 2023-11-15)

主引用文献

Agniswamy, J.,Fang, B.,Weber, I.T.
Plasticity of S2-S4 specificity pockets of executioner caspase-7 revealed by structural and kinetic analysis.
Febs J., 274:4752-4765, 2007

PubMed Abstract: Many protein substrates of caspases are cleaved at noncanonical sites in comparison to the recognition motifs reported for the three caspase subgroups. To provide insight into the specificity and aid in the design of drugs to control cell death, crystal structures of caspase-7 were determined in complexes with six peptide analogs (Ac-DMQD-Cho, Ac-DQMD-Cho, Ac-DNLD-Cho, Ac-IEPD-Cho, Ac-ESMD-Cho, Ac-WEHD-Cho) that span the major recognition motifs of the three subgroups. The crystal structures show that the S2 pocket of caspase-7 can accommodate diverse residues. Glu is not required at the P3 position because Ac-DMQD-Cho, Ac-DQMD-Cho and Ac-DNLD-Cho with varied P3 residues are almost as potent as the canonical Ac-DEVD-Cho. P4 Asp was present in the better inhibitors of caspase-7. However, the S4 pocket of executioner caspase-7 has alternate regions for binding of small branched aliphatic or polar residues similar to those of initiator caspase-8. The observed plasticity of the caspase subsites agrees very well with the reported cleavage of many proteins at noncanonical sites. The results imply that factors other than the P4-P1 sequence, such as exosites, contribute to the in vivo substrate specificity of caspases. The novel peptide binding site identified on the molecular surface of the current structures is suggested to be an exosite of caspase-7. These results should be considered in the design of selective small molecule inhibitors of this pharmacologically important protease.

PubMed: 17697120
DOI: 10.1111/j.1742-4658.2007.05994.x

実験手法

X-RAY DIFFRACTION (2.34 Å)