3IUR

apPEP_D266Nx+H2H3 opened state

3IUR の概要

• エントリーDOI: 10.2210/pdb3iur/pdb
• 関連するPDBエントリー: 3IUJ 3IUL 3IUM 3IUN 3IUQ 3IVM
• 分子名称: Prolyl Endopeptidase, H2H3 helices from villin headpiece subdomain HP35, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: prolyl endopeptidase, hydrolase
• 由来する生物種: Aeromonas punctata (Aeromonas caviae); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 84592.37

構造登録者

Chiu, T.K. (登録日: 2009-08-31, 公開日: 2010-05-05, 最終更新日: 2024-03-13)

主引用文献

Li, M.,Chen, C.,Davies, D.R.,Chiu, T.K.
Induced-fit mechanism for prolyl endopeptidase
J.Biol.Chem., 285:21487-21495, 2010

PubMed Abstract: Prolyl peptidases cleave proteins at proline residues and are of importance for cancer, neurological function, and type II diabetes. Prolyl endopeptidase (PEP) cleaves neuropeptides and is a drug target for neuropsychiatric diseases such as post-traumatic stress disorder, depression, and schizophrenia. Previous structural analyses showing little differences between native and substrate-bound structures have suggested a lock-and-key catalytic mechanism. We now directly demonstrate from seven structures of Aeromonus punctata PEP that the mechanism is instead induced fit: the native enzyme exists in a conformationally flexible opened state with a large interdomain opening between the beta-propeller and alpha/beta-hydrolase domains; addition of substrate to preformed native crystals induces a large scale conformational change into a closed state with induced-fit adjustments of the active site, and inhibition of this conformational change prevents substrate binding. Absolute sequence conservation among 28 orthologs of residues at the active site and critical residues at the interdomain interface indicates that this mechanism is conserved in all PEPs. This finding has immediate implications for the use of conformationally targeted drug design to improve specificity of inhibition against this family of proline-specific serine proteases.

PubMed: 20444688
DOI: 10.1074/jbc.M109.092692

実験手法

X-RAY DIFFRACTION (2.05 Å)