5MJ6

Ligand-induced conformational change of Insulin-regulated aminopeptidase: insights on catalytic mechanism and active site plasticity.

5MJ6 の概要

• エントリーDOI: 10.2210/pdb5mj6/pdb
• 分子名称: Leucyl-cystinyl aminopeptidase, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• 機能のキーワード: insulin-regulated aminopeptidase, endoplasmatic reticulum aminopeptidases, generation of antigenic peptides for cross-presentation, phosphinic pseudotripeptides, ligand-induced conformational changes, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 217245.27

構造登録者

Mpakali, A.,Stratikos, E.,Saridakis, E.,Giastas, P. (登録日: 2016-11-30, 公開日: 2017-04-05, 最終更新日: 2024-11-06)

主引用文献

Mpakali, A.,Saridakis, E.,Harlos, K.,Zhao, Y.,Kokkala, P.,Georgiadis, D.,Giastas, P.,Papakyriakou, A.,Stratikos, E.
Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity.
J. Med. Chem., 60:2963-2972, 2017

PubMed Abstract: Insulin-regulated aminopeptidase (IRAP) is an enzyme with several important biological functions that is known to process a large variety of different peptidic substrates, although the mechanism behind this wide specificity is not clearly understood. We describe a crystal structure of IRAP in complex with a recently developed bioactive and selective inhibitor at 2.53 Å resolution. In the presence of this inhibitor, the enzyme adopts a novel conformation in which domains II and IV are juxtaposed, forming a hollow structure that excludes external solvent access to the catalytic center. A loop adjacent to the enzyme's GAMEN motif undergoes structural reconfiguration, allowing the accommodation of bulky inhibitor side chains. Atomic interactions between the inhibitor and IRAP that are unique to this conformation can explain the strong selectivity compared to homologous aminopeptidases ERAP1 and ERAP2. This conformation provides insight on IRAP's catalytic cycle and reveals significant active-site plasticity that may underlie its substrate permissiveness.

PubMed: 28328206
DOI: 10.1021/acs.jmedchem.6b01890

実験手法

X-RAY DIFFRACTION (2.53 Å)