6YDX

Insulin-regulated aminopeptidase complexed with a macrocyclic peptidic inhibitor

6YDX の概要

• エントリーDOI: 10.2210/pdb6ydx/pdb
• 分子名称: Leucyl-cystinyl aminopeptidase, TETRAETHYLENE GLYCOL, PHOSPHATE ION, ... (13 entities in total)
• 機能のキーワード: aminopeptidase, antigen presentation, complex, irap, 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: 216168.70

構造登録者

Mpakali, A.,Saridakis, E.,Giastas, P.,Stratikos, E. (登録日: 2020-03-21, 公開日: 2020-07-22, 最終更新日: 2025-10-01)

主引用文献

Mpakali, A.,Saridakis, E.,Giastas, P.,Maben, Z.,Stern, L.J.,Larhed, M.,Hallberg, M.,Stratikos, E.
Structural Basis of Inhibition of Insulin-Regulated Aminopeptidase by a Macrocyclic Peptidic Inhibitor.
Acs Med.Chem.Lett., 11:1429-1434, 2020

PubMed Abstract: Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains elusive. Here, we report the first crystal structure of IRAP with the macrocyclic peptide inhibitor HA08 that combines structural elements from angiotensin IV and the physiological substrates oxytocin and vasopressin. The compound is found in the catalytic site in a near canonical substrate-like configuration and inhibits by a competitive mechanism. Comparison with previously solved structures of IRAP along with small-angle X-ray scattering experiments suggests that IRAP is in an open conformation in solution but undergoes a closing conformational change upon inhibitor binding. Stabilization of the closed conformation in combination with catalytic water exclusion by the tightly juxtaposed GAMEN loop is proposed as a mechanism of inhibition.

PubMed: 32676150
DOI: 10.1021/acsmedchemlett.0c00172

実験手法

X-RAY DIFFRACTION (3.2 Å)