7ZYF

Insulin regulated aminopeptidase (IRAP) in complex with a nanomolar alpha hydroxy beta amino acid based inhibitor.

7ZYF の概要

• エントリーDOI: 10.2210/pdb7zyf/pdb
• 分子名称: Leucyl-cystinyl aminopeptidase, pregnancy serum form, DI(HYDROXYETHYL)ETHER, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (12 entities in total)
• 機能のキーワード: insulin regulated aminopeptidase, irap, hsplap, bestatin analogues, alpla hydroxy beta amino acid based inhibitor, 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: 210241.13

構造登録者

Mpakali, A.,Stratikos, E.,Giastas, P.,Papakyriakou, A. (登録日: 2022-05-24, 公開日: 2022-07-20, 最終更新日: 2024-11-13)

主引用文献

Vourloumis, D.,Mavridis, I.,Athanasoulis, A.,Temponeras, I.,Koumantou, D.,Giastas, P.,Mpakali, A.,Magrioti, V.,Leib, J.,van Endert, P.,Stratikos, E.,Papakyriakou, A.
Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on alpha-Hydroxy-beta-amino Acid Derivatives of Bestatin.
J.Med.Chem., 65:10098-10117, 2022

PubMed Abstract: The oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the α-hydroxy-β-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that α-hydroxy-β-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases.

PubMed: 35833347
DOI: 10.1021/acs.jmedchem.2c00904

実験手法

X-RAY DIFFRACTION (2.81 Å)