7PFS

Crystal structure of ERAP2 aminopeptidase in complex with phosphinic pseudotripeptide ((1R)-1-Amino-3-phenylpropyl){2-([1,1:3,1-terphenyl]-5-ylmethyl)-3-[((2S)-1-amino-1-oxo-3-phenylpropan-2-yl)-amino]-3-oxopropyl}phosphinic acid

7PFS の概要

• エントリーDOI: 10.2210/pdb7pfs/pdb
• 関連するPDBエントリー: 5AB0
• 分子名称: Endoplasmic reticulum aminopeptidase 2, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 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: erap2, transition state analogues, antigen presentation, hydrolase, phosphinic pseudotripeptides, aminopeptidase
• 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: 230221.34

構造登録者

Giastas, P.,Stratikos, E.,Mpakali, A. (登録日: 2021-08-12, 公開日: 2022-01-26, 最終更新日: 2024-11-13)

主引用文献

Mpakali, A.,Georgiadis, D.,Stratikos, E.,Giastas, P.
Inhibitor-Dependent Usage of the S1' Specificity Pocket of ER Aminopeptidase 2.
Acs Med.Chem.Lett., 13:218-224, 2022

PubMed Abstract: Endoplasmic reticulum aminopeptidase 2 (ERAP2) is an intracellular enzyme involved in the processing of antigenic peptides intended for presentation by major histocompatibility complex class I (MHCI) molecules. Because of its role in regulating immune responses, ERAP2 is an emerging pharmacological target. Phosphinic pseudopeptides are potent transition-state analogue inhibitors of ERAP2. Previous structure-activity studies have revealed a complex but ambiguous relationship between the occupation of putative specificity pockets and the inhibitor efficacy. To address these problems, we solved crystal structures of ERAP2 in complex with two phosphinic pseudotripeptide inhibitors. Both compounds are found in the catalytic site in a canonical orientation for transition-state analogues and utilize the S1 and S2' pockets in a similar fashion. Strikingly, their P1' side chains exhibit different orientations and make interactions with distinct shallow pockets near the ERAP2 active site. These structures suggest that S1' pocket usage in ERAP2 may be inhibitor-dependent and constitute useful starting templates for the further optimization of this class of compounds.

PubMed: 35178178
DOI: 10.1021/acsmedchemlett.1c00582

実験手法

X-RAY DIFFRACTION (2.7 Å)