6I6Z

Crystal structure of the human CARBOXYPEPTIDASE A1 in complex with the PHOSPHINIC INHIBITOR Acetyl-Tyr-Ala-Y(PO2CH2)-homoPhe-OH

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6I6Z の概要

• エントリーDOI: 10.2210/pdb6i6z/pdb
• 分子名称: Carboxypeptidase A1, (2S)-2-{[(S)-{(1R)-1-[(N-acetyl-L-tyrosyl)amino]ethyl}(hydroxy)phosphoryl]methyl}-4-phenylbutanoic acid, ZINC ION, ... (4 entities in total)
• 機能のキーワード: protease, 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: 70195.12

構造登録者

Gallego, P.,Reverter, D. (登録日: 2018-11-15, 公開日: 2018-12-12, 最終更新日: 2024-10-09)

主引用文献

Covaleda, G.,Gallego, P.,Vendrell, J.,Georgiadis, D.,Lorenzo, J.,Dive, V.,Aviles, F.X.,Reverter, D.,Devel, L.
Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes.
J. Med. Chem., 62:1917-1931, 2019

PubMed Abstract: Metallocarboxypeptidases (MCPs) of the M14 family are Zn-dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media.

PubMed: 30688452
DOI: 10.1021/acs.jmedchem.8b01465

実験手法

X-RAY DIFFRACTION (1.72 Å)