6I6Z

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

Replaces:  4UEF

Summary for 6I6Z

• Entry DOI: 10.2210/pdb6i6z/pdb
• Descriptor: 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)
• Functional Keywords: protease, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70195.12

Authors

Gallego, P.,Reverter, D. (deposition date: 2018-11-15, release date: 2018-12-12, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.72 Å)