6i6z
From Proteopedia
Crystal structure of the human CARBOXYPEPTIDASE A1 in complex with the PHOSPHINIC INHIBITOR Acetyl-Tyr-Ala-Y(PO2CH2)-homoPhe-OH
Structural highlights
FunctionCBPA1_HUMAN Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro.[1] Publication Abstract from PubMedMetallocarboxypeptidases (MCPs) of the M14 family are Zn(2+)-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. Synthesis and Structural/Functional Characterization of Selective M14 Metallocarboxypeptidase Inhibitors Based on Phosphinic Pseudopeptide Scaffold: Implications on the Design of Specific Optical Probes.,Covaleda G, Gallego P, Vendrell J, Georgiadis D, Lorenzo J, Dive V, Aviles FX, Reverter D, Devel L J Med Chem. 2019 Feb 28;62(4):1917-1931. doi: 10.1021/acs.jmedchem.8b01465. Epub , 2019 Feb 13. PMID:30688452[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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