5om9
Crystal structure of the human CARBOXYPEPTIDASE A1 in complex with a thiirane mechanism-based inhibitorCrystal structure of the human CARBOXYPEPTIDASE A1 in complex with a thiirane mechanism-based inhibitor
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) are involved in many biological processes such as fibrinolysis or inflammation, development, Alzheimer's disease, and various types of cancer. We describe the synthesis and kinetic characterization of a focused library of 22 thiirane- and oxirane-based potential mechanism-based inhibitors, which led to discovery of an inhibitor for the human pro-carboxypeptidase A1. Our structural analyses show that the thiirane-based small-molecule inhibitor penetrates the barrier of the pro-domain to bind within the active site. This binding leads to a chemical reaction that covalently modifies the catalytic Glu270. These results highlight the importance of combined structural, biophysical, and biochemical evaluation of inhibitors in design strategies for the development of spectroscopically nonsilent probes as effective beacons for in vitro, in cellulo, and/or in vivo localization in clinical and industrial applications. Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library.,Testero SA, Granados C, Fernandez D, Gallego P, Covaleda G, Reverter D, Vendrell J, Aviles FX, Pallares I, Mobashery S ACS Med Chem Lett. 2017 Sep 22;8(10):1122-1127. doi:, 10.1021/acsmedchemlett.7b00346. eCollection 2017 Oct 12. PMID:29057062[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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