5OM9

Crystal structure of the human CARBOXYPEPTIDASE A1 in complex with a thiirane mechanism-based inhibitor

Replaces:  4UF4

Summary for 5OM9

• Entry DOI: 10.2210/pdb5om9/pdb
• Descriptor: Carboxypeptidase A1, (2~{R})-4-methyl-2-[(1~{S})-1-sulfanylethyl]pentanoic acid, ZINC ION, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P15085
• Total number of polymer chains: 2
• Total formula weight: 94928.83

Authors

Gallego, P.,Granados, C.,Fernandez, D.,Pallares, I.,Covaleda, G.,Aviles, F.X.,Vendrell, J.,Reverter, D. (deposition date: 2017-07-28, release date: 2017-08-09, Last modification date: 2025-10-01)

Primary citation

Testero, S.A.,Granados, C.,Fernandez, D.,Gallego, P.,Covaleda, G.,Reverter, D.,Vendrell, J.,Aviles, F.X.,Pallares, I.,Mobashery, S.
Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library.
ACS Med Chem Lett, 8:1122-1127, 2017

PubMed Abstract: Metallocarboxypeptidases (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 , , and/or localization in clinical and industrial applications.

PubMed: 29057062
DOI: 10.1021/acsmedchemlett.7b00346

Experimental method

X-RAY DIFFRACTION (1.8 Å)