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Structural characterization of angiotensin-I converting enzyme in complex with a selenium analogue of captopril

DOI: 10.1111/j.1742-4658.2011.08276.x DOI Help
PMID: 21810173 PMID Help

Authors: Akif Mohd (University of Bath) , Geoffrey Masuyer (University of Bath) , Sylva L. U. Schwager (University of Cape Town) , Bhaskar J. Bhuyan (Indian Institute of Science) , Govindasamy Mugesh (Indian Institute of Science) , R Elwyn Isaac (University of Leeds) , Edward Sturrock (University of Cape Town) , Ravi Acharya (University of Bath)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Journal

State: Published (Approved)
Published: August 2011

Open Access Open Access

Abstract: Human somatic angiotensin-I converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin-angiotensin aldosterone system. It is a well known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem., (2011) 9, 1356-1365] it was shown that the selenium analogues of captopril (a well known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 Å and 2.35 Å resolution respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein-selenolate interaction. These new structures of tACE-SeCap and AnCE-SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity.

Journal Keywords: Animals; Captopril; Catalytic; Drosophila; Drosophila; Humans; Male; Models; Molecular;Peptidyl-Dipeptidase; Protein; Selenium; Testis; X-Ray Diffraction

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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