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

Reference:

Akif, M., Masuyer, G., Schwager, S. L. U., Bhuyan, B. J., Mugesh, G., Isaac, R. E., Sturrock, E. D. and Acharya, K. R., 2011. Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril. FEBS Journal, 278 (19), pp. 3644-3650.

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Official URL:

http://dx.doi.org/10.1111/j.1742-4658.2011.08276.x

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 and 2.35 angstrom 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.

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