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

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 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.

Fig. 1

Chemical structures of captopril and SeCap.

Fig. 2

(A) Structure of tACE (cyan) with inhibitor SeCap bound at the active site cavity (shown in spheres). The zinc ion (green sphere) bound in the active site and N-glycosylated sugars (brown sticks) at potential sites, Asn72, Asn109 are shown. Protein termini are labelled. (B) Structure of AnCE (blue) with inhibitor SeCap bound at the active site cavity (shown in spheres). The zinc ion (green sphere) bound in the active site and N-glycosylated sugars (brown sticks) at potential sites, Asn53, Asn196, Asn311 are shown.

Fig. 3

(A) A stereo representation of tACE active site with bound inhibitor. The inhibitor molecule is shown in a stick model (brown) with the electron density map contoured at 1σ level. The zinc ion is shown as a green sphere and water molecules in light blue colour. Interacting residues are labeled and atoms are coloured as follows: red for oxygen, blue for nitrogen and purple for selenium. Hydrogen bonds are shown as dotted lines. (B) Comparison of SeCap (this study, left) and captopril (yellow sticks) binding [24] to tACE (right).

Fig. 4

(A) A stereo representation of AnCE active site with bound inhibitor. The inhibitor molecule is shown in a stick model (brown) with the electron density map contoured at 1σ level. The zinc ion is shown as a green sphere and water molecules in light blue colour. Interacting residues are labeled and atoms are coloured as follows: red for oxygen, blue for nitrogen and purple for selenium. Hydrogen bonds are shown as dotted lines. (B) Comparison of SeCap (this study, left) and captopril (yellow sticks) binding [22] to AnCE (right).