title: 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.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, UK.
authors.forename: Mohd
authors.initials: M
authors.lastname: Akif
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Masuyer
authors.forename: Sylva L U
authors.initials: SL
authors.lastname: Schwager
authors.forename: Bhaskar J
authors.initials: BJ
authors.lastname: Bhuyan
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Mugesh
authors.forename: R Elwyn
authors.initials: RE
authors.lastname: Isaac
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002216:Captopril / Q000031:analogs & derivatives* / Q000378:metabolism; D020134:Catalytic Domain; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000201:enzymology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012643:Selenium / Q000737:chemistry*; D013737:Testis / Q000201:enzymology; D014961:X-Ray Diffraction
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D029721:Drosophila Proteins; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012643:Selenium