title: High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.
abstract: Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Building 4 South, Bath BA2 7AY, UK.
authors.forename: Mohd
authors.initials: M
authors.lastname: Akif
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Aman
authors.initials: A
authors.lastname: Mahajan
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
authors.forename: R Elwyn
authors.initials: RE
authors.lastname: Isaac
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D029721:Drosophila Proteins / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000737:chemistry / Q000201:enzymology*; D008666:Metalloendopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D000959:Antihypertensive Agents; D029721:Drosophila Proteins; D011480:Protease Inhibitors; C104431:Ance protein, Drosophila; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases