title: Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme.
abstract: Human somatic angiotensin-I converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and a central component of the renin angiotensin aldosterone system (RAAS). Its involvement in the modulation of physiological actions of peptide hormones has positioned ACE as an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the crystal structures of the two catalytic domains of human ACE (N- and C-) in complex with FI, the S enantiomer of the phosphinic ACE/ECE-1 (endothelin converting enzyme) dual inhibitor FII, to a resolution of 1.91 and 1.85 Å, respectively. In addition, we have determined the structure of AnCE (an ACE homologue from Drosophila melanogaster) in complex with both isomers. The inhibitor FI (S configuration) can adapt to the active site of ACE catalytic domains and shows key differences in its binding mechanism mostly through the reorientation of the isoxazole phenyl side group at the P₁' position compared with FII (R configuration). Differences in binding are also observed between FI and FII in complex with AnCE. Thus, the new structures of the ACE-inhibitor complexes presented here provide useful information for further exploration of ACE inhibitor pharmacophores involving phosphinic peptides and illustrate the role of chirality in enhancing drug specificity.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Masuyer
authors.forename: Mohd
authors.initials: M
authors.lastname: Akif
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Sylva L U
authors.initials: SL
authors.lastname: Schwager
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
authors.forename: R Elwyn
authors.initials: RE
authors.lastname: Isaac
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D020134:Catalytic Domain; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000201:enzymology; D006801:Humans; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010721:Phosphinic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity; D014961:X-Ray Diffraction
chemical_list: C587670:ACE-ECE-1 dual inhibitor FI; D000806:Angiotensin-Converting Enzyme Inhibitors; D029721:Drosophila Proteins; D019476:Insect Proteins; D008024:Ligands; D050505:Mutant Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010721:Phosphinic Acids; D011994:Recombinant Proteins; C104431:Ance protein, Drosophila; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A
keywords: Drosophila melanogaster; X-ray crystallography; angiotensin-I converting enzyme (ACE); inhibitor binding; stereochemistry; zinc metallopeptidase