title: The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme.
abstract: Enzyme-inhibitor recognition is considered one of the most fundamental aspects in the area of drug discovery. However, the molecular mechanism of this recognition process (induced fit or prebinding and adaptive selection among multiple conformers) in several cases remains unexplored. In order to shed light toward this step of the recognition process in the case of human angiotensin I converting enzyme (hACE) and its inhibitor captopril, we have established a novel combinatorial approach exploiting solution NMR, flexible docking calculations, mutagenesis, and enzymatic studies. We provide evidence that an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Tzakos
authors.forename: Nawazish
authors.initials: N
authors.lastname: Naqvi
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Comporozos
authors.forename: Roberta
authors.initials: R
authors.lastname: Pierattelli
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Theodorou
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Gerothanassis
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002216:Captopril / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016296:Mutagenesis; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D007703:Peptidyl-Dipeptidase A