Structural Details on the Binding of Antihypertensive Drugs Captopril and Enalaprilat to Human Testicular Angiotensin I-Converting Enzyme^,

Abstract

Angiotensin converting enzyme (ACE) plays a critical role in the circulating or endocrine renin-angiotensin system (RAS) as well as the local regulation that exists in tissues such as the myocardium and skeletal muscle. Here we report the high-resolution crystal structures of testis ACE (tACE) in complex with the first successfully designed ACE inhibitor captopril and enalaprilat, the Phe-Ala-Pro analogue. We have compared these structures with the recently reported structure of a tACE-lisinopril complex [Natesh et al. (2003) Nature 421, 551-554]. The analyses reveal that all three inhibitors make direct interactions with the catalytic Zn(2+) ion at the active site of the enzyme: the thiol group of captopril and the carboxylate group of enalaprilat and lisinopril. Subtle differences are also observed at other regions of the binding pocket. These are compared with N-domain models and discussed with reference to published biochemical data. The chloride coordination geometries of the three structures are discussed and compared with other ACE analogues. It is anticipated that the molecular details provided by these structures will be used to improve the binding and/or the design of new, more potent domain-specific inhibitors of ACE that could serve as new generation antihypertensive drugs.

Substrate interactions with human ferrochelatase

“…The proton on the side chain of S130 must also point toward the chloride atom because the ␥O of S130 serves as a hydrogen bond acceptor for another backbone proton (the peptide bond between residues 131 and 132). These observations are consistent with the binding of chloride in other crystallographic models (30)(31)(32). Given the findings with the E343K variant, it is proposed that one of the substrate propionates displaces the chloride ion upon substrate binding.…”

Predictive modelling of angiotensin converting enzyme inhibitory dipeptides

“…6 AutoDock Vina was used to dock all 529 possible dipeptides (from the twenty standard amino acids and three phosphorylated amino acids, i.e., Tyr, Ser and Thr) and six synthetic drug inhibitors (captopril, enalaprilat, lisinopril, RXPA380, kAF and kAW) against chain A of the PDB structure 1UZF (Natesh, Schwager, Evans, Sturrock, & Acharya, 2004). The structures of the six drug inhibitors were taken from their respective PDB files (see Table 1) and the initial poses of the PDB-formatted structures of dipeptides were generated using the Open Babel Package, version 2.1.1 (Guha et al, 2006).…”

“…In the case of ACE, this programme allows the docking of peptide sequences with the active site, e.g., against PDB structure 1UZF (complex of captopril and human testicular angiotensin converting enzyme, Natesh, Schwager, Evans, Sturrock, & Acharya, 2004). Additional in silico approaches to characterise ligandprotein interactions are also available.…”

Identification of critical active‐site residues in angiotensin‐converting enzyme‐2 (ACE2) by site‐directed mutagenesis

“…In this case, it is likely that ACE behaves more like ACE2, with only a single occupied site (CL1) contributing to the activation of substrate hydrolysis by chloride. Interestingly, Natesh et al [27] suggest that, compared with ACE, the CL1 binding site in AnCE may also be altered and the CL2 site may be absent.…”