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.
Highlights
Human angiotensin-I converting enzyme (ACE, EC 3.4.15.1) is a central component of the renin angiotensin aldosterone system (RAAS), which controls blood pressure, electrolyte homeostasis, renal and vascular function and myocardial remodelling
The structures presented here of FI bound to the three homologous ACE proteins and FII bound to ACE homologue from Drosophila melanogaster (AnCE) complete our understanding of the binding mechanisms of these inhibitors
The carboxyl termini of FI and FII are held in position by strong hydrogen bonds and peptidomimetic interactions seen with angiotensin II bound to C-ACE, namely Gln281, Lys511 and Tyr520 [45]
Summary
Human angiotensin-I converting enzyme (ACE, EC 3.4.15.1) is a central component of the renin angiotensin aldosterone system (RAAS), which controls blood pressure, electrolyte homeostasis, renal and vascular function and myocardial remodelling (for reviews see [1,2,3,4,5]). ACE is a membrane-bound zinc metalloprotease and a member of the gluzincin family. Its dipeptidyl carboxypeptidase activity cleaves many peptides in vivo, the major ones being angiotensin II (vasopressor octapeptide) [6] and bradykinin (vasodepressor nonapeptide) [7,8]. The activation of angiotensin I (the inactive decapeptide) to angiotensin II and the Abbreviations ACE, angiotensin-I converting enzyme; AnCE, ACE homologue from Drosophila melanogaster; ECE-1, endothelin converting enzyme-1. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS.
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