Novel mechanism of inhibition of human Angiotensin-I converting enzyme (ACE) by a highly specific phosphinic tripeptide

DOI: 10.1042/BJ20102123
PMID: 21352096

Authors: Mohd Akif (University of Bath) , Sylva L. Schwager (University of Cape Town) , Colin S. Anthony (University of Cape Town) , Bertrand Czarny (CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO)) , Fabrice Beau (CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO)) , Edward Sturrock (University of Cape Town) , Ravi Acharya (University of Bath)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal

State: Published (Approved)
Published: February 2011

Abstract: Human angiotensin-I converting enzyme (ACE) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc-metallopeptidases (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and endothelin converting enzyme (ECE-1). Here, we present the first structures of testis ACE (C-ACE, which is identical to the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å) and N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed the unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P1′ residue with the unusual R-configuration which, surprisingly, is accommodated by the large S2′ pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi-pi stacking interactions with the amino benzoyl group of the first molecule locking them in a ‘hand-shake’ conformation. These features for the first time highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors.

Journal Keywords: Aspartic; Binding; Humans; Metalloendopeptidases; Models; Molecular; Oligopeptides; Peptides; Peptidyl-Dipeptidase; Phosphinic; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

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