1. Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
2. Division of Medical Biochemistry and MRC/UCT Liver Research Centre, University of Cape Town Medical School, Observatory 7925, South Africa

Correspondence to: Edward D. Sturrock²K. Ravi Acharya¹ Correspondence and requests for materials should be addressed to K.R.A. (e-mail: Email: bsskra@bath.ac.uk) or E.D.S. (e-mail: Email: sturrock@curie.uct.ac.za). The X-ray coordinates of tACE and the tACE–lisinopril complex have been deposited in the Protein Data Bank under entry codes 1O8A and 1O86, respectively.

Abstract

Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A¹. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N²-[(S)-1-carboxy-3-phenylpropyl]-l-lysyl-l-proline; also known as Prinivil or Zestril), at 2.0 Å resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin² and Pyrococcus furiosus carboxypeptidase³—zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.