Crystal structure of the human angiotensin-converting enzyme–lisinopril complex

Ramanathan Natesh, Sylva L. U. Schwager, Edward D. Sturrock () and K. Ravi Acharya ()
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Ramanathan Natesh: University of Bath
Sylva L. U. Schwager: University of Cape Town Medical School
Edward D. Sturrock: University of Cape Town Medical School
K. Ravi Acharya: University of Bath

Nature, 2003, vol. 421, issue 6922, 551-554

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01370

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