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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin-I converting enzyme
FEBS Journal, Volume 281, No. 3, Year 2014
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Description
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. © Copyright 2014 Federation of European Biochemical Societies. All rights reserved.
Authors & Co-Authors
Masuyer, Geoffrey
United Kingdom, Bath
University of Bath
Akif, Mohd
United Kingdom, Bath
University of Bath
Czarny, Bertrand
France, Gif-sur-yvette
Service D'ingénierie Moléculaire Des Protéines
Beau, Fabrice
France, Gif-sur-yvette
Service D'ingénierie Moléculaire Des Protéines
Schwager, Sylva L.U.
South Africa, Cape Town
University of Cape Town
Sturrock, Edward D.
South Africa, Cape Town
University of Cape Town
Isaac, R. Elwyn
United Kingdom, Leeds
University of Leeds
Dive, Vincent
France, Gif-sur-yvette
Service D'ingénierie Moléculaire Des Protéines
Ravi Acharya, K.
United Kingdom, Bath
University of Bath
Statistics
Citations: 27
Authors: 9
Affiliations: 4
Identifiers
Doi:
10.1111/febs.12660
ISSN:
1742464X
e-ISSN:
17424658
Research Areas
Noncommunicable Diseases