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Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin‐ I converting enzyme
Author(s) -
Masuyer Geoffrey,
Akif Mohd,
Czarny Bertrand,
Beau Fabrice,
Schwager Sylva L. U.,
Sturrock Edward D.,
Isaac R. Elwyn,
Dive Vincent,
Acharya K. Ravi
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12660
Subject(s) - tripeptide , chemistry , stereochemistry , enantiomer , ace inhibitor , angiotensin converting enzyme , enzyme , renin–angiotensin system , pentapeptide repeat , active site , biochemistry , peptide , medicine , blood pressure
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 A n CE (an ACE homologue from D rosophila 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 P 1 ′ position compared with FII ( R configuration). Differences in binding are also observed between FI and FII in complex with A n CE . 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. Database Structural data are available in the Protein Data Bank databases under accession numbers 4ca5 , 4ca6 , 4ca7 , 4ca8 .