4CA7

Drosophila Angiotensin converting enzyme (AnCE) in complex with a phosphinic tripeptide FI

Summary for 4CA7

• Entry DOI: 10.2210/pdb4ca7/pdb
• Related: 4CA5 4CA6 4CA8
• Descriptor: ANGIOTENSIN-CONVERTING ENZYME, beta-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (6 entities in total)
• Functional Keywords: hydrolase, zinc metallopeptidase, inhibitor binding
• Biological source: DROSOPHILA MELANOGASTER (FRUIT FLY)
• Total number of polymer chains: 1
• Total formula weight: 71445.09

Authors

Masuyer, G.,Akif, M.,Czarny, B.,Beau, F.,Schwager, S.L.U.,Sturrock, E.D.,Isaac, R.E.,Dive, V.,Acharya, K.R. (deposition date: 2013-10-07, release date: 2013-12-11, Last modification date: 2023-12-20)

Primary citation

Masuyer, G.,Akif, M.,Czarny, B.,Beau, F.,Schwager, S.L.,Sturrock, E.D.,Isaac, R.E.,Dive, V.,Acharya, K.R.
Crystal Structures of Highly Specific Phosphinic Tripeptide Enantiomers in Complex with the Angiotensin-I Converting Enzyme.
FEBS J., 281:943-, 2014

PubMed Abstract: 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.

PubMed: 24289879
DOI: 10.1111/FEBS.12660

Experimental method

X-RAY DIFFRACTION (1.82 Å)