4CA7

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

4CA7 の概要

• エントリーDOI: 10.2210/pdb4ca7/pdb
• 関連するPDBエントリー: 4CA5 4CA6 4CA8
• 分子名称: 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)
• 機能のキーワード: hydrolase, zinc metallopeptidase, inhibitor binding
• 由来する生物種: DROSOPHILA MELANOGASTER (FRUIT FLY)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 71445.09

構造登録者

Masuyer, G.,Akif, M.,Czarny, B.,Beau, F.,Schwager, S.L.U.,Sturrock, E.D.,Isaac, R.E.,Dive, V.,Acharya, K.R. (登録日: 2013-10-07, 公開日: 2013-12-11, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.82 Å)