6SUK

Crystal structure of Neprilysin in complex with Omapatrilat.

6SUK の概要

• エントリーDOI: 10.2210/pdb6suk/pdb
• 関連するPDBエントリー: 6GID
• 分子名称: Neprilysin, ZINC ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: metallopeptidase, neural endopeptidase, omapatrilat, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 81738.15

構造登録者

Cozier, G.E.,Acharya, K.R.,Sharma, U. (登録日: 2019-09-15, 公開日: 2020-05-13, 最終更新日: 2024-10-23)

主引用文献

Sharma, U.,Cozier, G.E.,Sturrock, E.D.,Acharya, K.R.
Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme.
J.Med.Chem., 63:5488-5500, 2020

PubMed Abstract: Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.

PubMed: 32337993
DOI: 10.1021/acs.jmedchem.0c00441

実験手法

X-RAY DIFFRACTION (1.75 Å)