5MTF

A modular route to novel potent and selective inhibitors of rhomboid intramembrane proteases

5MTF の概要

• エントリーDOI: 10.2210/pdb5mtf/pdb
• 分子名称: Rhomboid protease GlpG, inhibitor, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: rhomboid protease, specificity, inhibition, ketoamide, hydrolase
• 由来する生物種: Escherichia coli O45:K1 (strain S88 / ExPEC); 詳細
• 細胞内の位置: Cell inner membrane ; Multi-pass membrane protein : B7MDQ0
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23930.46

構造登録者

Ticha, A.,Stanchev, S.,Vinothkumar, K.R.,Mikles, D.C.,Pachl, P.,Svehlova, K.,Nguyen, M.T.N.,Verhelst, S.H.L.,Johnson, D.,Bachovchin, D.,Lepsik, M.,Majer, P.,Strisovsky, K. (登録日: 2017-01-09, 公開日: 2017-11-15, 最終更新日: 2024-01-17)

主引用文献

Ticha, A.,Stanchev, S.,Vinothkumar, K.R.,Mikles, D.C.,Pachl, P.,Began, J.,Skerle, J.,Svehlova, K.,Nguyen, M.T.N.,Verhelst, S.H.L.,Johnson, D.C.,Bachovchin, D.A.,Lepsik, M.,Majer, P.,Strisovsky, K.
General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases.
Cell Chem Biol, 24:1523-1536.e4, 2017

PubMed Abstract: Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.

PubMed: 29107700
DOI: 10.1016/j.chembiol.2017.09.007

実験手法

X-RAY DIFFRACTION (1.79 Å)