7WMI

Threonyl-tRNA synthetase from Salmonella enterica in complex with an inhibitor

7WMI の概要

• エントリーDOI: 10.2210/pdb7wmi/pdb
• 分子名称: Threonine--tRNA ligase, 1,2-ETHANEDIOL, ZINC ION, ... (5 entities in total)
• 機能のキーワード: ligase-inhibitor complex, ligase/inhibitor
• 由来する生物種: Salmonella enterica subsp. enterica serovar Cubana str. 76814
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97375.77

構造登録者

Cai, Z.,Chen, B.,Yu, Y.,Zhou, H. (登録日: 2022-01-14, 公開日: 2022-04-27, 最終更新日: 2023-11-29)

主引用文献

Cai, Z.,Chen, B.,Yu, Y.,Guo, J.,Luo, Z.,Cheng, B.,Xu, J.,Gu, Q.,Zhou, H.
Design, Synthesis, and Proof-of-Concept of Triple-Site Inhibitors against Aminoacyl-tRNA Synthetases.
J.Med.Chem., 65:5800-5820, 2022

PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) are promising drug targets due to their essential roles in protein translation. Although current inhibitors primarily occupy one or two of the three substrate binding sites on aaRSs, we report here the structure-based design of the first class of triple-site aaRS inhibitors by targeting threonyl-tRNA synthetase (ThrRS). Competition of our compounds with all three substrates on ThrRS binding was confirmed isothermal titration calorimetry assays. Cocrystal structures of three compounds bound to ThrRS unambiguously confirmed their substrate-mimicking triple-site binding mode. Compound exhibited the best enzyme activity against ThrRS with IC = 19 nM and = 35.4 nM. Compounds , , and exhibited antibacterial activities with minimum inhibitory concentration values of 2-8 μg/mL against the tested bacteria, which are superior to those of the reported dual-site ThrRS inhibitors. Our study provides the first proof-of-concept for developing triple-site inhibitors against aaRSs, inspiring future aaRS-based drug discoveries.

PubMed: 35363470
DOI: 10.1021/acs.jmedchem.2c00134

実験手法

X-RAY DIFFRACTION (2 Å)