7CBH

Crystal structure of threonyl-tRNA synthetase (ThrRS) from Salmonella enterica in complex with an inhibitor

7CBH の概要

• エントリーDOI: 10.2210/pdb7cbh/pdb
• 分子名称: Threonine--tRNA ligase, [(E)-4-(7-bromanyl-6-chloranyl-4-oxidanylidene-quinazolin-3-yl)but-2-enyl] (2S,3R)-2-azanyl-3-oxidanyl-butanoate, ZINC ION, ... (4 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: 96490.52

構造登録者

Guo, J.,Chen, B.,Zhou, H. (登録日: 2020-06-12, 公開日: 2020-10-07, 最終更新日: 2023-11-29)

主引用文献

Guo, J.,Chen, B.,Yu, Y.,Cheng, B.,Ju, Y.,Tang, J.,Cai, Z.,Gu, Q.,Xu, J.,Zhou, H.
Structure-guided optimization and mechanistic study of a class of quinazolinone-threonine hybrids as antibacterial ThrRS inhibitors.
Eur.J.Med.Chem., 207:112848-112848, 2020

PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) are an attractive class of antibacterial drug targets due to their essential roles in protein translation. While most traditional aaRS inhibitors target the binding pockets of substrate amino acids and/or ATP, we recently developed a class of novel tRNA-amino acid dual-site inhibitors including inhibitor 3 ((2S,3R)-2-amino-N-((E)-4-(6,7-dichloro-4-oxoquinazolin-3(4H)-yl)but-2-en-1-yl)-3-hydroxybutanamide) against threonyl-tRNA synthetase (ThrRS). Here, the binding modes and structure-activity relationships (SARs) of these inhibitors were analyzed by the crystal structures of Salmonella enterica ThrRS (SeThrRS) in complex with three of them. Based on the cocrystal structures, twelve quinazolinone-threonine hybrids were designed and synthesized, and their affinities, enzymatic inhibitory activities, and cellular potencies were evaluated. The best derivative 8g achieved a K value of 0.40 μM, an IC value of 0.50 μM against SeThrRS and MIC values of 16-32 μg/mL against the tested bacterial strains. The cocrystal structure of the SeThrRS-8g complex revealed that 8g induced a bended conformation for Met332 by forming hydrophobic interactions, which better mimicked the binding of tRNA to ThrRS. Moreover, the inhibitory potency of 8g was less impaired than a reported ATP competitive inhibitor at high concentrations of ATP, supporting our hypothesis that tRNA site inhibitors are likely superior to ATP site inhibitors in vivo, where ATP typically reaches millimolar concentrations.

PubMed: 32980741
DOI: 10.1016/j.ejmech.2020.112848

実験手法

X-RAY DIFFRACTION (1.95 Å)