5ZNJ

Crystal structure of a bacterial ProRS with ligands

5ZNJ の概要

• エントリーDOI: 10.2210/pdb5znj/pdb
• 分子名称: Proline--tRNA ligase, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 7-bromo-6-chloro-3-{3-[(2R,3S)-3-hydroxypiperidin-2-yl]-2-oxopropyl}quinazolin-4(3H)-one, ... (7 entities in total)
• 機能のキーワード: aminoacyl-trna synthetase, protein biosynthesis, inhibitor, ligase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65070.22

構造登録者

Cheng, B.,Yu, Y.,Zhou, H. (登録日: 2018-04-09, 公開日: 2019-05-29, 最終更新日: 2023-11-29)

主引用文献

Cheng, B.,Cai, Z.,Luo, Z.,Luo, S.,Luo, Z.,Cheng, Y.,Yu, Y.,Guo, J.,Ju, Y.,Gu, Q.,Xu, J.,Jiang, X.,Li, G.,Zhou, H.
Structure-Guided Design of Halofuginone Derivatives as ATP-Aided Inhibitors Against Bacterial Prolyl-tRNA Synthetase.
J.Med.Chem., 65:15840-15855, 2022

PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) are promising antimicrobial targets due to their essential roles in protein translation, and expanding their inhibitory mechanisms will provide new opportunities for drug discovery. We report here that halofuginone (HF), an herb-derived medicine, moderately inhibits prolyl-tRNA synthetases (ProRSs) from various pathogenic bacteria. A cocrystal structure of ProRS (ProRS) with HF and an ATP analog was determined, which guided the design of new HF analogs. Compound potently inhibited ProRS at IC = 0.18 μM and = 30.3 nM and showed antibacterial activities with an MIC of 1-4 μg/mL . The bacterial drug resistance to only developed at a rate similar to or slower than those of clinically used antibiotics . Our study indicates that the scaffold and ATP-aided inhibitory mechanism of HF could apply to bacterial ProRS and also provides a chemical validation for using bacterial ProRS as an antibacterial target.

PubMed: 36394909
DOI: 10.1021/acs.jmedchem.2c01496

実験手法

X-RAY DIFFRACTION (1.84 Å)