6YKO

Neisseria gonorrhoeae Leucyl-tRNA Synthetase in Complex with Compound 11a

6YKO の概要

• エントリーDOI: 10.2210/pdb6yko/pdb
• 関連するPDBエントリー: 6YKL 6YKN
• 分子名称: Leucine--tRNA ligase, [(2~{R},3~{S},4~{S},5~{R})-3,4-bis(oxidanyl)-5-[3-[4-(4-pentylphenyl)-1,2,3-triazol-1-yl]propyl]oxan-2-yl]methyl ~{N}-[(2~{S})-2-azanyl-4-methyl-pentanoyl]sulfamate, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: protein-inhibitor complex, rossmann fold, trna synthetase, ligase
• 由来する生物種: Neisseria gonorrhoeae
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 98994.94

構造登録者

Pang, L.,Strelkov, S.V.,Weeks, S.D. (登録日: 2020-04-06, 公開日: 2020-12-02, 最終更新日: 2024-01-24)

主引用文献

De Ruysscher, D.,Pang, L.,Lenders, S.M.G.,Cappoen, D.,Cos, P.,Rozenski, J.,Strelkov, S.V.,Weeks, S.D.,Van Aerschot, A.
Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors.
Eur.J.Med.Chem., 211:113021-113021, 2021

PubMed Abstract: Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNA molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, K values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development.

PubMed: 33248851
DOI: 10.1016/j.ejmech.2020.113021

実験手法

X-RAY DIFFRACTION (2.21 Å)