7A0P

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

Summary for 7A0P

• Entry DOI: 10.2210/pdb7a0p/pdb
• Related: 6YKK 6YKL 6YKN 6YKQ 6YKS 6YKT 6YKU 6YKV 6YKW 6YKX
• Descriptor: Leucine--tRNA ligase, 1,2-ETHANEDIOL, ZINC ION, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, rossmann fold, trna synthetase, ligase
• Biological source: Neisseria gonorrhoeae
• Total number of polymer chains: 1
• Total formula weight: 99043.93

Authors

Pang, L.,Strelkov, S.V.,Weeks, S.D. (deposition date: 2020-08-10, release date: 2020-12-02, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.18 Å)