6ykl | pdb_00006ykl

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

spinqualitylabelsall models 6ykl, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ykl is a 1 chain structure with sequence from "diplococcus_gonorrhoeae"_(zopf_1885)_lehmann_and_neumann_1896 "diplococcus gonorrhoeae" (zopf 1885) lehmann and neumann 1896. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, MG, OVH, ZN Gene: leuS, VT05_02036, WHOO_00006, WHOO_00455 ("Diplococcus gonorrhoeae" (Zopf 1885) Lehmann and Neumann 1896) Activity: Leucine--tRNA ligase, with EC number 6.1.1.4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNA(Leu) 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, Ki(app) 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. Synthesis and structure-activity studies of novel anhydrohexitol-based Leucyl-tRNA synthetase inhibitors.,De Ruysscher D, Pang L, Lenders SMG, Cappoen D, Cos P, Rozenski J, Strelkov SV, Weeks SD, Van Aerschot A Eur J Med Chem. 2020 Nov 16:113021. doi: 10.1016/j.ejmech.2020.113021. PMID:33248851 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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