7WMF

Threonyl-tRNA synthetase from Salmonella enterica in complex with an inhibitor

Summary for 7WMF

• Entry DOI: 10.2210/pdb7wmf/pdb
• Descriptor: Threonine--tRNA ligase, (2S,3R)-2-azanyl-N-[(1R)-2-[3-[6,7-bis(chloranyl)-4-oxidanylidene-quinazolin-3-yl]propanoylamino]-1-[3-[4-(trifluoromethyl)phenyl]phenyl]ethyl]-3-oxidanyl-butanamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: ligase-inhibitor complex, ligase/inhibitor
• Biological source: Salmonella enterica subsp. enterica serovar Cubana str. 76814
• Total number of polymer chains: 2
• Total formula weight: 97422.86

Authors

Cai, Z.,Chen, B.,Yu, Y.,Zhou, H. (deposition date: 2022-01-14, release date: 2022-04-27, Last modification date: 2023-11-29)

Primary citation

Cai, Z.,Chen, B.,Yu, Y.,Guo, J.,Luo, Z.,Cheng, B.,Xu, J.,Gu, Q.,Zhou, H.
Design, Synthesis, and Proof-of-Concept of Triple-Site Inhibitors against Aminoacyl-tRNA Synthetases.
J.Med.Chem., 65:5800-5820, 2022

PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) are promising drug targets due to their essential roles in protein translation. Although current inhibitors primarily occupy one or two of the three substrate binding sites on aaRSs, we report here the structure-based design of the first class of triple-site aaRS inhibitors by targeting threonyl-tRNA synthetase (ThrRS). Competition of our compounds with all three substrates on ThrRS binding was confirmed isothermal titration calorimetry assays. Cocrystal structures of three compounds bound to ThrRS unambiguously confirmed their substrate-mimicking triple-site binding mode. Compound exhibited the best enzyme activity against ThrRS with IC = 19 nM and = 35.4 nM. Compounds , , and exhibited antibacterial activities with minimum inhibitory concentration values of 2-8 μg/mL against the tested bacteria, which are superior to those of the reported dual-site ThrRS inhibitors. Our study provides the first proof-of-concept for developing triple-site inhibitors against aaRSs, inspiring future aaRS-based drug discoveries.

PubMed: 35363470
DOI: 10.1021/acs.jmedchem.2c00134

Experimental method

X-RAY DIFFRACTION (2.1 Å)