7CBG
Crystal structure of threonyl-tRNA synthetase (ThrRS) from Salmonella enterica in complex with an inhibitor
Summary for 7CBG
| Entry DOI | 10.2210/pdb7cbg/pdb |
| Descriptor | Threonine--tRNA ligase, (2S,3R)-N-[(E)-4-[6,7-bis(chloranyl)-4-oxidanylidene-quinazolin-3-yl]but-2-enyl]-2-(methylamino)-3-oxidanyl-butanamide, ZINC ION, ... (4 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 | 96858.39 |
| Authors | |
| Primary citation | Guo, J.,Chen, B.,Yu, Y.,Cheng, B.,Ju, Y.,Tang, J.,Cai, Z.,Gu, Q.,Xu, J.,Zhou, H. Structure-guided optimization and mechanistic study of a class of quinazolinone-threonine hybrids as antibacterial ThrRS inhibitors. Eur.J.Med.Chem., 207:112848-112848, 2020 Cited by PubMed Abstract: Aminoacyl-tRNA synthetases (aaRSs) are an attractive class of antibacterial drug targets due to their essential roles in protein translation. While most traditional aaRS inhibitors target the binding pockets of substrate amino acids and/or ATP, we recently developed a class of novel tRNA-amino acid dual-site inhibitors including inhibitor 3 ((2S,3R)-2-amino-N-((E)-4-(6,7-dichloro-4-oxoquinazolin-3(4H)-yl)but-2-en-1-yl)-3-hydroxybutanamide) against threonyl-tRNA synthetase (ThrRS). Here, the binding modes and structure-activity relationships (SARs) of these inhibitors were analyzed by the crystal structures of Salmonella enterica ThrRS (SeThrRS) in complex with three of them. Based on the cocrystal structures, twelve quinazolinone-threonine hybrids were designed and synthesized, and their affinities, enzymatic inhibitory activities, and cellular potencies were evaluated. The best derivative 8g achieved a K value of 0.40 μM, an IC value of 0.50 μM against SeThrRS and MIC values of 16-32 μg/mL against the tested bacterial strains. The cocrystal structure of the SeThrRS-8g complex revealed that 8g induced a bended conformation for Met332 by forming hydrophobic interactions, which better mimicked the binding of tRNA to ThrRS. Moreover, the inhibitory potency of 8g was less impaired than a reported ATP competitive inhibitor at high concentrations of ATP, supporting our hypothesis that tRNA site inhibitors are likely superior to ATP site inhibitors in vivo, where ATP typically reaches millimolar concentrations. PubMed: 32980741DOI: 10.1016/j.ejmech.2020.112848 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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