6L2P

Threonyl-tRNA synthetase from Salmonella enterica in the apo form

Summary for 6L2P

• Entry DOI: 10.2210/pdb6l2p/pdb
• Descriptor: Threonine--tRNA ligase, ZINC ION (3 entities in total)
• Functional Keywords: trna synthetase, drug target, homodimer, ligase
• Biological source: Salmonella enterica subsp. enterica serovar Cubana str. 76814
• Total number of polymer chains: 2
• Total formula weight: 96059.84

Authors

Guo, J.,Chen, B.,Zhou, H. (deposition date: 2019-10-05, release date: 2020-01-15, Last modification date: 2023-11-22)

Primary citation

Guo, J.,Chen, B.,Yu, Y.,Cheng, B.,Cheng, Y.,Ju, Y.,Gu, Q.,Xu, J.,Zhou, H.
Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping.
Eur.J.Med.Chem., 187:111941-111941, 2019

PubMed Abstract: Threonyl-tRNA synthetase (ThrRS) is a key member of the aminoacyl-tRNA synthetase (aaRS) family that plays essential roles in protein biosynthesis, and ThrRS inhibitors have potential in the therapy of multiple diseases, such as microbial infections and cancers. Based on a unique tRNA-amino acid dual-site inhibitory mechanism identified recently with the herb-derived prolyl-tRNA synthetase (ProRS) inhibitor halofuginone (HF), a series of compounds have been designed and synthesized by employing a fragment-based target hopping approach to simultaneously target the tRNA and l-threonine binding pockets of ThrRS. Among them, compound 30d showed an IC value of 1.4 μM against Salmonella enterica ThrRS (SeThrRS) and MIC values of 16-32 μg/mL against the tested bacterial strains. The cocrystal structure of SeThrRS in complex with 30d was determined at high resolution, revealing that 30d simultaneously occupies both binding pockets for the nucleotide A76 of tRNA and l-threonine in an ATP-independent manner, a novel mechanism compared to all other reported ThrRS inhibitors. Our study provides a new class of ThrRS inhibitors, and more importantly, it presents the first experimental evidence that the tRNA-amino acid dual-site inhibitory mechanism could apply to other aaRSs beyond ProRS, thus providing great opportunities for designing new mechanistic inhibitors for aaRS-based therapeutics.

PubMed: 31821989
DOI: 10.1016/j.ejmech.2019.111941

Experimental method

X-RAY DIFFRACTION (2.3 Å)