6l2q

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

spinqualitylabelsall models 6l2q, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6l2q is a 2 chain structure with sequence from Salmonella enterica subsp. enterica serovar Cubana str. 76814. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: E4O, EDO, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function V7II86_SALET Publication Abstract from PubMed 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(Thr) and l-threonine binding pockets of ThrRS. Among them, compound 30d showed an IC(50) value of 1.4 muM against Salmonella enterica ThrRS (SeThrRS) and MIC values of 16-32 mug/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(Thr) 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. Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping.,Guo J, Chen B, Yu Y, Cheng B, Cheng Y, Ju Y, Gu Q, Xu J, Zhou H Eur J Med Chem. 2020 Feb 1;187:111941. doi: 10.1016/j.ejmech.2019.111941. Epub , 2019 Dec 4. PMID:31821989 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA