7bt5

Crystal structure of plasmodium LysRS complexing with an antitumor compoundCrystal structure of plasmodium LysRS complexing with an antitumor compound

Structural highlights 7bt5 is a 2 chain structure with sequence from Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.493Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8IDJ8_PLAF7 Publication Abstract from PubMed Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 A, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases. Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor.,Zhou J, Huang Z, Zheng L, Hei Z, Wang Z, Yu B, Jiang L, Wang J, Fang P Nucleic Acids Res. 2020 Oct 14. pii: 5923426. doi: 10.1093/nar/gkaa862. PMID:33053158 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

spinqualitylabelsall models 7bt5, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image