8k9s

Crystal structure of plasmodium LysRS complexing with ASP3026 derived LysRS inhibitor 1 (ADKI1)

spinqualitylabelsall models 8k9s, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8k9s is a 2 chain structure with sequence from Plasmodium falciparum CAMP/Malaysia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: JRU, LYS, MES Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A024X378_PLAFC Publication Abstract from PubMed Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS. Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors.,Zhou J, Xia M, Huang Z, Qiao H, Yang G, Qian Y, Li P, Zhang Z, Gao X, Jiang L, Wang J, Li W, Fang P Commun Biol. 2024 Jun 18;7(1):742. doi: 10.1038/s42003-024-06455-4. PMID:38890421 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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