5fof

Crystal structure of the P.knowlesi cytosolic leucyl-tRNA synthetase editing domain

spinqualitylabelsall models 5fof, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5fof is a 4 chain structure with sequence from Plasmodium knowlesi strain H. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A384L319_PLAKH Publication Abstract from PubMed There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (IC50 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (ED90 7.4 and 16.2 mg/kg, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with step-wise increases in concentration of AN6426. Resistant clones were characterized by whole genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild type, but not resistant parasites. The growth of resistant, but not wild type parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity, and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS. Anti-malarial benzoxaboroles target P. falciparum leucyl-tRNA synthetase.,Sonoiki E, Palencia A, Guo D, Ahyong V, Dong C, Li X, Hernandez VS, Zhang YK, Choi W, Gut J, Legac J, Cooper R, Alley MR, Freund YR, DeRisi J, Cusack S, Rosenthal PJ Antimicrob Agents Chemother. 2016 Jun 6. pii: AAC.00820-16. PMID:27270277 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

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