5fom | pdb_00005fom

Crystal structure of the Cryptosporidium muris cytosolic leucyl-tRNA synthetase editing domain complex with the adduct AMP-AN6426

spinqualitylabelsall models 5fom, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5fom is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: A2H, PO4 Related: 5fo4, 5foc, 5fod, 5fof, 5fog, 5fol, 5fon Activity: Leucine--tRNA ligase, with EC number 6.1.1.4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The apicomplexan parasites Cryptosporidium and Toxoplasma are serious threats to human health. Cryptosporidiosis is a severe diarrheal disease in malnourished children and immunocompromised individuals, with the only FDA approved drug treatment currently being nitazoxanide. The existing therapies for toxoplasmosis, an important pathology in immunocompromised individuals and pregnant women, also have serious limitations. With the aim of developing alternative therapeutic options to address these health problems, we tested a number of benzoxaboroles, boron-containing compounds shown to be active against various infectious agents, for growth inhibition of Cryptosporidium parasites in mammalian cells. A 3-aminomethyl benzoxaborole, AN6426, with activity in the micromolar range and comparable to nitazoxanide, was identified and further characterised using biophysical measurements of affinity and crystal structures of complexes with the editing domain of Cryptosporidium leucyl-tRNA synthetase (LeuRS). The same compound was shown to be active against Toxoplasma parasites, with the activity being enhanced in the presence of norvaline, an amino acid that can be mischarged by LeuRS. Our observations are consistent with AN6426 inhibiting protein synthesis in both Cryptosporidium and Toxoplasma by forming a covalent adduct with tRNALeu in the LeuRS editing active site, which suggest that further exploitation of the benzoxaboroles scaffold is a valid strategy to develop novel, much needed antiparasitic agents. Cryptosporidium and Toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-tRNA synthetase.,Palencia A, Liu RJ, Lukarska M, Gut J, Bougdour A, Touquet B, Wang ED, Li X, Alley MR, Freund YR, Rosenthal PJ, Hakimi MA, Cusack S Antimicrob Agents Chemother. 2016 Jul 18. pii: AAC.00873-16. PMID:27431220 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminoacyl tRNA synthetase 3D structures

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