4zdk

Crystal structure of the M. tuberculosis CTP synthase PyrG in complex with UTP, AMP-PCP and oxonorleucine

spinqualitylabelsall models 4zdk, resolution 3.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zdk is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.49Å Ligands: ACP, MG, ONL, UTP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PYRG_MYCTU Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Publication Abstract from PubMed To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.,Mori G, Chiarelli LR, Esposito M, Makarov V, Bellinzoni M, Hartkoorn RC, Degiacomi G, Boldrin F, Ekins S, de Jesus Lopes Ribeiro AL, Marino LB, Centarova I, Svetlikova Z, Blasko J, Kazakova E, Lepioshkin A, Barilone N, Zanoni G, Porta A, Fondi M, Fani R, Baulard AR, Mikusova K, Alzari PM, Manganelli R, de Carvalho LP, Riccardi G, Cole ST, Pasca MR Chem Biol. 2015 Jun 18. pii: S1074-5521(15)00201-X. doi:, 10.1016/j.chembiol.2015.05.016. PMID:26097035 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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