4ZDJ
Crystal structure of the M. tuberculosis CTP synthase PyrG in complex with two UTP molecules
Summary for 4ZDJ
| Entry DOI | 10.2210/pdb4zdj/pdb |
| Descriptor | CTP synthase, URIDINE 5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | ctp synthase, pyrg, amidotransferase, utp, ligase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 64879.94 |
| Authors | Bellinzoni, M.,Barilone, N.,Alzari, P.M. (deposition date: 2015-04-17, release date: 2015-07-01, Last modification date: 2024-01-10) |
| Primary citation | Mori, G.,Chiarelli, L.R.,Esposito, M.,Makarov, V.,Bellinzoni, M.,Hartkoorn, R.C.,Degiacomi, G.,Boldrin, F.,Ekins, S.,de Jesus Lopes Ribeiro, A.L.,Marino, L.B.,Centarova, I.,Svetlikova, Z.,Blasko, J.,Kazakova, E.,Lepioshkin, A.,Barilone, N.,Zanoni, G.,Porta, A.,Fondi, M.,Fani, R.,Baulard, A.R.,Mikusova, K.,Alzari, P.M.,Manganelli, R.,de Carvalho, L.P.,Riccardi, G.,Cole, S.T.,Pasca, M.R. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG. Chem.Biol., 22:917-927, 2015 Cited by PubMed Abstract: 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. PubMed: 26097035DOI: 10.1016/j.chembiol.2015.05.016 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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