4ZDI

Crystal structure of the M. tuberculosis CTP synthase PyrG (apo form)

4ZDI の概要

• エントリーDOI: 10.2210/pdb4zdi/pdb
• 分子名称: CTP synthase, CALCIUM ION (2 entities in total)
• 機能のキーワード: ctp synthase, pyrg, amidotransferase, ligase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 510488.25

構造登録者

Bellinzoni, M.,Barilone, N.,Alzari, P.M. (登録日: 2015-04-17, 公開日: 2015-07-01, 最終更新日: 2024-01-10)

主引用文献

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

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: 26097035
DOI: 10.1016/j.chembiol.2015.05.016

実験手法

X-RAY DIFFRACTION (3.52 Å)