7RWI

Mycobacterium tuberculosis RNA polymerase sigma L holoenzyme open promoter complex containing TNP-2198

7RWI の概要

• エントリーDOI: 10.2210/pdb7rwi/pdb
• 分子名称: DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (8 entities in total)
• 機能のキーワード: mycobacterium tuberculosis, rna polymerase, transcription inhibitor, tnp-2198, open promoter complex, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 400329.70

構造登録者

Molodtsov, V.,Ebright, R.H. (登録日: 2021-08-19, 公開日: 2022-03-02, 最終更新日: 2023-10-18)

主引用文献

Ma, Z.,He, S.,Yuan, Y.,Zhuang, Z.,Liu, Y.,Wang, H.,Chen, J.,Xu, X.,Ding, C.,Molodtsov, V.,Lin, W.,Robertson, G.T.,Weiss, W.J.,Pulse, M.,Nguyen, P.,Duncan, L.,Doyle, T.,Ebright, R.H.,Lynch, A.S.
Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens.
J.Med.Chem., 65:4481-4495, 2022

PubMed Abstract: TNP-2198, a stable conjugate of a rifamycin pharmacophore and a nitroimidazole pharmacophore, has been designed, synthesized, and evaluated as a novel dual-targeted antibacterial agent for the treatment of microaerophilic and anaerobic bacterial infections. TNP-2198 exhibits greater activity than a 1:1 molar mixture of the parent drugs and exhibits activity against strains resistant to both rifamycins and nitroimidazoles. A crystal structure of TNP-2198 bound to a RNA polymerase transcription initiation complex reveals that the rifamycin portion of TNP-2198 binds to the rifamycin binding site on RNAP and the nitroimidazole portion of TNP-2198 interacts directly with the DNA template-strand in the RNAP active-center cleft, forming a hydrogen bond with a base of the DNA template strand. TNP-2198 is currently in Phase 2 clinical development for the treatment of infection, infection, and bacterial vaginosis.

PubMed: 35175750
DOI: 10.1021/acs.jmedchem.1c02045

実験手法

X-RAY DIFFRACTION (3.7 Å)