6FBV

Single particle cryo em structure of Mycobacterium tuberculosis RNA polymerase in complex with Fidaxomicin

6FBV の概要

• エントリーDOI: 10.2210/pdb6fbv/pdb
• EMDBエントリー: 4230
• 分子名称: DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (9 entities in total)
• 機能のキーワード: lipiarmycin, rna pol, rnap, inhibitor, drug, clostridium difficile, antibiotic, tiacumicin b, ccdc 114782, transcription
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 423419.92

構造登録者

Das, K.,Lin, W.,Ebright, E. (登録日: 2017-12-19, 公開日: 2018-02-28, 最終更新日: 2024-05-15)

主引用文献

Lin, W.,Das, K.,Degen, D.,Mazumder, A.,Duchi, D.,Wang, D.,Ebright, Y.W.,Ebright, R.Y.,Sineva, E.,Gigliotti, M.,Srivastava, A.,Mandal, S.,Jiang, Y.,Liu, Y.,Yin, R.,Zhang, Z.,Eng, E.T.,Thomas, D.,Donadio, S.,Zhang, H.,Zhang, C.,Kapanidis, A.N.,Ebright, R.H.
Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3).
Mol. Cell, 70:60-71.e15, 2018

PubMed Abstract: Fidaxomicin is an antibacterial drug in clinical use for treatment of Clostridium difficile diarrhea. The active ingredient of fidaxomicin, lipiarmycin A3 (Lpm), functions by inhibiting bacterial RNA polymerase (RNAP). Here we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5-Å resolution. The structure shows that Lpm binds at the base of the RNAP "clamp." The structure exhibits an open conformation of the RNAP clamp, suggesting that Lpm traps an open-clamp state. Single-molecule fluorescence resonance energy transfer experiments confirm that Lpm traps an open-clamp state and define effects of Lpm on clamp dynamics. We suggest that Lpm inhibits transcription by trapping an open-clamp state, preventing simultaneous interaction with promoter -10 and -35 elements. The results account for the absence of cross-resistance between Lpm and other RNAP inhibitors, account for structure-activity relationships of Lpm derivatives, and enable structure-based design of improved Lpm derivatives.

PubMed: 29606590
DOI: 10.1016/j.molcel.2018.02.026

実験手法

ELECTRON MICROSCOPY (3.52 Å)