6FBV

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

Summary for 6FBV

• Entry DOI: 10.2210/pdb6fbv/pdb
• EMDB information: 4230
• Descriptor: DNA-directed RNA polymerase subunit alpha, DNA-directed RNA polymerase subunit beta, DNA-directed RNA polymerase subunit beta', ... (9 entities in total)
• Functional Keywords: lipiarmycin, rna pol, rnap, inhibitor, drug, clostridium difficile, antibiotic, tiacumicin b, ccdc 114782, transcription
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 6
• Total formula weight: 423419.92

Authors

Das, K.,Lin, W.,Ebright, E. (deposition date: 2017-12-19, release date: 2018-02-28, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.52 Å)