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CBR antimicrobials alter coupling between the bridge helix and the β subunit in RNA polymerase

Author

Listed:
  • Anssi M. Malinen

    (University of Turku)

  • Monali NandyMazumdar

    (The Ohio State University)

  • Matti Turtola

    (University of Turku)

  • Henri Malmi

    (University of Turku)

  • Thadee Grocholski

    (University of Turku)

  • Irina Artsimovitch

    (The Ohio State University)

  • Georgiy A Belogurov

    (University of Turku)

Abstract

Bacterial RNA polymerase (RNAP) is a validated target for antibacterial drugs. CBR703 series antimicrobials allosterically inhibit transcription by binding to a conserved α helix (β′ bridge helix, BH) that interconnects the two largest RNAP subunits. Here we show that disruption of the BH-β subunit contacts by amino-acid substitutions invariably results in accelerated catalysis, slowed-down forward translocation and insensitivity to regulatory pauses. CBR703 partially reverses these effects in CBR-resistant RNAPs while inhibiting catalysis and promoting pausing in CBR-sensitive RNAPs. The differential response of variant RNAPs to CBR703 suggests that the inhibitor binds in a cavity walled by the BH, the β′ F-loop and the β fork loop. Collectively, our data are consistent with a model in which the β subunit fine tunes RNAP elongation activities by altering the BH conformation, whereas CBRs deregulate transcription by increasing coupling between the BH and the β subunit.

Suggested Citation

  • Anssi M. Malinen & Monali NandyMazumdar & Matti Turtola & Henri Malmi & Thadee Grocholski & Irina Artsimovitch & Georgiy A Belogurov, 2014. "CBR antimicrobials alter coupling between the bridge helix and the β subunit in RNA polymerase," Nature Communications, Nature, vol. 5(1), pages 1-9, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4408
    DOI: 10.1038/ncomms4408
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    Cited by:

    1. Alaksh Choudhury & Benoit Gachet & Zoya Dixit & Roland Faure & Ryan T. Gill & Olivier Tenaillon, 2023. "Deep mutational scanning reveals the molecular determinants of RNA polymerase-mediated adaptation and tradeoffs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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