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

Anssi M. Malinen, Monali NandyMazumdar, Matti Turtola, Henri Malmi, Thadee Grocholski, Irina Artsimovitch and Georgiy A Belogurov ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4408

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