A1 Refereed original research article in a scientific journal

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




AuthorsMalinen AM, Nandymazumdar M, Turtola M, Malmi H, Grocholski T, Artsimovitch I, Belogurov GA.

Publication year2014

JournalNature Communications

Article number3408

Volume5

Number of pages9

ISSN2041-1723

DOIhttps://doi.org/10.1038/ncomms4408

Web address http://www.nature.com/ncomms/2014/140306/ncomms4408/full/ncomms4408.html


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.



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