CBR antimicrobials inhibit RNA polymerase via at least two bridge-helix cap-mediated effects on nucleotide addition.

摘要: RNA polymerase inhibitors like the CBR class that target enzyme’s complex catalytic center are attractive leads for new antimicrobials. Catalysis by involves multiple rearrangements of bridge helix, trigger loop, and active-center side chains isomerize triphosphate bound NTP two Mg2+ ions from a preinsertion state to reactive configuration. crevice between N-terminal portion helix surrounding cap region within which is thought rearrange during nucleotide addition cycle. We report crystal structures inhibitor/Escherichia coli complexes as well biochemical tests establish distinct effects on site. One effect inhibition trigger-loop folding via F loop in cap, affects both hydrolysis 3′-terminal dinucleotides certain backtracked complexes. The second independent, only pyrophosphorolysis, may involve bridge-helix movements facilitate alignment.