Bacterial DNA-directed RNA polymerase switch-region (RNAP switch-region)

The bacterial DNA-directed RNA polymerase (RNAP) switch-region is a critical regulatory site located at the base of the clamp domain of the enzyme. This region acts as a molecular hinge, allowing the clamp to open and close to facilitate the entry of promoter DNA into the active site cleft (Belogurov et al., 2009, Nature). Drugs targeting this pocket, such as the alpha-pyrone antibiotics myxopyronin and corallopyronin, bind to the switch region and lock the clamp in a specific conformation, effectively preventing the formation of a functional transcription initiation complex (Mukhopadhyay et al., 2008, Cell). Because this site is highly conserved across diverse bacterial species but structurally distinct from eukaryotic RNA polymerases, it serves as an attractive target for the development of broad-spectrum antibacterial agents (Srivastava et al., 2011, Curr Opin Microbiol). Targeting the switch region is particularly valuable in clinical settings as it does not show cross-resistance with rifampicin, which binds to a different site on the RNAP, making it a viable option for treating multi-drug resistant infections like tuberculosis (Mayer et al., 2022, Angewandte Chemie).

Other names

Switch-region pocketClamp-hinge pocketRNAP switch regionMyxopyronin binding siteSwitch-region/clamp-hinge pocket

Inhibition of transcription initiation by binding to the switch region, which acts as a hinge for the RNAP clamp, thereby preventing the conformational changes (clamp closure) necessary for DNA template binding and promoter melting.