Article

The RNA Polymerase “Switch Region” Is a Target for Inhibitors

Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ 08854, USA.
Cell (Impact Factor: 33.12). 11/2008; 135(2):295-307. DOI: 10.1016/j.cell.2008.09.033
Source: PubMed

ABSTRACT The alpha-pyrone antibiotic myxopyronin (Myx) inhibits bacterial RNA polymerase (RNAP). Here, through a combination of genetic, biochemical, and structural approaches, we show that Myx interacts with the RNAP "switch region"--the hinge that mediates opening and closing of the RNAP active center cleft--to prevent interaction of RNAP with promoter DNA. We define the contacts between Myx and RNAP and the effects of Myx on RNAP conformation and propose that Myx functions by interfering with opening of the RNAP active-center cleft during transcription initiation. We further show that the structurally related alpha-pyrone antibiotic corallopyronin (Cor) and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip) function analogously to Myx. The RNAP switch region is distant from targets of previously characterized RNAP inhibitors, and, correspondingly, Myx, Cor, and Rip do not exhibit crossresistance with previously characterized RNAP inhibitors. The RNAP switch region is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents.

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Available from: Kalyan Das, Aug 27, 2015
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    • "Several natural products targeting the switch region, namely corallopyronin, lipiarmycin, myxopyronin, and ripostatin have been discovered (Mukhopadhyay et al., 2008; Sergio et al., 1975). Common to all of these molecules is their potent activity against drug-sensitive and drug-resistant strains of Gram-positive bacteria. "
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    • "Several natural products targeting the switch region, namely corallopyronin, lipiarmycin, myxopyronin, and ripostatin have been discovered (Mukhopadhyay et al., 2008; Sergio et al., 1975). Common to all of these molecules is their potent activity against drug-sensitive and drug-resistant strains of Gram-positive bacteria. "
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    • "Flexibility of the clamp domain has been documented in both bacterial and eukaryotic RNA polymerases (Cramer et al., 2001; Darst et al., 2002), and the clamp of archaeal polymerase has been recently identified as an important target for regulation of RNAPII initiation and processivity (Grohmann et al., 2011). Clamp opening appears to be critical for promoter engagement in bacterial RNA polymerase (Belogurov et al., 2009; Mukhopadhyay et al., 2008) and recent studies suggest that changes in the conformation of bacterial polymerase similar to the ones described here are involved in initiation regulation (Tagami et al., 2010). Finely regulated changes in Mediator structure would modulate interaction with RNAPII, with opening of the clamp by the Head functioning as a final effect. "
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