scholarly journals Cooperativity and interaction energy threshold effects in recognition of the −10 promoter element by bacterial RNA polymerase

2013 ◽  
Vol 41 (15) ◽  
pp. 7276-7285 ◽  
Author(s):  
Vladimir Mekler ◽  
Konstantin Severinov
Keyword(s):  
Rna Polymerase ◽  
Interaction Energy ◽  
Energy Threshold ◽  
Threshold Effects ◽  
Promoter Element ◽  
Bacterial Rna

scholarly journals Ureidothiophene inhibits interaction of bacterial RNA polymerase with –10 promotor element

2020 ◽  
Vol 48 (14) ◽  
pp. 7914-7923
Author(s):  
John Harbottle ◽  
Nikolay Zenkin
Keyword(s):  
Complex Formation ◽  
Rna Polymerase ◽  
Conformational Changes ◽  
Early Stage ◽  
Chemical Compounds ◽  
Initiation Factor ◽  
Promoter Element ◽  
Bacterial Transcription ◽  
Bacterial Rna ◽  
Novel Target

Abstract Bacterial RNA polymerase is a potent target for antibiotics, which utilize a plethora of different modes of action, some of which are still not fully understood. Ureidothiophene (Urd) was found in a screen of a library of chemical compounds for ability to inhibit bacterial transcription. The mechanism of Urd action is not known. Here, we show that Urd inhibits transcription at the early stage of closed complex formation by blocking interaction of RNA polymerase with the promoter –10 element, while not affecting interactions with –35 element or steps of transcription after promoter closed complex formation. We show that mutation in the region 1.2 of initiation factor σ decreases sensitivity to Urd. The results suggest that Urd may directly target σ region 1.2, which allosterically controls the recognition of –10 element by σ region 2. Alternatively, Urd may block conformational changes of the holoenzyme required for engagement with –10 promoter element, although by a mechanism distinct from that of antibiotic fidaxomycin (lipiarmycin). The results suggest a new mode of transcription inhibition involving the regulatory domain of σ subunit, and potentially pinpoint a novel target for development of new antibacterials.

Computer-aided structural and molecular insights into the mechanisms by which Pseudouridimycin (PUM) disrupts cleft extension in bacterial RNA polymerase to block DNA entry and exit

2020 ◽  
Vol 17 ◽  
Author(s):  
Ali H. Rabbad ◽  
Fisayo A. Olotu ◽  
Mahmoud E. Soliman
Keyword(s):  
Rna Polymerase ◽  
Bacterial Infections ◽  
Entry And Exit ◽  
Dynamic Binding ◽  
Binding Behavior ◽  
Bacterial Rna ◽  
Nucleotide Addition ◽  
Switch Regions ◽  
Cleft Extension ◽  
Key Residues

Background: The ability of Pseudouridimycin (PUM) to occupy the nucleotide addition site of bacterial RNA Polymerase (RNAP) underlies its inhibitory potency as previously reported. PUM has gained high research interest as a broad-spectrum nucleoside analog that has demonstrated exciting potentials in treating drug-resistant bacterial infections. Objective: Herein, we identified, for the first time, a novel complementary mechanism by which PUM elicits its inhibitory effects on bacterial RNAP. Methods: The dynamic binding behavior of PUM to bacterial RNAP was studied using various dynamic analyses approaches. Results and Discussion: Findings revealed that in addition to occupying the nucleotide addition site, PUM also interrupts the unimpeded entry and exit of DNA by reducing the mechanistic extension of the RNAP cleft and perturbing the primary conformations of the switch regions. Moreover, PUM binding reduced the distances between key residues in the β and β’ subunits that extend to accommodate the DNA. Conclusion: This study’s findings present structural insights that would contribute to the structure-based design of potent and selective PUM inhibitors.

Sign in / Sign up

Export Citation Format

Share Document