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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

[ Vol. 18 , Issue. 6 ]

Author(s):

Ali H. Rabbad, Fisayo A. Olotu and Mahmoud E. Soliman*   Pages 542 - 550 ( 9 )

Abstract:


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.

Materials and Methods: The dynamic binding behavior of PUM to bacterial RNAP was studied using various dynamic analysis approaches.

Results: 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 structurebased design of potent and selective PUM inhibitors.

Keywords:

Pseudouridimycin, nucleoside analog, RNA polymerase, switch regions, cleft extension, molecular dynamics simulations.

Affiliation:

Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001

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