Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 298, Issue 8, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2022.102208
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Funding
- Fondation pour la Recherche Medicale
- Institut Universitaire de France (IUF)
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Antibiotic resistance through epigenetic methylation of ribosomal RNA is a common strategy used by multidrug resistant pathogens. This study reveals the importance of a specific RNA structure in methylation at the pathogenic site. Fluorescent nucleotide-labeled RNA sequences show that base flipping is necessary for effective methylation, and distal bases assist in recognition and flipping. Molecular dynamic simulation studies demonstrate significant conformational changes in RNA during protein-rRNA handshake.
Antibiotic resistance via epigenetic methylation of ribosomal RNA is one of the most prevalent strategies adopted by multidrug resistant pathogens. The erythromycin-resistance methyltransferase (Erm) methylates rRNA at the conserved A2058 position and imparts resistance to macrolides such as erythromycin. However, the precise mechanism adopted by Erm methyltransferases for locating the target base within a complicated rRNA scaffold remains unclear. Here, we show that a conserved RNA architecture, including specific bulge sites, present more than 15 angstrom from the reaction center, is key to methylation at the pathogenic site. Using a set of RNA sequences site-specifically labeled by fluorescent nucleotide surrogates, we show that base flipping is a prerequisite for effective methylation and that distal bases assist in the recognition and flipping at the reaction center. The Erm-RNA complex model revealed that intrinsically flipped-out bases in the RNA serve as a putative anchor point for the Erm. Molecular dynamic simulation studies demonstrated the RNA undergoes a substantial change in conformation to facilitate an effective protein-rRNA handshake. This study highlights the importance of unique architectural features exploited by RNA to impart fidelity to RNA methyltransferases via enabling allosteric crosstalk. Moreover, the distal trigger sites identified here serve as attractive hotspots for the development of combination drug therapy aimed at reversing resistance.
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