Abstract of the PDB Structure's related Publication:
Post-translational methylation of rRNA at select positions is a prevalent resistance mechanism adopted by pathogens. In this work, KsgA, a housekeeping ribosomal methyltransferase (rMtase) involved in ribosome biogenesis, was exploited as a model system to delineate the specific targeting determinants that impart substrate specificity to rMtases. With a combination of evolutionary and structure-guided approaches, a set of chimeras were created that altered the targeting specificity of KsgA such that it acted similarly to erythromycin-resistant methyltransferases (Erms), rMtases found in multidrug-resistant pathogens. The results revealed that specific loop embellishments on the basic Rossmann fold are key determinants in the selection of the cognate RNA. Moreover, in vivo studies confirmed that chimeric constructs are competent in imparting macrolide resistance. This work explores the factors that govern the emergence of resistance and paves the way for the design of specific inhibitors useful in reversing antibiotic resistance.
RsmA (formerly KsgA) dimethylates two very conserved adjacent adenosines (positions 1518 and 1519 in E. coli numbering) in the loop of a conserved hairpin h45 near the 3'-end of 16S rRNA. AdoMet is the methyl group donor. Mutation in ksgA gene confers a modest level of resistance to kasugamycin. RsmA belongs to the erm family of methyltransferases responsible for certain antibiotic resistance.