Decoding the Mechanism of Specific RNA Targeting by Ribosomal Methytransferases
Singh, J.; Raina, R.; Vinothkumar, K. R.; Anand, R.
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Methylation of specific nucleotides is integral for ribosomal biogenesis and serves as a common way to confer antibiotic resistance by pathogenic bacteria. Here, by determining the high-resolution structure of 30S-KsgA by cryo-EM, a state was captured, where KsgA juxtaposes between helices h44 and h45, separating them, thereby enabling remodeling of the surrounded rRNA and allowing the cognate site to enter the methylation pocket. With the structure as a guide, factors that direct the enzyme to its cognate site with high fidelity were unearthed by creating several mutant versions of the ribosomes, where interacting bases in the catalytic helix h45 and surrounding helices h44, h24, and h27 were mutated and evaluated for their methylation efficiency. The biochemical studies delineated specificity hotspots that enable KsgA to achieve an induced fit. This study enables the identification of distal exclusive allosteric pocket and other divergent structural elements in each rMTase, which can be exploited to develop strategies to reverse methylation, mediated drug resistance.
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