Structure and mechanism of the methyltransferase ribozyme MTR1

RNA-catalyzed RNA methylation was recently shown to be part of the catalytic repertoire of ribozymes. The methyltransferase ribozyme MTR1 catalyzes the site-specific synthesis of 1-methyladenosine (m(1)A) in RNA, using O-6-methylguanine (m(6)G) as a methyl group donor. Here, we report the crystal structure of MTR1 at a resolution of 2.8 angstrom, which reveals a guanine-binding site reminiscent of natural guanine riboswitches. The structure represents the postcatalytic state of a split ribozyme in complex with the m(1)A-containing RNA product and the demethylated cofactor guanine. The structural data suggest the mechanistic involvement of a protonated cytidine in the methyl transfer reaction. A synergistic effect of two 2'-O-methylated ribose residues in the active site results in accelerated methyl group transfer. Supported by these results, it seems plausible that modified nucleotides may have enhanced early RNA catalysis and that metabolite-binding riboswitches may resemble inactivated ribozymes that have lost their catalytic activity during evolution.

Automated summary

RNA-catalyzed RNA methylation has been found to be part of the catalytic repertoire of ribozymes. The crystal structure of methyltransferase ribozyme MTR1 has been determined, revealing a guanine-binding site similar to natural guanine riboswitches. The structure also suggests the involvement of a protonated cytidine in the methyl transfer reaction. The synergistic effect of 2'-O-methylated ribose residues in the active site accelerates methyl group transfer. These findings suggest that modified nucleotides may have played a role in early RNA catalysis and that metabolite-binding riboswitches resemble inactivated ribozymes.