Institute of Organic Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, Würzburg, Germany.
Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
Nat Chem Biol. 2022 May;18(5):547-555. doi: 10.1038/s41589-022-00976-x. Epub 2022 Mar 17.
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 (mA) in RNA, using O-methylguanine (mG) as a methyl group donor. Here, we report the crystal structure of MTR1 at a resolution of 2.8 Å, 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 mA-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.
RNA 催化的 RNA 甲基化最近被证明是核酶催化谱的一部分。甲基转移酶核酶 MTR1 以 O-甲基鸟嘌呤 (mG) 作为甲基供体，催化 RNA 中 1-甲基腺苷 (mA) 的位点特异性合成。在这里，我们报告了分辨率为 2.8Å 的 MTR1 的晶体结构，该结构揭示了一个类似于天然鸟嘌呤核糖开关的鸟嘌呤结合位点。该结构代表了分裂核酶与含有 mA 的 RNA 产物和去甲基辅因子鸟嘌呤形成的复合后催化状态。结构数据表明，在甲基转移反应中涉及质子化胞嘧啶。活性位点中两个 2'-O-甲基核糖的协同作用导致甲基转移加速。这些结果表明，修饰核苷酸可能增强了早期 RNA 催化作用，并且代谢物结合的核糖开关可能类似于在进化过程中失去催化活性的失活核酶。
