报告题目：RNA catalysis beyond phosphoryl transfer reaction - expanding the range of chemistry ribozymes can catalyze
报告人：David Lilley FRS 教授
主持人：任艾明 研究员
时 间：2024年10月29日（周二）上午10点
地 点：纳米楼457报告厅
报告人简介：
Professor Lilley has a long-standing interest in nucleic acid chemistry, structure and function going back more than forty years.Lilley was the first to solve the structure of the Holliday junction in DNA, and has made extensive studies of its interaction with junction-resolving enzymes. Lilley also has had detailed study of the role of general acid-base catalysis in ribozymes and the involvement of nucleobases, the structure and folding of the k-turn motif and how site-specific formation of N6-methyladenine blocks the key first stage of box C/D snoRNP assembly. Lastly Lilley has developed fluorescence and FRET (in bulk and in single molecules) in the study of nucleic acid structure and dynamics.
讲座摘要：
Expanding the chemical limits of RNA catalysis
The RNA world hypothesis for the early development of life on the planet requires that RNA molecules (ribozymes) could have catalysed a wide variety of chemical reactions. Known ribozymes in contemporary biology carry out a limited range of chemical catalysis, mostly involving phosphoryl transfer, and we have a good understanding of many of these. in vitro selection has generated species catalysing a broader range of chemistry. To gauge the feasibility of an RNA world it is useful to explore if ribozymes can exploit sophisticated catalytic strategies.
A ribozyme has recently been selected that can catalyse a methyl transfer reaction using O6-methylguanine as donor. We have solved the crystal structure of this ribozyme at a resolution of 2.3 Å, showing how the RNA folds to generate a very specific binding site for the methyl donor substrate. The structure immediately suggests a catalytic mechanism, involving a combination of proximity and orientation, and nucleobase-mediated general acid catalysis. The mechanism is supported by the pH dependence of the rate of catalysis, detailed atomic mutagenesis and by quantum mechanical calculation. This small chemical machine employs a relatively sophisticated catalytic mechanism, broadening the range of known RNA-catalysed chemistry. This lends new support to the RNA world hypothesis.
Lilley Classification of the nucleolytic ribozymes based upon catalytic mechanism. F1000Research, 8. 1462 (2019) Deng et al Structure and mechanism of a methyl transferase ribozyme Nature Chem Biol 18, 556–564 (2022) McCarthy et al Catalytic mechanism and pH-dependence of a methyl transferase ribozyme (MTR1) from computational enzymology Nucleic Acids res. 51. 4508-4518 (2023) Wilson et al The role of general acid catalysis in the mechanism of an alkyl transferase ribozyme ACS Catalysis In the press Wilson and Lilley The potential versatility of RNA catalysis WIREs RNA 12, e1651 (2021).
