UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Functional and computational identification of a rescue mutation near the active site of an mRNA methyltransferase

Colin, P-Y; Dalby, PA; (2020) Functional and computational identification of a rescue mutation near the active site of an mRNA methyltransferase. Scientific Reports , 10 , Article 21841. 10.1038/s41598-020-79026-2. Green open access

[thumbnail of s41598-020-79026-2.pdf]
Preview
Text
s41598-020-79026-2.pdf - Published Version

Download (3MB) | Preview

Abstract

RNA-based drugs are an emerging class of therapeutics combining the immense potential of DNA gene-therapy with the absence of genome integration-associated risks. While the synthesis of such molecules is feasible, large scale in vitro production of humanised mRNA remains a biochemical and economical challenge. Human mRNAs possess two post-transcriptional modifcations at their 5′ end: an inverted methylated guanosine and a unique 2′O-methylation on the ribose of the penultimate nucleotide. One strategy to precisely methylate the 2′ oxygen is to use viral mRNA methyltransferases that have evolved to escape the host’s cell immunity response following virus infection. However, these enzymes are ill-adapted to industrial processes and sufer from low turnovers. We have investigated the efects of homologous and orthologous active-site mutations on both stability and transferase activity, and identifed new functional motifs in the interaction network surrounding the catalytic lysine. Our fndings suggest that despite their low catalytic efciency, the active-sites of viral mRNA methyltransferases have low mutational plasticity, while mutations in a defned third shell around the active site have strong efects on folding, stability and activity in the variant enzymes, mostly via network-mediated efects.

Type: Article
Title: Functional and computational identification of a rescue mutation near the active site of an mRNA methyltransferase
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-020-79026-2
Publisher version: https://doi.org/10.1038/s41598-020-79026-2
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10118428
Downloads since deposit
31Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item