Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations

Author:

Bueren-Calabuig Juan A1ORCID,G. Bage Marcus1,Cowling Victoria H2,Pisliakov Andrei V13

Affiliation:

1. Computational Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

2. Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

3. Physics, School of Science and Engineering, University of Dundee, Dundee, DD1 4HN, UK

Abstract

Abstract The RNA guanine-N7 methyltransferase (RNMT) in complex with RNMT-activating miniprotein (RAM) catalyses the formation of a N7-methylated guanosine cap structure on the 5′ end of nascent RNA polymerase II transcripts. The mRNA cap protects the primary transcript from exonucleases and recruits cap-binding complexes that mediate RNA processing, export and translation. By using microsecond standard and accelerated molecular dynamics simulations, we provide for the first time a detailed molecular mechanism of allosteric regulation of RNMT by RAM. We show that RAM selects the RNMT active site conformations that are optimal for binding of substrates (AdoMet and the cap), thus enhancing their affinity. Furthermore, our results strongly suggest the likely scenario in which the cap binding promotes the subsequent AdoMet binding, consistent with the previously suggested cooperative binding model. By employing the network community analyses, we revealed the underlying long-range allosteric networks and paths that are crucial for allosteric regulation by RAM. Our findings complement and explain previous experimental data on RNMT activity. Moreover, this study provides the most complete description of the cap and AdoMet binding poses and interactions within the enzyme’s active site. This information is critical for the drug discovery efforts that consider RNMT as a promising anti-cancer target.

Funder

University of Dundee

Scottish Universities Physics Alliance

Medical Research Council

Royal Society Wolfson Research Merit Award

ERC

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference71 articles.

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