S C
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IC H
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3 7 I H I G H L I G H T S 2 0 2 2
Fig 27: a) The mechanism of MTR1-catalysed RNA methylation. The m6G cofactor forms hydrogen bonds to U42 and the protonated cytidine C12, which donates its proton to
guanine when the methyl group is transferred upon nucleophilic attack from N1 of the target adenosine (A7). b) The methylation
rate increases upon lowering the pH from pH 7.5 to pH 6.0, consistent with general acid catalysis, and upon concomitant
2 -ribose methylation of C12 and U42.
PRINCIPAL PUBLICATION AND AUTHORS
Structure and mechanism of the methyltransferase ribozyme MTR1, C.P.M. Scheitl (a), M. Mieczkowski (a), H. Schindelin (b), C. Höbartner (a,c), Nat. Chem. Biol. 18, 547-555 (2022); https:/doi.org/10.1038/s41589-022-00976-x (a) Institute of Organic Chemistry, Julius-Maximilians-Universität Würzburg (Germany) (b) Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg (Germany) (c) Center for Nanosystems Chemistry (CNC), Julius-Maximilians-Universität Würzburg (Germany)
REFERENCES
[1] C.P.M. Scheitl et al., Nature 587, 663-667 (2020). [2] A. Serganov et al., Chem. Biol. 11, 1729-1741 (2004).
This research also implies that by installing small chemical modifications, the activity of other ribozymes could be increased as well. It may also be possible that RNA with modified nucleosides could catalyse numerous reactions for which no ribozymes have yet been identified. Future projects will therefore attempt to find such catalytically active RNAs, thereby expanding the spectrum of ribozymes and RNA-catalysed reactions.
Towards a deeper understanding of tick-borne encephalitis virus
X-ray crystallography was used to determine the crystal structure of a previously elusive intermediate in the infectivity-activation process of tick-borne encephalitis virus, an important human-pathogenic flavivirus closely related to a range of mosquito- transmitted viruses of global importance.
Every year, more than 10,000 people come down with a serious disease of the central nervous system in parts of Europe and Asia because of infection with tick-borne encephalitis (TBE) virus that is usually transmitted by the bites of infected ticks. However, infections and small outbreaks in humans can also occur after the consumption of raw milk or cheese, primarily from tick-infected goats. Recently, one such outbreak of alimentary infection was documented in Ain, in eastern France, where the virus had never been detected previously [1], corroborating its potential of geographical expansion to previously unaffected regions as observed in other parts of Europe. TBE virus has a cousin (Powassan virus) that is also encephalitogenic and occurs in North America and the far
east of Russia. Importantly, these viruses form a larger group (flaviviruses) with other closely related pathogens that are transmitted by mosquitoes. The related human diseases include yellow fever, dengue, Zika, West Nile and Japanese encephalitis. Although there are successful vaccines against some of these pathologies, specific antiviral drugs have not yet become available. The common property of vector-transmission of flaviviruses makes them prone to becoming an increasing threat because of global warming and the spread of viral vectors, especially by mosquitoes, to new and yet more temperate regions.
All flaviviruses share a similar genome and particle structure, with the basic processes of virus replication including virion assembly, maturation and release being closely related [2]. Decades of intense studies have provided crucial insight into the structural reorganisation of the flavivirus particle required for fusing the viral membrane with a cellular membrane for entry [3]. This fusion step is induced by the acidic pH of the endosomes, following uptake of the particle by the target cell. Yet understanding at the molecular level how this essential viral function is controlled and activated during virus assembly and particle release has remained elusive.
