PT - JOURNAL ARTICLE AU - Alex Matsuda AU - Jacek Plewka AU - Yuliya Chykunova AU - Alisha N. Jones AU - Magdalena Pachota AU - Michał Rawski AU - André Mourão AU - Abdulkarim Karim AU - Leanid Kresik AU - Kinga Lis AU - Igor Minia AU - Kinga Hartman AU - Ravi Sonani AU - Grzegorz Dubin AU - Michael Sattler AU - Piotr Suder AU - Paweł Mak AU - Grzegorz M. Popowicz AU - Krzysztof Pyrć AU - Anna Czarna TI - Despite the odds: formation of the SARS-CoV-2 methylation complex AID - 10.1101/2022.01.25.477673 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.01.25.477673 4099 - http://biorxiv.org/content/early/2022/03/01/2022.01.25.477673.short 4100 - http://biorxiv.org/content/early/2022/03/01/2022.01.25.477673.full AB - Coronaviruses protect their single-stranded RNA genome with a methylated cap during replication. The capping process is initiated by several nonstructural proteins (nsp) encoded in the viral genome. The methylation is performed by two methyltransferases, nsp14 and nsp16 where nsp10 acts as a co-factor to both. Aditionally, nsp14 carries an exonuclease domain, which operates in the proofreading system during RNA replication of the viral genome. Both nsp14 and nsp16 were reported to independently bind nsp10, but the available structural information suggests that the concomitant interaction between these three proteins should be impossible due to steric clashes. Here, we show that nsp14, nsp10, and nsp16 can form a heterotrimer complex. This interaction is expected to encourage formation of mature capped viral mRNA, modulating the nsp14’s exonuclease activity, and protecting the viral RNA. Our findings show that nsp14 is amenable to allosteric regulation and may serve as a novel target for therapeutic approaches.Competing Interest StatementThe authors have declared no competing interest.