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Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin

Author

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  • Petra Krafcikova

    (v.v.i., Flemingovo nam. 2.)

  • Jan Silhan

    (v.v.i., Flemingovo nam. 2.)

  • Radim Nencka

    (v.v.i., Flemingovo nam. 2.)

  • Evzen Boura

    (v.v.i., Flemingovo nam. 2.)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2′-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is associated with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the preparation of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.

Suggested Citation

  • Petra Krafcikova & Jan Silhan & Radim Nencka & Evzen Boura, 2020. "Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin," Nature Communications, Nature, vol. 11(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17495-9
    DOI: 10.1038/s41467-020-17495-9
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    Cited by:

    1. Wei Lu & Jixian Zhang & Weifeng Huang & Ziqiao Zhang & Xiangyu Jia & Zhenyu Wang & Leilei Shi & Chengtao Li & Peter G. Wolynes & Shuangjia Zheng, 2024. "DynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Jan Silhan & Martin Klima & Tomas Otava & Petr Skvara & Dominika Chalupska & Karel Chalupsky & Jan Kozic & Radim Nencka & Evzen Boura, 2023. "Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    3. Filip Mihalič & Caroline Benz & Eszter Kassa & Richard Lindqvist & Leandro Simonetti & Raviteja Inturi & Hanna Aronsson & Eva Andersson & Celestine N. Chi & Norman E. Davey & Anna K. Överby & Per Jemt, 2023. "Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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