Structural Basis of RNA Cap Modification by SARS-CoV-2 Coronavirus

Viswanathan, T.; Arya, S.; Chan, S.-H.; Qi, S.; Dai, N.; Hromas, R. A.; Park, J.-G.; Oladunni, F.; Martinez-Sobrido, L.; Gupta, Y. K.

doi:10.1101/2020.04.26.061705

bioRxiv · 10.1101/2020.04.26.061705

Structural Basis of RNA Cap Modification by SARS-CoV-2 Coronavirus

Viswanathan, T.·Arya, S.·Chan, S.-H.·Qi, S.·Dai, N.·Hromas, R. A.·Park, J.-G.·Oladunni, F.·Martinez-Sobrido, L.·Gupta, Y. K.

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Abstract

The novel severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused over 2 million infections worldwide in four months. In SARS coronaviruses, the non-structural protein 16 (nsp16) methylates the 5-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of full-length nsp16 and nsp10 of SARS-CoV-2 in the presence of cognate RNA substrate and a methyl donor, S-adenosyl methionine. The nsp16/nsp10 heterodimer was captured in the act of 2-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We reveal large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This structure provides new mechanistic insights into the 2-O methylation of the viral mRNA cap. We also discovered a distantly located ligand-binding site unique to SARS-CoV-2 that may serve as an alternative target site for antiviral development.

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Viswanathan, T., Arya, S., Chan, S.-H., Qi, S., Dai, N., Hromas, R. A., Park, J.-G., Oladunni, F., Martinez-Sobrido, L., Gupta, Y. K.. 2020-04-26. Structural Basis of RNA Cap Modification by SARS-CoV-2 Coronavirus. https://doi.org/10.1101/2020.04.26.061705

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