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High-resolution structures of the SARS-CoV-2 2’-O-methyltransferase reveal strategies for structure-based inhibitor design

M. Rosas-Lemus,G. Minasov,L. Shuvalova,Nicole l. Inniss,O. Kiryukhina,J. Brunzelle,Karla J. F. Satchell

Published 2020 in Science Signaling

ABSTRACT

Crystal structures of an mRNA-capping enzyme from SARS-CoV-2 in complex with its substrates suggest targets for drug design. Structural analysis of SARS-CoV-2 mRNA capping The development of antiviral drugs that impair SARS-CoV-2 replication or prevent it from evading the host immune system is critical for fighting the COVID-19 pandemic. The methyltransferase that caps viral mRNAs is a potential target for antiviral therapies because capping both enhances the translation of viral proteins and prevents viral mRNAs from being recognized by the host immune system. Rosas-Lemus et al. solved crystal structures for the SARS-CoV-2 methyltransferase, the nsp16-nsp10 heterodimer, in complex with various combinations of its methyl donor and cap structure substrates, a reaction product, and an inhibitor. Together, these structures suggest potential strategies for developing antiviral therapies by disrupting the formation of the active enzyme complex or blocking its catalytic activity. There are currently no antiviral therapies specific for SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an x-ray crystallographic study of the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase complex, which methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. We determined the structures for nsp16-nsp10 heterodimers bound to the methyl donor S-adenosylmethionine (SAM), the reaction product S-adenosylhomocysteine (SAH), or the SAH analog sinefungin (SFG). We also solved structures for nsp16-nsp10 in complex with the methylated Cap-0 analog m7GpppA and either SAM or SAH. Comparative analyses between these structures and published structures for nsp16 from other betacoronaviruses revealed flexible loops in open and closed conformations at the m7GpppA-binding pocket. Bound sulfates in several of the structures suggested the location of the ribonucleic acid backbone phosphates in the ribonucleotide-binding groove. Additional nucleotide-binding sites were found on the face of the protein opposite the active site. These various sites and the conserved dimer interface could be exploited for the development of antiviral inhibitors.

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