Abstract
Capping viral messenger RNAs is essential for efficient translation and prevents their detection by host innate immune responses. For SARS-CoV-2, RNA capping includes 2′-O-methylation of the first ribonucleotide by methyltransferase nsp16 in complex with activator nsp10. The reaction requires substrates, a short RNA and SAM, and is catalyzed by divalent cations, with preference for Mn2+. Crystal structures of nsp16-nsp10 with capped RNAs revealed a critical role of metal ions in stabilizing interactions between ribonucleotides and nsp16, resulting in precise alignment of the substrates for methyl transfer. An aspartate residue that is highly conserved among coronaviruses alters the backbone conformation of the capped RNA in the binding groove. This aspartate is absent in mammalian methyltransferases and is a promising site for designing coronavirus-specific inhibitors.
Competing Interest Statement
K.J.F.S. has a significant financial interest in Situ Biosciences, LLC, a contract research organization that conducts antimicrobial testing for industrial products, including antiviral testing. This work has no overlap with the interests of the company. K.J.F.S. is a consultant for a healthcare firm on public health topics related to COVID-19 that are unrelated to this article. A.D.M. has pending intellectual property related to coronaviruses including SARS-CoV-2 but none are related to this project. A.D.M. serves as a consultant for pharmaceutical companies on topics related to SARS-CoV-2 and COVID-19 that are unrelated to this article. All other authors declare no conflicts of interest.