Structural biology of SARS-CoV-2 exoribonuclease/N7–methyltransferase (nsp14), 2′–O–methyltransferase (nsp16) and their enhancing protein (nsp10)

Coronaviruses have a very large genome of up to 32 kb in length, almost two thirds of which encode for proteins involved in the production of the virus’s own RNA. Due to the inherent mutations that occur during RNA polymerization, and the large genome size of members of the Coronaviridae family, a proofreading exoribonuclease (ExoN domain within nsp14) has evolved within these viruses to maintain high fidelity of their RNA. This proofreading exoribonuclease not only requires an enhancing protein (nsp10) to function but also performs a secondary methyltransferase of the 5′ end of produced RNA. A further 2’O-methyltransferase (nsp16) also requires the enhancing protein (nsp10) to perform the further final methylation that protects the viral RNA from the host immune system. The structural investigation of these enzymes from SARS-CoV-2 has led to a better understanding of their role in the fidelity regulation and finalization of RNA production and has enabled the development of new drugs to treat COVID-19.