In coronaviruses, 3'-to-5' exoribonuclease (ExoN) in non-structural protein 14 (nsp14) is responsible for the high-fidelity replication of the RNA genome by excising nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp). A 1.6-Å resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10 is elucidated in this study.<br/>The structure is highly similar to the SARS-CoV ExoN-nsp10 complex overall. Modeling suggests that a highly basic and concave surface flanking the active site and comprising several Lys residues of nsp14 as well as the N-terminal amino group of nsp10 can play an important role in positioning the 3' end of RNA substrates in the ExoN active site. Mutation analyses corroborate this hypothesis. Molecular dynamics simulations of the multi-domain nsp14 show remarkable flexibility and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. The structure and dynamics of the SARS-CoV-2 ExoN-nsp10 complex presented in this study provide opportunities for future development of anti-coronaviral drugs.

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease exon

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.