Structural basis and functional analysis of the SARS coronavirus nsp14–nsp10 complex

TLDR

Proofreading exonucleases are known to ensure replication fidelity in DNA viruses and cellular organisms, but RNA virus proofreading was unclear until coronavirus nsp14 was discovered to function as an exoribonuclease and guanine‑N7 methyltransferase essential for viral replication and transcription. The study reports the crystal structures of SARS‑CoV nsp14 bound to its activator nsp10 and functional ligands. Structural analysis, mutagenesis, and functional assays were employed to elucidate nsp14’s enzymatic functions. The structures reveal unique binding pockets that could be exploited for potent antiviral drug development.

Abstract

Significance Proofreading exonucleases contributing to replication fidelity in DNA viruses and cellular organisms are well known; however, proofreading in RNA viruses was unknown until recently. Coronavirus nonstructural protein 14 (nsp14) has been shown to function as a proofreading exoribonuclease. Additionally, nsp14 shows (guanine-N7) methyl transferase activity for viral mRNA capping. Both roles are important for viral replication and transcription. Here, we report the structures of severe acute respiratory syndrome-coronavirus nsp14 in complex with its activator nonstructural protein 10 (nsp10) and functional ligands. Structural observations coupled with mutagenesis and functional assays provide a better understanding of the function of nsp14. Furthermore, the structures of the nsp14–nsp10 complex demonstrate several unique niches that could be targeted for development of potent antiviral drugs.