📄 Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA

Coronaviruses (Co. Vs) stand out among RNA viruses because of their unusually large genomes (~30 kb) associated with low mutation rates. Co. Vs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3′-5′ exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3′-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase. Through this pathway, the antiviral compound ribavirin 5′-monophosphate is significantly incorporated but also readily excised from RNA, which may explain its limited efficacy in vivo. The crystal structure at 3.38 Å resolution of SARS-CoV nsp14 in complex with its cofactor nsp10 adds to the uniqueness of Co. Vs among RNA viruses: The MTase domain presents a new fold that differs sharply from the canonical Rossmann fold.

keywords 🔗 severe acute (1373) 🔗 respiratory syndrome (2004) 🔗 acute respiratory (1734) 🔗 crystal structure (114)

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