Abstract
Coronavirus 3′-to-5′ exoribonuclease (ExoN), residing in the nonstructural protein (nsp) 10–nsp14 complex, boosts replication fidelity by proofreading RNA synthesis and is critical for the virus life cycle. ExoN also recognizes and excises nucleotide analog inhibitors incorporated into the nascent RNA, undermining the effectiveness of nucleotide analog–based antivirals. Here we present cryo–electron microscopy structures of both wild-type and mutant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp10-nsp14 in complex with an RNA substrate bearing a 3′-end mismatch at resolutions ranging from 2.5 to 3.9 angstroms. The structures reveal the molecular determinants of ExoN substrate specificity and offer insight into the molecular mechanisms of mismatch correction during coronavirus RNA synthesis. Our findings provide guidance for rational design of improved anticoronavirus therapies.
Highlights
SARS-CoV-2, the causative agent of the COVID-19 pandemic, has infected over 160 million people and led to over 3 million deaths worldwide
The efficacy of nucleotide analog inhibitors on coronavirus RNAdependent RNA polymerase (RdRp) is compromised by the presence of the viral nsp14 exoribonuclease (ExoN) [8, 9], an RNA proofreader specific to coronaviruses and a few other closely related virus families of the Nidovirales order and crucial to maintain the integrity of their unusually large RNA genome [9,10,11]
ExoNs from coronaviruses and other RNA viruses play an important role in the evasion of host immune responses by degrading the viral doublestranded RNA intermediates that would otherwise be recognized by host pathogen recognition receptors [12,13,14,15]
Summary
SARS-CoV-2, the causative agent of the COVID-19 pandemic, has infected over 160 million people and led to over 3 million deaths worldwide (https://covid19.who.int). Previous studies of the SARS-CoV nsp10-nsp14 complex defined the nsp14 ExoN domain as a DED/EDh-type exonuclease and identified the five active site residues through structural comparison and mutagenesis analyses [19].
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