Abstract
There are currently no antiviral therapies specific for SARS-CoV-2, the virus responsible for the global pandemic disease COVID-19. To facilitate structure-based drug design, we conducted an X-ray crystallographic study of the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase complex, which methylates Cap-0 viral mRNAs to improve viral protein translation and to avoid host immune detection. We determined the structures for nsp16-nsp10 heterodimers bound to the methyl donor S-adenosylmethionine (SAM), the reaction product S-adenosylhomocysteine (SAH), or the SAH analog sinefungin (SFG). We also solved structures for nsp16-nsp10 in complex with the methylated Cap-0 analog m7GpppA and either SAM or SAH. Comparative analyses between these structures and published structures for nsp16 from other betacoronaviruses revealed flexible loops in open and closed conformations at the m7GpppA-binding pocket. Bound sulfates in several of the structures suggested the location of the ribonucleic acid backbone phosphates in the ribonucleotide-binding groove. Additional nucleotide-binding sites were found on the face of the protein opposite the active site. These various sites and the conserved dimer interface could be exploited for the development of antiviral inhibitors.
Highlights
On 31 December 2019, the World Health Organization (WHO) was alerted of a pneumonia outbreak with an unknown etiology, originating in the Chinese province of Wuhan, Hubei
The severe acute respiratory syndrome (SARS)-CoV-2 proteins nsp10 and nsp16 are encoded by the polycistronic orf1ab of the (+) single-stranded RNA (Fig. 1A) and are released from the polyproteins pp1a and pp1ab by the protease nsp5 [28]
The SARS-CoV-2 pandemic has yielded an urgent worldwide effort to understand the molecular mechanisms involved in coronavirus transmission, virulence, and replication [1]
Summary
On 31 December 2019, the World Health Organization (WHO) was alerted of a pneumonia outbreak with an unknown etiology, originating in the Chinese province of Wuhan, Hubei. The etiological agent was identified as a coronavirus, closely related to the virus responsible for severe acute respiratory syndrome (SARS). The new SARS coronavirus-2 (SARS-CoV-2) causes the severe respiratory infection, coronavirus disease 2019 (COVID-19). Within 4 months, SARS-CoV-2 rapidly spread, sparking a global pandemic. The COVID-19 pandemic has forced governments to enact “stayat-home” orders around the world, seriously damaging the global economy [1]. According to the WHO, nearly 25 million SARS-CoV-2 infections have been confirmed, of which more than 800,000 were fatal as of 30 August 2020 (www.who.int). These data are similar to those from the Johns Hopkins University tracking system [2]
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