Recent history is punctuated by the emergence of highly pathogenic coronaviruses such as SARS- and MERS-CoV into human circulation. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Here, we present the 3.1 Å resolution structure of the SARS-CoV nsp12 polymerase bound to its essential co-factors, nsp7 and nsp8, using single particle cryo-electron microscopy. nsp12 possesses an architecture common to all viral polymerases as well as a large N-terminal extension containing a kinase-like fold and is bound by two nsp8 co-factors. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity and acts as a template for the design of novel antiviral therapeutics.
Coronaviruses (CoV) represent a diverse family of positive-sense RNA viruses capable of causing respiratory and enteric disease in human and animal hosts. Though there are several human CoV responsible for a mild respiratory disease1, most notable are the highly pathogenic human CoVs: SARS-CoV and MERS-CoV capable of causing a severe respiratory disease. The zoonotic SARS-CoV emerged into human populations in 2002, spreading to 26 countries during its brief 9-month circulation in humans2. This epidemic resulted in >8000 infections with a ~10% case fatality rate and was eventually contained through public health measures, as there are no specific treatments approved for human CoV infections. With the exception of a smaller second SARS-CoV outbreak in 20043, SARS-CoV has been absent from human circulation since the initial outbreak ended. Despite the lack of recent human infections, SARS-CoV-like viruses continue to circulate in bat reservoirs4. Outbreaks of highly pathogenic human CoVs remain an emerging threat to global health security and are likely to continue to occur.
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