A novel coronavirus (COVID-19 virus) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12) is the central component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. We report the cryo-EM structure of COVID-19 virus fulllength nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-Å resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified βhairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics targeting viral RdRp.

Highlights d Structures of SARS-CoV-2 RNA polymerase in complexes with RNA revealed d Conformational changes in nsp8 and its interaction with the exiting RNA are observed d Incorporation and delayed-chain-termination mechanism of remdesivir is elucidated d Transition model from primase complex to polymerase complex is proposed

Transcription of SARS-CoV-2 mRNA requires sequential reactions facilitated by the r eplication and t ranscription c omplex (RTC). Here, we present a structural snapshot of SARS-CoV-2 RTC as it transition towards cap structure synthesis. We determine the atomic cryo-EM structure of an extended RTC assembled by nsp7-nsp8 2 -nsp12-nsp13 2 -RNA and a single RNA binding protein nsp9. Nsp9 binds tightly to nsp12 (RdRp) NiRAN, allowing nsp9 N-terminus inserting into the catalytic center of nsp12 NiRAN, which then inhibits activity. We also show that nsp12 NiRAN possesses guanylyltransferase activity, catalyzing the formation of cap core structure (GpppA). The orientation of nsp13 that anchors the 5’ extension of template RNA shows a remarkable conformational shift, resulting in zinc finger 3 of its ZBD inserting into a minor groove of paired template-primer RNA. These results reason an intermediate state of RTC towards mRNA synthesis, pave a way to understand the RTC architecture, and provide a target for antiviral development.

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