Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication-transcription complex
Patrick M. M. Shelton,
Paul Dominic B Olinares,
Edward T Eng,
Tarun M Kapoor,
Seth A Darst,
Elizabeth A. Campbell
Posted 08 Jul 2020
bioRxiv DOI: 10.1101/2020.07.08.194084 (published DOI: 10.1016/j.cell.2020.07.033)
Posted 08 Jul 2020
SARS-CoV-2 is the causative agent of the 2019-2020 pandemic. The SARS-CoV-2 genome is replicated-transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp82/nsp12) along with a cast of accessory factors. One of these factors is the nsp13 helicase. Both the holo-RdRp and nsp13 are essential for viral replication and are targets for treating the disease COVID-19. Here we present cryo-electron microscopic structures of the SARS-CoV-2 holo-RdRp with an RNA template-product in complex with two molecules of the nsp13 helicase. The Nidovirus-order-specific N-terminal domains of each nsp13 interact with the N-terminal extension of each copy of nsp8. One nsp13 also contacts the nsp12-thumb. The structure places the nucleic acid-binding ATPase domains of the helicase directly in front of the replicating-transcribing holo-RdRp, constraining models for nsp13 function. We also observe ADP-Mg2+ bound in the nsp12 N-terminal nidovirus RdRp-associated nucleotidyltransferase domain, detailing a new pocket for anti-viral therapeutic development. ### Competing Interest Statement The authors have declared no competing interest.
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