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Structure of replicating SARS-CoV-2 polymerase

View ORCID ProfileHauke S. Hillen, View ORCID ProfileGoran Kokic, View ORCID ProfileLucas Farnung, View ORCID ProfileChristian Dienemann, View ORCID ProfileDimitry Tegunov, View ORCID ProfilePatrick Cramer
doi: https://doi.org/10.1101/2020.04.27.063180
Hauke S. Hillen
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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Goran Kokic
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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Lucas Farnung
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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Christian Dienemann
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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Dimitry Tegunov
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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Patrick Cramer
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Göttingen, Germany
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  • For correspondence: patrick.cramer@mpibpc.mpg.de
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Abstract

The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. Here we present the cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its replicating form. The structure comprises the viral proteins nsp12, nsp8, and nsp7, and over two turns of RNA template-product duplex. The active site cleft of nsp12 binds the first turn of RNA and mediates RdRp activity with conserved residues. Two copies of nsp8 bind to opposite sides of the cleft and position the RNA duplex as it exits. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged ‘sliding poles’ that may enable processive replication of the long coronavirus genome. Our results will allow for a detailed analysis of the inhibitory mechanisms used by antivirals such as remdesivir, which is currently in clinical trials for the treatment of coronavirus disease 2019 (COVID-19).

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 27, 2020.
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Structure of replicating SARS-CoV-2 polymerase
Hauke S. Hillen, Goran Kokic, Lucas Farnung, Christian Dienemann, Dimitry Tegunov, Patrick Cramer
bioRxiv 2020.04.27.063180; doi: https://doi.org/10.1101/2020.04.27.063180
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Structure of replicating SARS-CoV-2 polymerase
Hauke S. Hillen, Goran Kokic, Lucas Farnung, Christian Dienemann, Dimitry Tegunov, Patrick Cramer
bioRxiv 2020.04.27.063180; doi: https://doi.org/10.1101/2020.04.27.063180

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