Structure of replicating SARS-CoV-2 polymerase

By H. S. Hillen, G. Kokic, L. Farnung, C. Dienemann, D. Tegunov, Patrick Cramer. Nature, 2020

741 citations recorded by the source corpus.

The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes1–3. Here we present a cryo-electron microscopy structure of the SARS-CoV-2 RdRp in an active form that mimics the replicating enzyme. The structure comprises the viral proteins non-structural protein 12 (nsp12), nsp8 and nsp7, and more than two turns of RNA template–product duplex. The active-site cleft of nsp12 binds to 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 second turn of RNA. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged ‘sliding poles’. These sliding poles can account for the known processivity of RdRp that is required for replicating the long genome of coronaviruses3. Our results enable a detailed analysis of the inhibitory mechanisms that underlie the antiviral activity of substances such as remdesivir, a drug for the treatment of coronavirus disease 2019 (COVID-19)4. A cryo-electron microscopy structure of the RNA-dependent RNA polymerase of SARS-CoV-2 sheds light on coronavirus replication and enables the analysis of the inhibitory mechanisms of candidate antiviral drugs.

Subfields: Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/79e628ce022b876b076a8fc66f1ce9d284ca3b12

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Mei-Yue Wang
Ji-min Cao
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Citations in the corpus

SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development (2020, background): “For example, the non-replicating Ad5 vectored COVID-19 vaccine produced by CanSino Biologics lnc, the mRNA-1273 COVID-19 vaccine developed by Moderna, the DNA vaccine of Inovio Pharmaceuticals, the BioNTech’s mRNA COVID-19 vaccine, the vaccine ChAdOx1 nCoV-19 of University of Oxford (Zhu et al., 202”
Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase (2020, neutral): “While this paper was under review, a studywas posted as a pre-print reporting a cryo-EM structure of the SARS-CoV-2 RdRP complex with a 24-base-pair (bp) template-primer RNA (Hillen et al., 2020), which is formed by three repetitive RNA pairs connected through palindromic GUAC sticky ends.”