EMD-30275
COVID-19 RNA-dependent RNA polymerase pre-translocated catalytic complex
EMD-30275
Single-particle2.93 Å
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Map released: 03/06/2020
Last modified: 13/11/2024
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
Foot-and-mouth disease virus
Sample: COVID-19 RNA-dependent RNA polymerase pre-translocated catalytic complex
Fitted models: 7c2k (Avg. Q-score: 0.581)
Deposition Authors: Wang Q, Gao Y, Ji W
,
Mu A,
Rao Z
Sample: COVID-19 RNA-dependent RNA polymerase pre-translocated catalytic complex
Fitted models: 7c2k (Avg. Q-score: 0.581)
Deposition Authors: Wang Q, Gao Y, Ji W
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Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Wang Q,
Wu J,
Wang H,
Gao Y,
Liu Q,
Mu A,
Ji W
,
Yan L,
Zhu Y,
Zhu C,
Fang X,
Yang X,
Huang Y,
Gao H,
Liu F,
Ge J,
Sun Q,
Yang X,
Xu W
,
Liu Z,
Yang H,
Lou Z,
Jiang B,
Guddat LW,
Gong P,
Rao Z
(2020) Cell , 182 , 417 - 428.e13
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(2020) Cell , 182 , 417 - 428.e13
Abstract:
Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.