National Natural Science Foundation of China (NSFC)
81520108019
China
National Natural Science Foundation of China (NSFC)
813300237
China
National Natural Science Foundation of China (NSFC)
32041007
China
Citation
Journal: Cell Rep / Year: 2021 Title: Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex. Authors: Jiqin Wu / Haofeng Wang / Qiaojie Liu / Rui Li / Yan Gao / Xiang Fang / Yao Zhong / Meihua Wang / Quan Wang / Zihe Rao / Peng Gong / Abstract: Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA- ...Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an "i+3" delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1'-cyano at the -4 position is responsible for the "i+3" intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1'-modified nucleotide analogs in anti-RNA virus drug development.
History
Deposition
Jan 4, 2021
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Header (metadata) release
Oct 20, 2021
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Map release
Oct 20, 2021
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Update
Jun 5, 2024
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Current status
Jun 5, 2024
Processing site: PDBj / Status: Released
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