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Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
- Source :
-
Cell . Jul2020, Vol. 182 Issue 2, p417-417. 1p. - Publication Year :
- 2020
-
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. • Structures of SARS-CoV-2 RNA polymerase in complexes with RNA revealed • Conformational changes in nsp8 and its interaction with the exiting RNA are observed • Incorporation and delayed-chain-termination mechanism of remdesivir is elucidated • Transition model from primase complex to polymerase complex is proposed Cryo-EM structures of the SARS-CoV-2 RNA polymerase in complexes with RNA, before and after RNA translocation, reveals structural rearrangements that the RNA-dependent RNA polymerase (RdRp) nsp12 and its co-factors (nsp7 and nsp8) undergo to accommodate nucleic acid binding. Further insights into how the complex is inhibited by remdesivir, and into the primase to polymerase transition, are also presented. [ABSTRACT FROM AUTHOR]
- Subjects :
- *SARS-CoV-2
*RNA replicase
*RNA polymerases
*RNA
*COVID-19
Subjects
Details
- Language :
- English
- ISSN :
- 00928674
- Volume :
- 182
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 144670832
- Full Text :
- https://doi.org/10.1016/j.cell.2020.05.034