Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Cell
; 182(2): 417-428.e13, 2020 07 23.
Article
in English
| MEDLINE | ID: covidwho-342735
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.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
RNA-Dependent RNA Polymerase
/
Viral Nonstructural Proteins
/
Betacoronavirus
Type of study:
Experimental Studies
/
Prognostic study
Language:
English
Journal:
Cell
Year:
2020
Document Type:
Article
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