Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Antiviral Agents
/ chemistry
Betacoronavirus
/ chemistry
Catalytic Domain
Coronavirus RNA-Dependent RNA Polymerase
Cryoelectron Microscopy
Models, Chemical
Models, Molecular
RNA, Viral
/ metabolism
RNA-Dependent RNA Polymerase
/ chemistry
SARS-CoV-2
Transcription, Genetic
Viral Nonstructural Proteins
/ chemistry
Virus Replication
2019-nCoV
COVID-19
RdRP
SARS-CoV-2
favipiravir
nsp12
nsp8
polymerase
remdesivir
virus
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
23 07 2020
23 07 2020
Historique:
received:
27
04
2020
revised:
12
05
2020
accepted:
18
05
2020
pubmed:
12
6
2020
medline:
31
7
2020
entrez:
12
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32526208
pii: S0092-8674(20)30629-2
doi: 10.1016/j.cell.2020.05.034
pmc: PMC7242921
pii:
doi:
Substances chimiques
Antiviral Agents
0
NS8 protein, SARS-CoV-2
0
RNA, Viral
0
Viral Nonstructural Proteins
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
Coronavirus RNA-Dependent RNA Polymerase
EC 2.7.7.48
NSP12 protein, SARS-CoV-2
EC 2.7.7.48
NSP7 protein, SARS-CoV-2
EC 2.7.7.48
RNA-Dependent RNA Polymerase
EC 2.7.7.48
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
417-428.e13Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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