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PDBsum entry 7b3c
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Viral protein
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PDB id
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7b3c
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Contents |
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814 a.a.
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115 a.a.
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62 a.a.
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References listed in PDB file
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Key reference
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Title
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Mechanism of sars-Cov-2 polymerase stalling by remdesivir.
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Authors
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G.Kokic,
H.S.Hillen,
D.Tegunov,
C.Dienemann,
F.Seitz,
J.Schmitzova,
L.Farnung,
A.Siewert,
C.Höbartner,
P.Cramer.
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Ref.
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Nat Commun, 2021,
12,
279.
[DOI no: ]
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PubMed id
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Abstract
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Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients.
The active form of remdesivir acts as a nucleoside analog and inhibits the
RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2.
Remdesivir is incorporated by the RdRp into the growing RNA product and allows
for addition of three more nucleotides before RNA synthesis stalls. Here we use
synthetic RNA chemistry, biochemistry and cryo-electron microscopy to establish
the molecular mechanism of remdesivir-induced RdRp stalling. We show that
addition of the fourth nucleotide following remdesivir incorporation into the
RNA product is impaired by a barrier to further RNA translocation. This
translocation barrier causes retention of the RNA 3'-nucleotide in the
substrate-binding site of the RdRp and interferes with entry of the next
nucleoside triphosphate, thereby stalling RdRp. In the structure of the
remdesivir-stalled state, the 3'-nucleotide of the RNA product is matched and
located with the template base in the active center, and this may impair
proofreading by the viral 3'-exonuclease. These mechanistic insights should
facilitate the quest for improved antivirals that target coronavirus replication.
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