期刊
CELL
卷 182, 期 2, 页码 417-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.05.034
关键词
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资金
- National Program on Key Research Project of China [2017YFC0840300, 2020YFA0707500, 2018YFA0507200]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB08020200]
- National Natural Science Foundation of China [81520108019, 813300237, 32041007]
- Science and Technology Commission of Shanghai Municipality, China [20431900200]
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.
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