|Title||Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.|
|Journal, issue, pages||Cell, Vol. 182, Issue 2, Page 417-428.e13, Year 2020|
|Publish date||Jul 23, 2020|
|Authors||Quan Wang / Jiqin Wu / Haofeng Wang / Yan Gao / Qiaojie Liu / An Mu / Wenxin Ji / Liming Yan / Yan Zhu / Chen Zhu / Xiang Fang / Xiaobao Yang / Yucen Huang / Hailong Gao / Fengjiang Liu / Ji Ge / Qianqian Sun / Xiuna Yang / Wenqing Xu / Zhijie Liu / Haitao Yang / Zhiyong Lou / Biao Jiang / Luke W Guddat / Peng Gong / Zihe Rao /|
|PubMed 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 ...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.|
|External links||Cell / PubMed:32526208 / PubMed Central|
|Methods||EM (single particle)|
|Resolution||2.93 - 3.26 Å|
|Keywords||VIRAL PROTEIN/RNA / COVID-19 / 2019-nCoV / SARS-CoV-2 / Virus / RdRp / nsp12 / nsp7 / nsp8 / RTC / cryo-EM / Viral protein / RNA polymerase / drug target / antiviral / replication transcription complex / VIRAL PROTEIN-RNA complex / pre-translocated catalytic complex|
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