上海科技大学饶子和、Quan Wang、中科院武汉病毒所Peng Gong等研究人员合作揭示新冠病毒（SARS-CoV-2）聚合酶介导RNA复制的结构基础。2020年5月22日，《细胞》杂志在线发表了这项成果。
Title: Structural basis for RNA replication by the SARS-CoV-2 polymerase
Author: 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
Issue&Volume: 2020-05-22
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-/post- translocated polymerase complexes. The structures show notable structural rearrangements occurring to nsp12 and its cofactors nsp7/nsp8 to accommodate the nucleic acid compared to the apo complex, while 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 mechanisms 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/replication machinery.
DOI: 10.1016/j.cell.2020.05.034
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30629-2