Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target

Yan Gao; Liming Yan; Yucen Huang; Fengjiang Liu; Yao Zhao; Lin Cao; Tao Wang; Qianqian Sun; Zhenhua Ming; Lianqi Zhang; Ji Ge; Litao Zheng; Ying Zhang; Haofeng Wang; Yan Zhu; Chen Zhu; Tianyu Hu; Tian Hua; Bing Zhang; Xiuna Yang; Jun Li; Haitao Yang; Zhijie Liu; Wenqing Xu; Luke W. Guddat; Quan Wang; Zhiyong Lou; Zihe Rao

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.16.993386 doi: bioRxiv preprint ns5b and has been approved for the treatment of chronic HCV infection) ( fig. S7 ), a model of 2019-nCoV nsp12 with remdesivir diphosphate is proposed (Fig. 4) . In 2019-nCoV nsp12, the 2' hydroxyl of the incoming NTP is likely to form hydrogen bonds with T680 and N691 in motif B (Figs. 4, A and B). In addition, D623 in motif A is positioned to interrogate the 3' hydroxyl through hydrogen bonding. Moreover, the hydrophobic side chain of V557 in motif F is likely to stack with 5 and stabilize the +1 template RNA uridine base to base pair with the incoming triphosphate remdesivir (ppp-remdesivir). In the structures of HCV ns5b elongation complex or its complex with pp-sofosbuvir, a key feature is that the incorporated pp-sofosbuvir disrupts the hydrogen bonding network between S282 and D225 (Figs. 4, C and D), which is necessary to stabilize the incoming natural nucleotide (12). However, key contacts formed by S282 with the incoming nucleotide and the surrounding environment can result in an S→T resistance mutation that is already observed in the clinic (17). In the structure of apo 2019-nCoV nsp12, the orientation of S682 and D623, which are strictly conserved with S282 and D225 in HCV ns5b, is similar to that observed in the HCV ns5b-pp-sofosbuvir complex, indicating a different recognition mechanism with that inhibitor. Nevertheless, the close distance of S682 with the incoming ppp-remdesivir and 15 the environment surrounding the inhibitor alters the appearance of a drug-resistant mutation associated with remdesivir treatments.