Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir

Wanchao Yin; Chunyou Mao; Xiaodong Luan; Dan-Dan Shen; Qingya Shen; Haixia Su; Xiaoxi Wang; Fulai Zhou; Wenfeng Zhao; Minqi Gao; Shenghai Chang; Yuan-Chao Xie; Guanghui Tian; He-Wei Jiang; Sheng-Ce Tao; Jingshan Shen; Yi Jiang; Hualiang Jiang; Yechun Xu; Shuyang Zhang; Yan Zhang; H. Eric Xu

The catalytic active site of the nsp12 RdRp is constructed by seven conserved motifs from A to G (Figure 1 and Figure S6 ). Motifs ABCD are from the palm subdomain with the SDD sequence (residues 759-761) in motif C forming the catalytic active center ( Figure 5B ). Both D760 and . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.08.032763 doi: bioRxiv preprint D761 are involved in coordination of the two magnesium ions at the catalytic center. Motifs F and G are located within the finger subdomain, with motifs F and G interacting with the template strand RNA and directing this strand into the active site. Motif F also interacts with the primer strand RNA with its side chains from K545 and R555 contacting the base at the +1 position, thus stabilizing the incoming nucleotide in the correct position for catalysis. Compared with the structures of the poliovirus RdRp elongation complex (28) and the HCV Ns5b RdRp inhibitor complex (29) , the mode of how template-primer RNA is orientated into the active site is exceedingly similar among these different viral RdRp complex ( Figure S7 ). The residues involved in RNA binding as well as residues comprising the catalytic active site are highly conserved in this viral RdRp (30, 31) , thus highlighting the highly conserved mechanism of genome replication by RdRp in these diverse RNA virus, and suggesting a possibility to develop broad spectrum antiviral inhibitors such as Remdesivir (18) and Galidisvir (BCX4430) (32) .