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 overall structure of the template-RTP RdRp complex is similar to the apo RdRp structure, with nsp12 in a closed conformation (Figure 2A and 3A) . The double-stranded helix, formed by 11 base-pairs from the template-primer RNA ( Figure 3B and Figure 4) , is hold by the fingerpalm-thumb subdomains. Extensive protein-RNA interactions are observed between the template-primer RNA and nsp12, with a total of 29 residues from nsp12 directly participating in the binding of the RNA ( Figure 4E) . Surprisingly no RNA interactions are mediated by nsp7 or nsp8 despite these two proteins are required for RNA binding by RdRp. Majority of protein-RNA interactions are mediated with the RNA phosphate-ribose backbones, with many interactions directly to 2'-OH groups ( Figure 4E ), thus providing a basis to distinguish RNA from DNA. There are no contacts from nsp12 to any base pairs of the template-primer RNA, suggesting no sequence-specific RNA binding by RdRp. This is consistent with the fact that no specific sequence is required for the enzymatic activity of RdRp at the elongation step.