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 second difference is observed in the loop that connects the first and second helix of the thumb subdomain, which moves outward by as much as 2.8 Å (as measured nsp12 residue I847) to accommodate the binding of the double stranded RNA helix ( Figure 3E ). Motif G residues K500 and S501 also move outward by 2.0 Å to accommodate the binding of the template strand RNA. Outside of these changes, the apo nsp12 and the complexed nsp12 are exceedingly similar, with an RMSD of 0.52 Å for all Cα atoms across the whole protein. In particular, the structural elements that make up the catalytic active site can be superimposed identically ( Figure S8 ), suggesting that SARS-CoV-2 RdRp is a relatively stable enzyme that is readily to function as a replicase upon the binding of RNA template. This is consistent with the fact that the purified RdRp complex had a relatively stable enzyme. Viral RdRp is a highly processive enzyme with rate of replication up to 100 nucleotides per second (33) . No significant conformational changes between the apo and the active enzyme structures are consistent with the high processivity of the viral RNA polymerase, which does not need to consume additional energy for switch active site conformation during the replication cycle.