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 nsp12 RdRp domain displays the canonical cupped right-hand configuration (25) , with the finger subdomain (resides 397-581 and residues 621-679) forming a closed circle with the thumb subdomain (blue residues 819-920). The closed conformation is stabilized by the binding of nsp7 and nsp8, with one nsp8 molecule sitting on the top of the finger subdomain and interacting with the interface domain. The closed conformation of nsp12 is further stabilized by the nsp7-nsp8 heterodimer, which is packed against the thumb-index finger interface ( Figure 2A -2B). In addition, we were able to assign two zinc ions in the conserved metal binding motifs composed by H295-C301-C306-C310 and C487-H642-C645-C646 ( Figure 2C ), which are also observed in the SARS-CoV RdRp structure (15) , and these zinc ions likely to serve as conserved structural components in maintaining the integrity of RdRp architecture.