Structural and Biochemical Characterization of the nsp12-nsp7-nsp8 Core Polymerase Complex from SARS-CoV-2

• Published in: Cell Reports Vol. 31; no. 11; p. 107774
• Main Authors: Peng, Qi, Peng, Ruchao, Yuan, Bin, Zhao, Jingru, Wang, Min, Wang, Xixi, Wang, Qian, Sun, Yan, Fan, Zheng, Qi, Jianxun, Gao, George F., Shi, Yi
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 16.06.2020; Elsevier BV; The Author(s); Elsevier
• Subjects: Amino Acid Substitution; Betacoronavirus - enzymology; cofactors; Coronavirus RNA-Dependent RNA Polymerase; cryo-EM; Cryoelectron Microscopy; Escherichia coli - genetics; Evolution, Molecular; Models, Molecular; Multiprotein Complexes - chemistry; non-structural proteins; polymerase; RNA synthesis; RNA-Dependent RNA Polymerase - chemistry; RNA-Dependent RNA Polymerase - metabolism; SARS-CoV-2; Severe acute respiratory syndrome-related coronavirus - enzymology; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; non-structural proteins; SARS-CoV-2; cofactors; RNA synthesis; cryo-EM; polymerase
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107774

The ongoing global pandemic of coronavirus disease 2019 (COVID-19) has caused a huge number of human deaths. Currently, there are no specific drugs or vaccines available for this virus (SARS-CoV-2). The viral polymerase is a promising antiviral target. Here, we describe the near-atomic-resolution structure of the SARS-CoV-2 polymerase complex consisting of the nsp12 catalytic subunit and nsp7-nsp8 cofactors. This structure highly resembles the counterpart of SARS-CoV with conserved motifs for all viral RNA-dependent RNA polymerases and suggests a mechanism of activation by cofactors. Biochemical studies reveal reduced activity of the core polymerase complex and lower thermostability of individual subunits of SARS-CoV-2 compared with SARS-CoV. These findings provide important insights into RNA synthesis by coronavirus polymerase and indicate adaptation of SARS-CoV-2 toward humans with a relatively lower body temperature than the natural bat hosts. [Display omitted] •Cryo-EM structure of SARS-CoV-2 nsp12-nsp7-nsp8 core polymerase complex•The core complex of SARS-CoV-2 has lower enzymatic activity than SARS-CoV•SARS-CoV-2 nsp7-8-12 subunits are less thermostable than the SARS-CoV counterpart Viral polymerase plays a central role in the virus life cycle and is an important antiviral drug target. Peng et al. report the cryo-EM structure of the SARS-CoV-2 core polymerase complex, finding that it has less efficient activity for RNA synthesis and lower thermostability of individual subunits compared with SARS-CoV.