Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

被引：880

作者：

Yin, Wanchao ^{[1
,2
,3
]}

Mao, Chunyou ^{[2
,3
]}

Luan, Xiaodong ^{[4
,5
,6
,7
]}

Shen, Dan-Dan ^{[2
,3
]}

Shen, Qingya ^{[2
,3
]}

Su, Haixia ^{[8
]}

Wang, Xiaoxi ^{[1
]}

Zhou, Fulai ^{[1
]}

Zhao, Wenfeng ^{[1
]}

Gao, Minqi ^{[9
]}

Chang, Shenghai ^{[10
,11
]}

Xie, Yuan-Chao ^{[1
]}

Tian, Guanghui ^{[1
]}

Jiang, He-Wei ^{[12
]}

Tao, Sheng-Ce ^{[12
]}

Shen, Jingshan ^{[1
,8
]}

Jiang, Yi ^{[1
,8
]}

Jiang, Hualiang ^{[1
,8
]}

Xu, Yechun ^{[1
,8
]}

Zhang, Shuyang ^{[4
,5
,6
,7
]}

Zhang, Yan ^{[2
,3
,13
]}

Xu, H. Eric ^{[1
,8
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[2] Zhejiang Univ, Dept Biophys, Sir Run Run Shaw Hosp, Sch Med, Hangzhou 310058, Peoples R China

[3] Zhejiang Univ, Dept Pathol, Sir Run Run Shaw Hosp, Sch Med, Hangzhou 310058, Peoples R China

[4] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China

[5] Peking Union Med Coll, Dept Cardiol, Peking Union Med Coll Hosp, Beijing 100730, Peoples R China

[6] Chinese Acad Med Sci, Beijing 100730, Peoples R China

[7] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China

[8] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[9] WuxiBiortus Biosci Co Ltd, Jiangyin 214437, Peoples R China

[10] Zhejiang Univ, Ctr Cryoelectron Microscopy, Sch Med, Hangzhou 310058, Peoples R China

[11] Zhejiang Univ, Sir Run Run Shaw Hosp, Ctr Diagnost Electron Microscopy, Sch Med, Hangzhou 310058, Peoples R China

[12] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai 200240, Peoples R China

[13] Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou 310058, Peoples R China

来源：

SCIENCE | 2020年 / 368卷 / 6498期

基金：

奥地利科学基金会; 国家重点研发计划; 中国国家自然科学基金; 美国国家科学基金会;

关键词：

CRYO-EM STRUCTURE; RESPIRATORY SYNDROME CORONAVIRUS; REPLICATION; PROTEIN; DISCOVERY; GS-5734; VIRUS; NSP12; EBOLA;

D O I：

10.1126/science.abc1560

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

引用

页码：1499 / +

页数：26

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