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Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity.
Lin, Sheng; Chen, Hua; Chen, Zimin; Yang, Fanli; Ye, Fei; Zheng, Yue; Yang, Jing; Lin, Xi; Sun, Honglu; Wang, Lingling; Wen, Ao; Dong, Haohao; Xiao, Qingjie; Deng, Dong; Cao, Yu; Lu, Guangwen.
  • Lin S; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Chen H; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Chen Z; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Yang F; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Ye F; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Zheng Y; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Yang J; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Lin X; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Sun H; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Wang L; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Wen A; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
  • Dong H; Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • Xiao Q; Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • Deng D; National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute (Zhangjiang Laboratory), Chinese Academy of Sciences, Shanghai 201210, China.
  • Cao Y; Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • Lu G; West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
Nucleic Acids Res ; 49(9): 5382-5392, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1387965
Semantic information from SemMedBD (by NLM)
1. Pivot AFFECTS Virus Replication
Subject
Pivot
Predicate
AFFECTS
Object
Virus Replication
2. Alpha 1|ADRA1D AFFECTS Protein Binding
Subject
Alpha 1|ADRA1D
Predicate
AFFECTS
Object
Protein Binding
3. Pivot AFFECTS Virus Replication
Subject
Pivot
Predicate
AFFECTS
Object
Virus Replication
4. Alpha 1|ADRA1D AFFECTS Protein Binding
Subject
Alpha 1|ADRA1D
Predicate
AFFECTS
Object
Protein Binding
ABSTRACT
The emergence of SARS-CoV-2 infection has posed unprecedented threat to global public health. The virus-encoded non-structural protein 14 (nsp14) is a bi-functional enzyme consisting of an exoribonuclease (ExoN) domain and a methyltransferase (MTase) domain and plays a pivotal role in viral replication. Here, we report the structure of SARS-CoV-2 nsp14-ExoN domain bound to its co-factor nsp10 and show that, compared to the SARS-CoV nsp10/nsp14-full-length complex, SARS-CoV-2 nsp14-ExoN retains an integral exoribonuclease fold and preserves an active configuration in the catalytic center. Analysis of the nsp10/nsp14-ExoN interface reveals a footprint in nsp10 extensively overlapping with that observed in the nsp10/nsp16 structure. A marked difference in the co-factor when engaging nsp14 and nsp16 lies in helix-α1', which is further experimentally ascertained to be involved in nsp14-binding but not in nsp16-engagement. Finally, we also show that nsp10/nsp14-ExoN is enzymatically active despite the absence of nsp14-MTase domain. These data demonstrate that SARS-CoV-2 nsp10/nsp14-ExoN functions as an exoribonuclease with both structural and functional integrity.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Nonstructural Proteins / Exoribonucleases / Viral Regulatory and Accessory Proteins / Biocatalysis / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: Nucleic Acids Res Year: 2021 Document Type: Article Affiliation country: NAR

Full text: Available Collection: International databases Database: MEDLINE Main subject: Viral Nonstructural Proteins / Exoribonucleases / Viral Regulatory and Accessory Proteins / Biocatalysis / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: Nucleic Acids Res Year: 2021 Document Type: Article Affiliation country: NAR