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Literature detail

Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species.

Kefang Liu1 Xiaoqian Pan2,3 Linjie Li2,3 Feng Yu4 Anqi Zheng1 Pei Du1 Pengcheng Han2,5 Yumin Meng1 Yanfang Zhang2,6 Lili Wu1 Qian Chen2,7 Chunli Song7 Yunfei Jia2,8 Sheng Niu2,8 Dan Lu1 Chengpeng Qiao1 Zhihai Chen9 Dongli Ma10 Xiaopeng Ma10 Shuguang Tan1 Xin Zhao1 Jianxun Qi2,11 George F Gao2,12 Qihui Wang2,13
Affiliations 13 institutions
  1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  2. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
  3. University of the Chinese Academy of Sciences, Beijing 100049, China.
  4. Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
  5. Department of Biomedical Engineering, Emory University, Atlanta, GA 10033, USA.
  6. Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
  7. Institute of Physical Science and Information, Anhui University, Hefei 230039, China.
  8. College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China.
  9. Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, 100015 Beijing, China.
  10. Shenzhen Children's Hospital, Shenzhen 518036, China.
  11. University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  12. University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  13. University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID 34139177 2021 Cell eng ppublish
PubMed DOI Browse context

Article

Publication summary

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.

ACE2 COVID-19 intermediate horseshoe bat RaTG13 RBD SARS-CoV-2 Amino Acid Sequence Angiotensin-Converting Enzyme 2 Animals Antibodies, Monoclonal Binding Sites Chiroptera COVID-19 Host Specificity Humans Phylogeny Protein Binding Receptors, Virus

Structured evidence records

Evidence records

6 total
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.90
Key finding

RaTG13 RBD was experimentally shown to bind human ACE2 and ACE2 orthologs from 24 other species, indicating potential host range diversity.

Virus
SARSr-CoV
Location
Not specified
Supporting text

Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs.

Method
binding assay; receptor binding domain analysis; structural complex determination
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.90
Key finding

SARS-CoV-2 monoclonal antibody CB6 cross-neutralized RaTG13 pseudovirus, demonstrating functional entry and immune cross-reactivity in pseudovirus assays.

Virus
SARSr-CoV
Location
Not specified
Supporting text

We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus.

Method
neutralization assay; pseudovirus assay
Experimental system
pseudovirus assay
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.70
Key finding

Phylogenetic and sequence comparison between SARS-CoV-2 and RaTG13 identified residue 501 in the RBD as critical for host range evolution.

Virus
SARSr-CoV
Location
Not specified
Supporting text

Bat-origin RaTG13 is currently the most phylogenetically related virus. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501 plays a key role in determining the potential host range of RaTG13. MeSH terms include Phylogeny and Sequence Alignment.

Genes or proteins
RBD
Analysis methods
phylogenetic analysis; sequence alignment
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

Residue 501 in the RaTG13 receptor binding domain determines its binding and host range adaptation to ACE2 across species, demonstrating a molecular adaptation mechanism.

Virus
SARSr-CoV
Host
Not specified
Location
Not specified
Supporting text

By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13.

Genes or proteins
RBD
Receptors
ACE2
Mutations
residue 501
Mechanism types
receptor_binding; host_range_determination
Receptor Usage 1 records
Receptor Usage Extraction confidence 1.00
Key finding

RaTG13 coronavirus binds human ACE2 and ACE2 orthologs from other species, indicating receptor usage that contributes to host range determination.

Virus
SARSr-CoV
Location
Not specified
Supporting text

Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs.

Method
structural analysis; binding assay
Receptors
ACE2
Serological Evidence 1 records
Serological Evidence Extraction confidence 0.80
Key finding

SARS-CoV-2 infection generated cross-reactive and cross-neutralizing antibodies against the bat coronavirus RaTG13, indicating shared antigenic determinants.

Virus
SARSr-CoV
Location
Not specified
Supporting text

SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus.

Method
neutralization test
Sample type
serum