Literature detail

Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution.

Shuyuan Zhang¹ Shuyuan Qiao¹ Jinfang Yu¹ Jianwei Zeng¹ Sisi Shan² Long Tian¹ Jun Lan¹ Linqi Zhang² Xinquan Wang³

Affiliations 3 institutions

The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
Center for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing, China.
The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, 100084, Beijing, China. [email protected].

PMID 33707453 2021 Nat Commun eng epublish

Article

Publication summary

In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the "down" conformation, indicating they are more prone to adopt the receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. We further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes. These results collectively indicate that tight RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.

Amino Acid Sequence Angiotensin-Converting Enzyme 2 Animals Chiroptera Coronavirus COVID-19 Cryoelectron Microscopy Evolution, Molecular Host Microbial Interactions Humans Models, Molecular Pandemics Pangolins Protein Domains SARS-CoV-2 Sequence Homology, Amino Acid Species Specificity Spike Glycoprotein, Coronavirus

Structured evidence records

Evidence records

6 total

Genomic Evolution 3 records

Genomic Evolution Extraction confidence 0.90

Key finding

Structural and amino acid sequence comparisons of bat RaTG13 and pangolin PCoV_GX spike proteins revealed RBD residues associated with SARS-CoV-2 evolution and receptor-binding capability.

Virus

Host

Location

Supporting text

We determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2, and identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes.

Genes or proteins: spike; receptor-binding domain
Analysis methods: cryo-EM structural analysis; amino acid sequence comparison

Genomic Evolution Extraction confidence 0.90

Key finding

Bat RaTG13 and pangolin PCoV_GX coronavirus spike structures were resolved, showing distinct RBD conformations and residue-level differences relevant to SARS-CoV-2 evolutionary divergence.

Virus

Host

Location

Supporting text

Cryo-EM structures of bat (RaTG13) and pangolin (PCoV_GX) coronavirus spikes were determined, revealing all RBDs in the 'down' conformation and identifying residues explaining differences in their activity compared to SARS-CoV-2.

Genes or proteins: spike; receptor-binding domain
Analysis methods: cryo-EM structural analysis; comparative structural analysis

Genomic Evolution Extraction confidence 0.90

Key finding

Structural and residue-level comparison of the pangolin PCoV_GX spike with SARS-CoV-2 showed high similarity and capacity for human ACE2 binding, indicating evolutionary convergence toward efficient human infection.

Virus

Host

Location

Supporting text

Cryo-EM structures of the pangolin coronavirus PCoV_GX spike were compared to SARS-CoV-2, showing equivalent receptor binding and providing evolutionary insight into efficient infection acquisition by SARS-CoV-2.

Genes or proteins: spike; receptor-binding domain
Analysis methods: cryo-EM structural analysis; comparative molecular analysis

Molecular Adaptation 2 records

Molecular Adaptation Extraction confidence 0.95

Key finding

Pangolin coronavirus PCoV_GX spike, unlike the bat RaTG13 spike, exhibits human ACE2 binding and cell entry comparable to SARS-CoV-2, with structural residues in the receptor-binding domain mediating this adaptation.

Virus

Host

Location

Supporting text

We found that the pangolin PCoV_GX, but not the bat RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. We further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes.

Genes or proteins: spike; receptor-binding domain
Receptors: ACE2
Mechanism types: receptor_binding; cell_entry

Molecular Adaptation Extraction confidence 0.90

Key finding

Efficient human infection by SARS-CoV-2 depends on strong receptor-binding domain interaction with ACE2 and conformational flexibility of the spike protein, indicating molecular adaptation in the spike for receptor engagement.

Virus

Host

Location

Supporting text

Tight RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.

Genes or proteins: spike; receptor-binding domain
Receptors: ACE2
Mechanism types: receptor_binding; cell_entry

Receptor Usage 1 records

Receptor Usage Extraction confidence 1.00

Key finding

The pangolin coronavirus PCoV_GX spike binds human ACE2 and mediates pseudovirus entry, while the bat RaTG13 spike does not, demonstrating receptor usage differences.

Virus

Host

Location

Supporting text

We found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry.

Method: binding assay; pseudovirus cell entry assay
Receptors: ACE2

Citation context

References

46 references

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Evidence overview

Evidence 6

Types 3

Virus 2

Host 5

Evidence types

Genomic Evolution 3 Molecular Adaptation 2 Receptor Usage 1

Linked entities

Viruses

Hosts

Locations

Publication metadata

Journal: Nature communications
Volume / Issue / Pages: 12 / 1 / 1607
ISSN: 2041-1723
Journal country: England
DOI: 10.1038/s41467-021-21767-3