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The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses.

Junsen Chen1 Junqing Sun2,3 Zepeng Xu2,4 Linjie Li5 Xinrui Kang5 Chunliang Luo5 Qi Wang1 Xueyang Guo1 Yan Li5 Kefang Liu6 Ying Wu7
Affiliations 7 institutions
  1. State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China.
  2. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
  3. Beijing Life Science Academy, Beijing, 102209, China.
  4. Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, China.
  5. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
  6. Beijing Life Science Academy, Beijing, 102209, China. Electronic address: [email protected].
  7. State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
PMID 38866203 2024 Virol Sin eng ppublish
PubMed DOI Browse context

Article

Publication summary

Foxes are susceptible to SARS-CoV-2 in laboratory settings, and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes. In this study, we assessed the binding capacities of fox ACE2 to important sarbecoviruses, including SARS-CoV, SARS-CoV-2, and animal-origin SARS-CoV-2 related viruses. Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains (RBDs) of sarbecoviruses. We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV, SARS-CoV-2 prototype (PT), and Omicron BF.7. Through structural analysis, we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2, thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants. In addition, the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-π interaction with K353 in the fox ACE2 receptor. This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD. These results indicate that foxes serve as potential hosts for numerous sarbecoviruses, highlighting the critical importance of surveillance efforts.

Cryo-EM structure Fox ACE2 Omicron Sarbecoviruses SARS-CoV SARS-CoV-2 Angiotensin-Converting Enzyme 2 Foxes Protein Binding SARS-CoV-2 Animals Binding Sites COVID-19 Cryoelectron Microscopy Humans Models, Molecular Mutation Protein Domains

Structured evidence records

Evidence records

5 total
Receptor Usage 3 records
Receptor Usage Extraction confidence 0.98
Key finding

Fox ACE2 receptor binds broadly to the receptor-binding domains of SARS-CoV, SARS-CoV-2, and related sarbecoviruses, indicating receptor compatibility across these viruses.

Virus
SARS-CoV
Host
Vulpes
Location
Not specified
Supporting text

We assessed the binding capacities of fox ACE2 to important sarbecoviruses, including SARS-CoV, SARS-CoV-2, and animal-origin SARS-CoV-2 related viruses. Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains (RBDs) of sarbecoviruses.

Method
binding assay; cryo-EM structural analysis
Receptors
ACE2
Receptor Usage Extraction confidence 0.98
Key finding

A K417 mutation in SARS-CoV-2 sub-variants reduces binding affinity to fox ACE2, suggesting decreased receptor-mediated susceptibility.

Virus
SARS-CoV-2
Host
Vulpes
Location
Not specified
Supporting text

Through structural analysis, we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2, thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.

Method
cryo-EM structural analysis
Receptors
ACE2
Receptor Usage Extraction confidence 0.98
Key finding

A cation-π interaction between SARS-CoV RBD residue Y498 and K353 in fox ACE2 determines the higher binding affinity of SARS-CoV to fox ACE2 compared with SARS-CoV-2.

Virus
SARS-CoV
Host
Vulpes
Location
Not specified
Supporting text

The Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-π interaction with K353 in the fox ACE2 receptor. This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.

Method
cryo-EM structural analysis
Receptors
ACE2
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.92
Key finding

The K417 mutation in SARS-CoV-2 subvariants decreases binding to fox ACE2 and may reduce susceptibility of foxes to these variants.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

Through structural analysis, we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2, thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.

Genes or proteins
spike; RBD
Receptors
ACE2
Mutations
K417
Mechanism types
receptor_binding; host_range_adaptation
Molecular Adaptation Extraction confidence 0.92
Key finding

The Y498 residue in SARS-CoV RBD enhances affinity to fox ACE2 through a cation-π interaction with K353, explaining stronger binding relative to SARS-CoV-2.

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

The Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-π interaction with K353 in the fox ACE2 receptor. This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.

Genes or proteins
spike; RBD
Receptors
ACE2
Mutations
Y498
Mechanism types
receptor_binding; host_range_adaptation