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Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin.

Sheng Niu1,2 Jia Wang3 Bin Bai2 Lili Wu2 Anqi Zheng2 Qian Chen2,4 Pei Du2 Pengcheng Han5 Yanfang Zhang2,6 Yunfei Jia1,2 Chengpeng Qiao2 Jianxun Qi2,7 Wen-Xia Tian1 Hong-Wei Wang3 Qihui Wang1,2,4,7 George Fu Gao1,2
Affiliations 7 institutions
  1. College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.
  2. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  3. Ministry of Education Key Laboratory of Protein Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center of Biological Structures, School of Life Sciences, Tsinghua University, Beijing, China.
  4. Institute of Physical Science and Information, Anhui University, Hefei, China.
  5. Department of biomedical engineering, Emory University, Atlanta, GA, USA.
  6. Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
  7. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
PMID 34018203 2021 EMBO J eng ppublish
PubMed DOI Browse context

Article

Publication summary

Pangolins have been suggested as potential reservoir of zoonotic viruses, including SARS-CoV-2 causing the global COVID-19 outbreak. Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Additionally, cryo-EM structures of GX/P2V/2017 and GD/1/2019 RBDs in complex with hACE2 show their molecular binding in modes similar to SARS-CoV-2 RBD. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. These findings suggest that these two pangolin CoVs may infect humans, highlighting the necessity of further surveillance of pangolin CoVs.

ACE2 COVID-19 Cryo-EM pangolin CoVs SARS-CoV-2 Amino Acid Substitution Angiotensin-Converting Enzyme 2 Animals Betacoronavirus Binding Sites Hedgehogs HEK293 Cells Host Specificity Humans Mice Models, Molecular Pangolins Phylogeny

Structured evidence records

Evidence records

8 total
Receptor Usage 4 records
Receptor Usage Extraction confidence 1.00
Key finding

Pangolin SARS-CoV-2-like viruses GX/P2V/2017 and GD/1/2019 bind human ACE2 and mediate cell entry via hACE2 with similar efficiency to SARS-CoV-2.

Virus
SARSr-CoV
Location
Not specified
Supporting text

Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells.

Method
binding assay; pseudovirus assay
Receptors
human angiotensin-converting enzyme 2 (hACE2)
Receptor Usage Extraction confidence 1.00
Key finding

The Q498H residue substitution in the SARS-CoV-2 spike receptor-binding domain enhances receptor compatibility by enabling binding to ACE2 homologs from mouse, rat, and European hedgehog.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog.

Method
binding assay; structural analysis
Receptors
ACE2
Receptor Usage Extraction confidence 1.00
Key finding

The Q498H substitution in the SARS-CoV-2 RBD increases receptor compatibility with rat ACE2.

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

Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog.

Method
binding assay; structural analysis
Receptors
ACE2
Receptor Usage Extraction confidence 1.00
Key finding

The Q498H substitution in SARS-CoV-2 RBD enables binding to ACE2 homolog derived from European hedgehog.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog.

Method
binding assay; structural analysis
Receptors
ACE2
Host Range Experiment 2 records
Host Range Experiment Extraction confidence 0.90
Key finding

Pseudotyped vesicular stomatitis virus bearing pangolin CoV spike RBDs successfully entered human ACE2-expressing cells and bound ACE2 orthologs from multiple species, demonstrating broadened host range potential.

Virus
SARSr-CoV
Location
Not specified
Supporting text

Incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2.

Method
pseudovirus entry assay; ACE2 binding assay
Experimental system
pseudovirus assay
Host Range Experiment Extraction confidence 0.90
Key finding

The Q498H mutation derived from pangolin CoVs enabled the SARS-CoV-2 RBD to bind ACE2 homologs from mouse, rat, and European hedgehog, indicating expanded host receptor usage.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog.

Method
ACE2 binding assay; mutagenesis study
Experimental system
in vitro cell culture
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.90
Key finding

Comparative genomic and structural analyses identified the Q498H substitution in pangolin CoV spike RBD that alters ACE2 receptor interactions, demonstrating evolutionary similarity between pangolin CoVs and SARS-CoV-2.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. MeSH terms include 'Phylogeny' and 'Spike Glycoprotein, Coronavirus / genetics'.

Genes or proteins
spike; RBD
Analysis methods
comparative genomic analysis; phylogenetic analysis; structural analysis (Cryo-EM)
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

The Q498H substitution in the SARS-CoV-2 spike RBD enhances binding to ACE2 from mouse, rat, and hedgehog, showing molecular adaptation that broadens host range across species.

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

Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog.

Genes or proteins
spike; RBD
Receptors
ACE2
Mutations
Q498H
Mechanism types
receptor_binding; host_range_expansion; cell_entry