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Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin.
EMBO J. 2021 08 16; 40(16):e107786.EJ

Abstract

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.

Authors+Show Affiliations

College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.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.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Institute of Physical Science and Information, Anhui University, Hefei, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.Department of biomedical engineering, Emory University, Atlanta, GA, USA.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.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.College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Institute of Physical Science and Information, Anhui University, Hefei, China. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34018203

Citation

Niu, Sheng, et al. "Molecular Basis of Cross-species ACE2 Interactions With SARS-CoV-2-like Viruses of Pangolin Origin." The EMBO Journal, vol. 40, no. 16, 2021, pp. e107786.
Niu S, Wang J, Bai B, et al. Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin. EMBO J. 2021;40(16):e107786.
Niu, S., Wang, J., Bai, B., Wu, L., Zheng, A., Chen, Q., Du, P., Han, P., Zhang, Y., Jia, Y., Qiao, C., Qi, J., Tian, W. X., Wang, H. W., Wang, Q., & Gao, G. F. (2021). Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin. The EMBO Journal, 40(16), e107786. https://doi.org/10.15252/embj.2021107786
Niu S, et al. Molecular Basis of Cross-species ACE2 Interactions With SARS-CoV-2-like Viruses of Pangolin Origin. EMBO J. 2021 08 16;40(16):e107786. PubMed PMID: 34018203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin. AU - Niu,Sheng, AU - Wang,Jia, AU - Bai,Bin, AU - Wu,Lili, AU - Zheng,Anqi, AU - Chen,Qian, AU - Du,Pei, AU - Han,Pengcheng, AU - Zhang,Yanfang, AU - Jia,Yunfei, AU - Qiao,Chengpeng, AU - Qi,Jianxun, AU - Tian,Wen-Xia, AU - Wang,Hong-Wei, AU - Wang,Qihui, AU - Gao,George Fu, Y1 - 2021/06/08/ PY - 2021/05/08/revised PY - 2021/01/20/received PY - 2021/05/14/accepted PY - 2021/5/22/pubmed PY - 2021/8/19/medline PY - 2021/5/21/entrez KW - ACE2 KW - COVID-19 KW - Cryo-EM KW - SARS-CoV-2 KW - pangolin CoVs SP - e107786 EP - e107786 JF - The EMBO journal JO - EMBO J VL - 40 IS - 16 N2 - 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. SN - 1460-2075 UR - https://www.unboundmedicine.com/medline/citation/34018203/Molecular_basis_of_cross_species_ACE2_interactions_with_SARS_CoV_2_like_viruses_of_pangolin_origin_ L2 - https://doi.org/10.15252/embj.2021107786 DB - PRIME DP - Unbound Medicine ER -