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Structural Basis for Human Receptor Recognition by SARS-CoV-2 Omicron Variant BA.1.
J Virol. 2022 04 27; 96(8):e0024922.JV

Abstract

The highly contagious and fast-spreading omicron variant of SARS-CoV-2 infects the respiratory tracts efficiently. The receptor-binding domain (RBD) of the omicron spike protein recognizes human angiotensin-converting enzyme 2 (ACE2) as its receptor and plays a critical role in the tissue tropism of SARS-CoV-2. Here, we showed that the omicron RBD (strain BA.1) binds to ACE2 more strongly than does the prototypic RBD from the original Wuhan strain. We also measured how individual omicron mutations affect ACE2 binding. We further determined the crystal structure of the omicron RBD (engineered to facilitate crystallization) complexed with ACE2 at 2.6 Å. The structure shows that omicron mutations caused significant structural rearrangements of two mutational hot spots at the RBD/ACE2 interface, elucidating how each omicron mutation affects ACE2 binding. The enhanced ACE2 binding by the omicron RBD may facilitate the omicron variant's infection of the respiratory tracts where ACE2 expression level is low. Our study provides insights into the receptor recognition and tissue tropism of the omicron variant. IMPORTANCE Despite the scarcity of the SARS-CoV-2 receptor-human angiotensin-converting enzyme 2 (ACE2)-in the respiratory tract, the omicron variant efficiently infects the respiratory tract, causing rapid and widespread infections of COVID-19. The omicron variant contains extensive mutations in the receptor-binding domain (RBD) of its spike protein that recognizes human ACE2. Here, using a combination of biochemical and X-ray crystallographic approaches, we showed that the omicron RBD binds to ACE2 with enhanced affinity and also elucidated the role of each of the omicron mutations in ACE2 binding. The enhanced ACE2 binding by the omicron RBD may contribute to the omicron variant's new viral tropism in the respiratory tract despite the low level of ACE2 expression in the tissue. These findings help us to understand tissue tropism of the omicron variant and shed light on the molecular evolution of SARS-CoV-2.

Authors+Show Affiliations

Department of Veterinary and Biomedical Sciences, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA. Center for Coronavirus Research, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA.Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesotagrid.17635.36, Minneapolis, Minnesota, USA.Department of Veterinary and Biomedical Sciences, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA. Center for Coronavirus Research, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA.Department of Veterinary and Biomedical Sciences, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA. Center for Coronavirus Research, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA.Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesotagrid.17635.36, Minneapolis, Minnesota, USA.Department of Veterinary and Biomedical Sciences, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA. Center for Coronavirus Research, University of Minnesotagrid.17635.36, Saint Paul, Minnesota, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35343765

Citation

Geng, Qibin, et al. "Structural Basis for Human Receptor Recognition By SARS-CoV-2 Omicron Variant BA.1." Journal of Virology, vol. 96, no. 8, 2022, pp. e0024922.
Geng Q, Shi K, Ye G, et al. Structural Basis for Human Receptor Recognition by SARS-CoV-2 Omicron Variant BA.1. J Virol. 2022;96(8):e0024922.
Geng, Q., Shi, K., Ye, G., Zhang, W., Aihara, H., & Li, F. (2022). Structural Basis for Human Receptor Recognition by SARS-CoV-2 Omicron Variant BA.1. Journal of Virology, 96(8), e0024922. https://doi.org/10.1128/jvi.00249-22
Geng Q, et al. Structural Basis for Human Receptor Recognition By SARS-CoV-2 Omicron Variant BA.1. J Virol. 2022 04 27;96(8):e0024922. PubMed PMID: 35343765.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural Basis for Human Receptor Recognition by SARS-CoV-2 Omicron Variant BA.1. AU - Geng,Qibin, AU - Shi,Ke, AU - Ye,Gang, AU - Zhang,Wei, AU - Aihara,Hideki, AU - Li,Fang, Y1 - 2022/03/28/ PY - 2022/3/29/pubmed PY - 2022/4/30/medline PY - 2022/3/28/entrez KW - COVID-19 KW - X-ray crystallography KW - angiotensin-converting enzyme 2 KW - mutational hotspots KW - omicron variant KW - receptor-binding domain (RBD) KW - receptor-binding motif (RBM) SP - e0024922 EP - e0024922 JF - Journal of virology JO - J Virol VL - 96 IS - 8 N2 - The highly contagious and fast-spreading omicron variant of SARS-CoV-2 infects the respiratory tracts efficiently. The receptor-binding domain (RBD) of the omicron spike protein recognizes human angiotensin-converting enzyme 2 (ACE2) as its receptor and plays a critical role in the tissue tropism of SARS-CoV-2. Here, we showed that the omicron RBD (strain BA.1) binds to ACE2 more strongly than does the prototypic RBD from the original Wuhan strain. We also measured how individual omicron mutations affect ACE2 binding. We further determined the crystal structure of the omicron RBD (engineered to facilitate crystallization) complexed with ACE2 at 2.6 Å. The structure shows that omicron mutations caused significant structural rearrangements of two mutational hot spots at the RBD/ACE2 interface, elucidating how each omicron mutation affects ACE2 binding. The enhanced ACE2 binding by the omicron RBD may facilitate the omicron variant's infection of the respiratory tracts where ACE2 expression level is low. Our study provides insights into the receptor recognition and tissue tropism of the omicron variant. IMPORTANCE Despite the scarcity of the SARS-CoV-2 receptor-human angiotensin-converting enzyme 2 (ACE2)-in the respiratory tract, the omicron variant efficiently infects the respiratory tract, causing rapid and widespread infections of COVID-19. The omicron variant contains extensive mutations in the receptor-binding domain (RBD) of its spike protein that recognizes human ACE2. Here, using a combination of biochemical and X-ray crystallographic approaches, we showed that the omicron RBD binds to ACE2 with enhanced affinity and also elucidated the role of each of the omicron mutations in ACE2 binding. The enhanced ACE2 binding by the omicron RBD may contribute to the omicron variant's new viral tropism in the respiratory tract despite the low level of ACE2 expression in the tissue. These findings help us to understand tissue tropism of the omicron variant and shed light on the molecular evolution of SARS-CoV-2. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/35343765/Structural_Basis_for_Human_Receptor_Recognition_by_SARS_CoV_2_Omicron_Variant_BA_1_ DB - PRIME DP - Unbound Medicine ER -