Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape

Zhennan Zhao, Jingya Zhou, Mingxiong Tian, Min Huang, Sheng Liu, Yufeng Xie, Pu Han, Chongzhi Bai, Pengcheng Han, Anqi Zheng, Lutang Fu, Yuanzhu Gao, Qi Peng, Ying Li, Yan Chai, Zengyuan Zhang, Xin Zhao, Hao Song (), Jianxun Qi (), Qihui Wang (), Peiyi Wang () and George F. Gao ()
Additional contact information
Zhennan Zhao: Chinese Academy of Sciences
Jingya Zhou: University of Chinese Academy of Sciences
Mingxiong Tian: Shanxi University
Min Huang: University of Science and Technology of China
Sheng Liu: Southern University of Science and Technology
Yufeng Xie: Chinese Academy of Sciences
Pu Han: Chinese Academy of Sciences
Chongzhi Bai: Shanxi Province Hospital of Traditional Chinese Medicine
Pengcheng Han: Chinese Academy of Sciences
Anqi Zheng: Chinese Academy of Sciences
Lutang Fu: Southern University of Science and Technology
Yuanzhu Gao: Southern University of Science and Technology
Qi Peng: Chinese Academy of Sciences
Ying Li: Chinese Academy of Sciences
Yan Chai: Chinese Academy of Sciences
Zengyuan Zhang: Chinese Academy of Sciences
Xin Zhao: Chinese Academy of Sciences
Hao Song: Chinese Academy of Sciences
Jianxun Qi: Chinese Academy of Sciences
Qihui Wang: Chinese Academy of Sciences
Peiyi Wang: Southern University of Science and Technology
George F. Gao: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Omicron SARS-CoV-2 is rapidly spreading worldwide. To delineate the impact of emerging mutations on spike’s properties, we performed systematic structural analyses on apo Omicron spike and its complexes with human ACE2 or S309 neutralizing antibody (NAb) by cryo-EM. The Omicron spike preferentially adopts the one-RBD-up conformation both before and after ACE2 binding, which is in sharp contrast to the orchestrated conformational changes to create more up-RBDs upon ACE2 binding as observed in the prototype and other four variants of concern (VOCs). Furthermore, we found that S371L, S373P and S375F substitutions enhance the stability of the one-RBD-up conformation to prevent exposing more up-RBDs triggered by ACE2 binding. The increased stability of the one-RBD-up conformation restricts the accessibility of S304 NAb, which targets a cryptic epitope in the closed conformation, thus facilitating the immune evasion by Omicron. These results expand our understanding of Omicron spike’s conformation, receptor binding and antibody evasion mechanism.

Date: 2022
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DOI: 10.1038/s41467-022-32665-7

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