Structural basis of human ACE2 higher binding affinity to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1

Linjie Li; Hanyi Liao; Yumin Meng; Weiwei Li; Pengcheng Han; Kefang Liu; Qing Wang; Dedong Li; Yanfang Zhang; Liang Wang; Zheng Fan; Yuqin Zhang; Qiyue Wang; Xin Zhao; Yeping Sun; Niu Huang; Jianxun Qi; George Fu Gao

doi:10.1016/j.cell.2022.06.023

Structural basis of human ACE2 higher binding affinity to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1

Cell. 2022 Aug 4;185(16):2952-2960.e10. doi: 10.1016/j.cell.2022.06.023. Epub 2022 Jun 16.

Authors

Linjie Li¹, Hanyi Liao¹, Yumin Meng¹, Weiwei Li¹, Pengcheng Han², Kefang Liu³, Qing Wang⁴, Dedong Li³, Yanfang Zhang³, Liang Wang³, Zheng Fan³, Yuqin Zhang³, Qiyue Wang³, Xin Zhao⁵, Yeping Sun⁶, Niu Huang⁷, Jianxun Qi¹, George Fu Gao⁸

Affiliations

¹ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; School of Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, China.
³ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁴ National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
⁵ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhaoxin@im.ac.cn.
⁶ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: sunyeping@im.ac.cn.
⁷ National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: huangniu@nibs.ac.cn.
⁸ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: gaof@im.ac.cn.

Abstract

The currently circulating Omicron sub-variants are the SARS-CoV-2 strains with the highest number of known mutations. Herein, we found that human angiotensin-converting enzyme 2 (hACE2) binding affinity to the receptor-binding domains (RBDs) of the four early Omicron sub-variants (BA.1, BA.1.1, BA.2, and BA.3) follows the order BA.1.1 > BA.2 > BA.3 ≈ BA.1. The complex structures of hACE2 with RBDs of BA.1.1, BA.2, and BA.3 reveal that the higher hACE2 binding affinity of BA.2 than BA.1 is related to the absence of the G496S mutation in BA.2. The R346K mutation in BA.1.1 majorly affects the interaction network in the BA.1.1 RBD/hACE2 interface through long-range alterations and contributes to the higher hACE2 affinity of the BA.1.1 RBD than the BA.1 RBD. These results reveal the structural basis for the distinct hACE2 binding patterns among BA.1.1, BA.2, and BA.3 RBDs.

Keywords: Omicron; RBDs; SARS-CoV-2; hACE2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2 / chemistry*
Angiotensin-Converting Enzyme 2 / metabolism
COVID-19*
Humans
Mutation
Peptidyl-Dipeptidase A / metabolism
Protein Binding
Receptors, Virus / metabolism
SARS-CoV-2 / genetics

Substances

Receptors, Virus
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Supplementary concepts

SARS-CoV-2 variants