OmniVira

Literature detail

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins.

Youwei Xu1 Canrong Wu1 Xiaodan Cao2 Chunyin Gu2 Heng Liu1 Mengting Jiang1,3 Xiaoxi Wang1 Qingning Yuan1,4 Kai Wu1,4 Jia Liu2 Deyi Wang2 Xianqing He2 Xueping Wang2 Su-Jun Deng5 H Eric Xu6,7,8 Wanchao Yin9,10,11
Affiliations 11 institutions
  1. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  2. Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai, China.
  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  4. The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  5. Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai, China. [email protected].
  6. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  7. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  8. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  9. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
  10. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  11. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China. [email protected].
PMID 35641567 2022 Cell Res eng ppublish
PubMed DOI Browse context

Article

Publication summary

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle, which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections.

COVID-19 Immune Evasion Angiotensin-Converting Enzyme 2 Animals Antibodies, Neutralizing Mice SARS-CoV-2 Spike Glycoprotein, Coronavirus JMB2002 spike protein, SARS-CoV-2

Structured evidence records

Evidence records

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

Omicron BA.2 spike trimer binds human ACE2 with greatly increased affinity and all RBDs adopt an open conformation facilitating receptor engagement.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding.

Method
receptor binding study; structural analysis
Receptors
human ACE2
Receptor Usage Extraction confidence 1.00
Key finding

Omicron BA.1 and BA.2 spike trimers show high-affinity binding to mouse ACE2, supported by structural analyses, unlike the wildtype spike.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions.

Method
receptor binding study; structural analysis
Receptors
mouse ACE2
Receptor Usage Extraction confidence 1.00
Key finding

Omicron BA.1 spike trimer binds mouse ACE2 with high affinity.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency.

Method
receptor binding study
Receptors
mouse ACE2
Receptor Usage Extraction confidence 1.00
Key finding

Wildtype SARS-CoV-2 spike binds cat ACE2 but does not bind mouse ACE2 efficiently.

Virus
Not specified
Location
Not specified
Supporting text

In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2.

Method
receptor binding study
Receptors
cat ACE2
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.70
Key finding

Structural evidence indicates that SARS-CoV-2 Omicron BA.1 and BA.2 spike proteins evolved to bind mouse ACE2 efficiently, suggesting possible interspecies adaptation and a human-cat-mouse-human evolutionary route.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle.

Genes or proteins
spike
Analysis methods
structural analysis; comparative evolution reconstruction
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

The Omicron BA.2 spike glycoprotein displays structural adaptations that increase its binding affinity to human and mouse ACE2, supporting enhanced infectivity and potential host adaptation mechanisms.

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

Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals all three receptor-binding domains in open conformation, ready for ACE2 binding. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency, suggesting possible evolution via a human-cat-mouse-human circle.

Genes or proteins
spike glycoprotein
Receptors
ACE2
Mechanism types
receptor_binding; cell_entry; immune_escape; host_range_expansion