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In a study recently posted to the biorxiv* pre-print server, researchers used cryogenic electron microscopy (cryo-EM) analysis to capture the open and closed states of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant’s spike protein.

Study: Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization. Image Credit: natatravel/Shutterstock

The open and closed states of the Omicron spike appeared more compact compared to that of the SARS-CoV-2 G614 strain, 40 panadol overdose which is likely due to the enhanced protomer-protomer and S1-S2 subunit interactions induced by the unique substitution mutations in the Omicron variant.

The SARS-CoV-2 Omicron variant has 37 mutations in its S protein which confer significant immune evasion to the variant. Out of the 37 Omicron spike mutations, 15 are in the receptor-binding domain (RBD) which mediates the binding of the virus to the host angiotensin-converting enzyme 2 (ACE2) receptor. The RBD is also a major target for neutralizing antibodies.

Although nine mutations within the receptor-binding motif (RBM) interact directly with the ACE2, Omicron still uses ACE2 as an entry receptor. Compared to the wild-type (WT) spike protein, the Omicron spike also has an increased binding affinity to the host ACE2 receptor. According to recent reports, the Omicron spike also shows reduced furin cleavage and S1 shedding.

Given that Omicron is spreading across the globe at an unprecedented speed causing considerable morbidity, it is essential to achieve a better understanding of the structural basis of the increased transmissibility and enhanced immune escape of Omicron.

The study

In the present study, researchers addressed the structural aspects of Omicron spike protein binding to the ACE2 receptor and how Omicron identifies or evades neutralizing antibodies against the original strain. They obtained two cryo-EM structures of the Omicron S trimer in the open and closed states at 3.21 and 3.08 Å resolution, respectively.

Bio-layer interferometry (BLI) assay was used to determine the binding affinities of S trimers to the ACE2 receptor. An enzyme-linked immunosorbent assay (ELISA) was used to test the binding of recombinant Omicron spike with anti-SARS-CoV-2 monoclonal antibodies (MAbs) previously developed by the researchers. Recombinant S trimer proteins from the SARS-CoV-2 WT, Delta, or Omicron strains were used in the assay and the data were analyzed using non-linear regression using GraphPad Prism 8.


The results showed that, compared to the S trimer of the Delta, Beta, and Kappa variants, the S-closed and S-open structures of the Omicron variant appeared more twisted or compact. This could be due to the unique Omicron substitution mutations in the SD1 and S2 regions – T547K, N856K, and N764K – that induce more interactions between the protomers and between Omicron S1 and S2 subunits. The Omicron substitutions may hinder its spike transformation towards the open state, which is prone to fusion, and towards S1 shielding.

Interestingly, the cryo-EM analysis revealed a dominantly populated (61%) conformation for the closed state of the Omicron S trimer where all the RBDs were buried. This results in conformational masking, which prevents antibody binding and neutralization at the receptor binding sites. This conformational masking may be the underlying mechanism of immune evasion for the Omicron spike protein. Comparatively, a previous work by the researchers showed that the Delta S trimer had an open-transition ratio of 75.3%-24.7%, which indicates the conformational masking mechanism of the Delta variant may be less effective.

The researchers also captured two states for the Omicron spike-ACE2 complex with the spike binding to one or two ACE2 receptors. This shows that the substitutions on the Omicron RBD lead to new salt bridges and H-bonds and more beneficial electrostatic surface properties. This strengthens the interaction of the spike protein with ACE2, which is in line with the increased ACE2 affinity of the Omicron variant compared to the G614 strain.

The team also analyzed the cryo-EM structures of the complex formed between the Omicron spike and S3H3 Fab, which is an antibody that can cross-neutralize major variants of concern (VOC) including the Omicron. This illustrates the structural basis for S3H3-mediated broad-spectrum antibody neutralization.


The study shows that Omicron escapes the majority of the RBD-directed MAbs due to its relatively higher residue changes in the RBD and conformational masking. However, this variant of concern is still sensitive to the neutralizing MAb S3H3 which targets SD1.

To summarize, the study findings provide structural insights into the immune evasion and high transmissibility of the Omicron variant and could also help the development of broad-spectrum vaccines against emerging SARS-CoV-2 variants.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Qin Hong, Wenyu Han, Jiawei Li, Shiqi Xu, Yifan Wang, Zuyang Li, Yanxing Wang, Chao Zhang, Zhong Huang, Yao Cong. (2022). Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization. bioRxiv. doi:

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Assay, binding affinity, Coronavirus, Coronavirus Disease COVID-19, Electron, Electron Microscopy, Enzyme, Microscopy, Omicron, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Written by

Susha Cheriyedath

Susha has a Bachelor of Science (B.Sc.) degree in Chemistry and Master of Science (M.Sc) degree in Biochemistry from the University of Calicut, India. She always had a keen interest in medical and health science. As part of her masters degree, she specialized in Biochemistry, with an emphasis on Microbiology, Physiology, Biotechnology, and Nutrition. In her spare time, she loves to cook up a storm in the kitchen with her super-messy baking experiments.

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