World’s first molecular-level structural analysis of the Omicron variant spike protein


Researchers at UBC’s faculty of medicine have conducted the world’s first molecular-level structural analysis of the Omicron variant spike protein.

The analysis – done at near atomic resolution using cryo-electron microscopy – reveals how the heavily mutated Omicron variant attaches to and infects human cells.

“Understanding the molecular structure of the viral spike protein is important as it will allow us to develop more effective treatments against Omicron and related variants in the future,” said lead author Dr. Sriram Subramaniam (he/him), professor in UBC’s department of biochemistry and molecular biology. “By analyzing the mechanisms by which the virus infects human cells, we can develop better treatments that disrupt that process and neutralize the virus.”

The spike protein, which is located on the outside of a coronavirus, enables SARS-CoV-2 to enter human cells. The Omicron variant has an unprecedented 37 mutations on its spike protein—three to five times more than previous variants.

The structural analysis revealed that several mutations (R493, S496 and R498) create new salt bridges and hydrogen bonds between the spike protein and the human cell receptor known as ACE2.

The researchers concluded that these new bonds appear to increase binding affinity – how strongly the virus attaches to human cells – while other mutations (K417N) decrease the strength of this bond.

The spike protein comprises 2 domains, the S1 domain, which contains the receptor binding domain (RBD) and the S2 domain responsible for membrane fusion. The Omicron variant has 37 mutations (Fig. 1A) in the spike protein relative to the initial Wuhan-Hu-1 strain, with 15 of them present in the receptor binding domain (RBD) (1).

The RBD mediates attachment to human cells through the ACE2 receptor and is the primary target of neutralizing antibodies (2, 3). The Delta variant, which was the predominant SARS-CoV-2 lineage until the emergence of Omicron, has 7 mutations in the spike protein relative to the Wuhan-Hu-1 strain, with 2 mutations falling within its RBD.

Of the Delta spike mutations, two (T478K in the RBD and D614G at the C terminus of S1) are shared with the Omicron strain. Analysis of the sequence of the Omicron genome suggests that it is not derived from any of the currently circulating variants, and may have a different origin (4).

FIG. 1. Cryo-EM structure of the Omicron spike protein.
(A) A schematic diagram illustrating the domain arrangement of the spike protein. Mutations present in the Omicron variant spike protein are labeled. (B) Cryo-EM map of the Omicron spike protein at 2.79 Å resolution. Protomers are colored in different shades of purple. (C) Cryo-EM structure of Omicron spike protein indicating the locations of modeled mutations on one protomer. (D) The Omicron spike receptor-binding domain (RBD) shown in two orthogonal orientations with Cα positions of the mutated residues shown as red spheres.

“Overall, the findings show that Omicron has greater binding affinity than the original virus, with levels more comparable to what we see with the Delta variant,” said Dr. Subramaniam. “It is remarkable that the Omicron variant evolved to retain its ability to bind with human cells despite such extensive mutations.”

The researchers conducted further experiments showing that the Omicron spike protein exhibits increased antibody evasion. In contrast to previous variants, Omicron showed measurable evasion from all six monoclonal antibodies tested, with complete escape from five.

The variant also displayed increased evasion of antibodies collected from vaccinated individuals and unvaccinated COVID-19 patients.

“Notably, Omicron was less evasive of the immunity created by vaccines, compared to immunity from natural infection in unvaccinated patients. This suggests that vaccination remains our best defense,” said Dr. Subramaniam. Based on the observed increase in binding affinity and antibody evasion, the researchers say that the spike protein mutations are likely contributing factors to the increased transmissibility of the Omicron variant.

Next, Dr. Subramaniam says his research team will leverage this knowledge to support the development of more effective treatments.

“An important focus for our team is to better understand the binding of neutralizing antibodies and treatments that will be effective across the entire range of variants, and how those can be used to develop variant-resistant treatments.”

Cryo-EM structure of the Omicron spike protein-ACE2 complex.
(A) Cryo-EM map of the Omicron spike protein in complex with human ACE2 at 2.45 Å resolution after global refinement. The three protomers are colored in different shades of purple and the density for bound ACE2 is colored in blue. (B) Cryo-EM map of the Omicron spike RBD in complex with ACE2 at 2.66 Å resolution after focused refinement. The inset box indicates the region highlighted in (C). (C) Cryo-EM density mesh at the Omicron spike RBD-ACE2 interface, with fitted atomic model. Yellow and red dashed lines represent new hydrogen bonds and ionic interactions, respectively. (D to F) Comparison of the RBD-ACE2 interface between the Omicron (upper) and Delta (lower) variants. Compared to the Delta variant, new interactions are formed as a result of the mutations Q493R, G496S, and Q498R (D), and local structural changes due to the N501Y and Y505H mutations present (E) in the Omicron variant. The salt bridge between Delta RBD K417 and ACE2 D30 that is present in the Delta variant spike protein but lost in the Omicron variant is highlighted in (F). Yellow and red dashed lines represent hydrogen bonds and ionic interactions, respectively.



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