Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant

Cui, Z.; Liu, P.; Wang, N.; Wang, L.; Fan, K.; Zhu, Q.; Wang, K.; Chen, R.; Feng, R.; Jia, Z.; Yang, M.; Zhu, B.; Fu, W.; Chu, T.; Feng, L.; Wang, Y.; Pei, X.; Yang, P.; Xie, X. S.; Cao, L.; Cao, Y. R.; Wang, X.

doi:10.1101/2021.12.29.474402

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bioRxiv · 10.1101/2021.12.29.474402

Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant

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Abstract

The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging new interactions that stably maintain an "active" conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Apart from already existing mutations, we have identified three new immune escape sites: 1) Q493R, 2) G446S and 3) S371L/S373P/S375F that confers greater resistance to five of the six classes of RBD-antibodies. Structure of the Omicron S bound with human ACE2, together with analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

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Cui, Z., Liu, P., Wang, N., Wang, L., Fan, K., Zhu, Q., Wang, K., Chen, R., Feng, R., Jia, Z., Yang, M., Zhu, B., Fu, W., Chu, T., Feng, L., Wang, Y., Pei, X., Yang, P., Xie, X. S., Cao, L., Cao, Y. R., Wang, X.. 2021-12-30. Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant. https://doi.org/10.1101/2021.12.29.474402

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