Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

Yan, R.; Wang, R.; Ju, B.; Yu, J.; Zhang, Y.; Liu, N.; Wang, J.; Zhang, Q.; Chen, P.; Zhou, B.; Li, Y.; Zhang, S.; Tian, L.; Zhong, X.; Cheng, L.; Ge, X.; Zhao, J.; Wang, H.-w.; Wang, X.; Zhang, Z.; Zhang, L.; Zhou, Q.

doi:10.1101/2020.10.13.336800

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bioRxiv · 10.1101/2020.10.13.336800

Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies

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Abstract

Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the "up" conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

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Yan, R., Wang, R., Ju, B., Yu, J., Zhang, Y., Liu, N., Wang, J., Zhang, Q., Chen, P., Zhou, B., Li, Y., Zhang, S., Tian, L., Zhong, X., Cheng, L., Ge, X., Zhao, J., Wang, H.-w., Wang, X., Zhang, Z., Zhang, L., Zhou, Q.. 2020-10-13. Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection by human potent neutralizing antibodies. https://doi.org/10.1101/2020.10.13.336800

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