Cryo-EM reveals conformational variability in the SARS-CoV-2 spike protein RBD induced by two broadly neutralizing monoclonal antibodies.

SARS-CoV-2 spike proteins play a critical role in infection by interacting with the ACE2 receptors. Their receptor-binding domains and N-terminal domains exhibit remarkable flexibility and can adopt various conformations that facilitate receptor engagement. Previous structural studies have reported the RBD of the spike protein in "up", "down", and various intermediate states, as well as its different conformational changes during ACE2 binding. This flexibility also influences its interactions with the neutralizing antibodies, yet its role in the antibody complexes remains understudied. In this study, we used cryo-electron microscopy to investigate the structural properties of two broadly neutralizing monoclonal antibodies, THSC20.HVTR04 and THSC20.HVTR26. These antibodies were isolated from an unvaccinated individual and demonstrated potent neutralization of multiple SARS-CoV-2 variants. Our analysis revealed distinct binding characteristics and conformational changes in the spike RBD upon binding with the monoclonal antibodies. The structural characterization of the spike protein-monoclonal antibody complexes provided valuable insights into the structural variability of the spike protein and the possible mechanisms for antibody-mediated neutralization.