Structural Studies of Coronavirus Fusion Glycoproteins

NIH COVID-19 SIG Lecture Series SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic. Coronavirus spike (S) glycoprotein trimers promote the virus ’ s entry into cells and are the main targets of the humoral immune response. We demonstrated that Angiotensin-converting enzyme 2 (ACE2) is a functional entry receptor for this novel coronavirus and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We used cryo-electron microscopy to determine the structures of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, indicating that vaccination can elicit cross-neutralizing antibodies targeting conserved S epitopes. We subsequently isolated a monoclonal antibody (termed S309) from the memory B cells of an individual who recovered from SARS-CoV in 2003 and showed that S309 potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a receptor-binding domain--glycan-containing epitope, which is conserved within the sarbecovirus subgenus--without competing with receptor attachment. Antibody ...
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