Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia
Copyright policy )Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity.
- Ecole Normale Supérieure de Lyon France
- Inserm France
- University of California, San Francisco United States
- Claude Bernard University Lyon 1 France
- Howard Hughes Medical Institute United States
Biomedical and clinical sciences, recombinant monoclonal antibody, Coronaviruses, coronavirus, Antigen-Antibody Complex, Medical and Health Sciences, Giant Cells, Membrane Fusion, Coronaviruses Therapeutics and Interventions, Cricetinae, 2.1 Biological and endogenous factors, Lung, Neutralizing, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, receptor binding domain, SARS-CoV, Biological Sciences, Spike Glycoprotein, Biological sciences, Infectious Diseases, receptor binding domain (RBD), [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Angiotensin-Converting Enzyme 2, phage display, Infection, Protein Binding, 570, Protein Structure, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, 610, CHO Cells, Spike protein, Antibodies, Article, Quaternary, Cricetulus, Protein Domains, Peptide Library, Biodefense, Animals, Humans, syncytia, Protein Structure, Quaternary, Binding Sites, Biomedical and Clinical Sciences, SARS-CoV-2, Cryoelectron Microscopy, COVID-19, Antibodies, Neutralizing, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, Immunization, Developmental Biology
Biomedical and clinical sciences, recombinant monoclonal antibody, Coronaviruses, coronavirus, Antigen-Antibody Complex, Medical and Health Sciences, Giant Cells, Membrane Fusion, Coronaviruses Therapeutics and Interventions, Cricetinae, 2.1 Biological and endogenous factors, Lung, Neutralizing, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, receptor binding domain, SARS-CoV, Biological Sciences, Spike Glycoprotein, Biological sciences, Infectious Diseases, receptor binding domain (RBD), [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, [SDV.IMM]Life Sciences [q-bio]/Immunology, Angiotensin-Converting Enzyme 2, phage display, Infection, Protein Binding, 570, Protein Structure, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, 610, CHO Cells, Spike protein, Antibodies, Article, Quaternary, Cricetulus, Protein Domains, Peptide Library, Biodefense, Animals, Humans, syncytia, Protein Structure, Quaternary, Binding Sites, Biomedical and Clinical Sciences, SARS-CoV-2, Cryoelectron Microscopy, COVID-19, Antibodies, Neutralizing, Coronavirus, Emerging Infectious Diseases, Good Health and Well Being, Immunization, Developmental Biology
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