An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain

• Published in: Cell reports (Cambridge) Vol. 33; no. 3; p. 108274
• Main Authors: Wu, Nicholas C., Yuan, Meng, Liu, Hejun, Lee, Chang-Chun D., Zhu, Xueyong, Bangaru, Sandhya, Torres, Jonathan L., Caniels, Tom G., Brouwer, Philip J.M., van Gils, Marit J., Sanders, Rogier W., Ward, Andrew B., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.10.2020; Elsevier; Cell Press
• Subjects: antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Betacoronavirus - immunology; Complementarity Determining Regions - immunology; Coronavirus Infections - virology; COVID-19; Crystallography, X-Ray; Humans; Immunoglobulin Heavy Chains - immunology; Neutralization Tests; Pandemics; Pneumonia, Viral - virology; Protein Domains - immunology; receptor-binding domain; SARS-CoV-2; Spike Glycoprotein, Coronavirus - immunology; spike protein; x-ray crystallography; COVID-19; x-ray crystallography; SARS-CoV-2; antibodies; spike protein; receptor-binding domain
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108274

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization. [Display omitted] •Crystal structures of IGHV3-53 antibodies that frequently bind SARS-CoV-2 RBD•Binding modes (A and B) of these IGHV3-53 antibodies depend on CDR H3 length•Germline-encoded CDR H1 and H2 motifs dominate the two binding poses•CDR H3 length of IGHV3-53 antibodies is associated with light chain preference Antibodies to the SARS-CoV-2 receptor-binding domain are commonly encoded by IGHV3-53, and most have a short CDR H3. Wu et al. show that IGHV3-53 antibodies with a long CDR H3 adopt an alternative binding mode, demonstrating that IGHV3-53 is even more versatile than previously thought in targeting SARS-CoV-2.