An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain
Nicholas C. Wu,
Meng Yuan,
Hejun Liu,
Chang-Chun D. Lee,
Xueyong Zhu,
Sandhya Bangaru,
Jonathan L. Torres,
Tom G. Caniels,
Philip J.M. Brouwer,
Marit J. van Gils,
Rogier W. Sanders,
Andrew B. Ward,
Ian A. Wilson
Affiliations
Nicholas C. Wu
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Meng Yuan
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Hejun Liu
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Chang-Chun D. Lee
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Xueyong Zhu
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Sandhya Bangaru
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Jonathan L. Torres
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Tom G. Caniels
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands
Philip J.M. Brouwer
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands
Marit J. van Gils
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands
Rogier W. Sanders
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
Andrew B. Ward
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
Ian A. Wilson
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA; Corresponding author
Summary: 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.
