Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain
Gabriele Cerutti,
Yicheng Guo,
Pengfei Wang,
Manoj S. Nair,
Maple Wang,
Yaoxing Huang,
Jian Yu,
Lihong Liu,
Phinikoula S. Katsamba,
Fabiana Bahna,
Eswar R. Reddem,
Peter D. Kwong,
David D. Ho,
Zizhang Sheng,
Lawrence Shapiro
Affiliations
Gabriele Cerutti
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Yicheng Guo
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Pengfei Wang
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Manoj S. Nair
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Maple Wang
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Yaoxing Huang
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Jian Yu
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Lihong Liu
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Phinikoula S. Katsamba
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Fabiana Bahna
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Eswar R. Reddem
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Peter D. Kwong
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
David D. Ho
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Corresponding author
Zizhang Sheng
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Corresponding author
Lawrence Shapiro
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: Antibodies that potently neutralize SARS-CoV-2 target mainly the receptor-binding domain or the N-terminal domain (NTD). Over a dozen potently neutralizing NTD-directed antibodies have been studied structurally, and all target a single antigenic supersite in NTD (site 1). Here, we report the cryo-EM structure of a potent NTD-directed neutralizing antibody 5-7, which recognizes a site distinct from other potently neutralizing antibodies, inserting a binding loop into an exposed hydrophobic pocket between the two sheets of the NTD β sandwich. Interestingly, this pocket was previously identified as the binding site for hydrophobic molecules, including heme metabolites, but we observe that their presence does not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains neutralization potency with many variants of concern (VOCs). Overall, we reveal that a hydrophobic pocket in NTD proposed for immune evasion can be used by the immune system for recognition.
