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

doi:10.1016/j.celrep.2021.109928

Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain

Cell Rep. 2021 Nov 2;37(5):109928. doi: 10.1016/j.celrep.2021.109928. Epub 2021 Oct 16.

Authors

Affiliations

¹ Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
² Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
³ 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.
⁴ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: dh2994@cumc.columbia.edu.
⁵ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: zs2248@cumc.columbia.edu.
⁶ 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. Electronic address: lss8@columbia.edu.

Abstract

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.

Keywords: COVID-19; N-terminal domain; NTD; SARS-CoV-2; antigenic supersite; cryo-EM; neutralizing antibody; variants of concern.

Abstract

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