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

By Gabriele Cerutti, Yicheng Guo, Pengfei Wang, Manoj S. Nair, Yaoxing Huang, Jian Yu, Lihong Liu, Phinikoula S. Katsamba, Fabiana Bahna, Eswar R. Reddem, Peter D Kwong, David D Ho, Zizhang Sheng, Lawrence Shapiro

Posted 29 Jun 2021
bioRxiv DOI: 10.1101/2021.06.29.450397

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 3.7 [A] resolution 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 {beta}-sandwich. Interestingly, this pocket has been previously identified as the binding site for hydrophobic molecules including heme metabolites, but we observe their presence to not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains a distinctive neutralization potency with variants of concern (VOC). Overall, we reveal a hydrophobic pocket in NTD proposed for immune evasion can actually be used by the immune system for recognition.

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