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 3.7 Å 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 β-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.
Highlights
Cryo-EM structure of neutralizing antibody 5-7 in complex with SARS CoV-2 spike
5-7 recognizes NTD outside of the previously identified antigenic supersite
5-7 binds to a site known to accommodate numerous hydrophobic ligands
Structural basis of 5-7 neutralization tolerance to some variants of concern
Competing Interest Statement
DDH, YH, JY, LL and PW are inventors of a patent describing some of the antibodies reported on here.
Footnotes
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