Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determine the structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three use VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy-chain N53I-enhancing binding and light-chain tyrosines recognizing F486(RBD). Despite these similarities, class members bind both RBD-up and -down conformations of the spike, with a subset of antibodies using elongated CDRH3s to recognize glycan N343 on a neighboring RBD-a quaternary interaction accommodated by an increase in RBD separation of up to 12 angstrom. The VH1-2 antibody class, thus, uses modular recognition encoded by modular genetic elements to effect potent neutralization, with the VH-gene component specifying recognition of RBD and the CDRH3 component specifying quaternary interactions.

Automated summary

Antibodies derived from the VH1-2 gene have been shown to be potent neutralizing antibodies against SARS-CoV-2, with three VH1-2-derived antibodies (2-15, 2-43, and H4) using VH1-2-encoded motifs to recognize the receptor-binding domain (RBD) of the virus spike protein. Despite genetic similarities, these antibodies are able to recognize both up and down conformations of the RBD, with some antibodies using elongated CDRH3s to interact with glycan N343 on a neighboring RBD. The VH1-2 antibody class utilizes modular genetic elements for modular recognition, with VH gene specifying RBD recognition and CDRH3 specifying quaternary interactions.