LAUSR

Significance The immune response to Galα1–3Galβ1–4GlcNAc (α-gal) has been linked to human allergy and inflammation, and to resistance to xenotransplantation and infection. Here we investigate structural and genetic features that shape the antibody response to α-gal. Using crystallography, single-cell sorting, and sequencing, we observe a conserved sequence motif (W33 motif) in the complementarity-determining region of the antibody heavy chain. The germline-encoded aromatic residue directly contacts the α-gal antigen, analogous to what has been observed in broadly neutralizing antibodies in HIV and other infectious diseases. Our findings outline common binding modes and germline usage underpinning the α-gal response, providing molecular insights and guidance for drug development efforts.