Botulinum neurotoxins (BoNTs) and
tetanus neurotoxin are the causative agents of the paralytic diseases
botulism and
tetanus, respectively. The potency of the clostridial
neurotoxins (CNTs) relies primarily on their highly specific binding to nerve terminals and cleavage of
SNARE proteins. Although individual CNTs utilize distinct
proteins for entry, they share common
ganglioside co-receptors. Here, we report the crystal structure of the BoNT/F receptor-binding domain in complex with the
sugar moiety of
ganglioside GD1a. GD1a binds in a shallow groove formed by the conserved
peptide motif E … H … SXWY … G, with additional stabilizing interactions provided by two
arginine residues. Comparative analysis of BoNT/F with other CNTs revealed several differences in the interactions of each toxin with
ganglioside. Notably, exchange of BoNT/F His-1241 with the corresponding
lysine residue of BoNT/E resulted in increased affinity for GD1a and conferred the ability to bind
ganglioside GM1a. Conversely, BoNT/E was not able to bind GM1a, demonstrating a discrete mechanism of
ganglioside recognition. These findings provide a structural basis for
ganglioside binding among the CNTs and show that individual toxins utilize unique
ganglioside recognition strategies.