Crystal structure of botulinum neurotoxin subtype A3 cell binding domain in complex with GD1a co‐receptor ganglioside

Botulinum neurotoxins (BoNTs) are one of the most toxic proteins known to humans. Their molecular structure is comprised of three essential domains—a cell binding domain (H(C)), translocation domain and catalytic domain (light chain) . The H(C) domain facilitates the highly specific binding of BoNTs to the neuronal membrane via a dual‐receptor complex involving a protein receptor and a ganglioside. Variation in activity/toxicity across subtypes of serotype A has been attributed to changes in protein and ganglioside interactions, and their implications are important in the design of novel BoNT‐based therapeutics. Here, we present the structure of BoNT/A3 cell binding domain (H(C)/A3) in complex with the ganglioside GD1a at 1.75 Å resolution. The structure revealed that six residues interact with the three outermost monosaccharides of GD1a through several key hydrogen bonding interactions. A detailed comparison of structures of H(C)/A3 with H(C)/A1 revealed subtle conformational differences at the ganglioside binding site upon carbohydrate binding.