Abstract
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.