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 (HC), translocation domain and catalytic domain (light chain) . The HC 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 (HC/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 HC/A3 with HC/A1 revealed subtle conformational differences at the ganglioside binding site upon carbohydrate binding.
Highlights
Botulinum neurotoxins (BoNTs) are one of the most toxic proteins known to humans
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
BoNTs are generally produced by Clostridium botulinum; bont gene clusters have recently been identified in different bacterial species [2,3]
Summary
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 (HC), translocation domain and catalytic domain (light chain). Botulinum neurotoxin (BoNT) causes the disease botulism by targeting cells of the neuromuscular junction and cleaving a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein(s). /A, /B, /E and /F are associated with human botulism making them potential candidates for the development of BoNT-based therapeutics These serotypes are further divided into subtypes (e.g., /A1-/A8) based on minor amino acid variations that may affect toxicity [4,5,6]. Abbreviations BoNT, botulinum neurotoxin; GalNAc, N-acetylgalactosamine; GBS, ganglioside binding site; Glu, glucose; HC, cell binding domain; HC, heavy chain; HN, translocation domain; LC, light chain; Sia, sialic acid; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor
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