Department of Biology and Biochemistry, Claverton Down, University of Bath, UK.
Ipsen Bioinnovation Limited, Abingdon, UK.
FEBS Open Bio. 2020 Mar;10(3):298-305. doi: 10.1002/2211-5463.12790. Epub 2020 Jan 28.
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 ), translocation domain and catalytic domain (light chain) . The H 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 /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 /A3 with H /A1 revealed subtle conformational differences at the ganglioside binding site upon carbohydrate binding.
肉毒神经毒素（BoNTs）是人类已知的最毒蛋白之一。其分子结构由三个必需结构域组成 - 细胞结合域（H ）、易位结构域和催化结构域（轻链）。H 结构域通过涉及蛋白质受体和神经节苷脂的双重受体复合物促进 BoNTs 与神经元膜的高度特异性结合。血清型 A 各亚型之间活性/毒性的差异归因于蛋白质和神经节苷脂相互作用的变化，其影响对于新型 BoNT 为基础的治疗剂的设计非常重要。在这里，我们以 1.75 Å 的分辨率展示了 BoNT/A3 细胞结合域（H /A3）与神经节苷脂 GD1a 形成复合物的结构。该结构表明，六个残基通过几个关键氢键相互作用与 GD1a 的三个最外层单糖相互作用。H /A3 与 H /A1 的结构详细比较表明，在碳水化合物结合时，神经节苷脂结合位点的构象存在细微差异。
