Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Protein Sciences Department, Ipsen Bioinnovation Limited, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK.
Toxins (Basel). 2022 May 19;14(5):356. doi: 10.3390/toxins14050356.
Botulinum neurotoxins (BoNT) are a group of clostridial toxins that cause the potentially fatal neuroparalytic disease botulism. Although highly toxic, BoNTs are utilized as therapeutics to treat a range of neuromuscular conditions. Several serotypes (BoNT/A-/G, /X) have been identified with vastly differing toxicological profiles. Each serotype can be further sub-categorised into subtypes due to subtle variations in their protein sequence. These minor changes have been attributed to differences in both the duration of action and potency for BoNT/A subtypes. BoNTs are composed of three domains-a cell-binding domain, a translocation domain, and a catalytic domain. In this paper, we present the crystal structures of the botulinum neurotoxin A2 cell binding domain, both alone and in complex with its receptor ganglioside GD1a at 1.63 and 2.10 Å, respectively. The analysis of these structures reveals a potential redox-dependent Lys-O-Cys bridge close to the ganglioside binding site and a hinge motion between the H and H subdomains. Furthermore, we make a detailed comparison with the previously reported H/A2:SV2C structure for a comprehensive structural analysis of H/A2 receptor binding.
肉毒杆菌神经毒素（BoNT）是一组梭菌毒素，可导致潜在致命的神经麻痹性疾病肉毒中毒。尽管具有高度毒性，但 BoNT 已被用作治疗一系列神经肌肉疾病的药物。已经确定了几种血清型（BoNT/A-/G、/X），它们具有截然不同的毒理学特征。由于其蛋白质序列的细微差异，每种血清型都可以进一步细分为亚型。这些微小的变化归因于 BoNT/A 亚型的作用持续时间和效力的差异。BoNT 由三个结构域组成 - 细胞结合结构域、易位结构域和催化结构域。在本文中，我们展示了肉毒杆菌神经毒素 A2 细胞结合结构域的晶体结构，分别单独和与受体神经节苷脂 GD1a 复合的结构，分辨率分别为 1.63 和 2.10 Å。对这些结构的分析揭示了靠近神经节苷脂结合位点的潜在氧化还原依赖性 Lys-O-Cys 桥和 H 和 H 亚结构域之间的铰链运动。此外，我们与之前报道的 H/A2:SV2C 结构进行了详细比较，对 H/A2 受体结合进行了全面的结构分析。
