Rao Krishnamurthy N, Kumaran Desigan, Binz Thomas, Swaminathan Subramanyam
Brookhaven National Laboratory, Biology Department, Upton, NY 11973, USA.
Toxicon. 2005 Jun 1;45(7):929-39. doi: 10.1016/j.toxicon.2005.02.032. Epub 2005 Apr 13.
Clostridium neurotoxins, comprising the tetanus neurotoxin and the seven antigenically distinct botulinum neurotoxins (BoNT/A-G), are among the known most potent bacterial protein toxins to humans. Although they have similar function, sequences and three-dimensional structures, the substrate specificity and the selectivity of peptide bond cleavage are different and unique. Tetanus and botulinum type B neurotoxins enzymatically cleave the same substrate, vesicle-associated membrane protein, at the same peptide bond though the optimum length of substrate peptide required for cleavage by them is different. Here, we present the first experimentally determined three-dimensional structure of the catalytic domain of tetanus neurotoxin and analyze its active site. The structure provides insight into the active site of tetanus toxin's proteolytic activity and the importance of the nucleophilic water and the role of the zinc ion. The probable reason for different modes of binding of vesicle-associated membrane protein to botulinum neurotoxin type B and the tetanus toxin is discussed. The structure provides a basis for designing a novel recombinant vaccine or structure-based drugs for tetanus.
梭菌神经毒素，包括破伤风神经毒素和七种抗原性不同的肉毒杆菌神经毒素（BoNT/A - G），是已知对人类毒性最强的细菌蛋白毒素之一。尽管它们具有相似的功能、序列和三维结构，但底物特异性和肽键裂解的选择性却不同且独特。破伤风神经毒素和B型肉毒杆菌神经毒素在相同的肽键处酶解相同的底物——囊泡相关膜蛋白，不过它们裂解所需的底物肽最佳长度不同。在此，我们展示了破伤风神经毒素催化结构域首个通过实验确定的三维结构，并分析了其活性位点。该结构揭示了破伤风毒素蛋白水解活性的活性位点、亲核水的重要性以及锌离子的作用。文中还讨论了囊泡相关膜蛋白与B型肉毒杆菌神经毒素和破伤风毒素结合方式不同的可能原因。该结构为设计新型破伤风重组疫苗或基于结构的药物提供了依据。
