透过蛋白结构的分析，科学家首度的观察到，为什么单一微小的肉毒杆菌毒素，可以发挥神奇的魔力，透过麻痹神经细胞的过程，瘫痪一个健康的个体。
肉毒杆菌毒素是由 Clostridium botulinum这个细菌所产生的一种毒性分子，上常见于腐败污染的食物中，部份伤口组织中，或是肠胃道所分离出的菌落中，也看得到这种菌株的踪迹，由于它所产生的毒性分子，可以在几分钟内，引发肌肉无力、麻痹和呼吸衰竭因而致死，因此临床这类减毒性毒素的应用虽然不少，但它也被恐怖份子拿来做成具有威胁性的生物武器。
这次由 Scripps研究所(Scripps Research) 威斯康辛大学(University of Wisconsin) 与霍华休斯医学研究所(Howard Hughes Medical Institute) 共同组成的研究团队，首先从肉毒杆菌毒素的结构上下手，透过了解与神经细胞上毒素受体蛋白质的接触接口，分析可能的作用机制，结果研究人员发现，毒素分子先以其上两条狭窄平行的沟槽(grooves) 与受体蛋白质接合，接着毒性分子的另外一部份，会与受体蛋白质附近的糖类分子，像是醣脂质中的神经节醣甘(ganglioside) 黏合，因而稳固的黏着上神经细胞。
目前治疗肉毒杆菌毒素感染的药物，是由马只所制成的抗体制剂，因此所并发的副反应也不少，因此毒素的关键区域的解密，将有助于未来抗毒素药物的发展。
英文原文：
Study reveals molecular basis of botulism toxin's deadly activity
New research leads to improved understanding of the toxin and opens door to potential new treatments for food poisoning, nervous system diseases and other threats
In the study, the scientists reveal the mysterious structural basis of the remarkably strong interaction that botulinum toxins form with nerve cells, a union so robust that a single toxin molecule can completely incapacitate a nerve cell. Because of this action, even in minute quantities these toxins are potentially deadly, leading to muscle weakness, paralysis, and sometimes respiratory failure.
"The structure finally helps to answer part of the mystery of how a very large protein can search through the body and locate the neuromuscular junction with such high affinity and specificity," says Scripps Research Professor Raymond Stevens, an author of the paper who has studied botulinum toxins for many years.
The toxins responsible for botulism are produced by the bacterium Clostridium botulinum. Humans can get the toxins from tainted food, certain wounds, and gastrointestinal tract colonization by the bacteria, the latter being particularly dangerous for infants. There is also growing concern that botulinum toxins might be used as weapons, with the Centers for Disease Control ranking them as one of the six highest-risk threats for bioterrorism.
Scientists had suspected for many years that botulinum toxins bind with nerve cells through a two-step process, but the details were unknown. Using x-ray crystallography on type B (there are seven structurally and functionally related botulinum neurotoxins, serotypes A through G) in action with receptors, the Scripps Research investigators took a molecular snapshot of regions critical to the process. Analyzing the data along with colleagues at the University of Wisconsin, Madison, and the Howard Hughes Medical Institute led to the discovery of just how the binding proceeds.
Botulinum toxins first attach to a portion of a protein found on the surface of nerve cells that mates with two parallel, narrow grooves on the toxin. Because this protein receptor is only exposed on active cells, the toxins target those nerves that are most important to a victim, such as muscles needed for breathing that are constantly in use.
The team was also able to model the structure of the second step in the process, where a separate region of a botulinum toxin binds with a sugar known as a ganglioside that acts as a second receptor. The gangliosides are found on the nerve cell surface close to the protein receptor. This double binding to the nerve cell orients the toxin in such a way that it can penetrate the nerve cell and break apart proteins that are essential to proper transmission of nerve signals.
Solving the structures opens the possibility of developing new botulism treatments, including improved small molecule drugs, vaccines, and antibody therapies.
Currently, botulism treatment rests on a cocktail of antibodies derived from horses. Because the antibodies are not human, rejection is a pervasive problem with severe potential side effects, including anaphylactic shock. The development of new types of antibodies could be a boon for treatment, and this possibility is explored by Stevens and colleagues in a paper to be published in Nature Biotechnology later this week.
In addition, the structure will help the development of other types of therapeutics to treat botulism infection. "You could essentially design smaller compounds that mimic those interactions," says Joseph Arndt, a Scripps Research postdoctoral fellow in the Stevens lab, who conducted the x-ray crystallography work for the study along with Qing Chai, another Scripps Research postdoctoral fellow. "If you block that step of recognition of the receptor, the toxin can't be internalized into the nerve cell, so it's basically shut down."
Another application for the new understanding of botulinum toxins is equally intriguing. Although botulinum toxins can have devastating effects, in very small concentrations injected directly into a specific muscle they can actually be a beneficial treatment for diseases such as cerebral palsy and multiple sclerosis that are caused by overactive nerve signaling, which the toxins can reduce. However, for reasons not completely clear, some patients do not respond to current treatments. This could be due to variations in their nerve cells that prevent the toxins from binding. If that is the case, researchers may be able to engineer toxins that bind to these variant receptors.
