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Study reveals molecular basis of botulism toxin's deadly activity

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
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Contact: Marisela Chevez
mchevez@scripps.edu
858-784-2171
Scripps Research Institute
14-Dec-2006


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