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