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30 March 2007

  Taming a Potent Toxin

summary written by Brad Plummer, SLAC Communication Office

 
 


Botulinum neurotoxin is produced by the bacteria Clostridium botulinum and is the most potent toxin known, inducing a potentially fatal paralysis known as "botulism." Botulism can occur in a number of ways, including infection through open wounds or in the intestinal tract, or after consuming contaminated food in which toxin has been produced. In the USA, infant botulism is the most common manifestation of the disease-some speculate whether its prevalence is linked to sudden infant death syndrome. On the other hand, these neurotoxins have also become a powerful therapeutic tool for treating a variety of neurological, ophthalmic, and other disorders manifested by abnormal, excessive, or inappropriate muscle contractions.

In a recent series of x-ray crystallography studies conducted in part at SSRL, two research groups have determined the mechanism by which the botulinum neurotoxin binds to nerve receptors and causes infection, which could lead to new preventive and therapeutic treatments. The work is published in the December 13, 2006, issue of Nature.

Recently, researchers from a collaboration led by The Scripps Research Institute completed studies on the structures of botulinum toxin in complex with a neuronal cell surface receptor and botulinum toxin with two different neutralizing antibodies, each to a resolution of 2.6 . The group also performed biochemical, mutagenesis, and neurobiology experiments to complement the structural work. The interdisciplinary research projects provide insight into the atomic details on the intoxication process, and the means by which antibodies neutralize the effects. These structures open the possibility of developing improved broad-spectrum therapeutics, including antibodies, small molecule drugs and vaccines against the toxin.

In an adjoining study published in the same issue of Nature, Axel Brunger's group at Stanford University determined the first crystal structure of a botulinum neurotoxin in complex with its protein receptor to a resolution of 2.15 . The results could lead to development of preventive vaccines or inhibitors against these neurotoxins. Additionally, owing to the specific geometry of the binding mechanism, this study suggests that appropriately modified botulinum neurotoxins could also be used as drug delivery systems.

To learn more about this research see the Brunger and Stevens scientific highlight at:
http://www-ssrl.slac.stanford.edu/research/highlights_archive/bont-brunger.html
http://www-ssrl.slac.stanford.edu/research/highlights_archive/bont-stevens.html

Jin, R., Rummel, A., Binz, T., and Brunger, A. T. (2006) Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature, 444, 1092-1095.

Chai, Q., Arndt, J. W., Dong, M., Tepp, W. H., Johnson, E.A., Chapman, E. R., and Stevens, R. C. (2006) Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature, 444, 1096-1100

Garcia-Rodriguez, C., Levy, R., Arndt, J. W., Forsyth, C. M., Razai, A., Lou, J., Geren, I., and Stevens, R. C. (2007) Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nature Biotechnol., 25, 107-116