Wednesday, January 22, 2014

How botox binds to neurons

Researchers elucidate how botulinum neurotoxin A binds to its protein receptor and thus provide a basis for the development of new drugs

Botulinum neurotoxin A, better known as botox, is a highly dangerous toxin that causes paralysis in man that may prove fatal. In cosmetic applications the paralysing action of small doses is used in a specific manner for the temporary elimination of wrinkles and in medicine as a treatment for migraine or to correct strabismus. An international research team from the Paul Scherrer Institute, Utrecht University and the pharmaceutical company UCB has now taken an important step towards understanding the action of botulinum neurotoxin A. They have determined the x-ray crystal structure of a protein complex which clearly shows how the toxin molecule binds to the protein receptor, synaptic vesicle protein 2. The findings may prove useful for the development of improved botox drugs with a lower risk of overdosage. The structure was determined at the Swiss Light Source synchrotron at the Paul Scherrer Institute. The findings are to be published in the renowned scientific journal Nature.

The consumption of spoiled tinned food can lead to botulism in man, an intoxication that causes life-threatening paralysis. One of the causative factors is the toxin botulinum neurotoxin A which is produced by the bacterium Clostridium botulinum. It can only replicate in the oxygen-free atmosphere of the tin. The toxin attacks the neurons and prevents the passing on of neuronal signals to the muscles. In recent decades, increasingly practical applications of the toxin have been developed. Its use in cosmetics where the substance is called botox is particularly well known. When injected subcutaneously the toxin leads to relaxation of muscles and makes wrinkles disappear temporarily. This agent is also frequently used in medicine to treat migraine. In people suffering from strabismus, botulinum neurotoxin A can be used specifically to slightly weaken the eye muscle and facilitate normal vision.


This film illustrates in detail how a botulinum neurotoxin A molecule (botox) binds to a receptor in the cell membrane of a neuron whose activity is then blocked by the toxin.
The crystal structure of the complex between the receptor binding domain of botulinum neurotoxin A (BoNT/A-RBD, shown in green) and the luminal domain of its protein receptor synaptic vesicle glycoprotein 2 (SV2C-LD, shown in blue) reveals molecular details how the toxin actually binds to SV2C-LD. The stick models in the magnification represent the amino acids at the toxin-receptor interface. The dotted lines show hydrogen bonds. The amino acids, which appear later in the film on the inner side of SV2C-LD, are phenylalanines which form the inner core of the receptor domain.

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