Researchers show how botulism toxin ensnares ...( ch for the location of the exosites Br...)

ch for the location of the exosites, Breidenbach created crystals of a particular botulinum neurotoxin bound to its target SNARE. The researchers determined the structure of the bound proteins using x-ray diffraction, a widely used analytical technique whereby beams of x-rays are directed through crystallized proteins. The resulting pattern of diffraction is analyzed to deduce the protein's atomic structure.

Their structural analysis revealed that the neurotoxin wraps itself in a segment of the SNARE protein by attaching at numerous exosites. This interaction enables the toxin to recognize the SNARE protein with high specificity, said Brunger.

"Our structure has shown for the first time that it's a very extensive interaction on the protein surface, far from the active site, that actually determines specificity," said Brunger. "This extensive interaction is very unusual for a protease. Up to this point, it's the largest known interface area for such a complex, with numerous points of contact."

Another notable finding, said Brunger, was that binding of the toxin to its target causes significant conformational change of the enzyme, which quite likely activates its ability to cleave the protein.

When the researchers compared the amino acid sequences of the type of botulinum toxin they studied with other known toxin sequences, they found that the region they had found to contact the SNARE was variable. They theorize that such differences among toxins give them their specificity for their target SNAREs; among toxins that recognize the same SNARE, amino acid variations in the contact region might allow each to cleave its target at different sites.

According to Brunger, the discovery of the mechanism by which the toxins recognize their target proteins could provide new information that will aid in developing drugs that can block the toxins more quickly. "Finding these remote exosites suggests the possibility of developing drugs that c
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
12-Dec-2004

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