This thesis describes structural and biochemical studies conducted on the most potent toxins known to man--clostridial neurotoxins. These remarkably well-adapted proteins block neurotransmitter release resulting in the paralytic conditions botulism and tetanus. The toxins deliver highly specialized proteases inside nerve cell where they act on essential neuronal proteins called SNAREs with unparalleled selectivity. Here, x-ray crystallography is employed to obtain a high-resolution structure of a botulinum neurotoxin protease in complex with its target SNARE. The determinants of the protease's exquisite specificity are shown to be an array of previously unknown binding sites that enhance catalytic efficiency. Additionally, structural studies of tetanus neurotoxin were conducted and are described within. The function of clostridial neurotoxins is beautifully reflected in their architecture; the molecular structures described here reveal how these amazing proteins seek and destroy their intracellular targets. Ultimately, this research could be applied to the development of novel and extremely specific inhibitors of these extraordinarily powerful neurotoxins.

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