A STRUCTURAL BASIS FOR CLOSTRIDIAL NEUROTOXIN TARGET SPECIFICITY

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 andtetanus. 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.

Autorentext
Mark received his undergraduate degree from Cornell University where he was advised by P. Andrew Karplus. His doctoral research was conducted under the mentorship of Axel T. Brunger at both Yale and Stanford Universities. Mark received postdoctoral training in Carolyn Bertozzi's lab at the University of California, Berkeley.

Klappentext
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.