Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism,
a potential biological weapon and an effective therapeutic drug for involuntary
muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain
neurotoxin was determined at 3.3 Å resolution. The structure reveals
that the translocation domain contains a central pair of helices 105
Å long and a ~50 residue loop or belt that wraps around the catalytic
domain. This belt partially occludes a large channel leading to a buried,
negative active site — a feature that calls for radically different
inhibitor design strategies from those currently used. The fold of the translocation
domain suggests a mechanism of pore formation different from other toxins.
Lastly, the toxin appears as a hybrid of varied structural motifs and suggests
a modular assembly of functional subunits to yield pathogenesis.
helices 105
Å long and a ~50 residue loop or belt that wraps around the catalytic
domain. This belt partially occludes a large channel leading to a buried,
negative active site — a feature that calls for radically different
inhibitor design strategies from those currently used. The fold of the translocation
domain suggests a mechanism of pore formation different from other toxins.
Lastly, the toxin appears as a hybrid of varied structural motifs and suggests
a modular assembly of functional subunits to yield pathogenesis.
