Crystal structure of botulinum neurotoxin type A and implications for toxicity.
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 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 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.
Lacy
D B
DB
Department of Chemistry and Earnest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley, 94720, USA.
Tepp
W
W
Cohen
A C
AC
DasGupta
B R
BR
Stevens
R C
RC
D001665:Binding Sites; D019274:Botulinum Toxins, Type A / Q000737:chemistry* / Q000633:toxicity; D002384:Catalysis; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D017433:Protein Structure, Secondary
D019274:Botulinum Toxins, Type A