Journal ArticleDOI
Crystal structure of botulinum neurotoxin type A and implications for toxicity.
TLDR
The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined and the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.Abstract:
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.read more
Citations
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Journal ArticleDOI
Classification of multi-family enzymes by multi-label machine learning and sequence-based descriptors
TL;DR: Three of seven pairs of homologous enzymes with different functions and eighteen of twenty-three distantly related enzymes with a similar family were correctly classified by the RAkEL-RF-CTD predictor, indicating the extensive applicability of the predictors.
Journal ArticleDOI
Structural insights into the functional role of the Hcn sub-domain of the receptor-binding domain of the botulinum neurotoxin mosaic serotype C/D
Yanfeng Zhang,Anna Gardberg,Thomas E. Edwards,Banumathi Sankaran,Howard Robinson,Susan M. Varnum,Garry W. Buchko +6 more
TL;DR: The crystal structure of BoNT/CD-HCR determined at 1.70 Å resolution is described with a tetraethylene glycol (PG4) moiety bound in a hydrophobic cleft between β-strands in the β-sheet jelly roll fold of the Hcn sub-domain of the BoNT-HCR.
Journal ArticleDOI
Engineering toxins for 21st century therapies.
John A. Chaddock,K. Ravi Acharya +1 more
TL;DR: The meeting explored how the current structural and mechanistic knowledge of toxins could be used to engineer future toxin‐based therapies and concluded that the clinical potential for development of novel biologics based on toxin domains was evident.
Journal ArticleDOI
Immune recognition of BoNTs A and B: how anti-toxin antibodies that bind to the heavy chain obstruct toxin action.
TL;DR: Some epitopes within the two toxins display substantial homology and occupy equivalent 3-D locations, occasionally showing a small shift relative to one another, consistent with recognition adjustments accommodating structural differences between the two BoNTs.
Book ChapterDOI
Absorption and Transport of Botulinum Neurotoxins
Michel R. Popoff,Chloé Connan +1 more
TL;DR: Botulinum neurotoxin is a potent toxin, which blocks the neurotransmitter release at neuromuscular junctions, and associates to nontoxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract.
References
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Atomic structure of the ectodomain from HIV-1 gp41
Winfried Weissenhorn,Andréa Dessen,Stephen C. Harrison,Stephen C. Harrison,John J. Skehel,Don C. Wiley,Don C. Wiley +6 more
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