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
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Patent
Activatable recombinant neurotoxins
TL;DR: In this article, the authors proposed a mixture of activatable recombinant neurotoxins and polypeptides derived from the recombinant protein synthesis process and nucleic acid-based methods of making them.
Journal ArticleDOI
Dynamin Inhibition Blocks Botulinum Neurotoxin Type A Endocytosis in Neurons and Delays Botulism
Callista B. Harper,Sally Martin,Tam H. Nguyen,Shari J. Daniels,Nickolas A. Lavidis,Michel R. Popoff,Gordana Hadzic,Anna Mariana,Ngoc Chau,Adam McCluskey,Phillip J. Robinson,Frederic A. Meunier +11 more
TL;DR: It is found that inhibiting dynamin with the novel potent Dynasore analog, Dyngo-4aTM, was sufficient to abolish BoNT/A-Hc internalization and BoNT-induced SNAP25 cleavage in hippocampal neurons and provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin-dependent uptake mechanisms.
Journal ArticleDOI
Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F
TL;DR: BoNT/F neuronal discrimination involves the recognition of ganglioside and protein (glycosylated SV2) carbohydrate moieties, providing a structural basis for the high affinity and specificity of BoNT/f for neurons.
Journal ArticleDOI
The structures of the H(C) fragment of tetanus toxin with carbohydrate subunit complexes provide insight into ganglioside binding.
Paul Emsley,Constantina Fotinou,Isobel Black,Neil F. Fairweather,Ian G. Charles,Colin Watts,Eric W. Hewitt,Neil W. Isaacs +7 more
TL;DR: The crystal structures of native HC and of HC soaked with carbohydrates reveal a number of binding sites and provide insight into the possible mode of ganglioside binding.
Journal ArticleDOI
Plasma membrane localization signals in the light chain of botulinum neurotoxin.
Ester Fernandez-Salas,Lance E. Steward,Helen Ho,Patton E. Garay,Sarah W. Sun,Marcella A. Gilmore,Joseph V. Ordas,Joanne Wang,Joseph Francis,K. Roger Aoki +9 more
TL;DR: Using confocal microscopy and site-specific mutagenesis, this paper determined that the protease domain of BoNT/A light chain localizes in a punctate manner to the plasma membrane, colocalizing with the cleaved product, SNAP25197.
References
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Journal ArticleDOI
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Journal ArticleDOI
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Journal ArticleDOI
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
TL;DR: X-ray crystallography determines the structure of the protease-resistant part of a gp41 ectodomain solubilized with a trimeric GCN4 coiled coil in place of the amino-terminal fusion peptide, and suggests a common mechanism for initiating fusion.
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