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
More filters
Journal ArticleDOI
Bacterial Toxins and the Nervous System: Neurotoxins and Multipotential Toxins Interacting with Neuronal Cells
Michel R. Popoff,Bernard Poulain +1 more
TL;DR: Enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process.
Journal ArticleDOI
Mechanism of substrate recognition by botulinum neurotoxin serotype A.
TL;DR: This work defines a multistep mechanism for recognition and cleavage of SNAP25 by BoNT/A and explains how the BoNTs recognize and cleave specific coiled SNARE substrates and provides insight into the development of inhibitors to prevent botulism.
Journal ArticleDOI
On Botulinum Neurotoxin Variability
TL;DR: It is suggested that researchers abandon an anthropocentric view of these neurotoxins as human botulism-causing agents or as human therapeutics, and begin to investigate in depth the role of botulinum neurotoxin in animalBotulism in the wilderness, and devote large efforts to next-generation sequencing of soil samples to identify novel botulinu toxin sequences.
Journal ArticleDOI
The C-terminus of botulinum neurotoxin type A light chain contributes to solubility, catalysis, and stability.
TL;DR: Kinetic studies showed that regions within the C-terminus of LC/A contribute to solubility, stability, and catalysis, while LC 1-418 catalyzed the cleavage of both the SNAP25 and the fluorescent substrate SNAPtide with a similar Km, but at a 10-fold slower kcat.
Journal ArticleDOI
A Single-Domain Llama Antibody Potently Inhibits the Enzymatic Activity of Botulinum Neurotoxin by Binding to the Non-Catalytic alpha-Exosite Binding Region.
Jianbo Dong,Aaron Thompson,Yongfeng Fan,Jianlong Lou,Fraser Conrad,Mengfei Ho,Melissa Pires-Alves,Brenda A. Wilson,Raymond C. Stevens,James D. Marks +9 more
TL;DR: The study validates the utility of non-immune llama VHH libraries as a source of enzyme inhibitors and identifies the BoNT/A Lc alpha-exosite as a target for inhibitor development.
References
More filters
Journal ArticleDOI
MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures
TL;DR: The MOLSCRIPT program as discussed by the authors produces plots of protein structures using several different kinds of representations, including simple wire models, ball-and-stick models, CPK models and text labels.
Journal ArticleDOI
Improved methods for building protein models in electron density maps and the location of errors in these models.
TL;DR: In this paper, the authors describe strategies and tools that help to alleviate this problem and simplify the model-building process, quantify the goodness of fit of the model on a per-residue basis and locate possible errors in peptide and side-chain conformations.
Journal ArticleDOI
Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons.
TL;DR: It is demonstrated in this work that the surface tension, water‐organic solvent, transfer‐free energies and the thermodynamics of melting of linear alkanes provide fundamental insights into the nonpolar driving forces for protein folding and protein binding reactions.
Journal ArticleDOI
Improved Fourier coefficients for maps using phases from partial structures with errors
TL;DR: In this article, a method is given to estimate the parameter σA in these phase probability expressions from the observed and calculated structure factor amplitudes, from which one can estimate the mean coordinate error for the model, and when there are coordinate errors, a new expression for the non-centric Fourier coefficients is required to suppress this model bias.
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.
Related Papers (5)
Botulinum Toxin as a Biological Weapon: Medical and Public Health Management
Stephen S. Arnon,Robert Schechter,Thomas V. Inglesby,Donald A. Henderson,John G. Bartlett,Michael S. Ascher,Edward M. Eitzen,Anne D. Fine,Jerome Hauer,Marcelle Layton,Scott R. Lillibridge,Michael T. Osterholm,Tara O'Toole,Gerald W. Parker,Trish M. Perl,Philip K. Russell,David L. Swerdlow,Kevin Tonat +17 more