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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Journal ArticleDOI
Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development
TL;DR: Some myths surrounding protein crystallography are examined and the inherent properties of protein crystals are highlighted as having practicable commonalities with today's patient-focused liquid drug products to make biologics drug development quicker, simpler, and cheaper.
Molecular Mechanism of Action of Botulinal Neurotoxins and the Synaptic Remodeling They Induce In Vivo at the Skeletal Neuromuscular Junction
TL;DR: Although botulinal neurotoxins are the most toxic substances known, the serotype A is now being used for therapeutic purposes, mainly to treat involuntary muscle contractions, but also for a number of other medical applications.
Journal ArticleDOI
Depolarization after resonance energy transfer (DARET): A sensitive fluorescence-based assay for botulinum neurotoxin protease activity
Marcella A. Gilmore,Dudley H. Williams,Yumiko Okawa,B. Holguin,Nicholas G. James,Justin A. Ross,K. Roger Aoki,David M. Jameson,Lance E. Steward +8 more
TL;DR: The DARET (depolarization after resonance energyTransfer) assay is a coupled Förster resonance energy transfer (FRET)-fluorescence polarization assay for botulinum neurotoxin type A or E (BoNT/A or BoNT/E) proteolytic activity that relies on a fully recombinant substrate.
Reference EntryDOI
Clostridium botulinum and Clostridium tetani
TL;DR: This chapter discusses theGenus and Species Definitions, physiology of C. botulinum and C. tetani, and susceptibility of neurotoxigenic clostridia to chemical and physical agents, and toxin use in medicine.
Journal ArticleDOI
Spontaneous nicking in the nontoxic-nonhemagglutinin component of the Clostridium botulinum toxin complex.
Yoshimasa Sagane,Toshihiro Watanabe,Hirokazu Kouguchi,Hiroyuki Sunagawa,Shigehiro Obata,Keiji Oguma,Tohru Ohyama +6 more
TL;DR: The nontoxic-nonhemagglutinin (NTNHA) component was prepared protease-free from toxin complexes produced by Clostridium botulinum type D strain 4947 and found to be spontaneously converted to the nicked NTNHA form leading to 15- and 115-kDa fragments during long-term incubation.
References
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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.
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