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
Light Chain of Botulinum A Neurotoxin Expressed as an Inclusion Body from a Synthetic Gene Is Catalytically and Functionally Active
S. Ashraf Ahmed,Leonard A. Smith +1 more
TL;DR: A synthetic gene is constructed for the LC of the botulinum neurotoxin serotype A (BoNT/A), overexpressed it in Escherichia coli, and purified the gene product from inclusion bodies to make available a large amount of the biologically active toxin fragment in a soluble and stable form.
Patent
Transport protein which is used to introduce chemical compounds into nerve cells
TL;DR: A transport protein which can be obtained by modifying the heavy chain of the neurotoxin formed by Clostridium botulinum is described in this article, which binds specifically to nerve cells with a higher affinity as the native neurotoxin.
Journal ArticleDOI
Catalytic features of the botulinum neurotoxin A light chain revealed by high resolution structure of an inhibitory peptide complex.
TL;DR: The 1.4 A-resolution X-ray crystal structure of a complex between the BoNT/A-LC and the inhibitory peptide N-Ac-CRATKML suggests that the enzyme active site is prearranged to stabilize the tetrahedral intermediate of the protease reaction.
Journal ArticleDOI
A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate
Jorge E. Zuniga,James J. Schmidt,Timothy D. Fenn,James C. Burnett,Demet Araç,Rick Gussio,Robert G. Stafford,Shirin S. Badie,Sina Bavari,Axel T. Brunger +9 more
TL;DR: The crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (K(i)=41 nM) that resembles the local sequence of the SNAP-25 substrate is reported.
Journal ArticleDOI
Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting.
TL;DR: This review discusses the comparative structures of BoNT in crystal and solution for their relevance to the molecular mechanism ofBoNT action, especially in view of the recent discovery that the enzymatically active structure of the BoNT exists as a molten-globule and that of the endopeptidase domain as a novel PRIME conformation.
References
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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
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