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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Book ChapterDOI
CHAPTER 20 – Uptake and transport of Clostridium neurotoxins
TL;DR: The complexity of the CNT receptors, which are composed of multiple lipid and protein components, together with the high affinity of CNT for the neuronal membrane has led to the recent proposal that arrays of presynaptic receptors (APRs) are involved in CNT binding.
Journal ArticleDOI
Long-time molecular dynamics simulations of botulinum biotoxin type-A at different pH values and temperatures
Xin Chen,Yuefan Deng,Yuefan Deng +2 more
TL;DR: The results show that certain parts of the protein are active at acidic pH environments or at high temperatures, and theprotein is more stable in neutral environments at normal human body temperature, whereas, at high temperature, the protein is morestable in acidic environments.
Patent
Engineered botulinum neurotoxin
TL;DR: In this article, botulinum neurotoxin (BoNT) polypeptides with a modified receptor binding domain with substitution mutations corresponding to substitution mutations in serotype B, strain 1, V1118M, Y1183M, E1191M, S 1199L, E 1191Q and S 119 9Y, or E 119 1 Q andS 119 9F were disclosed.
Journal ArticleDOI
A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A.
Jianlong Lou,Weihua Wen,Fraser Conrad,Qi Meng,Jianbo Dong,Zhengda Sun,Consuelo Garcia-Rodriguez,Shauna Farr-Jones,Luisa W. Cheng,Thomas D. Henderson,Jennifer L Brown,Theresa J. Smith,Leonard A. Smith,Anthony Cormier,James D. Marks +14 more
TL;DR: The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination.
Journal ArticleDOI
Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors.
Geoffrey Masuyer,Geoffrey Masuyer,Jonathan R. Davies,Kevin Moore,John A. Chaddock,K. Ravi Acharya +5 more
TL;DR: The suitability of botulinum neurotoxin, and serotype D in particular, as a basis for engineering novel secretion inhibitors is demonstrated and the robustness of the ‘LHn fold’ across serotypes and its use in engineering additional polypeptide components with added functionality is demonstrated.
References
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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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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