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Bimodal modulation of the botulinum neurotoxin protein-conducting channel

Academic Article
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Overview

authors

  • Janda, Kim
  • Fischer, A.
  • Tepp, W. H.
  • Eubanks, L. M.
  • Clancy, C. M.
  • Montal, M.
  • Pellett, S.
  • Johnson, E. A.
  • Dickerson, Tobin
  • Nakai, Y.

publication date

  • February 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Clostridium botulinum neurotoxin (BoNT) is the causative agent of botulism, a neuroparalytic disease. We describe here a semisynthetic strategy to identify inhibitors based on toosendanin, a traditional Chinese medicine reported to protect from BoNT intoxication. Using a single molecule assay of BoNT serotypes A and E light chain (LC) translocation through the heavy chain (HC) channel in neurons, we discovered that toosendanin and its tetrahydrofuran analog selectively arrest the LC translocation step of intoxication with subnanomolar potency, and increase the unoccluded HC channel propensity to open with micromolar efficacy. The inhibitory profile on LC translocation is accurately recapitulated in 2 different BoNT intoxication assays, namely the mouse protection and the primary rat spinal cord cell assays. Toosendanin has an unprecedented dual mode of action on the protein-conducting channel acting as a cargo-dependent inhibitor of translocation and as cargo-free channel activator. These results imply that the bimodal modulation by toosendanin depends on the dynamic interactions between channel and cargo, highlighting their tight interplay during the progression of LC transit across endosomes.

subject areas

  • Animals
  • Botulinum Toxins
  • Cells, Cultured
  • Drugs, Chinese Herbal
  • Female
  • Mice
  • Patch-Clamp Techniques
  • Protein Transport
  • Rats
  • Spinal Cord
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Research

keywords

  • natural product
  • protein translocation
  • small molecule modulator
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Identity

PubMed Central ID

  • PMC2635780

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0812839106

PubMed ID

  • 19164566
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Additional Document Info

start page

  • 1330

end page

  • 1335

volume

  • 106

issue

  • 5

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