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Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity

Academic Article
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Overview

related to degree

  • Xue, Song, Ph.D. in Chemical Biology, Scripps Research 2013 - 2018

authors

  • Xue, Song
  • Javor, S.
  • Hixon, M. S.
  • Janda, Kim

publication date

  • November 2014

journal

  • Biochemistry  Journal

abstract

  • Botulinum neurotoxin serotype A (BoNT/A) is one of the most lethal toxins known. Its extreme toxicity is due to its light chain (LC), a zinc protease that cleaves SNAP-25, a synaptosome-associated protein, leading to the inhibition of neuronal activity. Studies on BoNT/A LC have revealed that two regions, termed exosites, can play an important role in BoNT catalytic activity. A clear understanding of how these exosites influence neurotoxin catalytic activity would provide a critical framework for deciphering the mechanism of SNAP-25 cleavage and the design of inhibitors. Herein, based on the crystallographic structure of BoNT/A LC complexed with its substrate, we designed an α-exosite binding probe. Experiments with this unique probe demonstrated that α-exosite binding enhanced both catalytic activity and stability of the LC. These data help delineate why α-exosite binding is needed for SNAP-25 cleavage and also provide new insights into the extended lifetime observed for BoNT/A LC in vivo.

subject areas

  • Binding Sites
  • Botulinum Toxins, Type A
  • Drug Design
  • Humans
  • Protease Inhibitors
  • Synaptosomal-Associated Protein 25
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Identity

PubMed Central ID

  • PMC4222541

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi500950x

PubMed ID

  • 25295706
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Additional Document Info

start page

  • 6820

end page

  • 6824

volume

  • 53

issue

  • 43

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