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The C-terminus of botulinum A protease has profound and unanticipated kinetic consequences upon the catalytic cleft

Academic Article
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Overview

authors

  • Silhar, P.
  • Lardy, M. A.
  • Hixon, M. S.
  • Shoemaker, C. B.
  • Barbieri, J. T.
  • Struss, A. K.
  • Lively, J. M.
  • Javor, S.
  • Janda, Kim

publication date

  • February 2013

journal

  • ACS Medicinal Chemistry Letters  Journal

abstract

  • Botulinum neurotoxins (BoNTs) are among the most deadly poisons known though ironically, they also are of great therapeutic utility. A number of research programs have been initiated to discover small molecule inhibitors of BoNTs metalloprotease activity. Many, though not all of these programs have screened against a truncated and more stable form of the enzyme, that possess comparable catalytic properties to the full length enzyme. Interestingly, several classes of inhibitors notably the hydroxamates, display a large shift in potency between the two enzyme forms. In this report we compare the kinetics of active-site, alpha-exosite and beta-exosite inhibitors versus truncated and full length enzyme. Molecular dynamics simulations conducted with the truncated and homology models of the fully length BoNT LC/A indicate the flexibility of the C-terminus of the full length enzyme is responsible for the potency shifts of active-site proximally binding inhibitors while distal binding (alpha-exosite) inhibitors remain equipotent.
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Research

keywords

  • Botulinum neurotoxin
  • natural product
  • protease inhibitor
  • small molecule inhibitor
  • zinc-dependent metalloprotease
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Identity

PubMed Central ID

  • PMC3615567

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml300428s

PubMed ID

  • 23565325
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Additional Document Info

start page

  • 283

end page

  • 287

volume

  • 4

issue

  • 2

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