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Structural characterization of three novel hydroxamate-based zinc chelating inhibitors of the clostridium botulinum serotype a neurotoxin light chain metalloprotease reveals a compact binding site resulting from 60/70 loop flexibility

Academic Article
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Overview

authors

  • Thompson, A. A.
  • Jiao, G. S.
  • Kim, S.
  • Thai, A.
  • Cregar-Hernandez, L.
  • Margosiak, S. A.
  • Johnson, A. T.
  • Han, G. W.
  • O'Malley, S.
  • Stevens, Raymond

publication date

  • May 2011

journal

  • Biochemistry  Journal

abstract

  • Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure--activity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar-potency hydroxamate-based inhibitors are reported here. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures.

subject areas

  • Binding Sites
  • Botulinum Toxins, Type A
  • Chelating Agents
  • Clostridium botulinum
  • Crystallography, X-Ray
  • Hydroxamic Acids
  • Ligands
  • Metalloproteases
  • Neurotoxins
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Zinc
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Identity

PubMed Central ID

  • PMC3092028

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi2001483

PubMed ID

  • 21434688
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Additional Document Info

start page

  • 4019

end page

  • 4028

volume

  • 50

issue

  • 19

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