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Inhibiting transthyretin conformational changes that lead to amyloid fibril formation

Academic Article
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Overview

related to degree

  • Purkey, Hans, Ph.D. in Biology, Scripps Research 1996 - 2002

authors

  • Peterson, S. A.
  • Klabunde, T.
  • Lashuel, H. A.
  • Purkey, Hans
  • Sacchettini, J. C.
  • Kelly, Jeffery

publication date

  • October 1998

journal

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

abstract

  • Insoluble protein fibrils resulting from the self-assembly of a conformational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familial amyloid polyneuropathy, and senile systemic amyloidosis. The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome. Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation. The crystal structure of TTR complexed with Flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit hydrogen bonds that stabilize the normal tetrameric fold of TTR. A small-molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a possible approach to treat amyloid diseases. Molecules such as Flu also provide the means to rigorously test the amyloid hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease.

subject areas

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amyloid
  • Amyloidosis
  • Crystallography, X-Ray
  • Escherichia coli
  • Flufenamic Acid
  • Humans
  • Lysosomes
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Sequence Data
  • Prealbumin
  • Protein Conformation
  • Protein Denaturation
  • Protein Structure, Secondary
  • Recombinant Proteins
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Identity

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.95.22.12956

PubMed ID

  • 9789022
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Additional Document Info

start page

  • 12956

end page

  • 12960

volume

  • 95

issue

  • 22

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