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Kinetic stabilization of an oligomeric protein by a single ligand binding event

Academic Article
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Overview

related to degree

  • Johnson, Steven, Ph.D. in Chemistry, Scripps Research 2001 - 2006
  • Foss, Ted, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2000 - 2006
  • Wiseman, R. Luke, Ph.D. in Chemistry, Scripps Research 2001 - 2005
  • Kelker, Matthew, Ph.D. in Biophysics, Scripps Research 2000 - 2005

authors

  • Wiseman, R. Luke
  • Johnson, Steven
  • Kelker, Matthew
  • Foss, Ted
  • Wilson, Ian
  • Kelly, Jeffery

publication date

  • April 2005

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (I) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of TTR.I in solution to the exclusion of TTR.I(2) and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K(d1) in nanomolar range and K(d2) in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.

subject areas

  • Amyloid
  • Benzoates
  • Crystallography, X-Ray
  • Kinetics
  • Ligands
  • Models, Molecular
  • Oligopeptides
  • Prealbumin
  • Protein Binding
  • Protein Conformation
  • Thyroxine
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Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja042929f

PubMed ID

  • 15826192
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Additional Document Info

start page

  • 5540

end page

  • 5551

volume

  • 127

issue

  • 15

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