Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors

FEBS Lett. 2013 Aug 2;587(15):2325-31. doi: 10.1016/j.febslet.2013.06.016. Epub 2013 Jun 20.


Several classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs.

Keywords: Amyloidosis; Fibrillogenesis inhibitor; HBP; PDB; Protein Data Bank; Protein misfolding; T4; TTR; Transthyretin; Transthyretin stabilizer; halogen binding pocket; thyroxine; transthyretin; wild type-TTR; wt-TTR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry*
  • Crystallography, X-Ray
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Neurofibrils / drug effects*
  • Prealbumin / chemistry*
  • Protein Conformation


  • Amyloid
  • Prealbumin

Associated data

  • PDB/4I85
  • PDB/4I87
  • PDB/4I89