Pharmacological folding chaperones act as allosteric ligands of Frizzled4

Nat Chem Biol. 2015 Apr;11(4):280-6. doi: 10.1038/nchembio.1770. Epub 2015 Mar 9.


Upon binding, ligands can chaperone their protein targets by preventing them from misfolding and aggregating. Thus, an organic molecule that works as folding chaperone for a protein might be its specific ligand, and, similarly, the chaperone potential could represent an alternative readout in a molecular screening campaign toward the identification of new hits. Here we show that small molecules selected for acting as pharmacological chaperones on a misfolded mutant of the Frizzled4 (Fz4) receptor bind and modulate wild-type Fz4, representing what are to our knowledge the first organic ligands of this until-now-undruggable GPCR. The novelty and the advantages of the screening platform, the allosteric binding site addressed by these new ligands and the mechanism they use to modulate Fz4 suggest new avenues for development of inhibitors of the Wnt-β-catenin pathway and for drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Amino Acid Motifs
  • Base Sequence
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Dose-Response Relationship, Drug
  • Drug Design
  • Frizzled Receptors / chemistry*
  • Glycerol / chemistry
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Ligands
  • Microscopy, Fluorescence
  • Molecular Chaperones / chemistry*
  • Molecular Sequence Data
  • Mutagenesis
  • Protein Binding
  • Protein Folding
  • Receptors, G-Protein-Coupled / chemistry


  • FZD4 protein, human
  • Frizzled Receptors
  • Ligands
  • Molecular Chaperones
  • Receptors, G-Protein-Coupled
  • Glycerol

Associated data

  • PubChem-Substance/241177002
  • PubChem-Substance/241177003
  • PubChem-Substance/241177004
  • PubChem-Substance/241177005
  • PubChem-Substance/241177006
  • PubChem-Substance/241177007
  • PubChem-Substance/241177008
  • PubChem-Substance/241177009
  • PubChem-Substance/241177010
  • PubChem-Substance/241177011
  • PubChem-Substance/241177012
  • PubChem-Substance/241177013
  • PubChem-Substance/241177014
  • PubChem-Substance/241177015
  • PubChem-Substance/241177016
  • PubChem-Substance/241177017
  • PubChem-Substance/241177018
  • PubChem-Substance/241177019
  • PubChem-Substance/241177020