Refolding of misfolded mutant GPCR: post-translational pharmacoperone action in vitro

Mol Cell Endocrinol. 2007 Jun 30;272(1-2):77-85. doi: 10.1016/j.mce.2007.04.012. Epub 2007 May 3.


All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct misfolding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • COS Cells
  • Chlorocebus aethiops
  • Drug Evaluation, Preclinical
  • HeLa Cells
  • Humans
  • Indoles / pharmacology
  • Inositol / pharmacology
  • Molecular Chaperones / pharmacology*
  • Molecular Mimicry
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Protein Folding*
  • Protein Processing, Post-Translational / drug effects*
  • Protein Transport / drug effects
  • Pyridines / pharmacology
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, LHRH / chemistry
  • Receptors, LHRH / genetics
  • Receptors, LHRH / metabolism*
  • Transfection


  • Bridged Bicyclo Compounds, Heterocyclic
  • IN3 compound
  • Indoles
  • Molecular Chaperones
  • Mutant Proteins
  • Pyridines
  • Receptors, G-Protein-Coupled
  • Receptors, LHRH
  • Inositol