A key agonist-induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand Org 27569

Jonathan F. Fay, David L. Farrens

Research output: Contribution to journalArticle

30 Scopus citations


Allosteric ligands that modulate how G protein-coupled receptors respond to traditional orthosteric drugs are an exciting and rapidly expanding field of pharmacology. An allosteric ligand for the cannabinoid receptor CB1, Org 27569, exhibits an intriguing effect; it increases agonist binding, yet blocks agonist-induced CB1 signaling. Here we explored the mechanism behind this behavior, using a site-directed fluorescence labeling approach. Our results show that Org 27569 blocks conformational changes in CB1 that accompanyGprotein binding and/or activation, and thus inhibit formation of a fully active CB1 structure. The underlying mechanism behind this behavior is that simultaneous binding of Org 27569 produces a unique agonistbound conformation, one that may resemble an intermediate structure formed on the pathway to full receptor activation.

Original languageEnglish (US)
Pages (from-to)33873-33882
Number of pages10
JournalJournal of Biological Chemistry
Issue number40
StatePublished - Sep 28 2012


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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