Molecular basis of inverse agonism in a G protein-coupled receptor

Nat Chem Biol. 2005 Jun;1(1):25-8. doi: 10.1038/nchembio705. Epub 2005 May 24.


G protein-coupled receptors (GPCRs) recognize a wide variety of extracellular ligands to control diverse physiological processes. Compounds that bind to such receptors can either stimulate, fully or partially (full or partial agonists), or reduce (inverse agonists) the receptors' basal activity and receptor-mediated signaling. Various studies have shown that the activation of receptors through binding of agonists proceeds by conformational changes as the receptor switches from a resting to an active state leading to G protein signaling. Yet the molecular basis for differences between agonists and inverse agonists is unclear. These different classes of compounds are assumed to switch the receptors' conformation in distinct ways. It is not known, however, whether such switching occurs along a linear 'on-off' scale or whether agonists and inverse agonists induce different switch mechanisms. Using a fluorescence-based approach to study the alpha2A-adrenergic receptor (alpha(2A)AR), we show that inverse agonists are differentiated from agonists in that they trigger a very distinct mode of a receptor's switch. This switch couples inverse agonist binding to the suppression of activity in the receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists
  • Cell Line
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Ligands
  • Protein Binding
  • Receptors, Adrenergic, alpha-2
  • Receptors, G-Protein-Coupled / agonists*
  • Signal Transduction / drug effects*


  • ADRA2A protein, human
  • Adrenergic alpha-2 Receptor Agonists
  • Ligands
  • Receptors, Adrenergic, alpha-2
  • Receptors, G-Protein-Coupled

Associated data

  • PubChem-Substance/840951
  • PubChem-Substance/840952
  • PubChem-Substance/840953
  • PubChem-Substance/840954
  • PubChem-Substance/840955
  • PubChem-Substance/840956
  • PubChem-Substance/840957
  • PubChem-Substance/840958
  • PubChem-Substance/840959
  • PubChem-Substance/840960
  • PubChem-Substance/840961
  • PubChem-Substance/840962