A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer

Nat Chem Biol. 2012 Jul;8(7):631-8. doi: 10.1038/nchembio.962. Epub 2012 May 27.


Differential targeting of heterotrimeric G protein versus β-arrestin signaling are emerging concepts in G protein-coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either β-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gβγ but not Gα signaling triggered upon activation of Gα(i)-βγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gβγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzeneacetamides / metabolism*
  • Benzothiazoles / metabolism*
  • Biopolymers / metabolism*
  • Calcium / metabolism
  • Cell Line
  • Cyclic AMP / metabolism
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Ligands
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*


  • Benzeneacetamides
  • Benzothiazoles
  • Biopolymers
  • Gue1654
  • Ligands
  • Receptors, G-Protein-Coupled
  • Cyclic AMP
  • GTP-Binding Proteins
  • Calcium

Associated data

  • PubChem-Substance/135668738
  • PubChem-Substance/135668739
  • PubChem-Substance/135668740
  • PubChem-Substance/135668741
  • PubChem-Substance/135668742
  • PubChem-Substance/135668743
  • PubChem-Substance/135668744
  • PubChem-Substance/135668745
  • PubChem-Substance/135668746
  • PubChem-Substance/135668747
  • PubChem-Substance/135668748
  • PubChem-Substance/135668749
  • PubChem-Substance/135668750
  • PubChem-Substance/135668751
  • PubChem-Substance/135668752
  • PubChem-Substance/135668753
  • PubChem-Substance/135668754
  • PubChem-Substance/135668755
  • PubChem-Substance/135668756
  • PubChem-Substance/135668757
  • PubChem-Substance/135668758
  • PubChem-Substance/135668759