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.
Stefanie Blättermann  1 ,  Lucas Peters ,  Philipp Aaron Ottersbach ,  Andreas Bock ,  Viktoria Konya ,  C David Weaver ,  Angel Gonzalez ,  Ralf Schröder ,  Rahul Tyagi ,  Petra Luschnig ,  Jürgen Gäb ,  Stephanie Hennen ,  Trond Ulven ,  Leonardo Pardo ,  Klaus Mohr ,  Michael Gütschow ,  Akos Heinemann ,  Evi Kostenis
Affiliations
  • 1. Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany.
PMID: 22634634 DOI: 10.1038/nchembio.962
Abstract

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.

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