2. Academic Validation
  3. A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer

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

Affiliation

  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110114
    OXE-R Modulator