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

Stefanie Blättermann; 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

doi:10.1038/nchembio.962

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.

Authors

Stefanie Blättermann¹, 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

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.

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*

Substances

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