TY - JOUR
T1 - A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
AU - Blättermann, Sefanie
AU - Peters, Lucas
AU - Ottersbach, Philipp Aaron
AU - Bock, Andreas
AU - Konya, Viktoria
AU - Weaver, C. David
AU - Gonzalez, Angel
AU - Schröder, Ralf
AU - Tyagi, Rahul
AU - Luschnig, Petra
AU - Gäb, Jürgen
AU - Hennen, Stephanie
AU - Ulven, Trond
AU - Pardo, Leonardo
AU - Mohr, Klaus
AU - Gütschow, Michael
AU - Heinemann, Akos
AU - Kostenis, Evi
PY - 2012/1/1
Y1 - 2012/1/1
N2 - 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 b-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 Ga signaling triggered upon activation of Gαi-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.
AB - 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 b-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 Ga signaling triggered upon activation of Gαi-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.
U2 - https://doi.org/10.1038/nchembio.962
DO - https://doi.org/10.1038/nchembio.962
M3 - Article
SN - 1552-4450
VL - 8
SP - 631
EP - 638
JO - Nature Chemical Biology
JF - Nature Chemical Biology
ER -