A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer.
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.
Molecular-, Cellular- and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany.
Stefanie
S
Blättermann
Lucas
L
Peters
Philipp Aaron
PA
Ottersbach
Andreas
A
Bock
Viktoria
V
Konya
C David
CD
Weaver
Angel
A
Gonzalez
Ralf
R
Schröder
Rahul
R
Tyagi
Petra
P
Luschnig
Jürgen
J
Gäb
Stephanie
S
Hennen
Trond
T
Ulven
Leonardo
L
Pardo
Klaus
K
Mohr
Michael
M
Gütschow
Akos
A
Heinemann
Evi
E
Kostenis
D044482:Benzeneacetamides / Q000378:metabolism*; D052160:Benzothiazoles / Q000378:metabolism*; D001704:Biopolymers / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
D044482:Benzeneacetamides; D052160:Benzothiazoles; D001704:Biopolymers; C000589032:Gue1654; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D002118:Calcium