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

Blättermann S, Peters L, Ottersbach PA, Bock A, Konya V, Weaver CD, Gonzalez A, Schröder R, Tyagi R, Luschnig P, Gäb J, Hennen S, Ulven T, Pardo L, Mohr K, Gütschow M, Heinemann A, Kostenis E
Nat Chem Biol. 2012 8 (7): 631-8

PMID: 22634634 · DOI:10.1038/nchembio.962

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.

MeSH Terms (11)

Benzeneacetamides Benzothiazoles Biopolymers Calcium Cell Line Cyclic AMP GTP-Binding Proteins Humans Ligands Receptors, G-Protein-Coupled Signal Transduction

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