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

Sefanie 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

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68 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)631-638
JournalNature Chemical Biology
Publication statusPublished - 1 Jan 2012


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