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

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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.
TidsskriftNature Chemical Biology
Udgave nummer7
Sider (fra-til)631-638
StatusUdgivet - 2012

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