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SHR Neuro Krebs Kardio Lipid Stoffw Microb

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.
A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer.
Nat Chem Biol. 2012; 8(7):631-638 Doi: 10.1038/nchembio.962
Web of Science PubMed FullText FullText_MUG

 

Führende Autor*innen der Med Uni Graz
Heinemann Akos
Co-Autor*innen der Med Uni Graz
Konya Viktoria
Luschnig Petra
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Abstract:
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.
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