A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer
Blättermann, Sefanie (University of Bonn)
Peters, Lucas (University of Bonn)
Ottersbach, Philipp Aaron (University of Bonn)
Bock, Andreas (University of Bonn)
Konya, Viktoria (Medical University of Graz)
Weaver, C. David (Vanderbilt University)
Gonzalez, Angel (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Schröder, Ralf (University of Bonn)
Tyagi, Rahul (University of Southern Denmark)
Luschnig, Petra (Medical University of Graz)
Gäb, Jürgen (University of Bonn)
Hennen, Stephanie (University of Bonn)
Ulven, Trond (University of Southern Denmark)
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Mohr, Klaus (University of Bonn)
Gütschow, Michael (University of Bonn)
Heinemann, Akos (Medical University of Graz)
Kostenis, Evi (University of Bonn)

Data:	2012
Resum:	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.
Nota:	Altres ajuts: Austrian Science Funds FWF (P-22521 to AH)
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Llengua:	Anglès
Document:	Article ; recerca ; Versió sotmesa a revisió
Publicat a:	Nature chemical biology, Vol. 8, Num. 7 (July 2012) , p. 631-638, ISSN 1552-4469

DOI: 10.1038/nchembio.962

Preprint 43 p, 1.2 MB

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