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

doi:10.1038/nchembio.962

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

61 Citationer (Scopus)

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 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 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.

Originalsprog	Engelsk
Tidsskrift	Nature Chemical Biology
Vol/bind	8
Udgave nummer	7
Sider (fra-til)	631-638
Antal sider	8
ISSN	1552-4450
DOI	https://doi.org/10.1038/nchembio.962
Status	Udgivet - jul. 2012

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10.1038/nchembio.962

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Blättermann, S., Peters, L., Ottersbach, P. A., Bock, A., Konya, V., Weaver, C. D., Gonzalez, A., Schröder, R., Tyagi, R., Luschnig, P., Gäb, J., Hennen, S., Ulven, T., Pardo, L., Mohr, K., Gütschow, M., Heinemann, A., & Kostenis, E. (2012). A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer. Nature Chemical Biology, 8(7), 631-638. https://doi.org/10.1038/nchembio.962

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 2012, 'A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer', Nature Chemical Biology, bind 8, nr. 7, s. 631-638. https://doi.org/10.1038/nchembio.962

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title = "A biased ligand for OXE-R uncouples Gα and Gβγ signaling within a heterotrimer",

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 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.",

author = "Stefanie Bl{\"a}ttermann and Lucas Peters and Ottersbach, {Philipp Aaron} and Andreas Bock and Viktoria Konya and Weaver, {C David} and Angel Gonzalez and Ralf Schr{\"o}der and Rahul Tyagi and Petra Luschnig and J{\"u}rgen G{\"a}b and Stephanie Hennen and Trond Ulven and Leonardo Pardo and Klaus Mohr and Michael G{\"u}tschow and Akos Heinemann and Evi Kostenis",

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AU - Blättermann, Stefanie

AU - Peters, Lucas

AU - Ottersbach, Philipp Aaron

AU - Bock, Andreas

AU - Konya, Viktoria

AU - Weaver, C David

AU - Gonzalez, Angel

AU - Schröder, Ralf

AU - Tyagi, Rahul

AU - Luschnig, Petra

AU - Gäb, Jürgen

AU - Hennen, Stephanie

AU - Ulven, Trond

AU - Pardo, Leonardo

AU - Mohr, Klaus

AU - Gütschow, Michael

AU - Heinemann, Akos

AU - Kostenis, Evi

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N2 - 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.

AB - 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.

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EP - 638

JO - Nature Chemical Biology

JF - Nature Chemical Biology

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ER -

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

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