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Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit.


ABSTRACT: The simultaneous activation of many distinct G protein-coupled receptors (GPCRs) and heterotrimeric G proteins play a major role in various pathological conditions. Pan-inhibition of GPCR signaling by small molecules thus represents a novel strategy to treat various diseases. To better understand such therapeutic approach, we have characterized the biomolecular target of BIM-46187, a small molecule pan-inhibitor of GPCR signaling. Combining bioluminescence and fluorescence resonance energy transfer techniques in living cells as well as in reconstituted receptor-G protein complexes, we observed that, by direct binding to the Galpha subunit, BIM-46187 prevents the conformational changes of the receptor-G protein complex associated with GPCR activation. Such a binding prevents the proper interaction of receptors with the G protein heterotrimer and inhibits the agonist-promoted GDP/GTP exchange. These observations bring further evidence that inhibiting G protein activation through direct binding to the Galpha subunit is feasible and should constitute a new strategy for therapeutic intervention.

SUBMITTER: Ayoub MA 

PROVIDER: S-EPMC2781458 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit.

Ayoub Mohammed Akli MA   Damian Marjorie M   Gespach Christian C   Ferrandis Eric E   Lavergne Olivier O   De Wever Olivier O   Banères Jean-Louis JL   Pin Jean-Philippe JP   Prévost Grégoire Pierre GP  

The Journal of biological chemistry 20090731 42


The simultaneous activation of many distinct G protein-coupled receptors (GPCRs) and heterotrimeric G proteins play a major role in various pathological conditions. Pan-inhibition of GPCR signaling by small molecules thus represents a novel strategy to treat various diseases. To better understand such therapeutic approach, we have characterized the biomolecular target of BIM-46187, a small molecule pan-inhibitor of GPCR signaling. Combining bioluminescence and fluorescence resonance energy trans  ...[more]

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