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J Biol Chem. 2009 Oct 16;284(42):29136-45. doi: 10.1074/jbc.M109.042333. Epub 2009 Jul 31.

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

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Institut de Génomique Fonctionnelle, CNRS-UMR5203, INSERM U661, Université de Montpellier, 34094 Montpellier, France.


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.

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