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

Mohammed Akli Ayoub, Marjorie Damian, Christian Gespach, Eric Ferrandis, Olivier Lavergne, Olivier De Wever, Jean Louis Banères, Jean Philippe Pin, Grégoire Pierre Prévost

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)


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 Gα 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 Gα subunit is feasible and should constitute a new strategy for therapeutic intervention.

Original languageEnglish
Pages (from-to)29136-29145
Number of pages10
JournalJournal of Biological Chemistry
Issue number42
Publication statusPublished - Oct 16 2009
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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