Inhibition of heterotrimeric G protein signaling by a small molecule acting on Galpha subunit.
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.
Ayoub
Mohammed Akli
MA
Institut de Génomique Fonctionnelle, CNRS-UMR5203, INSERM U661, Université de Montpellier, 34094 Montpellier, France.
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
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D003510:Cyclohexanes / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction
C533004:7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride; D003510:Cyclohexanes; D018076:DNA, Complementary; D044385:GTP-Binding Protein alpha Subunits; D011719:Pyrazines; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium