Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs

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Heterotrimeric G proteins are essential mediators of intracellular signaling of G protein-coupled receptors. The Gq/11subfamily consists of Gq, G11, G14 and G16 proteins of which all but G16 are inhibited by the structurally related natural products YM-254890 and FR900359. These inhibitors act by preventing the GDP/GTP exchange, which is necessary for activation of all G proteins. A homologous putative binding site for YM-254890/FR900359 can also be found in members of the other three G protein families; Gs, Gi/o and G12/13, but none of the published analogs of YM-254890/FR900359 have shown any inhibitory activity for any of these. To explain why the YM-254890/FR900359 scaffold only inhibits Gq/11/14, the present study delineated the molecular selectivity determinants by exchanging amino acid residues in the YM-254890/FR900359 binding site in Gq and Gs We found that the activity of a Gs mutant with a Gq-like binding site for YM-254890/FR900359 can be inhibited by FR900359 and a minimum of three mutations are necessary to introduce inhibition in Gs In all, this suggest that although the YM-254890/FR900359 scaffold has proven unsuccessful to derive Gs, Gi/o and G12/13 inhibitors, the mechanism of inhibition between families of G proteins is conserved opening up for targeting by other, novel inhibitor scaffolds. In lack of a selective Gαs inhibitor, FR900359 sensitive Gas mutants may prove useful in studies where delicate control over Gαs signaling would be of the essence.

Original languageEnglish
JournalJournal of Biological Chemistry
Issue number40
Pages (from-to)13850-13861
Publication statusPublished - 2020

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Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

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