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

Michael W. Boesgaard, Kasper Harpsøe, Michelle Malmberg, Christina R. Underwood, Asuka Inoue, Jesper M. Mathiesen, Gabriele M. König, Evi Kostenis, David E. Gloriam, Hans Bräuner-Osborne

研究成果: Article査読

5 被引用数 (Scopus)


Heterotrimeric G proteins are essential mediators of intracellular signaling of G protein-coupled receptors. The Gq/11 subfamily 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 suggests 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 the possibility of targeting by other, novel inhibitor scaffolds. In lack of a selective Gas inhibitor, FR900359-sensitive Gas mutants may prove useful in studies where delicate control over Gas signaling would be of the essence.

ジャーナルJournal of Biological Chemistry
出版ステータスPublished - 2020 10月 2

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学


「Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gas」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。