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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs. / Boesgaard, Michael W.; Harpsøe, Kasper; Malmberg, Michelle; Underwood, Christina R.; Inoue, Asuka; Mathiesen, Jesper M.; König, Gabriele M.; Kostenis, Evi; Gloriam, David E.; Bräuner-Osborne, Hans.

In: Journal of Biological Chemistry, Vol. 295, No. 40, 2020, p. 13850-13861.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Boesgaard, MW, Harpsøe, K, Malmberg, M, Underwood, CR, Inoue, A, Mathiesen, JM, König, GM, Kostenis, E, Gloriam, DE & Bräuner-Osborne, H 2020, 'Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs', Journal of Biological Chemistry, vol. 295, no. 40, pp. 13850-13861. https://doi.org/10.1074/jbc.RA120.013002

APA

Boesgaard, M. W., Harpsøe, K., Malmberg, M., Underwood, C. R., Inoue, A., Mathiesen, J. M., König, G. M., Kostenis, E., Gloriam, D. E., & Bräuner-Osborne, H. (2020). Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs. Journal of Biological Chemistry, 295(40), 13850-13861. https://doi.org/10.1074/jbc.RA120.013002

Vancouver

Boesgaard MW, Harpsøe K, Malmberg M, Underwood CR, Inoue A, Mathiesen JM et al. Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs. Journal of Biological Chemistry. 2020;295(40):13850-13861. https://doi.org/10.1074/jbc.RA120.013002

Author

Boesgaard, Michael W. ; Harpsøe, Kasper ; Malmberg, Michelle ; Underwood, Christina R. ; Inoue, Asuka ; Mathiesen, Jesper M. ; König, Gabriele M. ; Kostenis, Evi ; Gloriam, David E. ; Bräuner-Osborne, Hans. / Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs. In: Journal of Biological Chemistry. 2020 ; Vol. 295, No. 40. pp. 13850-13861.

Bibtex

@article{61e9e2a9a61d4749af4a19ed7edb0ee5,
title = "Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs",
abstract = "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.",
author = "Boesgaard, {Michael W.} and Kasper Harps{\o}e and Michelle Malmberg and Underwood, {Christina R.} and Asuka Inoue and Mathiesen, {Jesper M.} and K{\"o}nig, {Gabriele M.} and Evi Kostenis and Gloriam, {David E.} and Hans Br{\"a}uner-Osborne",
note = "Published under license by The American Society for Biochemistry and Molecular Biology, Inc.",
year = "2020",
doi = "10.1074/jbc.RA120.013002",
language = "English",
volume = "295",
pages = "13850--13861",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "40",

}

RIS

TY - JOUR

T1 - Delineation of molecular determinants for FR900359 inhibition of Gq/11 unlocks inhibition of Gαs

AU - Boesgaard, Michael W.

AU - Harpsøe, Kasper

AU - Malmberg, Michelle

AU - Underwood, Christina R.

AU - Inoue, Asuka

AU - Mathiesen, Jesper M.

AU - König, Gabriele M.

AU - Kostenis, Evi

AU - Gloriam, David E.

AU - Bräuner-Osborne, Hans

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.RA120.013002

DO - 10.1074/jbc.RA120.013002

M3 - Journal article

C2 - 32753482

VL - 295

SP - 13850

EP - 13861

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -

ID: 247170524