Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor. / Boyhus, Lotte Emilie; Danielsen, Mia; Bengtson, Nina Smidt; Kunze, Micha Ben Achim; Kubiak, Xavier; Sminia, Tjerk J.; Løper, Jacob Hartvig; Tran, Phuong Thu; Lindorff-Larsen, Kresten; Rasmussen, Søren G.F.; Mathiesen, Jesper Mosolff; Pedersen, Daniel Sejer.

In: RSC Advances, Vol. 8, No. 4, 2018, p. 2219-2228.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Boyhus, LE, Danielsen, M, Bengtson, NS, Kunze, MBA, Kubiak, X, Sminia, TJ, Løper, JH, Tran, PT, Lindorff-Larsen, K, Rasmussen, SGF, Mathiesen, JM & Pedersen, DS 2018, 'Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor', RSC Advances, vol. 8, no. 4, pp. 2219-2228. https://doi.org/10.1039/c7ra11713b

APA

Boyhus, L. E., Danielsen, M., Bengtson, N. S., Kunze, M. B. A., Kubiak, X., Sminia, T. J., ... Pedersen, D. S. (2018). Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor. RSC Advances, 8(4), 2219-2228. https://doi.org/10.1039/c7ra11713b

Vancouver

Boyhus LE, Danielsen M, Bengtson NS, Kunze MBA, Kubiak X, Sminia TJ et al. Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor. RSC Advances. 2018;8(4):2219-2228. https://doi.org/10.1039/c7ra11713b

Author

Boyhus, Lotte Emilie ; Danielsen, Mia ; Bengtson, Nina Smidt ; Kunze, Micha Ben Achim ; Kubiak, Xavier ; Sminia, Tjerk J. ; Løper, Jacob Hartvig ; Tran, Phuong Thu ; Lindorff-Larsen, Kresten ; Rasmussen, Søren G.F. ; Mathiesen, Jesper Mosolff ; Pedersen, Daniel Sejer. / Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor. In: RSC Advances. 2018 ; Vol. 8, No. 4. pp. 2219-2228.

Bibtex

@article{779a451aaab342689abd4cded6482c94,
title = "Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor",
abstract = "A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β2-Adrenergic receptor (β2AR) in complex with the Gs protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators that target the intracellular Gs protein binding site of the β2AR. Peptidomimetics were designed to mimic the 15 residue C-Terminal α-helix of the Gs protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled peptidomimetics were analysed by circular dichroism (CD) and characterised in a membrane-based cAMP accumulation assay and in a bimane fluorescence assay on purified β2AR. Several peptidomimetics inhibited agonist isoproterenol (ISO) induced cAMP formation by lowering the ISO maximal efficacy up to 61{\%}. Moreover, some peptidomimetics were found to significantly decrease the potency of ISO up to 39-fold. In the bimane fluorescence assay none of the tested peptidomimetics could stabilise an active-like conformation of β2AR. Overall, the obtained pharmacological data suggest that some of the peptidomimetics may be able to compete with the native Gs protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation.",
author = "Boyhus, {Lotte Emilie} and Mia Danielsen and Bengtson, {Nina Smidt} and Kunze, {Micha Ben Achim} and Xavier Kubiak and Sminia, {Tjerk J.} and L{\o}per, {Jacob Hartvig} and Tran, {Phuong Thu} and Kresten Lindorff-Larsen and Rasmussen, {S{\o}ren G.F.} and Mathiesen, {Jesper Mosolff} and Pedersen, {Daniel Sejer}",
year = "2018",
doi = "10.1039/c7ra11713b",
language = "English",
volume = "8",
pages = "2219--2228",
journal = "R S C Advances",
issn = "2046-2069",
publisher = "RSC Publishing",
number = "4",

}

RIS

TY - JOUR

T1 - Gs protein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

AU - Boyhus, Lotte Emilie

AU - Danielsen, Mia

AU - Bengtson, Nina Smidt

AU - Kunze, Micha Ben Achim

AU - Kubiak, Xavier

AU - Sminia, Tjerk J.

AU - Løper, Jacob Hartvig

AU - Tran, Phuong Thu

AU - Lindorff-Larsen, Kresten

AU - Rasmussen, Søren G.F.

AU - Mathiesen, Jesper Mosolff

AU - Pedersen, Daniel Sejer

PY - 2018

Y1 - 2018

N2 - A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β2-Adrenergic receptor (β2AR) in complex with the Gs protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators that target the intracellular Gs protein binding site of the β2AR. Peptidomimetics were designed to mimic the 15 residue C-Terminal α-helix of the Gs protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled peptidomimetics were analysed by circular dichroism (CD) and characterised in a membrane-based cAMP accumulation assay and in a bimane fluorescence assay on purified β2AR. Several peptidomimetics inhibited agonist isoproterenol (ISO) induced cAMP formation by lowering the ISO maximal efficacy up to 61%. Moreover, some peptidomimetics were found to significantly decrease the potency of ISO up to 39-fold. In the bimane fluorescence assay none of the tested peptidomimetics could stabilise an active-like conformation of β2AR. Overall, the obtained pharmacological data suggest that some of the peptidomimetics may be able to compete with the native Gs protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation.

AB - A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure of the active state β2-Adrenergic receptor (β2AR) in complex with the Gs protein (PDB 3SN6). We hypothesised that such peptidomimetics may function as allosteric modulators that target the intracellular Gs protein binding site of the β2AR. Peptidomimetics were designed to mimic the 15 residue C-Terminal α-helix of the Gs protein and were pre-organised in a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear and stapled peptidomimetics were analysed by circular dichroism (CD) and characterised in a membrane-based cAMP accumulation assay and in a bimane fluorescence assay on purified β2AR. Several peptidomimetics inhibited agonist isoproterenol (ISO) induced cAMP formation by lowering the ISO maximal efficacy up to 61%. Moreover, some peptidomimetics were found to significantly decrease the potency of ISO up to 39-fold. In the bimane fluorescence assay none of the tested peptidomimetics could stabilise an active-like conformation of β2AR. Overall, the obtained pharmacological data suggest that some of the peptidomimetics may be able to compete with the native Gs protein for the intracellular binding site to block ISO-induced cAMP formation, but are unable to stabilise an active-like receptor conformation.

U2 - 10.1039/c7ra11713b

DO - 10.1039/c7ra11713b

M3 - Journal article

AN - SCOPUS:85040919810

VL - 8

SP - 2219

EP - 2228

JO - R S C Advances

JF - R S C Advances

SN - 2046-2069

IS - 4

ER -

ID: 189357047