A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

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A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor. / Grundmann, Manuel; Tikhonova, Irina G; Hudson, Brian D; Smith, Nicola J; Mohr, Klaus; Ulven, Trond; Milligan, Graeme; Kenakin, Terry; Kostenis, Evi.

In: Cell Chemical Biology, Vol. 23, No. 3, 17.03.2016, p. 392-403.

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

Harvard

Grundmann, M, Tikhonova, IG, Hudson, BD, Smith, NJ, Mohr, K, Ulven, T, Milligan, G, Kenakin, T & Kostenis, E 2016, 'A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor', Cell Chemical Biology, vol. 23, no. 3, pp. 392-403. https://doi.org/10.1016/j.chembiol.2016.02.014

APA

Grundmann, M., Tikhonova, I. G., Hudson, B. D., Smith, N. J., Mohr, K., Ulven, T., Milligan, G., Kenakin, T., & Kostenis, E. (2016). A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor. Cell Chemical Biology, 23(3), 392-403. https://doi.org/10.1016/j.chembiol.2016.02.014

Vancouver

Grundmann M, Tikhonova IG, Hudson BD, Smith NJ, Mohr K, Ulven T et al. A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor. Cell Chemical Biology. 2016 Mar 17;23(3):392-403. https://doi.org/10.1016/j.chembiol.2016.02.014

Author

Grundmann, Manuel ; Tikhonova, Irina G ; Hudson, Brian D ; Smith, Nicola J ; Mohr, Klaus ; Ulven, Trond ; Milligan, Graeme ; Kenakin, Terry ; Kostenis, Evi. / A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor. In: Cell Chemical Biology. 2016 ; Vol. 23, No. 3. pp. 392-403.

Bibtex

@article{e289d196a3a94943b8cdd5af984c7050,
title = "A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor",
abstract = "Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.",
author = "Manuel Grundmann and Tikhonova, {Irina G} and Hudson, {Brian D} and Smith, {Nicola J} and Klaus Mohr and Trond Ulven and Graeme Milligan and Terry Kenakin and Evi Kostenis",
note = "Copyright {\textcopyright} 2016 Elsevier Ltd. All rights reserved.",
year = "2016",
month = mar,
day = "17",
doi = "10.1016/j.chembiol.2016.02.014",
language = "English",
volume = "23",
pages = "392--403",
journal = "Chemistry and Biology",
issn = "2451-9448",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

AU - Grundmann, Manuel

AU - Tikhonova, Irina G

AU - Hudson, Brian D

AU - Smith, Nicola J

AU - Mohr, Klaus

AU - Ulven, Trond

AU - Milligan, Graeme

AU - Kenakin, Terry

AU - Kostenis, Evi

N1 - Copyright © 2016 Elsevier Ltd. All rights reserved.

PY - 2016/3/17

Y1 - 2016/3/17

N2 - Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

AB - Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

U2 - 10.1016/j.chembiol.2016.02.014

DO - 10.1016/j.chembiol.2016.02.014

M3 - Journal article

VL - 23

SP - 392

EP - 403

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 3

ER -

ID: 189161795