Grundmann, Manuel and Tikhonova, Irina G and Hudson, Brian D and Smith, Nicola J and Mohr, Klaus and Ulven, Trond and Milligan, Graeme and Kenakin, Terry and Kostenis, Evi (2016) A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor. Cell Chemical Biology, 23 (3). pp.392-403. ISSN 2451-9456 (OA)
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Additional Information: | This article is available for free from the publisher's website (click link above) |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 04 Apr 2016 00:15 |
| Last Modified: | 16 Jan 2018 09:20 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/407 |
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