Title |
A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor
|
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Published in |
Cell Chemical Biology, March 2016
|
DOI | 10.1016/j.chembiol.2016.02.014 |
Pubmed ID | |
Authors |
Manuel Grundmann, Irina G. Tikhonova, Brian D. Hudson, Nicola J. Smith, Klaus Mohr, Trond Ulven, Graeme Milligan, Terry Kenakin, Evi Kostenis |
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. |
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France | 2 | 15% |
Taiwan | 1 | 8% |
United Kingdom | 1 | 8% |
India | 1 | 8% |
Unknown | 6 | 46% |
Demographic breakdown
Type | Count | As % |
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Scientists | 5 | 38% |
Science communicators (journalists, bloggers, editors) | 2 | 15% |
Mendeley readers
Geographical breakdown
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United Kingdom | 1 | <1% |
Netherlands | 1 | <1% |
Denmark | 1 | <1% |
Switzerland | 1 | <1% |
Unknown | 101 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 23 | 22% |
Student > Ph. D. Student | 21 | 20% |
Student > Master | 15 | 14% |
Professor | 8 | 8% |
Student > Bachelor | 7 | 7% |
Other | 16 | 15% |
Unknown | 15 | 14% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 19 | 18% |
Pharmacology, Toxicology and Pharmaceutical Science | 19 | 18% |
Chemistry | 11 | 10% |
Medicine and Dentistry | 4 | 4% |
Other | 12 | 11% |
Unknown | 18 | 17% |