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Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists

Kim, Soo-Kyung and Chen, Yalu and Abrol, Ravinder and Goddard, William A., III and Guthrie, Brian (2017) Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists. Proceedings of the National Academy of Sciences of the United States of America, 114 (10). pp. 2568-2573. ISSN 0027-8424. PMCID PMC5347580. doi:10.1073/pnas.1700001114.

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The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and γ-aminobutyric acid receptors. We report here the predicted 3D structure of the full-length TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed–open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer. We find that the initial effect of the agonist is to pull the bottom part of VFD3/TAS1R3 toward the bottom part of VFD2/TAS1R2 by ∼6 Å and that these changes get transmitted from VFD2 of TAS1R2 (where agonists bind) through the VFD3 and the CRD3 to the TMD3 of TAS1R3 (which couples to the G protein). These structural transformations provide a detailed atomistic mechanism for the activation process in GPCR, providing insights and structural details that can now be validated through mutation experiments.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Kim, Soo-Kyung0000-0002-4498-5441
Chen, Yalu0000-0002-0589-845X
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Guthrie, Brian0000-0002-3508-4625
Additional Information:© 2017 National Academy of Sciences. Contributed by William A. Goddard III, January 25, 2017 (sent for review August 15, 2016; reviewed by Charles L. Brooks III, Kenneth A. Jacobson, and Krzysztof Palczewski). Published ahead of print February 22, 2017. Funding for this project was provided by a grant from Cargill Global Food Research to Caltech. Author contributions: S.-K.K. and W.A.G. designed research; S.-K.K. and Y.C. performed research; S.-K.K., Y.C., W.A.G., and B.G. analyzed data; and S.-K.K., R.A., and W.A.G. wrote the paper. Reviewers: C.L.B., University of Michigan; K.A.J., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and K.P., Case Western Reserve University. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Cargill Global Food ResearchUNSPECIFIED
Subject Keywords:GPCR activation; class C GPCR; molecular dynamics; noncaloric sweetener
Issue or Number:10
PubMed Central ID:PMC5347580
Record Number:CaltechAUTHORS:20170223-110325516
Persistent URL:
Official Citation:Soo-Kyung Kim, Yalu Chen, Ravinder Abrol, William A. Goddard III, and Brian Guthrie Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists PNAS 2017 114 (10) 2568-2573; published ahead of print February 22, 2017, doi:10.1073/pnas.1700001114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74496
Deposited By: Tony Diaz
Deposited On:23 Feb 2017 21:06
Last Modified:04 Apr 2022 17:09

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