Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists
Abstract
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.
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 www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700001114/-/DCSupplemental.Attached Files
Published - PNAS-2017-Kim-2568-73.pdf
Supplemental Material - pnas.1700001114.sapp.pdf
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Additional details
- PMCID
- PMC5347580
- Eprint ID
- 74496
- Resolver ID
- CaltechAUTHORS:20170223-110325516
- Cargill Global Food Research
- Created
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2017-02-23Created from EPrint's datestamp field
- Updated
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2022-04-04Created from EPrint's last_modified field