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

作者：Kim Soo Kyung^*; Chen Yalu; Abrol Ravinder; Goddard William A III^*; Guthrie Brian

来源：Proceedings of the National Academy of Sciences, 2017, 114(10): 2568-2573.

DOI：10.1073/pnas.1700001114

• GPCR activation
• class C GPCR
• molecular dynamics
• noncaloric sweetener

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 gamma-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 similar to 6 angstrom 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.

• 出版日期2017-3-7