title: 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.
authors.affiliation: Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125; wag@wag.caltech.edu skkim@wag.caltech.edu.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125.
authors.forename: Yalu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.affiliation: Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, CA 91125; wag@wag.caltech.edu skkim@wag.caltech.edu.
authors.forename: William A
authors.identifier: 0000-0003-0097-5716
authors.initials: WA
authors.lastname: Goddard
authors.affiliation: Cargill Global Food Research, Wayzata, MN 55391.
authors.forename: Brian
authors.initials: B
authors.lastname: Guthrie
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains; D055503:Protein Multimerization / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry; D013549:Sweetening Agents / Q000737:chemistry / Q000494:pharmacology; D013649:Taste / Q000235:genetics; D055697:Taste Perception / Q000235:genetics*
chemical_list: D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D013549:Sweetening Agents; C431926:taste receptors, type 1
keywords: GPCR activation; class C GPCR; molecular dynamics; noncaloric sweetener