Characterization of the Modes of Binding between Human Sweet Taste Receptor and Low-Molecular-Weight Sweet Compounds

Masuda, Koichi; Koizumi, Ayako; Nakajima, Ken-ichiro; Tanaka, Takaharu; Abe, Keiko; Misaka, Takumi; Ishiguro, Masaji

doi:10.1371/journal.pone.0035380

Cited by 151 publications

(199 citation statements)

References 30 publications

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“…For example, gurmarin inhibits the effect of sucralose but effects of acesulfame-K and glycyrrhizin are totally insensitive to gurmarin . Since sucralose and acesulfame-K bind to a similar portion of the Venus flytrap of the sweet taste receptor (Masuda et al 2012), the mechanism underlying the preferential effects of gurmarin . In this regard, gurmarin acts as a biased antagonist for T1R3 in many respects and attenuates a limited signaling cascade evoked by a limited number of agonists.…”

Section: Discussionmentioning

confidence: 99%

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Hamano¹,

Nakagawa²,

Ohtsu³

et al. 2015

Journal of Endocrinology

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Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic b-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin.

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Section: Discussionmentioning

confidence: 99%

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Hamano¹,

Nakagawa²,

Ohtsu³

et al. 2015

Journal of Endocrinology

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“…Molecular Modeling-Based on the sequence alignment reported by previous studies (13,18,39), homology models of human/mouse T1Rs and their chimeras were constructed by residue replacement using the Modeler (40) as templates of metabotropic glutamate receptors (9,10,41). Structure of GA I, lactisole, and glucuronic acid were obtained from ZINC version12 (42).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies on chimera and mutation of the sweet taste receptor revealed multiple binding sites for its ligands. For example, artificial sweeteners aspartame and neotame and other low molecular weight sweet compounds interact with the binding site formed by the bottom of lobe 1 and the top of lobe 2 of ATD in hT1R2 (12,13). The taste-modifying protein neoculin binds the ATD of hT1R3 (14).…”

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confidence: 99%

Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids

Sanematsu

Kusakabe

Shigemura

et al. 2014

Journal of Biological Chemistry

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Background: Gymnemic acids inhibit sweet taste responses in humans. Results: Gymnemic acids and glucuronic acid inhibited human sweet receptor T1R2 ϩ T1R3. Conclusion: Interaction between transmembrane domains of human T1R3 and the glucuronosyl group of gymnemic acids is mainly required for the sweet-suppressing effect. Significance: Our model may provide further insights into drug design to modify sensitivity of sweet receptor.

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“…In addition, biophysical experiments on the class C sweet receptor, consisting of the TAS1R2/TAS1R3 heterodimer, indicate that sucrose and glucose bind to the VFD of both the TAS1R2 and TAS1R3 subunits (5,6), whereas other sweeteners, such as aspartame and stevioside (Stev), interact only with the VFD2 (VFD of TAS1R2) subunit (7)(8)(9). Moreover, the allosteric binding site at the TMD3 (TMD of TAS1R3) interacts with modulators of the receptor function, such as lactisole (9, 10).…”

mentioning

confidence: 99%

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

Kim

Chen

Abrol

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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 fulllength 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.GPCR activation | class C GPCR | molecular dynamics | noncaloric sweetener G protein-coupled receptors (GPCRs) play an essential signaling function throughout all eukaryote systems, serving as the basis for detecting light, smell, nociceptive signaling, and taste along with dopamine, serotonin, adrenaline, etc. (1). Generally, binding of a signaling ligand to the exterior of a cell causes a G protein at the intracellular interface to dissociate, which then triggers a sequence of events that respond to the signal. There are now structures for ∼32 human GPCRs, including 4 that have been activated (2); however, a detailed understanding of the activation mechanisms of monomeric GPCRs is still lacking (3). This is most unfortunate because about half the drugs under development involve GPCRs and it is most important to know whether the drug will serve as an agonist to activate the G protein or as an antagonist or inverse agonist.Particularly interesting here are the class C GPCRs, which in addition to a seven-helix transmembrane domain (TMD) include a large N-terminal segment consisting of a Venus Flytrap Domain (VFD) and a cysteine-rich domain (CRD). Biophysical measurements on the class C glutamate dimer receptor 2 (mGluR2) have shown that the inactive or resting state (R) dimer interface involves contacts between TMs 4 and 5 of each TMD, whereas formation of the fully active state is associated with motions in which the extracellular (EC) projections of the two TM6s move together to form a TM6-TM6 interface (4).In addition, biophysical experiments on the class C sweet receptor, consisting of the TAS1R2/TAS1R3 heterodimer, indicate that sucrose and glucose bind to the VFD of both the TAS1R2 and TAS1R3 subunits (5, 6), whereas other sweeteners, such as aspartame and st...

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Characterization of the Modes of Binding between Human Sweet Taste Receptor and Low-Molecular-Weight Sweet Compounds

Cited by 151 publications

References 30 publications

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids

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

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