The anatomy of mammalian sweet taste receptors

Chéron, Jean-Baptiste; Golebiowski, Jérôme; Antonczak, Serge; Fiorucci, Sébastien

doi:10.1002/prot.25228

Cited by 40 publications

(44 citation statements)

References 70 publications

(121 reference statements)

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“…After acceptance of our manuscript for publication, a paper appeared (28) that developed a homology model of the sweet taste receptor based on structures of other class C GPCRs. They compared the key residues in ligand binding and activation with ∼600 single-point site-directed mutations.…”

Section: Tm6/tm6 Tm56/tm56mentioning

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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Section: Tm6/tm6 Tm56/tm56mentioning

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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“…Regarding receptor interaction, glucose (1), sucrose (5), and sucralose (5a) in contrast to many other sweeteners, are known to bind to the orthosteric binding sites of both subunits [38]. Due to the structural similarities of the other saccharides, their relatively similar intensities, and the fact that the orthosteric binding sites are accessible to polar molecules, it can be assumed that these molecules show similar binding [9]. However, the reason for the much higher intensities of sucralose (5a) and other chlorinated sucrose derivatives seems to derive from the much higher affinity to the TAS1R3 subunit than its counterpart sucrose (5), while at the same time showing comparable affinities to the TAS1R2 binding site [38].…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the sweet taste has a great relevance, as most people respond positively to the sensation of sweetness [7]. The propensity to sweet foods and the thus resulting over-consumption of sugar in industrial countries has led to a significant number of people suffering from caries, diabetes, and hyperlipidemia [7][8][9]. Consequently, in the last four decades a market for non-caloric sweeteners and dietary products has evolved, addressing the needs of more than a billion people [10].…”

Section: Introductionmentioning

confidence: 99%

“…The extracellular domain contains a Venus fly trap domain (VFD) and a cysteine-rich domain (CRD), with nine cysteine residues forming four disulfide bonds and a fifth disulfide bond with the VFD. Even though several GPCRs have already been crystallized, a crystal structure for the sweet taste receptor is still missing [9,22]. However, the good sequence alignment with metabotropic glutamate receptors 1 and 5 allowed a homology 3D-model of the sweet taste receptor and a detailed discussion of the different binding sites [9].…”

Section: Introductionmentioning

confidence: 99%

“…Even though several GPCRs have already been crystallized, a crystal structure for the sweet taste receptor is still missing [9,22]. However, the good sequence alignment with metabotropic glutamate receptors 1 and 5 allowed a homology 3D-model of the sweet taste receptor and a detailed discussion of the different binding sites [9]. The orthosteric binding pockets both have a volume of about 4900 Å 3 in their open form and thus allow small as well as large sweeteners to bind to the receptor.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure-Dependent Activity of Plant-Derived Sweeteners

Ҫiçek

2020

Molecules

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Human sensation for sweet tastes and the thus resulting over-consumption of sugar in recent decades has led to an increasing number of people suffering from caries, diabetes, and obesity. Therefore, a demand for sugar substitutes has arisen, which increasingly has turned towards natural sweeteners over the last 20 years. In the same period, thanks to advances in bioinformatics and structural biology, understanding of the sweet taste receptor and its different binding sites has made significant progress, thus explaining the various chemical structures found for sweet tasting molecules. The present review summarizes the data on natural sweeteners and their most important (semi-synthetic) derivatives until the end of 2019 and discusses their structure–activity relationships, with an emphasis on small-molecule high-intensity sweeteners.

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Multiple interaction modes between saccharin and sweet taste receptors determine a species‐dependent response to saccharin

Zhao

Cui

et al. 2021

FEBS Open Bio

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Saccharin is a commonly used artificial sweetener that exhibits both sweetening and sweet inhibition activities. The species‐dependent response towards saccharin and the interaction between saccharin and the sweet taste receptor T1R2/T1R3 remain elusive. In this study we used mismatched chimeras of T1R2 and T1R3 and calcium mobilization functional analysis to reveal a detailed species‐dependent response towards saccharin of human, squirrel monkey, and mouse sweet taste receptors. Our findings, combined with previous results by others, suggest multiple and complex interaction modes between saccharin and the sweet taste receptor, which are helpful guidelines for effective modulation of the sweet taste by sweetener/sweet inhibitors.

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The anatomy of mammalian sweet taste receptors

Cited by 40 publications

References 70 publications

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

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

Structure-Dependent Activity of Plant-Derived Sweeteners

Multiple interaction modes between saccharin and sweet taste receptors determine a species‐dependent response to saccharin

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