Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14

Nowak, Stefanie; Pizio, Antonella Di; Levit, Anat; Niv, Masha Y.; Meyerhof, Wolfgang; Behrens, Maik

doi:10.1016/j.bbagen.2018.07.009

Cited by 59 publications

(86 citation statements)

References 43 publications

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“…Previously, several computational studies had been performed on partial monomeric structures of TAS2R10, TAS2R14 and TAS2R46 with their respective agonists. [47][48][49][50] Prior to our docking simulations on hTAS2R14, we explored appropriate formations under physiological conditions. However, the physiological and pharmacological significances of oligomerization of the receptor were not obvious.…”

Section: Prediction Of Dph Asp-asp or Glu-glu Binding Sites On Htas2r14mentioning

confidence: 99%

“…Kuhn et al showed that hTAS2Rs formed oligomers in vitro. 47) However, oligomerization of the receptors in vivo is impracticable due to the lack of specific antibodies for hTAS2Rs and limited availability of human tissue samples. Thus, in this study, a monomeric hTAS2R14 model was built and applied to docking simulations with feasible agonists.…”

Section: Prediction Of Dph Asp-asp or Glu-glu Binding Sites On Htas2r14mentioning

confidence: 99%

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Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

et al. 2020

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Diphenhydramine, a sedating antihistamine, is an agonist of human bitter taste receptor 14 (hTAS2R14). Diphenhydramine hydrochloride (DPH) was used as a model bitter medicine to evaluate whether the umami dipeptides (Glu-Glu and Asp-Asp) and their constituent amino acids (Glu, Asp) could suppress its bitterness intensity, as measured by human gustatory sensation testing and using the artificial taste sensor. Various concentrated (0.001-5.0 mM) Glu-Glu, Asp-Asp, Glu and Asp significantly suppressed the taste sensor output of 0.5 mM DPH solution in a dose-dependent manner. The effect of umami dipeptides and their constituent amino acids was tending to be ranked as follows, Asp-Asp > Glu-Glu >> Gly-Gly, and Asp > Glu >> Gly (control) respectively. Whereas human bitterness intensity of 0.5 mM DPH solution with various concentrated (0.5, 1.0, 1.5 mM) Glu-Glu, Asp-Asp, Glu and Asp all significantly reduced bitterness intensity of 0.5 mM DPH solution even though no statistical difference was observed among four substances. The taste sensor outputs and the human gustatory sensation test results showed a significant correlation. A surface plasmon resonance study using hTAS2R14 protein and these substances suggested that the affinity of Glu-Glu, Asp-Asp, Glu and Asp for hTAS2R14 protein was greater than that of Gly-Gly or Gly. The results of dockingsimulation studies involving DPH, Glu-Glu and Asp-Asp with hTAS2R14, suggested that DPH is able to bind to a space near the binding position of Glu-Glu and Asp-Asp. In conclusion, the umami dipeptides Glu-Glu and Asp-Asp, and their constituent amino acids, can all efficiently suppress the bitterness of DPH.

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Section: Prediction Of Dph Asp-asp or Glu-glu Binding Sites On Htas2r14mentioning

confidence: 99%

Section: Prediction Of Dph Asp-asp or Glu-glu Binding Sites On Htas2r14mentioning

confidence: 99%

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

et al. 2020

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“…In fact, at least the broadly tuned bitter taste receptors possess binding sites, which are tailored to accommodate multiple diverse bitter compounds at the expense of potentially higher sensitivities for individual agonists by providing different contact points, a feature discovered at the example of the TAS2R10 [ 91 ], which exhibited strongly improved responses for some of its agonists caused by point-mutations. Recently, a comprehensive structure-function study performed with the most broadly tuned human TAS2R, the TAS2R14, identified that almost all receptor positions that contribute to the ligand binding site of this receptor, exhibited agonist-selective effects [ 92 ]. As some of these positions were considered highly conserved among the TAS2R-family, a drop in agonist activation by point-mutating these positions have been seen with caution, because potential misfolding was suspected.…”

Section: Different Approaches To Investigate Tas2rsmentioning

confidence: 99%

Structure-Function Analyses of Human Bitter Taste Receptors—Where Do We Stand?

Behrens

Ziegler

2020

Molecules

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The finding that bitter taste receptors are expressed in numerous tissues outside the oral cavity and fulfill important roles in metabolic regulation, innate immunity and respiratory control, have made these receptors important targets for drug discovery. Efficient drug discovery depends heavily on detailed knowledge on structure-function-relationships of the target receptors. Unfortunately, experimental structures of bitter taste receptors are still lacking, and hence, the field relies mostly on structures obtained by molecular modeling combined with functional experiments and point mutageneses. The present article summarizes the current knowledge on the structure–function relationships of human bitter taste receptors. Although these receptors are difficult to express in heterologous systems and their homology with other G protein-coupled receptors is very low, detailed information are available at least for some of these receptors.

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“…have been identified by homology modelling and site-directed mutagenesis [5,[11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation

et al. 2019

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Bitter taste enables the detection of potentially harmful substances and is mediated by bitter taste receptors, TAS2Rs, in vertebrates. Few antagonists and inverse agonists of TAS2Rs have been identified, especially natural compounds. TAS2R16s in humans, apes and Old World monkeys (Catarrhini, Anthropoidea) recognize β-glucoside analogues as specific agonists. Here, we investigated responses of TAS2R16 to β-glucosides in non-anthropoid primates, namely lemurs (Lemuriformes, Strepsirrhini). Salicin acted as an agonist on lemur TAS2R16. Arbutin acted as an agonist in the ring-tailed lemur ( Lemur catta ) but as an inverse agonist in black lemur ( Eulemur macaco ) and black-and-white ruffed lemur ( Varecia variegata ). We identified a strepsirrhine-specific amino acid substitution responsible for the inverse agonism of arbutin. In a food preference test, salicin bitterness was inhibited by arbutin in the black lemur. Structural modelling revealed this locus was important for a rearrangement of the intracellular end of transmembrane helix 7 (TM7). Accordingly, arbutin is the first known natural inverse agonist of TAS2Rs, contributing to our understanding of receptor–ligand interactions and the molecular basis of the unique feeding habit diversification in lemurs. Furthermore, the identification of a causal point mutation suggests that TAS2R can acquire functional changes according to feeding habits and environmental conditions.

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Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14

Cited by 59 publications

References 43 publications

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

Bitterness-Suppressing Effect of Umami Dipeptides and Their Constituent Amino Acids on Diphenhydramine: Evaluation by Gustatory Sensation and Taste Sensor Testing

Structure-Function Analyses of Human Bitter Taste Receptors—Where Do We Stand?

A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation

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