Comparing Class A GPCRs to bitter taste receptors

Pizio, Antonella Di; Levit, Anat; Slutzki, Michal; Behrens, Maik; Karaman, Rafik; Niv, Masha Y.

doi:10.1016/bs.mcb.2015.10.005

Cited by 79 publications

(61 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have investigated the conformation assumed by guaifenesin in the receptor's binding pocket, [27] by Induced Fit docking simulations. [52,53] Guaifenesin establishes π-π interactions with Phe247 6.55 , hydrophobic interactions with Phe186 5.…”

Section: Structural Analysismentioning

confidence: 99%

“…[24][25][26] Despite low sequence similarity, TAS2Rs are classified as class A GPCRs. [27] The human sense of bitter taste is commonly categorized as a warning sense against the ingestion of toxic food components, although, in particular during later phases in life, moderate bitterness is well tolerated and even appreciated in the context of some food items and beverages. [28] On the tongue, subsets of TAS2R genes are co-expressed in bitter taste receptor cells that represent a subpopulation of type II cells within taste buds.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

et al. 2018

Self Cite

View full text Add to dashboard Cite

A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.

show abstract

Section: Structural Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The bitter taste receptors provide a primitive alarm system that prevents the ingestion of potentially toxic food items in human. 11,12) The bitter-responsive cells of taste buds located in the oral cavity express a subset of the 25 putatively functional human bitter taste receptors (hTAS2Rs) [13][14][15] that are distantly related to the class A G protein-coupled receptor (GPCR) family. 16) The functional characterization of hTAS2Rs has revealed that they can be grouped on the basis of their agonist spectra into broadly, narrowly, and intermediately tuned receptors.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…After the successful characterization of about half of the human TAS2Rs and the finding that TAS2Rs can be classified according to the number of agonists into broadly tuned receptors with numerous agonists, narrowly tuned receptors with very few agonists, receptors recognizing selective chemical classes and intermediately tuned receptors [ 16 ], the structural features determining the tuning characteristics especially of broadly tuned TAS2Rs moved into the focus of research. However, it was, and still is, a major obstacle that bitter taste receptors only exhibit very minor homology with other GPCR families [ 32 , 33 ] and that experimental structures of TAS2Rs are lacking. Hence, homology modeling was necessary despite the fact that homology was very low.…”

Section: Introductionmentioning

confidence: 99%

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

Behrens

Ziegler

2020

Molecules

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Comparing Class A GPCRs to bitter taste receptors

Cited by 79 publications

References 110 publications

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies

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?

Contact Info

Product

Resources

About