Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor

Sandal, Massimo; Behrens, Maik; Brockhoff, Anne; Musiani, Francesco; Giorgetti, Alejandro; Carloni, Paolo; Meyerhof, Wolfgang

doi:10.1021/acs.jctc.5b00472

Cited by 70 publications

(110 citation statements)

References 78 publications

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“…41 We validated this subdivision against the residues known to be involved in ligand-receptor interactions of both cavities in the crystal structures 42 . From our alignment, the orthosteric cavity reflects the full conservation of the residues 29, 43 (Fig.…”

Section: Resultsmentioning

confidence: 99%

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

Radu

Osculati

Suku

et al. 2017

Sci Rep

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Clinical and experimental studies indicate that muscarinic acetylcholine receptors are potential pharmacological targets for the treatment of neurological diseases. Although these receptors have been described in human, bovine and rat cerebral microvascular tissue, a subtype functional characterization in mouse brain endothelium is lacking. Here, we show that all muscarinic acetylcholine receptors (M1-M5) are expressed in mouse brain microvascular endothelial cells. The mRNA expression of M2, M3, and M5 correlates with their respective protein abundance, but a mismatch exists for M1 and M4 mRNA versus protein levels. Acetylcholine activates calcium transients in brain endothelium via muscarinic, but not nicotinic, receptors. Moreover, although M1 and M3 are the most abundant receptors, only a small fraction of M1 is present in the plasma membrane and functions in ACh-induced Ca2+ signaling. Bioinformatic analyses performed on eukaryotic muscarinic receptors demonstrate a high degree of conservation of the orthosteric binding site and a great variability of the allosteric site. In line with previous studies, this result indicates muscarinic acetylcholine receptors as potential pharmacological targets in future translational studies. We argue that research on drug development should especially focus on the allosteric binding sites of the M1 and M3 receptors.

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Section: Resultsmentioning

confidence: 99%

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

Radu

Osculati

Suku

et al. 2017

Sci Rep

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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%

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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“…Indeed, predictions of agonist binding to bitter taste and olfactory receptors using a variety of docking approaches showed that their predictive power is very limited [23], as they are not able to capture the residues shown experimentally to be important for binding. These initial binding poses can be further refined with MD simulations, in particular using our MM/CG approach, resulting in a dramatic improvement in the predictions [23,128,129].…”

Section: Applications To Human G-protein Coupled Receptorsmentioning

confidence: 99%

“…The MM/CG approach was subsequently used to investigate the binding structural determinants in another member of the human bitter taste receptor family, hTAS2R46, in complex with its potent agonist strychnine (Fig. 3) [129]. The initial model of the complex was built using the GOMoDo web-server [131], which combines MODELLER [119,120] and HADDOCK [122] in a single pipeline.…”

Section: Applications To Human G-protein Coupled Receptorsmentioning

confidence: 99%

Predicting ligand binding poses for low-resolution membrane protein models: Perspectives from multiscale simulations

Schneider

Korshunova

Musiani

et al. 2018

Biochemical and Biophysical Research Communications

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Membrane receptors constitute major targets for pharmaceutical intervention. Drug design efforts rely on the identification of ligand binding poses. However, the limited experimental structural information available may make this extremely challenging, especially when only low-resolution homology models are accessible. In these cases, the predictions may be improved by molecular dynamics simulation approaches. Here we review recent developments of multiscale, hybrid molecular mechanics/coarse-grained (MM/CG) methods applied to membrane proteins. In particular, we focus on our in-house MM/CG approach. It is especially tailored for G-protein coupled receptors, the largest membrane receptor family in humans. We show that our MM/CG approach is able to capture the atomistic details of the receptor/ligand binding interactions, while keeping the computational cost low by representing the protein frame and the membrane environment in a highly simplified manner. We close this review by discussing ongoing improvements and challenges of the current implementation of our MM/CG code.

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Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor

Cited by 70 publications

References 78 publications

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

All muscarinic acetylcholine receptors (M1-M5) are expressed in murine brain microvascular endothelium

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

Predicting ligand binding poses for low-resolution membrane protein models: Perspectives from multiscale simulations

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