Characterization of the β-d-Glucopyranoside Binding Site of the Human Bitter Taste Receptor hTAS2R16

Sakurai, Takanobu; Misaka, Takumi; Ishiguro, Masaji; Masuda, Koichi; Sugawara, Taishi; Ito, Keisuke; Kobayashi, Takuya; Matsuo, Shingo; Ishimaru, Yoshiro; Asakura, Tomiko; Abe, Keiko

doi:10.1074/jbc.m110.144444

Cited by 87 publications

(104 citation statements)

References 39 publications

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“…Human TAS2R16 responded to salicin with EC 50 of 0.48 + 0.09 mM, in agreement with reported values [5,10,11]. The TAS2R16s of non-human primates showed various responses to salicin.…”

Section: Resultssupporting

confidence: 78%

“…Human-specific amino acid substitution at position 172 results in high sensitivity to harmful cyanogenic glycosides, which may have been advantageous for avoidance of toxic compounds in early human diets [10]. Ligand-binding sites were identified by mutational studies of human TAS2R16 [11]. Mutation of amino acid resides in helices 3-6 causes decreases in sensitivity for natural and artificial ligands.…”

Section: Introductionmentioning

confidence: 99%

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Functional diversity of bitter taste receptor TAS2R16 in primates

et al. 2012

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In mammals, bitter taste is mediated by TAS2R genes, which belong to the large family of seven transmembrane G protein-coupled receptors. Because TAS2Rs are directly involved in the interaction between mammals and their dietary sources, it is likely that these genes evolved to reflect species-specific diets during mammalian evolution. Here, we investigated the sensitivities of TAS2R16s of various primates by using a cultured cell expression system, and found that the sensitivity of each primate species varied according to the ligand. Especially, the sensitivity of TAS2R16 of Japanese macaques to salicin was much lower than that of human TAS2R16, which was supported by behavioural tests. These results suggest the possibility that bitter-taste sensitivities evolved independently by replacing specific amino acid residues of TAS2Rs in different primate species to adapt to food items they use.

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“…Human TAS2R16 responded to salicin with EC 50 of 0.48 + 0.09 mM, in agreement with reported values [5,10,11]. The TAS2R16s of non-human primates showed various responses to salicin.…”

Section: Resultssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Functional diversity of bitter taste receptor TAS2R16 in primates

et al. 2012

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“…Thus, an important discovery of this work is the demonstration that natural compounds can simultaneously act as both agonists and antagonists of bitter receptors. The ability of the two compounds to block hTAS2R46 activation by structurally dissimilar agonists further supports the existence of only one binding site in hTAS2Rs (Biarnés et al, 2010;Brockhoff et al, 2010;Sakurai et al, 2010).…”

Section: Discussionmentioning

confidence: 80%

Receptor Agonism and Antagonism of Dietary Bitter Compounds

Brockhoff¹,

Behrens²,

Roudnitzky³

et al. 2011

J. Neurosci.

105

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Food contains complex blends of structurally diverse bitter compounds that trigger bitterness through activation of one or more of the ϳ25 human TAS2 bitter taste receptors. It remains unsolved, however, whether the perceived bitterness of binary bitter-compound mixtures can be considered an additive function of all bitter-inducing chemicals in the mouth, suggesting that little mutual interaction takes place among bitter substances or if mixture suppression and synergism occurs. Here we report on two natural sesquiterpene lactones from edible plants, which stimulate distinct sets of hTAS2Rs in transfected cells. Both chemicals also robustly inhibit different but overlapping subsets of agonist-activated hTAS2Rs. These findings demonstrate that mixtures of bitter compounds, because they normally occur in human foodstuff, likely elicit bitter perception in a complex and not in a merely additive manner. An unexpected implication of this discovery is that, during evolution, the naturally occurring bitter taste receptor antagonists have shaped some of the pharmacological properties of the receptors, such as overlapping recognition profiles and breadth of tuning.

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“…The involved residues include Glu86, Asn89, Phe93, Ala180, His181, Ala185, Phe240, Leu244, Arg255, Leu258, Trp259 and Glu262. Residues such as Glu86, Asn89, Phe93, His181 and Phe240 were also predicted to be key residues in binding of salicin with TAS2R16 by Sakurai et al [22], proving the reliability of our built structure again.…”

Section: Molecular Dynamics Simulations Of Salicin and Probenecidmentioning

confidence: 73%

Insights into the binding of agonist and antagonist to TAS2R16 receptor: a molecular simulation study

Chen

Dong

Meng

et al. 2017

Molecular Simulation

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The human bitter taste receptors (TAS2Rs) belong to the GPCR family, while the activation mechanism and how TAS2Rs recognise bitter ligands are poorly understood. In this study, 3D structure of TAS2R16 was constructed using homology modelling complemented with molecular dynamics method. Salicin and probenecid were docked to TAS2R16 receptor to investigate the possible activation mechanism of TAS2R16. The results show that salicin and probenecid locate at the binding pocket made up of transmembrane helices TM3, TM5 and TM7, and the second and third extracellular loops ECL2 and ECL3. Structural analysis reveals that the network interactions at the third intracellular loop ICL3 may play a crucial role in stabilising the inactive state of TAS2R16, and structural change in the intracellular region is correlated with the activation of TAS2R16. The binding energies of salicin and probenecid to TAS2R16 are −152.81 ± 15.09 and −271.90 ± 26.97 kJ/mol, respectively, indicating that a potential antagonist should have obviously stronger binding affinity.

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Characterization of the β-d-Glucopyranoside Binding Site of the Human Bitter Taste Receptor hTAS2R16

Cited by 87 publications

References 39 publications

Functional diversity of bitter taste receptor TAS2R16 in primates

Functional diversity of bitter taste receptor TAS2R16 in primates

Receptor Agonism and Antagonism of Dietary Bitter Compounds

Insights into the binding of agonist and antagonist to TAS2R16 receptor: a molecular simulation study

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