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Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Given that the precise functioning mechanisms of TAS2R remain poorly understood, this study employed molecular dynamics simulations combined with network-based analysis to investigate local conformational changes and global structural correlations in different states of the receptor. The focus was on the human TAS2R46 bitter taste receptor, recently resolved experimentally, both in the presence and absence of strychnine, a known bitter agonist. The results showed that the ligand-bound state of the receptor exhibited more correlated dynamics compared to the apo state, and the presence of the agonist mediated the allosteric network between two helices (TM3 and TM6) which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the conformational changes and allosteric network of TAS2R46 under varying conditions, this study has enabled the identification of the unique structural and dynamics features of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors.

TAS2R46, a bitter taste receptor, is crucial for detecting harmful substances. Understanding its molecular interactions with bitter compounds could help develop bitter taste modulators for the food and pharmaceutical industries. However, such interactions had remained underexplored. A computational method was utilized in this investigation to examine the binding interactions between TAS2R46 and the bitter components of liquid smoke. By utilizing molecular docking and molecular dynamics simulations, one may analyze the modes of binding, the stability of these interactions, and the essential residues at the binding site. The human TAS2R46 protein (PDB ID 7XP6) had been selected for this study. Molecular docking was employed to predict the binding modes and affinity of the liquid smoke's ligands to the TAS2R46 receptor. Subsequently, molecular dynamics simulations were conducted to analyze the stability and dynamics of the TAS2R46-liquid smoke ligand complexes over a 100 ns timeframe. Our computational findings revealed that the nine teen-reported compounds of liquid smoke could indeed bind to TAS2R46. Delta energy component calculations had indicated the stability of these ligand-receptor complexes, with 1-(2,4,6-trihydroxyphenyl)-ethanone showing the most favorable binding energy. These results provided crucial insights into the molecular basis of bitter taste perception and may have implications for the food industry and drug development. In conclusion, this research bridged a critical knowledge gap by providing a molecular-level understanding of how TAS2R46 interacted with bitter compounds in liquid smoke. [ABSTRACT FROM AUTHOR]

Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Given that the precise functioning mechanisms of TAS2R remain poorly understood, this study employed molecular dynamics simulations combined with network-based analysis to investigate local conformational changes and global structural correlations in different states of the receptor. The focus was on the human TAS2R46 bitter taste receptor, recently resolved experimentally, both in the presence and absence of strychnine, a known bitter agonist. The results showed that the ligand-bound state of the receptor exhibited more correlated dynamics compared to the apo state, and the presence of the agonist mediated the allosteric network between two helices (TM3 and TM6) which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the conformational changes and allosteric network of TAS2R46 under varying conditions, this study has enabled the identification of the unique structural and dynamics features of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors., Competing Interests: Author GDB was employed by 7HC s.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cannariato, Fanunza, Zizzi, Miceli, Di Benedetto, Deriu and Pallante.)

Human bitter taste receptors (hTAS2Rs) are the second largest group of chemosensory G-protein coupled receptors (25 members). hTAS2Rs are expressed in many tissues (e.g. tongue, gastrointestinal tract, respiratory system, brain, etc.), performing a variety of functions, from bitter taste perception to hormone secretion and bronchodilation. Due to the lack of experimental structural information, computations are currently the methods of choice to get insights into ligand–receptor interactions. Here we review our efforts at predicting the binding pose of agonists to hTAS2Rs, using state-of-the-art bioinformatics approaches followed by hybrid Molecular Mechanics/Coarse-Grained (MM/CG) simulations. The latter method, developed by us, describes atomistically only the agonist binding region, including hydration, and it may be particularly suited to be used when bioinformatics predictions generate very low-resolution models, such as the case of hTAS2Rs. Our structural predictions of the hTAS2R38 and hTAS2R46 receptors in complex with their agonists turn out to be fully consistent with experimental mutagenesis data. In addition, they suggest a two-binding site architecture in hTAS2R46, consisting of the usual orthosteric site together with a “vestibular” site toward the extracellular space, as observed in other GPCRs. The presence of the vestibular site may help to discriminate among the wide spectrum of bitter ligands.

[Display omitted] • A virtual screening procedure was successfully applied to fish bitter toxic compounds. • A trichothecenes selection was thoroughly analyzed as TAS2R46 binders. • Deoxynivalenol and its 15-acetyl derivative tested as possible TAS2R46 activators. • TAS2Rs may be involved in the adverse effects of deoxynivalenol and congeners. • TAS2Rs in the mechanisms of trichothecenes toxicity should be analyzed further. The bitter taste perception evolved in human and animals to rapidly perceive and avoid potential toxic compounds. This is mediated by taste receptors type 2 (TAS2R), expressed in various tissues, which recently proved to be involved in roles beyond the bitter perception itself. With this study, the interaction between food-related toxic compounds and TAS2R46 has been investigated via computational approaches, starting with a virtual screening and moving to molecular docking and dynamics simulations. The virtual screening analysis identified trichothecolone and the trichothecenes class it belongs to, which includes mycotoxins widespread in several commodities raising food safety concerns, as possible TAS2R46 binders. Molecular docking and dynamics simulations were performed to further explore the trichotecenes-TAS2R46 interaction. The results indicated that deoxynivalenol and its 15-acetylated derivative could activate TAS2R46. Eventually, this study provided initial evidence supporting the involvement of TAS2R46 in the underpinning mechanisms of deoxynivalenol action highlighting the need of digging into the involvement of TAS2R46 and TAS2Rs in the adverse effects of deoxynivalenol and congeners. [ABSTRACT FROM AUTHOR]

Human type 2 taste receptor (TAS2R) genes encode bitter-taste receptors that are activated by various bitter ligands. It has been said that TAS2R38 may detect bitter substances and then suppress their intake by controlling gustatory or digestive responses. The major haplotypes of TAS2R38 involve three non-synonymous, closely-linked single-nucleotide polymorphisms (SNPs), leading to three amino acid substitutions (A49P, V262A and I296V) and resulting in a PAV or AVI allele. The allele frequency of AVI/PAV was 0.42/0.58 in this study. The genotype frequency distributions of TAS2R38 were 18.32%, 46.95% and 33.95% for AVI/AVI, AVI/PAV and PAV/PAV, respectively, and were in Hardy-Weinberg equilibrium. Five haplotype combinations of minor alleles were identified: AVI/AAV, AVI/AVV, AAI/PAV, AVI/PVV, AVI/AAI, with corresponding frequencies of 0.49%, 0.10%, 0.10%, 0.05%, 0.05%, respectively, in 2,047 Japanese Tohoku Medical Megabank Organization (ToMMo) subjects (2KJPN). The 16 subjects with these minor alleles were excluded from the questionnaire analysis, which found no significant differences among the major TAS2R38 genotypes (AVI/AVI, AVI/PAV and PAV/PAV) in the intake frequency of cruciferous vegetables or in the frequency of drinking alcohol. This result differs from previous data using American and European subjects. This is the first study to analyze the relationship between TAS2R38 genotype and the eating and drinking habits of Japanese subjects. It was also shown that there were no relationships at all between the genetic polymorphism of TAS2R46 and the phenotypes such as clinical BMI, eating and drinking habits among the 3 genotypes of TAS2R46 (∗/∗, ∗/W, W/W) at position W250∗ (∗stop codon).

Type-2 bitter-taste receptors (TAS2Rs) are important for the evaluation of food quality and the nutritional control in animals. Mutations in some TAS2Rs including TAS2R38 are known to increase susceptibility to various diseases. However, the involvement of TAS2Rs in cancers has not been well understood. We conducted a pilot study by genotyping two TAS2R genes, TAS2R38 and TAS2R46, in Japanese cancer patients diagnosed with the following types of cancer: biliary tract cancer, hepatocellular carcinoma, pancreatic cancer, colorectal cancer and gastric cancer. We selected the two TAS2Rs because they carry virtually non-functional alleles in human populations. We found that cancer risk is not associated with any TAS2R46 genotypes since there were no significant differences in genotype frequencies between cancer patients and controls. On the other hand, we confirmed that phenylthiocarbamide (PTC) non-tasters homozygous (AVI/AVI) for TAS2R38 were more frequent among Japanese cancer patients than those among controls as suggested in a previous study. The AVI/AVI genotype was therefore considered to increases cancer risk. In contrast, we also found that homozygous (PAV/PAV) PTC tasters are less frequent among cancer patients, suggesting that the PAV/PAV is a cancer resistant genotype that decreases cancer risk. Genotype frequencies for heterozygous AVI/PAV genotype were not significantly different between the two groups. It is suggested that the risk and resistance of cancers is antagonistically controlled by the two TAS2R38 alleles, PAV and AVI, rather than by the AVI allele alone.