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Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.

ABSTRACT: The 25 human bitter taste receptors (TAS2Rs) are expressed on taste and extra-oral cells representing an integrated chemosensory system. The archetypal TAS2R14 is activated by > 150 topographically diverse agonists, raising the question of how this uncharacteristic accommodation is achieved for these GPCRs. We report the computationally derived structure of TAS2R14 with binding sites and energies for five highly diverse agonists. Remarkably, the binding pocket is the same for all five agonists. The energies derived from molecular dynamics are consistent with experiments determining signal transduction coefficients in live cells. TAS2R14 accommodates agonists through the breaking of a TMD3 H-bond instead of the prototypic strong salt bridge, a TMD1,2,7 interaction different from Class A GPCRs, and agonist-promoted TMD3 salt bridges for high affinity (which we confirmed by receptor mutagenesis). Thus, the broadly tuned TAS2Rs accommodate diverse agonists via a single (vs multiple) binding pocket through unique TM interactions for sensing disparate micro-environments.

SUBMITTER: Tokmakova A

PROVIDER: S-EPMC10121769 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.

Tokmakova Alina A Kim Donghwa D Guthrie Brian B Kim Soo-Kyung SK Goddard William A WA Liggett Stephen B SB

iScience 20230316 4

The 25 human bitter taste receptors (TAS2Rs) are expressed on taste and extra-oral cells representing an integrated chemosensory system. The archetypal TAS2R14 is activated by > 150 topographically diverse agonists, raising the question of how this uncharacteristic accommodation is achieved for these GPCRs. We report the computationally derived structure of TAS2R14 with binding sites and energies for five highly diverse agonists. Remarkably, the binding pocket is the same for all five agonists. ...[more]

PMID: 37096045

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Project description:Humans will eat almost anything, from caribou livers to rutabagas, but there are some types of foods, and their associated taste qualities, that are preferred by large groups of people regardless of culture or experience. When many choices are available, humans chose foods that taste good, that is, create pleasing sensations in the mouth. The concept of good taste for most people encompasses both flavor and texture of food, and these sensations merge with taste proper to form the concept of goodness. Although we acknowledge the universality of the goodness (sweet) or badness (bitter) of basic taste qualities, we also find that people differ, sometimes extremely so, in their ability to perceive and enjoy these qualities and, by extension, food and drink. The reasons for these differences among people are not clear but are probably due to a combination of experience beginning at an early age, perhaps in utero; learning, for example, as with conditioned taste aversions; sex and maturity; and perceptual differences that arise from genetic variation. In this review, we focus on individual variations that arise from genetic differences and review two domains of science: recent developments in the molecular biology of taste transduction, with a focus on the genes involved and second, studies that examine biological relatives to determine the heritability of taste perception. Because the receptors for sweet, savory (umami), and bitter have recently been discovered, we summarize what is known about their function by reviewing the effect of naturally occurring and man-made alleles of these receptors, their shape and function based on receptor modeling techniques, and how they differ across animal species that vary in their ability to taste certain qualities. We discuss this literature in the context of how taste genes may differ among people and give rise to individuated taste experience, and what is currently known about the genetic effects on taste perception in humans.

Project description:BackgroundInfants are born with the biological predisposition to reject bitterness. Dark green vegetables contain essential nutrients but also bitter compounds, making them more difficult to like.ObjectiveThe Good Tastes Study was designed to determine whether reducing bitterness by adding small amounts of sugar or salt would alter infant acceptance of kale purées.MethodsCaregivers (n = 106, 94% mothers, 82% Non-Hispanic White) and children (53% male, aged 6-24 mo) participated in a videorecorded laboratory visit during which infants were offered 4 versions of puréed kale: plain, 1.2% or 1.8% added sugar, or 0.2% added salt. Caregivers rated their children's liking for each kale version. Videos were coded for the number of tastes accepted and for children's behaviors and acceptance of each kale version. A multilevel ordered logistic model was fit for the number of accepted tastes and caregiver ratings of child liking of kale versions with age, breastfeeding history, order effects, and kale version as predictors.ResultsInfants 6 to <12 mo accepted more tastes (b = 2.911, P < 0.001) and were rated by caregivers as liking the kale more than older toddlers (≥18 mo; b = 1.874, P = 0.014). The plain kale was more likely to be accepted (P < 0.001); also, the first version offered was more likely to be rejected (b = -0.586, P < 0.007). Older infants (≥18 mo) exhibited more avoidant behaviors (b = 1.279, P < 0.001), more playing (b = 2.918, P < 0.001), and more self-feeding (b = 1.786, P = 0.005) than younger infants (6 to <12 mo). Children who were reported to have been breastfed more in the last 7 d were more likely to self-feed (b = 0.246, P < 0.001) and play with food (b = 0.207, P < 0.005).ConclusionsOur findings support that there may be a sensitive period, during the early phase of complementary feeding, to improve success of introducing a novel, bitter, more difficult-to-like food. When low levels of sugar or salt were added, no advantage of bitterness reduction was observed. This study has been registered with ClinicalTrials.gov as NCT04549233.

Dataset Information

Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.

Publications

Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.

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