Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Fierro, Fabrizio; Peri, Lior; Hübner, Harald; Tabor-Schkade, Alina; Waterloo, Lukas; Löber, Stefan; Pfeiffer, Tara; Weikert, Dorothée; Dingjan, Tamir; Margulis, Eitan; Gmeiner, Peter; Niv, Masha Y.

doi:10.1007/s00018-023-04765-0

Cited by 10 publications

(14 citation statements)

References 63 publications

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“…5 and 6b). Moreover, pocket-2 is in proximity to activation-related motifs, HS/P 7 .50 FIL and FY 3 .50 L, as previously identified for TAS2Rs 24,26 . Thus, agonist binding in pocket-2 is crucial for activation and active conformation stabilization of TAS2R14 (Fig.…”

Section: Resultssupporting

confidence: 65%

“…5b,e,h). Y107 3.50 and H276 7.49 are two conserved residues in TAS2Rs, mutation of Y107 3 .50 A or H276 7 .49 A abolishes the receptor activation induced by AA (Fig. 2k, Extended Data Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The cholesterol is located within pocket-1, forming π-π interaction with W89 3.32 (Fig. 2h), and the mutation of W89 3 .32 A also affects FFA’s activity toward TAS2R14, indicating the role of W89 3.32 in stabilizing the conformation of this region. Accordingly, single mutations of other residues in pocket-1 also slightly affect FFA-induced activation of TAS2R14 in both calcium mobilization and G protein dissociation assays (Fig.…”

Section: Resultsmentioning

confidence: 99%

“… AbstractBitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents 1–3 . In addition, TAS2R14 has broad expression in non-gustatory tissues, suggesting its important roles in selective physiological processes and therapeutic potential 4 .…”

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confidence: 99%

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Unlocking TAS2R14 activation through intricate multi-ligand binding networks

Hu,

Ao,

Gao

et al. 2024

Preprint

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Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1-3. In addition, TAS2R14 has broad expression in non-gustatory tissues, suggesting its important roles in selective physiological processes and therapeutic potential4. Here, we present cryo-electron microcopy structures of TAS2R14 in complex with flufenamic acid and aristolochic acid, coupling with G protein subtypes gustducin and Gi. Distinct from most known GPCRs, agonists of TAS2R14 bind to multiple intracellular pockets. We highlight the cholesterol molecules occupying an upper transmembrane site, typically the orthosteric pocket in other GPCRs, also binding in the entrance to an intracellular agonist binding pocket, suggesting an endogenous modulatory function5. The structural and mutagenesis analysis illuminate the receptor's broad-spectrum ligand recognition and activation via intricate multiple ligand-binding sites. Furthermore, we unveil the structural configuration of gustducin and its interaction with TAS2R14, as well as the coupling mode of Gi1. This investigation should be instrumental in advancing our knowledge of the mechanisms underlying bitter taste recognition and response, with broader relevance to sensory biology and pharmacology.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Unlocking TAS2R14 activation through intricate multi-ligand binding networks

Hu,

Ao,

Gao

et al. 2024

Preprint

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“…Novel TAS2R14 agonists from recent publications were also included. , Due to the fact that the activation of only one TAS2R14 receptor was investigated, those compounds that have not been experimentally confirmed as agonists cannot be labeled as “nonbitter” since they may activate other TAS2Rs. Thus, 261 bitter compounds that are TAS2R14 agonists were added.…”

Section: Methodsmentioning

confidence: 99%

BitterMasS: Predicting Bitterness from Mass Spectra

Ziaikin,

Tello,

Peterson

et al. 2024

J. Agric. Food Chem.

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Bitter compounds are common in nature and among drugs. Previously, machine learning tools were developed to predict bitterness from the chemical structure. However, known structures are estimated to represent only 5−10% of the metabolome, and the rest remain unassigned or "dark". We present BitterMasS, a Random Forest classifier that was trained on 5414 experimental mass spectra of bitter and nonbitter compounds, achieving precision = 0.83 and recall = 0.90 for an internal test set. Next, the model was tested against spectra newly extracted from the literature 106 bitter and nonbitter compounds and for additional spectra measured for 26 compounds. For these external test cases, BitterMasS exhibited 67% precision and 93% recall for the first and 58% accuracy and 99% recall for the second. The spectrum−bitterness prediction strategy was more effective than the spectrum−structure−bitterness prediction strategy and covered more compounds. These encouraging results suggest that BitterMasS can be used to predict bitter compounds in the metabolome without the need for structural assignment of individual molecules. This may enable identification of bitter compounds from metabolomics analyses, for comparing potential bitterness levels obtained by different treatments of samples and for monitoring bitterness changes overtime.

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Membrane-bound chemoreception of bitter bile acids and peptides is mediated by the same subset of bitter taste receptors

Schaefer,

Ziegler,

Lang

et al. 2024

Cell. Mol. Life Sci.

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The vertebrate sense of taste allows rapid assessment of the nutritional quality and potential presence of harmful substances prior to ingestion. Among the five basic taste qualities, salty, sour, sweet, umami, and bitter, bitterness is associated with the presence of putative toxic substances and elicits rejection behaviors in a wide range of animals including humans. However, not all bitter substances are harmful, some are thought to be health-beneficial and nutritious. Among those compound classes that elicit a bitter taste although being non-toxic and partly even essential for humans are bitter peptides and l-amino acids. Using functional heterologous expression assays, we observed that the 5 dominant human bitter taste receptors responsive to bitter peptides and amino acids are activated by bile acids, which are notorious for their extreme bitterness. We further demonstrate that the cross-reactivity of bitter taste receptors for these two different compound classes is evolutionary conserved and can be traced back to the amphibian lineage. Moreover, we show that the cross-detection by some receptors relies on “structural mimicry” between the very bitter peptide l-Trp-Trp-Trp and bile acids, whereas other receptors exhibit a phylogenetic conservation of this trait. As some bile acid-sensitive bitter taste receptor genes fulfill dual-roles in gustatory and non-gustatory systems, we suggest that the phylogenetic conservation of the rather surprising cross-detection of the two substance classes could rely on a gene-sharing-like mechanism in which the non-gustatory function accounts for the bitter taste response to amino acids and peptides.

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Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands

Cited by 10 publications

References 63 publications

Unlocking TAS2R14 activation through intricate multi-ligand binding networks

Unlocking TAS2R14 activation through intricate multi-ligand binding networks

BitterMasS: Predicting Bitterness from Mass Spectra

Membrane-bound chemoreception of bitter bile acids and peptides is mediated by the same subset of bitter taste receptors

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