EMD-38587
Structure of human class T GPCR TAS2R14-DNGi complex with Flufenamic acid.
EMD-38587
Single-particle3.3 Å
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Map released: 10/07/2024
Last modified: 16/10/2024
Sample Organism:
Homo sapiens,
synthetic construct
Sample: Structure of human class T GPCR TAS2R14-DNGi complex with Flufenamic acid.
Fitted models: 8xqs (Avg. Q-score: 0.396)
Deposition Authors: Hu XL, Wu LJ, Hua T
,
Liu ZJ
Sample: Structure of human class T GPCR TAS2R14-DNGi complex with Flufenamic acid.
Fitted models: 8xqs (Avg. Q-score: 0.396)
Deposition Authors: Hu XL, Wu LJ, Hua T
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Bitter taste TAS2R14 activation by intracellular tastants and cholesterol.
Hu X,
Ao W,
Gao M,
Wu L
,
Pei Y
,
Liu S,
Wu Y
,
Zhao F,
Sun Q,
Liu J,
Jiang L,
Wang X,
Li Y,
Tan Q,
Cheng J
,
Yang F
,
Yang C
,
Sun J
,
Hua T
,
Liu ZJ
(2024) Nature , 631 , 459 - 466
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(2024) Nature , 631 , 459 - 466
Abstract:
Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1,2. TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications3. Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery.
Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1,2. TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications3. Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery.