Bitter taste TAS2R14 activation by intracellular tastants and cholesterol

Xiaolong Hu, Weizhen Ao, Mingxin Gao, Lijie Wu, Yuan Pei, Shenhui Liu, Yiran Wu, Fei Zhao, Qianqian Sun, Junlin Liu, Longquan Jiang, Xin Wang, Yan Li, Qiwen Tan, Jie Cheng, Fan Yang, Chi Yang (), Jinpeng Sun (), Tian Hua () and Zhi-Jie Liu ()
Additional contact information
Xiaolong Hu: ShanghaiTech University
Weizhen Ao: ShanghaiTech University
Mingxin Gao: Shandong University
Lijie Wu: ShanghaiTech University
Yuan Pei: ShanghaiTech University
Shenhui Liu: ShanghaiTech University
Yiran Wu: ShanghaiTech University
Fei Zhao: ShanghaiTech University
Qianqian Sun: ShanghaiTech University
Junlin Liu: ShanghaiTech University
Longquan Jiang: ShanghaiTech University
Xin Wang: ShanghaiTech University
Yan Li: Shanghai Jiao Tong University School of Medicine
Qiwen Tan: ShanghaiTech University
Jie Cheng: Shandong University
Fan Yang: Shandong University
Chi Yang: Shanghai Jiao Tong University School of Medicine
Jinpeng Sun: Shandong University
Tian Hua: ShanghaiTech University
Zhi-Jie Liu: ShanghaiTech University

Nature, 2024, vol. 631, issue 8020, 459-466

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07569-9

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