1. Academic Validation
  2. Bitter taste TAS2R14 activation by intracellular tastants and cholesterol

Bitter taste TAS2R14 activation by intracellular tastants and cholesterol

  • Nature. 2024 May 22. doi: 10.1038/s41586-024-07569-9.
Xiaolong Hu # 1 2 Weizhen Ao # 1 2 Mingxin Gao # 3 Lijie Wu # 1 Yuan Pei 1 Shenhui Liu 1 2 Yiran Wu 1 Fei Zhao 1 Qianqian Sun 1 Junlin Liu 1 Longquan Jiang 1 2 Xin Wang 1 2 Yan Li 4 5 Qiwen Tan 1 Jie Cheng 3 Fan Yang 3 Chi Yang 6 7 Jinpeng Sun 8 Tian Hua 9 10 Zhi-Jie Liu 11 12
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 4 Department of Oral Surgery, Shanghai Ninth People's Hospital and College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 National Center for Stomatology and National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China.
  • 6 Department of Oral Surgery, Shanghai Ninth People's Hospital and College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 7 National Center for Stomatology and National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. [email protected].
  • 8 NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China. [email protected].
  • 9 iHuman Institute, ShanghaiTech University, Shanghai, China. [email protected].
  • 10 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 11 iHuman Institute, ShanghaiTech University, Shanghai, China. [email protected].
  • 12 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • # Contributed equally.
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 extra-gustatory tissues, suggesting its additional roles in diverse physiological processes and potential therapeutic applications3. Here, we present cryo-electron microcopy 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 GPCRs. 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 simulations studies, illuminate the receptor's broad-spectrum ligand recognition and activation via intricate multiple ligand-binding sites. Additionally, our study uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing our knowledge underlying bitter taste perception and its broader implications in sensory biology and drug discovery.

Figures
Products