Bitter taste TAS2R14 activation by intracellular tastants and cholesterol.

Autor: Hu X; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Ao W; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Gao M; NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, China., Wu L; iHuman Institute, ShanghaiTech University, Shanghai, China., Pei Y; iHuman Institute, ShanghaiTech University, Shanghai, China., Liu S; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Wu Y; iHuman Institute, ShanghaiTech University, Shanghai, China., Zhao F; iHuman Institute, ShanghaiTech University, Shanghai, China., Sun Q; iHuman Institute, ShanghaiTech University, Shanghai, China., Liu J; iHuman Institute, ShanghaiTech University, Shanghai, China., Jiang L; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Wang X; iHuman Institute, ShanghaiTech University, Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Li Y; Department of Oral Surgery, Shanghai Ninth People's Hospital and College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; 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., Tan Q; iHuman Institute, ShanghaiTech University, Shanghai, China., Cheng J; NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, China., Yang F; NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, China., Yang C; Department of Oral Surgery, Shanghai Ninth People's Hospital and College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yangchi63@hotmail.com.; 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. yangchi63@hotmail.com., Sun J; NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, China. sunjinpengsdu@126.com., Hua T; iHuman Institute, ShanghaiTech University, Shanghai, China. huatian@shanghaitech.edu.cn.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huatian@shanghaitech.edu.cn., Liu ZJ; iHuman Institute, ShanghaiTech University, Shanghai, China. liuzhj@shanghaitech.edu.cn.; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. liuzhj@shanghaitech.edu.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jul; Vol. 631 (8020), pp. 459-466. Date of Electronic Publication: 2024 May 22.
DOI: 10.1038/s41586-024-07569-9
Abstrakt: Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents 1,2 . TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications 3 . 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 G i1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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