Journal Article

Bitter taste TAS2R14 activation by intracellular tastants and cholesterol

Liu, Zhi-Jie, Wang, Xin, Gao, Mingxin, Yang, Chi, Hu, Xiaolong, Liu, Junlin, Wu, Yiran, Jiang, Longquan, Wu, Lijie, Tan, Qiwen, Sun, Jinpeng, Hua, Tian, Liu, Shenhui, Zhao, Fei, Cheng, Jie, Yang, Fan, Li, Yan, Ao, Weizhen, Pei, Yuan, Sun, Qianqian

2024

Overview

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. A cryogenic electron microcopy study of structures of a human receptor for bitter taste finds that cholesterol can activate the receptor, while the tastant molecule acts allosterically on the receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/154/436 / 631/535/1258 / 82/80 / 82/83 / 96/95 / Acids / Activation analysis / Aristolochic acid / Aristolochic Acids - chemistry / Aristolochic Acids - metabolism / Aristolochic Acids - pharmacology / Binding sites / Binding Sites - drug effects / Bitter taste / Cholesterol / Cholesterol - chemistry / Cholesterol - metabolism / Cholesterol - pharmacology / Coupling (molecular) / Cryoelectron Microscopy / Electron microscopy / Flufenamic Acid - chemistry / Flufenamic Acid - metabolism / Flufenamic Acid - pharmacology / G protein-coupled receptors / Gnat3 protein / GTP-Binding Protein alpha Subunits, Gi-Go - chemistry / GTP-Binding Protein alpha Subunits, Gi-Go - metabolism / Humanities and Social Sciences / Humans / Intracellular / Ligands / Microscopy / Models, Molecular / Molecular dynamics / Molecular Dynamics Simulation / multidisciplinary / Mutagenesis / Mutation / Physiology / Proteins / Receptors / Receptors, G-Protein-Coupled - agonists / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Receptors, G-Protein-Coupled - ultrastructure / Science / Science (multidisciplinary) / Structural analysis / Taste / Taste - drug effects / Taste - physiology / Taste perception / Taste receptors / Taste Receptors, Type 2 / Transducin - chemistry / Transducin - metabolism