دورية أكاديمية
Bitter taste TAS2R14 activation by intracellular tastants and cholesterol.
| العنوان: | Bitter taste TAS2R14 activation by intracellular tastants and cholesterol. |
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| المؤلفون: | 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. |
| المصدر: | Nature [Nature] 2024 Jul; Vol. 631 (8020), pp. 459-466. Date of Electronic Publication: 2024 May 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Aristolochic Acids*/metabolism , Aristolochic Acids*/chemistry , Aristolochic Acids*/pharmacology , Cholesterol*/chemistry , Cholesterol*/metabolism , Cholesterol*/pharmacology , Flufenamic Acid*/chemistry , Flufenamic Acid*/metabolism , Flufenamic Acid*/pharmacology , Receptors, G-Protein-Coupled*/agonists , Receptors, G-Protein-Coupled*/genetics , Receptors, G-Protein-Coupled*/metabolism , Receptors, G-Protein-Coupled*/ultrastructure , Taste*/drug effects , Taste*/physiology, Humans ; Binding Sites/drug effects ; Cryoelectron Microscopy ; GTP-Binding Protein alpha Subunits, Gi-Go/chemistry ; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Mutation ; Transducin/chemistry ; Transducin/metabolism |
| مستخلص: | 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 (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.) |
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| المشرفين على المادة: | 94218WFP5T (aristolochic acid I) 0 (Aristolochic Acids) 97C5T2UQ7J (Cholesterol) 60GCX7Y6BH (Flufenamic Acid) EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go) 147979-21-3 (gustducin) 0 (Ligands) 0 (Receptors, G-Protein-Coupled) 0 (taste receptors, type 2) EC 3.6.5.1 (Transducin) |
| تواريخ الأحداث: | Date Created: 20240522 Date Completed: 20240710 Latest Revision: 20240711 |
| رمز التحديث: | 20240712 |
| DOI: | 10.1038/s41586-024-07569-9 |
| PMID: | 38776963 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-4687 |
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| DOI: | 10.1038/s41586-024-07569-9 |