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Structure paper

タイトル	Bitter taste receptor activation by cholesterol and an intracellular tastant.
ジャーナル・号・ページ	Nature, Vol. 628, Issue 8008, Page 664-671, Year 2024
掲載日	2024年4月10日
著者	Yoojoong Kim / Ryan H Gumpper / Yongfeng Liu / D Dewran Kocak / Yan Xiong / Can Cao / Zhijie Deng / Brian E Krumm / Manish K Jain / Shicheng Zhang / Jian Jin / Bryan L Roth /
PubMed 要旨	Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors. Among the 26 members of the TAS2Rs, TAS2R14 ...Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with G (also known as gustducin) and G. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of G and G. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.
リンク	Nature / PubMed:38600377
手法	EM (単粒子)
解像度	2.68 - 3.3 Å
構造データ	43647 8vy7 EMDB-43647, PDB-8vy7: CryoEM structure of Gi-coupled TAS2R14 with cholesterol and an intracellular tastant 手法: EM (単粒子) / 解像度: 2.68 Å 43650 8vy9 EMDB-43650, PDB-8vy9: CryoEM structure of Ggust-coupled TAS2R14 with cholesterol and an intracellular tastant 手法: EM (単粒子) / 解像度: 2.88 Å EMDB-43656: CryoEM structure of Gi-coupled TAS2R14 with cholesterol and an intracellular tastant (Locally refined map) 手法: EM (単粒子) / 解像度: 2.9 Å EMDB-43657: CryoEM structure of Ggust-coupled TAS2R14 with cholesterol and an intracellular tastant (Locally refined map) 手法: EM (単粒子) / 解像度: 3.3 Å
化合物	PDB-1aei: CRYSTAL STRUCTURE OF THE ANNEXIN XII HEXAMER ChemComp-CLR: CHOLESTEROL / コレステロ-ル / コレステロール
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	SIGNALING PROTEIN / GPCR (Gタンパク質共役受容体) / Complex / Taste receptor