美国北卡罗来纳大学Bryan L. Roth团队近期取得重要工作进展，他们研究提出了胆固醇和细胞内味觉剂对苦味受体的激活作用。相关研究成果2024年4月10日在线发表于《自然》杂志上。

据介绍，苦味感知是由2型味觉受体（TAS2R，也称为T2R）介导的，它代表了一类独特的G蛋白偶联受体。在TAS2R的26个成员中，TAS2R14在口腔外组织中高度表达，并介导对100多种结构不同的味觉剂的反应，尽管人们对识别不同化学物质和启动细胞信号传导的分子机制仍知之甚少。

研究人员报道了TAS2R14与G_gust（也称为gustducin）和Gi1复合的两种冷冻电镜结构。这两种结构都有一个被内源性胆固醇占据的正构结合口袋，以及一个被苦味物质cmpd28.1结合的细胞内变构位点，包括与G_gust和Gi1的α5螺旋直接相互作用。计算和生物化学研究证实了这两种配体的相互作用。研究人员通过功能分析确定胆固醇是一种正构激动剂，苦味剂cmpd28.1是一种在TAS2R14具有直接激动剂活性的正变构调节剂。

此外，正构口袋通过细长的空腔连接到变构位点，该空腔具有富含芳香残基的疏水核。这一发现为苦味受体的配体识别提供了深入的见解，并表明TAS2R14除了通过细胞内异位变味剂感知苦味之外，还具有其他活性。

附：英文原文

Title: Bitter taste receptor activation by cholesterol and an intracellular tastant

Author: Kim, Yoojoong, Gumpper, Ryan H., Liu, Yongfeng, Kocak, D. Dewran, Xiong, Yan, Cao, Can, Deng, Zhijie, Krumm, Brian E., Jain, Manish K., Zhang, Shicheng, Jin, Jian, Roth, Bryan L.

Issue&Volume: 2024-04-10

Abstract: Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2,3,4,5,6, 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 Ggust (also known as gustducin) and Gi1. 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 Ggust and Gi1. 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.

DOI: 10.1038/s41586-024-07253-y

Source: https://www.nature.com/articles/s41586-024-07253-y