上海科技大学刘志杰等研究人员合作发现，苦味TAS2R14被细胞内甜味剂和胆固醇激活。这一研究成果于2024年5月22日在线发表在国际学术期刊《自然》上。

研究人员展示了TAS2R14与马兜铃酸、氟芬那酸和化合物28.1复合物的冷冻电镜结构，以及与不同G蛋白亚型的耦合。与众不同的是，研究人员观察到一个胆固醇分子占据了A类GPCR的典型正交位点。这三种强效激动剂分别与细胞内的口袋结合，表明这种受体有独特的激活机制。

综合结构分析、诱变和分子动态模拟研究阐明了该受体通过错综复杂的多个配体结合位点进行广谱配体识别和激活的机制。此外，该研究还揭示了TAS2R14与味蛋白和G_i1蛋白的特定耦合模式。这些发现将有助于促进人们对苦味感知的认识，并对感官生物学和药物发现产生更广泛的影响。

据悉，苦味受体，尤其是TAS2R14，在分辨从食物成分到药物制剂等各种苦味物质方面发挥着核心作用。TAS2R14还在味觉以外的组织中广泛表达，这表明它在多种生理过程和潜在治疗应用中发挥着额外的作用。

附：英文原文

Title: Bitter taste TAS2R14 activation by intracellular tastants and cholesterol

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

Issue&Volume: 2024-05-22

Abstract: Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1,2. TAS2R14 is also widely expressed in extra-gustatory tissues, suggesting its additional roles in diverse physiological processes and potential therapeutic applications3. Here, we present cryo-electron microcopy 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 GPCRs. 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 simulations studies, illuminate the receptor’s broad-spectrum ligand recognition and activation via intricate multiple ligand-binding sites. Additionally, our study uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing our knowledge underlying bitter taste perception and its broader implications in sensory biology and drug discovery.

DOI: 10.1038/s41586-024-07569-9

Source: https://www.nature.com/articles/s41586-024-07569-9