Bitter taste receptor activation by cholesterol and an intracellular tastant

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6621
• DOI: 10.1038/s41586-024-07253-y
• 发表日期: 2024-04-18
• 关键词: crystal-structure; software news; charmm; cells; gui; insights

摘要

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 tastants2-6, 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 alpha 5 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. Cryo-electron microscopy structures of the type 2 taste receptor TAS2R14 in complex with Ggust and Gi1 identify cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator and agonist.