Bitter taste receptor activation by cholesterol and an intracellular tastant

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 and Bryan L. Roth ()
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Yoojoong Kim: University of North Carolina at Chapel Hill
Ryan H. Gumpper: University of North Carolina at Chapel Hill
Yongfeng Liu: University of North Carolina at Chapel Hill
D. Dewran Kocak: University of North Carolina at Chapel Hill
Yan Xiong: Icahn School of Medicine at Mount Sinai
Can Cao: University of Science and Technology of China
Zhijie Deng: Icahn School of Medicine at Mount Sinai
Brian E. Krumm: University of North Carolina at Chapel Hill
Manish K. Jain: University of North Carolina at Chapel Hill
Shicheng Zhang: University of North Carolina at Chapel Hill
Jian Jin: Icahn School of Medicine at Mount Sinai
Bryan L. Roth: University of North Carolina at Chapel Hill

Nature, 2024, vol. 628, issue 8008, 664-671

Abstract: 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 tastants2–6, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07253-y

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