한빛사논문
- 조회1,400
Yoojoong Kim1,5, Ryan H. Gumpper1,5, Yongfeng Liu1,5, D. Dewran Kocak1, Yan Xiong2, Can Cao3,4, Zhijie Deng2, Brian E. Krumm1, Manish K. Jain1, Shicheng Zhang1, Jian Jin2 & Bryan L. Roth1
1Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
3School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
4Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
5These authors contributed equally: Yoojoong Kim, Ryan H. Gumpper, Yongfeng Liu.
Corresponding author : Correspondence to Bryan L. Roth.
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.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-04-11)
- 국외 연구진
- 생명과학 > 구조생물 및 생물물리학
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