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Structural insights into the lipid and ligand regulation of serotonin receptors

Author

Listed:
  • Peiyu Xu

    (Zhejiang University School of Medicine
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Sijie Huang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Huibing Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Chunyou Mao

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • X. Edward Zhou

    (Van Andel Institute)

  • Xi Cheng

    (Chinese Academy of Sciences)

  • Icaro A. Simon

    (University of Copenhagen
    SARomics Biostructures AB, Medicon Village)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • Hsin-Yung Yen

    (University of Oxford)

  • Carol V. Robinson

    (University of Oxford)

  • Kasper Harpsøe

    (University of Copenhagen)

  • Bo Svensson

    (SARomics Biostructures AB, Medicon Village)

  • Jia Guo

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hualiang Jiang

    (University of Chinese Academy of Sciences
    ShanghaiTech University
    Chinese Academy of Sciences)

  • David E. Gloriam

    (University of Copenhagen)

  • Karsten Melcher

    (Van Andel Institute)

  • Yi Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter1,2 that activates the largest subtype family of G-protein-coupled receptors3. Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders4. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor–G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein–5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules—particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.

Suggested Citation

  • Peiyu Xu & Sijie Huang & Huibing Zhang & Chunyou Mao & X. Edward Zhou & Xi Cheng & Icaro A. Simon & Dan-Dan Shen & Hsin-Yung Yen & Carol V. Robinson & Kasper Harpsøe & Bo Svensson & Jia Guo & Hualiang, 2021. "Structural insights into the lipid and ligand regulation of serotonin receptors," Nature, Nature, vol. 592(7854), pages 469-473, April.
  • Handle: RePEc:nat:nature:v:592:y:2021:i:7854:d:10.1038_s41586-021-03376-8
    DOI: 10.1038/s41586-021-03376-8
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Song-Meng Wang & Yan-Fang Wang & Liping Huang & Li-Shuo Zheng & Hao Nian & Yu-Tao Zheng & Huan Yao & Wei Jiang & Xiaoping Wang & Liu-Pan Yang, 2023. "Chiral recognition of neutral guests by chiral naphthotubes with a bis-thiourea endo-functionalized cavity," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    6. Minfei Su & Navid Paknejad & Lan Zhu & Jinan Wang & Hung Nguyen Do & Yinglong Miao & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Shota Suzuki & Kotaro Tanaka & Kouki Nishikawa & Hiroshi Suzuki & Atsunori Oshima & Yoshinori Fujiyoshi, 2023. "Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Sandra Arroyo-Urea & Antonina L. Nazarova & Ángela Carrión-Antolí & Alessandro Bonifazi & Francisco O. Battiti & Jordy Homing Lam & Amy Hauck Newman & Vsevolod Katritch & Javier García-Nafría, 2024. "A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    11. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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