Structural insights into the lipid and ligand regulation of serotonin receptors

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 Jiang, David E. Gloriam, Karsten Melcher, Yi Jiang (), Yan Zhang () and H. Eric Xu ()
Additional contact information
Peiyu Xu: Zhejiang University School of Medicine
Sijie Huang: Chinese Academy of Sciences
Huibing Zhang: Zhejiang University School of Medicine
Chunyou Mao: Zhejiang University School of Medicine
X. Edward Zhou: Van Andel Institute
Xi Cheng: Chinese Academy of Sciences
Icaro A. Simon: University of Copenhagen
Dan-Dan Shen: Zhejiang University School of Medicine
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
Hualiang Jiang: University of Chinese Academy of Sciences
David E. Gloriam: University of Copenhagen
Karsten Melcher: Van Andel Institute
Yi Jiang: Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine
H. Eric Xu: Chinese Academy of Sciences

Nature, 2021, vol. 592, issue 7854, 469-473

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03376-8

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