Structural insights into the lipid and ligand regulation of serotonin receptors PMID: 33762731

ADC Targets in Oncology

2026-04-10

Structural insights into the lipid and ligand regulation of serotonin receptors

Nature. 2021 Apr;592(7854):469-473. doi: 10.1038/s41586-021-03376-8.

Peiyu Xu ^# ¹ ² ³ , Sijie Huang ^# ² ³ ⁴ , Huibing Zhang ^# ¹ ⁵ ⁶ ⁷ , Chunyou Mao ^# ¹ ⁵ ⁶ ⁷ , X Edward Zhou ^# ⁸ , Xi Cheng ^# ⁹ , Icaro A Simon ¹⁰ ¹¹ , Dan-Dan Shen ¹ ⁵ ⁶ ⁷ , Hsin-Yung Yen ¹² , Carol V Robinson ¹² , Kasper Harpsøe ¹⁰ , Bo Svensson ¹¹ , Jia Guo ² ³ , Hualiang Jiang ³ ⁴ ⁹ , David E Gloriam ¹⁰ , Karsten Melcher ⁸ , Yi Jiang ¹³ ¹⁴ , Yan Zhang ¹⁵ ¹⁶ ¹⁷ ¹⁸ , H Eric Xu ¹⁹ ²⁰ ²¹

Affiliations

1. Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3. University of Chinese Academy of Sciences, Beijing, China.
4. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
5. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
6. MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China.
7. Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, China.
8. Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.
9. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
10. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
11. SARomics Biostructures AB, Medicon Village, Lund, Sweden.
12. Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK.
13. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
14. University of Chinese Academy of Sciences, Beijing, China. [email protected].
15. Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
16. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. [email protected].
17. MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
18. Zheijang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou, China. [email protected].
19. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
20. University of Chinese Academy of Sciences, Beijing, China. [email protected].
21. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter^1,2 that activates the largest subtype family of G-protein-coupled receptors³. Drugs that target 5-HT_1A, 5-HT_1D, 5-HT_1E 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-HT_1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT_1D bound to 5-HT; and 5-HT_1E in complex with a 5-HT_1E- and 5-HT_1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT_1A interface, and is able to increase 5-HT_1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by Cholesterol molecules-particularly in the case of 5-HT_1A, 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-HT_1A 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.