Structural insights into the lipid and ligand regulation of serotonin receptors

受体 G蛋白偶联受体 兴奋剂 配体(生物化学) 血清素 5-羟色胺受体 化学 功能选择性 细胞生物学 跨膜结构域 生物化学 生物
作者
Peiyu Xu,Sijie Huang,Huibing Zhang,Chunyou Mao,X. Edward Zhou,Xi Cheng,I Simón,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,H. Eric Xu
出处
期刊:Nature [Springer Nature]
卷期号:592 (7854): 469-473 被引量:175
标识
DOI:10.1038/s41586-021-03376-8
摘要

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. Cryo-electron microscopy structures of three different serotonin receptors in complex with serotonin and other agonists provide insights into the role of lipids in regulating these receptors and the structural basis of ligand recognition.
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