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:184
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
NexusExplorer应助LisaZhang采纳,获得30
1秒前
白马爱毛驴完成签到,获得积分10
1秒前
高大涵梅发布了新的文献求助10
3秒前
科研通AI2S应助司空豁采纳,获得10
4秒前
5秒前
甜味白开水完成签到,获得积分10
8秒前
朴实的觅翠完成签到,获得积分10
9秒前
小梦发布了新的文献求助10
9秒前
duan完成签到 ,获得积分10
9秒前
清爽的亦云完成签到,获得积分10
9秒前
yyd完成签到,获得积分10
10秒前
天天快乐应助Fxxkme采纳,获得10
11秒前
MFiWanting完成签到,获得积分10
12秒前
小琦无敌完成签到,获得积分10
12秒前
yongzaizhuigan完成签到,获得积分0
14秒前
LIKUN完成签到,获得积分10
14秒前
科研狗完成签到,获得积分10
16秒前
16秒前
柠七完成签到,获得积分10
16秒前
Muran完成签到,获得积分10
16秒前
科研狗发布了新的文献求助10
19秒前
道道sy完成签到,获得积分10
19秒前
蛋妞儿完成签到,获得积分10
20秒前
20秒前
蛋炒饭不加蛋完成签到,获得积分10
21秒前
LW完成签到,获得积分10
21秒前
mg完成签到,获得积分10
21秒前
lemonlmm完成签到,获得积分0
22秒前
huihuiyve完成签到,获得积分10
23秒前
怡然猎豹完成签到,获得积分10
23秒前
23秒前
ziyuexu完成签到,获得积分20
23秒前
Fxxkme发布了新的文献求助10
23秒前
24秒前
张兔兔完成签到,获得积分10
25秒前
情怀应助小鱼采纳,获得10
26秒前
binfo发布了新的文献求助10
26秒前
虚心的半梅完成签到,获得积分10
26秒前
陈醋塔塔完成签到,获得积分10
27秒前
打工人发布了新的文献求助10
27秒前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
Rechtsphilosophie 1000
Bayesian Models of Cognition:Reverse Engineering the Mind 888
Le dégorgement réflexe des Acridiens 800
Defense against predation 800
A Dissection Guide & Atlas to the Rabbit 600
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3134060
求助须知:如何正确求助?哪些是违规求助? 2784861
关于积分的说明 7769049
捐赠科研通 2440325
什么是DOI,文献DOI怎么找? 1297361
科研通“疑难数据库(出版商)”最低求助积分说明 624959
版权声明 600792