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Structural basis of psychedelic LSD recognition at dopamine D1 receptor

文献类型：期刊论文

作者Fan, Luyu9; Zhuang, Youwen1,8; Wu, Hongyu7; Li, Huiqiong5,6; Xu, Youwei8; Wang, Yue; He, Licong7; Wang, Shishan4; Chen, Zhangcheng7; Cheng, Jianjun5,6
刊名NEURON
出版日期2024-10-09
卷号112期号:19页码:25
ISSN号0896-6273
DOI10.1016/j.neuron.2024.07.003
通讯作者Fan, Luyu(fanluyu2018@sibcb.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Wang, Sheng(wangsheng@sibcb.ac.cn)
英文摘要Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's interactions with serotonin 2A and 2B receptors, its behavior on other targets, including dopamine receptors, has remained elusive. Here, we present cryo-EM structures of LSD/PF6142-bound dopamine D1 1 receptor (DRD1)-legobody complexes, accompanied by a b-arrestin-mimicking nanobody, NBA3, shedding light on the determinants of G protein coupling versus b-arrestin coupling. Structural analysis unveils a distinctive binding mode of LSD in DRD1, particularly with the ergoline moiety oriented toward TM4. Kinetic investigations uncover an exceptionally rapid dissociation rate of LSD in DRD1, attributed to the flexibility of extracellular loop 2 (ECL2). Moreover, G protein can stabilize ECL2 conformation, leading to a significant slowdown in ligand's dissociation rate. These findings establish a solid foundation for further exploration of G protein- coupled receptor (GPCR) dynamics and their relevance to signal transduction.
WOS关键词G-PROTEIN ; BETA(2)-ADRENERGIC RECEPTOR ; CRYSTAL-STRUCTURE ; TERNARY COMPLEX ; GS-PROTEIN ; SEROTONIN ; LIGAND ; PHARMACOLOGY ; SELECTIVITY ; ACTIVATION
资助项目National Natural Science Foundation of China[82225045] ; National Natural Science Foundation of China[32071197] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; Ministry of Science and Technology of China[2020YFA0509102] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; National Key R&D Program of China[2018YFA0507002] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001] ; Sailing Program of Shanghai Venus Project[23YF1456700] ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2023298] ; Natural Science Foundation of Shanghai, China[23ZR1475300]
WOS研究方向Neurosciences & Neurology
语种英语
WOS记录号WOS:001333198200001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/313826]  
专题新药研究国家重点实验室
通讯作者Fan, Luyu; Xu, H. Eric; Wang, Sheng
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Med Chem & Bioinformat Ctr, Shanghai 200025, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Shandong Second Med Univ, Sch Anesthesiol, Lab Anesthesia & Crit Care Med Coll & Univ Shandon, Weifang 261021, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
6.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China
7.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai 201203, Peoples R China
9.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Fan, Luyu,Zhuang, Youwen,Wu, Hongyu,et al. Structural basis of psychedelic LSD recognition at dopamine D1 receptor[J]. NEURON,2024,112(19):25.
APA Fan, Luyu.,Zhuang, Youwen.,Wu, Hongyu.,Li, Huiqiong.,Xu, Youwei.,...&Wang, Sheng.(2024).Structural basis of psychedelic LSD recognition at dopamine D1 receptor.NEURON,112(19),25.
MLA Fan, Luyu,et al."Structural basis of psychedelic LSD recognition at dopamine D1 receptor".NEURON 112.19(2024):25.

入库方式： OAI收割

来源：上海药物研究所

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