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Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1

文献类型：期刊论文

作者Xu, Jiuyin6,7; Wu, Yanli7; Xu, Youwei7; Li, Yang7; He, Xinheng7; Zhang, Heng7; Wang, James Jiqi4,5; Hou, Jingjing3,7; Li, Junrui7; Hu, Wen7
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2025-06-03
卷号122期号:22页码:11
关键词prostaglandin D2 receptor 1 receptor activation drug design
ISSN号0027-8424
DOI10.1073/pnas.2501902122
英文摘要The prostaglandin D2 receptor 1 (DP1), a rhodopsin-like Class A GPCR, orchestrates critical physiological and pathological processes, ranging from sleep regulation to inflammatory responses and cardiovascular function. Despite its therapeutic significance, structural insights into DP1 activation mechanisms have remained elusive. Here, using cryoelectron microscopy (cryo-EM), we determined high-resolution structures of human DP1 in both inactive and active states, with the latter captured in complex with its endogenous agonist PGD2 or the synthetic agonist BW245C, bound to the stimulatory G protein, Gs. Our structures, coupled with functional and mutagenesis studies, unveiled unique structural features of DP1, including an alternative activation mechanism, ligand-selectivity determinants, and G protein coupling characteristics. These molecular insights provide a rational framework for designing selective DP1-targeted therapeutics, both agonists and antagonists, with enhanced specificity and reduced off-target effects, opening broad avenues for treating DP1-associated disorders.
WOS关键词CRYO-EM STRUCTURE ; D-2 ; INFLAMMATION ; RHODOPSIN ; SOFTWARE ; MUTATION ; CLONING
资助项目Key R&D Program of China[2022YFC2703105] ; National Natural Science Foundation of China[32301016] ; National Natural Science Foundation of China[32130022] ; Chinese Academy of Sciences Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; China Postdoctoral Science Foundation Funded Project[2021 M703342] ; Shanghai Post-doctoral Excellence Program[2021429] ; Lingang Laboratory[LG-GG-202204-01] ; Sanofi Scholarship Program
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001504465300001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/318294]  
专题新药研究国家重点实验室
通讯作者Wu, Canrong; Xu, H. Eric
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China
3.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
4.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan 430000, Peoples R China
5.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Wuhan 430000, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
7.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Jiuyin,Wu, Yanli,Xu, Youwei,et al. Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(22):11.
APA Xu, Jiuyin.,Wu, Yanli.,Xu, Youwei.,Li, Yang.,He, Xinheng.,...&Xu, H. Eric.(2025).Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(22),11.
MLA Xu, Jiuyin,et al."Molecular basis for ligand recognition and receptor activation of the prostaglandin D2 receptor DP1".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.22(2025):11.

入库方式： OAI收割

来源：上海药物研究所

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