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Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2

文献类型：期刊论文

作者Xu, Jiuyin2,3,4; Xu, Youwei2; Hou, Li5; He, Xinheng2; Li, Yang2; Zhao, Jing6; Meng, Xue2; Wang, James Jiqi1; Wu, Yanli2; Zhang, Heng2
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2024-12-17
卷号121期号:51页码:12
关键词prostaglandin receptor DP2 lipid regulation receptor activation signal bias
ISSN号0027-8424
DOI10.1073/pnas.2403304121
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Wu, Canrong(wcr13215@rjh.com.cn)
英文摘要Prostaglandin D2 receptor 2 (DP2) is an important anti- inflammatory and antiallergic drug target. While inactive DP2 structures are known, its activation mechanisms and biased signaling remain unclear. Here, we report cryo-EM structures of an apo DP2-Gi complex, a DP2-Gi complex bound to the endogenous ligand Prostaglandin D2 (PGD2), and a DP2-Gi complex bound to indomethacin, an arrestin- biased ligand, at resolutions of 2.5 & Aring;, 2.8 & Aring;, and 2.3 & Aring;, respectively. These structures reveal a distinct binding pose of PGD2 and indomethacin and provide key insights into receptor activation and transducer coupling. Combining the structural data with functional studies, we uncover the molecular basis for biased signaling of indomethacin toward (3- arrestin over G proteins. Notably, a phospholipid binding site was identified at the DP2-G protein interface that modulates DP2-G protein interactions. Together, our functional and structural findings provide insights into DP2 activation, biased signaling, drug interactions, and lipid regulation, enabling rational design of safer antiallergy therapeutics targeting this key immune receptor.
WOS关键词D-2 RECEPTOR ; CRTH2 ; POTENT ; EOSINOPHILS ; PHARMACOLOGY ; ANTAGONISTS ; SOFTWARE ; AGONIST ; ROLES ; CELLS
资助项目CAS Strategic Priority Research Program[32171187] ; CAS Strategic Priority Research Program[82121005] ; CAS Strategic Priority Research Program[22225404] ; Shanghai Municipal Science and Technology Major Project ; China Postdoctoral Science Foundation[2019SHZDZX02] ; Shanghai Post-doctoral Excellence Program[2021M703342] ; Lingang Laboratory[2021429] ; Lingang Laboratory[LG202101-01-03] ; Lingang Laboratory[LG202101-01-640] ; Lingang Laboratory[LG202102-01-01] ; Sanofi Scholarship Program[LG-GG-202204-01]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001386041500001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/315276]  
专题中国科学院上海药物研究所
通讯作者Xu, H. Eric; Wu, Canrong
作者单位1.Huazhong Univ Sci & Technol, Tongji Hosp, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Div Cardiol,Dept Internal Med,Tongji Med Coll, Wuhan 430030, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Tsinghua Univ, Dept Chem, MOE Key Lab Bioorgan Phosphorus Chem & Chem Biol, Beijing 10084, Peoples R China
7.Xiamen Univ, Sch Life Sci, Xiamen 361005, Peoples R China
8.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai,Sch Med, State Key Lab Med Genom,Ruijin Hosp, Shanghai 200025, Peoples R China
9.Lingang Lab, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Jiuyin,Xu, Youwei,Hou, Li,et al. Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2024,121(51):12.
APA Xu, Jiuyin.,Xu, Youwei.,Hou, Li.,He, Xinheng.,Li, Yang.,...&Wu, Canrong.(2024).Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121(51),12.
MLA Xu, Jiuyin,et al."Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121.51(2024):12.

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来源：上海药物研究所

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