Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2

• 成果类型: Article
• 署名作者: Xu, Jiuyin; Xu, Youwei; Hou, Li; He, Xinheng; Li, Yang; Zhao, Jing; Meng, Xue; Wang, James Jiqi; Wu, Yanli; Zhang, Heng; Li, Yunhai; Hu, Wen; Yuan, Qingning; Wu, Kai; Cheng, Xi; Jiang, Yi; Xia, Yu; Xu, H. Eric; Wu, Canrong
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; ShanghaiTech University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Nanjing University of Chinese Medicine; Tsinghua University; Huazhong University of Science & Technology; Xiamen University; Chinese Academy of Sciences; Shanghai Jiao Tong University; Lingang Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11795
• DOI: 10.1073/pnas.2403304121
• 发表日期: 2024-12-17
• 关键词: d-2 receptor; crth2; potent; eosinophils; pharmacology; antagonists; software; agonist; roles; cells

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.