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

• 成果类型: Article
• 署名作者: Xu, Jiuyin; Wu, Yanli; Xu, Youwei; Li, Yang; He, Xinheng; Zhang, Heng; Wang, James Jiqi; Hou, Jingjing; Li, Junrui; Hu, Wen; Wu, Kai; Yuan, Qingning; Wu, Canrong; Xu, H. Eric
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; ShanghaiTech University; Huazhong University of Science & Technology; Huazhong University of Science & Technology; Fudan University; Shanghai Jiao Tong University; Chinese Academy of Sciences; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11468
• DOI: 10.1073/pnas.2501902122
• 发表日期: 2025-06-03
• 关键词: cryo-em structure; d-2; inflammation; rhodopsin; software; Mutation; cloning

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.