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

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.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-05-29
DOI
https://doi.org/10.1073/pnas.2501902122
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Yanli Wu, Wen Hu, Youwei Xu, Xinheng He et al.
Proceedings of the National Academy of Sciences
Receptor Mechanisms and Signaling
article

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

Yanli Wu, Wen Hu, Youwei Xu, Xinheng He, Canrong Wu, H. Eric Xu, Jingjing Hou, James Jiqi Wang, Kaichun Wu, Heng Zhang, Yang Li, Junrui Li, Qingning Yuan, Jiuyin Xu
article en

Abstract

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.

Proceedings of the National Academy of SciencesVol. 122(22)
Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Fudan University (CN), Ruijin Hospital (CN), ShanghaiTech University (CN), Shanghai Institute of Materia Medica (CN), Tongji Hospital (CN), University of Chinese Academy of Sciences (CN), Huazhong University of Science and Technology (CN)
National Natural Science Foundation of China
Good health and well-being
Openalex Percentile: Top 89%
Receptor Mechanisms and Signaling
DOIOpen Access PDFOpenAlex
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