Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2

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 D<sub>2</sub> (PGD<sub>2</sub>), and a DP2-Gi complex bound to indomethacin, an arrestin-biased ligand, at resolutions of 2.5 Å, 2.8Å, and 2.3 Å, respectively. These structures reveal a distinct binding pose of PGD<sub>2</sub> 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 β-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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-12-12
DOI
https://doi.org/10.1073/pnas.2403304121
Citations
9
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
2.10

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article

Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2

Xia Yu, Yiguo Jiang, Wen Hu, Youwei Xu et al.
9 citations
Proceedings of the National Academy of Sciences
Receptor Mechanisms and Signaling
2.10
article

Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2

Xia Yu, Yiguo Jiang, Wen Hu, Youwei Xu, Xinheng He, Canrong Wu, H. Eric Xu, Yanli Wu, James Jiqi Wang, Kai Wu, Li Hou, Xi Cheng, Y Li, Heng Zhang, Xue Meng, Yang Li, Qingning Yuan, Jing Zhao, Jiuyin Xu
article en
9 citations

Abstract

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 D<sub>2</sub> (PGD<sub>2</sub>), and a DP2-Gi complex bound to indomethacin, an arrestin-biased ligand, at resolutions of 2.5 Å, 2.8Å, and 2.3 Å, respectively. These structures reveal a distinct binding pose of PGD<sub>2</sub> 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 β-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.

Proceedings of the National Academy of SciencesVol. 121(51)
Nanjing University of Chinese Medicine (CN), Shanghai Jiao Tong University (CN), Xiamen University (CN), Chinese Academy of Sciences (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), Tsinghua University (CN)
Sanofi, National Natural Science Foundation of China, Chinese Academy of Sciences, China Postdoctoral Science Foundation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Good health and well-being
Openalex Percentile: Top 12%
Receptor Mechanisms and Signaling
2.10
DOIOpen Access PDFOpenAlex
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