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Structural and functional evidence that GPR30 is not a direct estrogen receptor

Cell Research (2024)Cite this article

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Dear Editor,

Estrogen is a pivotal hormone in human physiology, orchestrating a wide range of biological processes ranging from reproductive functions to cardiovascular health and bone integrity.1 The orphan receptor GPR30 has been hypothetically conceived as a G protein-coupled estrogen receptor that directly binds estrogen,2,3,4 offering mechanisms explaining non-genomic effects and tissue-selectivity of estrogen signaling.5 This provocative idea has a profound impact on our understanding of rapid estrogen biology.6,7 However, recent studies have produced conflicting results about whether GPR30 truly serves as an independent estrogen receptor.8,9,10,11,12,13 In this work, we combined biochemical, structural, and functional approaches to directly test whether GPR30 interacts with and signals in response to estrogen and estrogen-related compounds.

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Fig. 1: Structural and functional analyses contradicting GPR30 as a direct estrogen receptor and revealing ligand recognition of GPR30.

Data availability

Density maps and structure coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and the Protein Data Bank (PDB), respectively, with accession codes EMD-38527 and 8XOF for Lys05–GPR30–Gq complex, EMD-38528 and 8XOG for apo-GPR30–Gq complex, EMD-38529 and 8XOH for GPR30–Gq complex in the presence of E2, EMD-38530 and 8XOI for GPR30–Gq complex in the presence of fulvestrant, and EMD-38531 and 8XOJ for GPR30–Gq complex in the presence of G-1.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82121005 to X.X., H.E.X. and D.Y., 32130022 to H.E.X., 82330113 to X.X., 82273985 to D.Y., 82304579 to S.G.); CAS Strategic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to H.E.X.); Shanghai Municipal Science and Technology Major Project (H.E.X.); the Lingang Laboratory (LG-GG-202204-01 to H.E.X.); the National Key R&D Program of China (2022YFC2703105 to H.E.X.); Shanghai Municipality Science and Technology Development Fund (21JC1401600 to D.Y.) and Program of Shanghai Academic/Technology Research Leader (23XD1400900 to D.Y.). The cryo-EM data were collected at the Shanghai Advanced Electron Microscope Center, Shanghai Institute of Material Medica (SIMM), and the electron microscopy facility of SIMM, Chinese Academy of Sciences. We thank Q. Yuan, K. Wu, W. Hu, S. Li, and S. Zhang at the Shanghai Advanced Electron Microscope Center, SIMM for providing technical support and assistance during data collection. We thank all staff from the electron microscopy facility of SIMM for their support.

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Author notes

  1. These authors contributed equally: Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu.

Authors and Affiliations

  1. The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Heng Liu, Shimeng Guo, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Xin Xie & H. Eric Xu

  2. The State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Antao Dai & Dehua Yang

  3. University of Chinese Academy of Sciences, Beijing, China

    Xin Li, Xinheng He, Dehua Yang, Xin Xie & H. Eric Xu

  4. The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Kai Wu

  5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Xin Xie

  6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China

    Xin Xie

  7. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    H. Eric Xu

Authors
  1. Heng Liu
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  11. Xin Xie
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  12. H. Eric Xu
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Contributions

H.E.X. and P.X. initiated the project. H.L. designed and screened the expression constructs of GPR30 and prepared protein samples of apo-GPR30–Gq, Lys05–GPR30–Gq complexes for cryo-EM data collection, performed cryo-EM grid preparation, data acquisition, structure determination and model building, and prepared the draft of the manuscript and figures. S.G. performed cell-based functional assay and participated in figure preparation. A.D. performed the radioligand binding assay. P.X. designed and screened the expression constructs of GPR30 and prepared protein samples of GPR30–Gq complexes in the presence of E2, G-1, and fulvestrant for cryo-EM data collection, performed cryo-EM grid preparation, data acquisition and participated in structure determination. K.W. participated in sample screening and data collection. S.H. and X.Z. participated in protein sample preparation and structure determination. X.L. participated in cell-based functional assay. X.H. participated in figure preparation. D.Y. supervised the radioligand binding assay. X.X. supervised the cell-based functional assay. H.E.X., X.X., and D.Y. conceived and supervised the overall project and participated in manuscript editing. H.E.X. wrote the manuscript with inputs from all authors.

Corresponding authors

Correspondence to Dehua Yang, Xin Xie or H. Eric Xu.

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The authors declare no competing interests.

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Liu, H., Guo, S., Dai, A. et al. Structural and functional evidence that GPR30 is not a direct estrogen receptor. Cell Res (2024). https://doi.org/10.1038/s41422-024-00963-y

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