Reevaluating GPR30: A Paradigm Shift from Estrogen Receptor to Unique Hydrophilic Ligand Activation

Subjects: Pharmaceutical Science >> Structural Biology submitted time 2024-02-24

Heng Liu Shimeng Guo Antao Dai Peiyu Xu Xin Li Sijie Huang Xinheng He Kai Wu Xinyue Zhang Dehua Yang Xin Xie H. Eric Xu

Abstract： The orphan receptor GPR30, previously classified as a G protein-coupled estrogen receptor (GPER), has been a subject of debate regarding its ligand specificity. Through an integrative approach combining structure elucidation, biochemical binding, and cell signaling assays, we demonstrate that estrogen does not directly bind to or activate GPR30. Cryo-EM structures of GPR30 reveal an unexpected hydrophilic ligand-binding pocket, with striking differences from classical hydrophobic steroid-binding sites, inconsistent with estrogen binding. We further confirmed hydrophilic agonists like Lys05 as true activators of GPR30, providing structural insights into their binding mechanism and receptor activation. Our findings necessitate a paradigm shift in defining GPR30’s role in estrogen signaling, indicating that its activation occurs through mechanisms independent of estrogen binding. This study opens new avenues for developing targeted GPR30 ligands and reinterpreting its role in estrogen-mediated processes.

Peer Review Status:Awaiting Review

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