Abstract
Estrogen is a hormone critical in the development, normal physiology and pathophysiology1 of numerous human tissues2. The effects of estrogen have traditionally been solely ascribed to estrogen receptor α (ERα) and more recently ERβ, members of the soluble, nuclear ligand–activated family of transcription factors3. We have recently shown that the seven-transmembrane G protein–coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways4. To differentiate between the functions of ERα or ERβ and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
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Acknowledgements
This work was supported by US National Institutes of Health (NIH) grant AI36357 and a University of New Mexico Cancer Research and Treatment Center Translational Research Grant to E.R.P., by NIH grant EB00264 to L.A.S., and by support from the New Mexico Tobacco Settlement fund to C.G.B. and T.I.O. Additional support was provided by the New Mexico Cancer Research and Treatment Center (CRTC; NIH 1. P30 CA118100), the New Mexico Molecular Libraries Screening Center (NIH MH074425) and the New Mexico Center for Environmental Health Sciences (NIH ES012072). Flow cytometry data and confocal images in this study were generated in the Flow Cytometry and Fluorescence Microscopy Facilities, respectively, at the University of New Mexico Health Sciences Center, which received support from National Center for Research Resources (NCRR) 1 S10 RR14668, National Science Foundation MCB9982161, NCRR P20 RR11830, National Cancer Institute R24 CA88339, NCRR S10 RR19287, NCRR S10 RR016918, the University of New Mexico Health Sciences Center, and the University of New Mexico CRTC.
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Supplementary Table 1
Calculated and experimental affinity constants for ERα. (PDF 39 kb)
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Bologa, C., Revankar, C., Young, S. et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2, 207–212 (2006). https://doi.org/10.1038/nchembio775
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DOI: https://doi.org/10.1038/nchembio775
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