Bologa Cristian G, Revankar Chetana M, Young Susan M, Edwards Bruce S, Arterburn Jeffrey B, Kiselyov Alexander S, Parker Matthew A, Tkachenko Sergey E, Savchuck Nikolay P, Sklar Larry A, Oprea Tudor I, Prossnitz Eric R
Division of Biocomputing, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.
Nat Chem Biol. 2006 Apr;2(4):207-12. doi: 10.1038/nchembio775. Epub 2006 Mar 5.
Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. 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 pathways. To differentiate between the functions of ERalpha or ERbeta 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.
雌激素是一种对众多人体组织的发育、正常生理功能及病理生理过程至关重要的激素。传统上，雌激素的作用仅归因于雌激素受体α（ERα），最近又归因于ERβ，它们是可溶性核配体激活转录因子家族的成员。我们最近发现，七跨膜G蛋白偶联受体GPR30能以高亲和力结合雌激素，并定位于内质网，在那里它激活多种细胞内信号通路。为了区分ERα或ERβ与GPR30的功能，我们结合虚拟筛选和生物分子筛选来分离选择性结合GPR30的化合物。在此，我们描述了首个GPR30特异性激动剂G-1（1）的鉴定，它能够在经典和新型雌激素受体的复杂环境中激活GPR30。雌激素受体家族成员特异性化合物的开发为增进我们对这些受体及其对雌激素生物学贡献的理解提供了契机。
