Department of Pharmacology and Pharmacotherapy, University of Pécs, Szigeti út 12, 7624, Pécs, Hungary.
Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, 1117, Budapest, Hungary.
Sci Rep. 2017 Nov 1;7(1):14847. doi: 10.1038/s41598-017-14840-9.
Non-classical signaling in the intracellular second messenger system plays a pivotal role in the cytoprotective effect of estradiol. Estrogen receptor is a common target of sex steroids and important in mediating estradiol-induced neuroprotection. Whereas the mechanism of genomic effects of sex steroids is fairly understood, their non-classical effects have not been elucidated completely. We use real time molecular dynamics calculations to uncover the interaction network of estradiol and activator estren. Besides steroid interactions, we also investigate the co-activation of the receptor. We show how steroid binding to the alternative binding site of the non-classical action is facilitated by the presence of a steroid in the classical binding site and the absence of the co-activator peptide. Uncovering such dynamic mechanisms behind steroid action will help the structure-based design of new drugs with non-classical responses and cytoprotective potential.
非经典信号在细胞内第二信使系统中起着关键作用，对雌二醇的细胞保护作用至关重要。雌激素受体是性激素的常见靶标，在介导雌二醇诱导的神经保护中起着重要作用。虽然类固醇的基因组效应机制已经相当清楚，但它们的非经典效应尚未完全阐明。我们使用实时分子动力学计算来揭示雌二醇和激动剂雌三醇的相互作用网络。除了甾体相互作用外，我们还研究了受体的共激活。我们展示了类固醇与非经典作用的替代结合位点的结合如何通过经典结合位点中类固醇的存在和共激活肽的不存在而得到促进。揭示类固醇作用背后的这种动态机制将有助于基于结构的设计具有非经典反应和细胞保护潜力的新型药物。
