Zhang Junhui, Simisky Jessica, Tsai Francis T F, Geller David S
Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2707-12. doi: 10.1073/pnas.0409663102. Epub 2005 Feb 14.
The ligand-binding domains of steroid hormone receptors possess a conserved structure with 12 alpha-helices surrounding a central hydrophobic core. On agonist binding, a repositioned helix 12 forms a pocket with helix 3 (H3) and helix 5 (H5), where transcriptional coactivators bind. The precise molecular interactions responsible for activation of these receptors remain to be elucidated. We previously identified a H3-H5 interaction that permits progesterone-mediated activation of a mutant mineralocorticoid receptor. We were intrigued to note that the potential for such interaction is widely conserved in the nuclear receptor family, indicating a possible functional significance. Here, we demonstrate via transcriptional activation studies in cell culture that alteration of residues involved in H3-H5 interaction consistently produces a gain of function in steroid hormone receptors. These data suggest that H3-H5 interaction may function as a molecular switch regulating the activity of nuclear receptors and suggest this site as a general target for pharmacologic intervention. Furthermore, they reveal a general mechanism for the creation of nuclear receptors bearing increased activity, providing a potentially powerful tool for the study of physiologic pathways in vivo.
类固醇激素受体的配体结合结构域具有保守结构，由围绕中央疏水核心的12个α螺旋组成。在激动剂结合时，重新定位的螺旋12与螺旋3（H3）和螺旋5（H5）形成一个口袋，转录共激活因子在此结合。负责激活这些受体的精确分子相互作用仍有待阐明。我们之前鉴定出一种H3-H5相互作用，它允许孕酮介导的突变型盐皮质激素受体的激活。我们饶有兴趣地注意到，这种相互作用的可能性在核受体家族中广泛保守，表明可能具有功能意义。在这里，我们通过细胞培养中的转录激活研究证明，参与H3-H5相互作用的残基的改变在类固醇激素受体中始终会产生功能增强。这些数据表明，H3-H5相互作用可能作为调节核受体活性的分子开关，并表明该位点是药物干预的一般靶点。此外，它们揭示了产生具有增强活性的核受体的一般机制，为体内生理途径的研究提供了一个潜在的强大工具。
