Department of Medicine, 0693 University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA.
Steroids. 2012 Oct;77(12):1192-7. doi: 10.1016/j.steroids.2012.07.014. Epub 2012 Aug 13.
Recently, binding of 5-androsten-3β,17β-diol (Δ(5)-androstenediol) to human estrogen receptor-beta (ERβ) was found to repress microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, binding of estradiol to ERβ resulted in little or no repression of microglia-mediated inflammation. Binding of Δ(5)-androstenediol to ERβ, as well as to ERα, is unexpected because unlike estradiol, Δ(5)-androstenediol has a saturated A ring and a C19 methyl group. To begin to elucidate the interaction of Δ(5)-androstenediol with both ERs, we constructed 3D models of Δ(5)-androstenediol with human ERα and ERβ for comparison with the crystal structures of estradiol in ERα and ERβ. Conformational flexibility in human ERα and ERβ accommodates the C19 methyl on Δ(5)-androstenediol. This conformational flexibility may be relevant for binding of other Δ(5)-steroids with C19 methyl substituents, such as 25-hydroxycholesterol and 27-hydroxycholesterol, to ERs.
最近，发现 5-雄烯-3β,17β-二醇（Δ(5)-雄烯二醇）与人类雌激素受体-β（ERβ）结合可抑制小胶质细胞介导的炎症，这与多种神经退行性疾病有关，如多发性硬化症。相比之下，雌二醇与 ERβ 结合几乎不会抑制小胶质细胞介导的炎症。Δ(5)-雄烯二醇与 ERβ 以及 ERα 的结合是出乎意料的，因为与雌二醇不同，Δ(5)-雄烯二醇的 A 环饱和且 C19 位有一个甲基。为了开始阐明 Δ(5)-雄烯二醇与两种 ER 之间的相互作用，我们构建了人 ERα 和 ERβ 与 Δ(5)-雄烯二醇的 3D 模型，以与雌二醇在 ERα 和 ERβ 中的晶体结构进行比较。人 ERα 和 ERβ 的构象灵活性容纳了 Δ(5)-雄烯二醇上的 C19 甲基。这种构象灵活性可能与其他带有 C19 甲基取代基的 Δ(5)-类固醇（如 25-羟基胆固醇和 27-羟基胆固醇）与 ER 结合有关。
