Brooks Sam C, Skafar Debra F
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Steroids. 2004 Jun;69(6):401-18. doi: 10.1016/j.steroids.2004.03.014.
A variety of compounds, including the selective estrogen receptor (ER) modulators tamoxifen and raloxifene, phytoestrogens such as genistein, and xenoestrogens such as bisphenol, bind to the estrogen receptor and elicit biological responses. Structural studies have linked the altered activity of compounds such as 4-hydroxytamoxifen, raloxifene, genistein, and tetrahydrochrysene, which have substantially different structures from estradiol (E2), to differences in the positioning of the critical "helix 12" within the ligand-binding domain (LBD) of the ER-ligand complex. However, subtle permutations of the E2 molecule would also be expected to modulate the pattern of responses within a cell. Forty-two ligands were constructed by the addition or relocation of double bonds, hydroxyl, keto, amino, and nitro substituents throughout the estra-l,3,5(10)-triene (estratriene) ring system. In this review, we summarize the effects of subtle changes in the estratriene molecule on the ability of the receptor complex to stimulate the growth of MCF-7 cells, or affect the expression of four estrogen-regulated genes (progesterone receptor, pS2 protein, cathepsin D, and tissue plasminogen activator), as well as undergo nuclear processing and downregulate ERalpha mRNA. The affinity of these ligands for, and mechanism of their binding with, the ERalpha have been measured, along with their effect on the conformation of the ER-ERE complex. In particular, two A-ring isomers of E2, 2- and 4-hydroxyestratriene-17beta-ol, display gene selective activity within MCF-7 cells which is dependent on complex endogenous promoters, an intact AF-2 and is sensitive to the level of SRC-1. Both of these A-ring isomers function as antiestrogens. Molecular modeling of these two A-ring isomers complexed with the ER ligand-binding domain supports the idea that the conformation of the LBD is affected by subtle changes in the estratriene structure.
多种化合物，包括选择性雌激素受体（ER）调节剂他莫昔芬和雷洛昔芬、植物雌激素如染料木黄酮以及外源性雌激素如双酚，都能与雌激素受体结合并引发生物学反应。结构研究表明，4-羟基他莫昔芬、雷洛昔芬、染料木黄酮和四氢 Chrysene 等化合物的活性改变与雌激素受体-配体复合物配体结合域（LBD）内关键“螺旋 12”的定位差异有关，这些化合物的结构与雌二醇（E2）有很大不同。然而，E2 分子的细微排列也有望调节细胞内的反应模式。通过在雌-1,3,5(10)-三烯（雌三烯）环系统中添加或重新定位双键、羟基、酮基、氨基和硝基取代基，构建了 42 种配体。在本综述中，我们总结了雌三烯分子的细微变化对受体复合物刺激 MCF-7 细胞生长的能力、影响四个雌激素调节基因（孕激素受体、pS2 蛋白、组织蛋白酶 D 和组织纤溶酶原激活剂）表达的能力，以及对核加工和下调 ERα mRNA 的影响。还测定了这些配体与 ERα的亲和力及其结合机制，以及它们对 ER-ERE 复合物构象的影响。特别是，E2 的两种 A 环异构体，2-和 4-羟基雌三烯-17β-醇，在 MCF-7 细胞内表现出基因选择性活性，这取决于复杂的内源性启动子、完整的 AF-2，并且对 SRC-1 的水平敏感。这两种 A 环异构体均发挥抗雌激素作用。这两种 A 环异构体与 ER 配体结合域复合的分子模型支持了 LBD 构象受雌三烯结构细微变化影响的观点。
