Studies of estrogen receptor structure using molecular dynamics

利用分子动力学研究雌激素受体结构

基本信息

批准号：
12836001
负责人：
MORI Tsukasa
金额：
$ 2.37万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12836001/
关键词：
Estrogen receptor rainbow trout molecular dynamics 環境ホルモン

项目摘要

In primary cultures of immature male rainbow trout (rt) hepatocytes, vitellogenin (Vg) gene expression regulated by E2 via the estrogen receptor (ER). However, steroids other than estrogens can also stimulate Vg gene expression. These steroids are hardly converted into E2 during incubation and their stimulatory activity is completely inhibited by tamoxifen implying rtER involvement. These steroids have no or a slightly positive charge on the Connolly surface. In contrast, steroids that failed to stimulate Vg gene expression had a strong positive or negative charge around rings C and D due to polarization. The ammo acid sequences of the ligand binding domains (LBD) of rtER and human ERa have 57.7% homology; only one amino acid differs in the presumed steroid binding site. We modeled the three-dimensional structure of the LBD of rtER using X-ray crystallographic data for hERa in order to investigate the fit (structural and electrostatic) between steroid and rtER. Two factors are essential for binding to rtER: (i) hydroxyl or carbonyl groupsi near C3 andI C17 of the steroids (hydrophilic regions) that can form hydrogen bonds with His(489), Arg(359) and Glu(318), (ii) a hydrophobic steroid nucleus that interacts with a hydrophobic region of the rtER LBD through van der Waals forces. If polar functional groups are present, the hydrophobic interaction between steroid and the rtER LBD is considerably weakened.

在未成熟雄性虹鳟鱼 (rt) 肝细胞的原代培养物中，卵黄蛋白原 (Vg) 基因表达通过雌激素受体 (ER) 受 E2 调节。然而，雌激素以外的类固醇也可以刺激Vg基因表达。这些类固醇在培养过程中几乎不会转化为 E2，并且它们的刺激活性被他莫昔芬完全抑制，这表明 rtER 参与其中。这些类固醇在康诺利表面上没有或带有轻微的正电荷。相比之下，未能刺激 Vg 基因表达的类固醇由于极化而在 C 环和 D 环周围具有很强的正电荷或负电荷。 rtER与人ERa的配体结合域(LBD)的氨基酸序列具有57.7%的同源性；推测的类固醇结合位点只有一个氨基酸不同。我们使用 hERa 的 X 射线晶体学数据对 rtER 的 LBD 的三维结构进行建模，以研究类固醇和 rtER 之间的配合（结构和静电）。有两个因素对于与 rtER 结合至关重要：(i) 类固醇（亲水区域）的 C3 和 I C17 附近的羟基或羰基可与 His(489)、Arg(359) 和 Glu(318) 形成氢键，(ii) ) 疏水类固醇核，通过范德华力与 rtER LBD 的疏水区域相互作用。如果存在极性官能团，类固醇和 rtER LBD 之间的疏水相互作用就会大大减弱。