参与16α-碘-7β-雌二醇选择性的雌激素受体α和雌激素受体β的分子决定因素。

Molecular determinants of ER alpha and ER beta involved in selectivity of 16 alpha-iodo-7 beta estradiol.

作者信息

Bhat Ramesh A, Stauffer Barbara, Unwalla Rayomand J, Xu Zhangbao, Harris Heather A, Komm Barry S

机构信息

Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.

出版信息

J Steroid Biochem Mol Biol. 2004 Jan;88(1):17-26. doi: 10.1016/j.jsbmb.2003.10.009.

DOI:10.1016/j.jsbmb.2003.10.009

PMID:15026080

Abstract

The two known estrogen receptors, ER alpha and ER beta, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17 beta-estradiol (E2), binds with high affinity to both ER alpha and ER beta. However, a close analogue, 16 alpha-iodo-17 beta-estradiol (16 alpha IE2) showed about 10-fold selectivity for ER alpha over ER beta. From X-ray studies, it has been shown that the ligand-binding domains (LBD) of the two receptors are strikingly similar, and that only two changes fall within the binding cavity (ER alpha Leu384 to ER beta Met336, and ER alpha Met421 to ER beta Ile373). To understand the molecular basis for the ER alpha selectivity of 16 alpha IE2, mutants and chimeras of ER alpha and ER beta were generated, and ligand-binding and transactivation functions were studied. The ER alpha Leu384 Met mutant behaved like ER alpha WT in the presence of 16 alpha IE2; whereas the profile of the ER alpha Met421 Ile mutant was similar to that of ER beta WT. The ER beta mutant Ile373 Met behaved like ER alpha with 16 alpha IE2. The results clearly demonstrate the role of ER alpha Met421 in the ER alpha selectivity of 16 alpha IE2.

摘要

已知的两种雌激素受体，即雌激素受体α（ERα）和雌激素受体β（ERβ），是激素诱导型转录因子，在调节细胞增殖和分化中具有不同作用。天然配体17β-雌二醇（E2）与ERα和ERβ均具有高亲和力结合。然而，一种紧密类似物16α-碘-17β-雌二醇（16α IE2）对ERα的选择性比对ERβ高约10倍。X射线研究表明，两种受体的配体结合结构域（LBD）非常相似，且只有两个变化位于结合腔内（ERα的Leu384变为ERβ的Met336，以及ERα的Met421变为ERβ的Ile373）。为了解16α IE2对ERα选择性的分子基础，构建了ERα和ERβ的突变体及嵌合体，并研究了配体结合和反式激活功能。在16α IE2存在的情况下，ERα Leu384 Met突变体的表现与ERα野生型（WT）相似；而ERα Met421 Ile突变体的情况与ERβ WT相似。ERβ突变体Ile373 Met在16α IE2作用下的表现与ERα相似。结果清楚地证明了ERα的Met421在16α IE2对ERα选择性中的作用。