Molecular determinants of ERα and ERβ involved in selectivity of 16α-iodo-17β estradiol
- 作者：Bhat ; Ramesh A. ; Stauffer ; Barbara ; Unwalla ; Rayomand J. ; Xu ; Zhangbao ; Harris ; Heather A. ; et. al.
- 关键词：Estrogen receptors ; ERα ; ERβ ; Estradiol ; 16α ; -Iodo&ndash ; 17β ; estradiol ; Molecular modeling
- 刊名：The Journal of Steroid Biochemistry and Molecular Biology
- 出版年：2004
- 期刊代码：172_09600760
- 类别：med
- 出版时间：January, 2004
- 卷：88
- 期：1
- 页码：17-26
- 文件大小：444 K
摘要
The two known estrogen receptors, ERα and ERβ, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17β-estradiol (E2), binds with high affinity to both ERα and ERβ. However, a close analogue, 16α-iodo-17β-estradiol (16αIE2) showed about 10-fold selectivity for ERα over ERβ. 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 (ERα Leu384 to ERβ Met336, and ERα Met421 to ERβ Ile373). To understand the molecular basis for the ERα selectivity of 16αIE2, mutants and chimeras of ERα and ERβ were generated, and ligand-binding and transactivation functions were studied. The ERα Leu384 Met mutant behaved like ERα WT in the presence of 16αIE2; whereas the profile of the ERα Met421 Ile mutant was similar to that of ERβ WT. The ERβ mutant Ile373 Met behaved like ERα with 16αIE2. The results clearly demonstrate the role of ERα Met421 in the ERα selectivity of 16αIE2.