Molecular determinants of ERα and ERβ involved in selectivity of 16α-iodo-17β estradiol

The two known estrogen receptors, ERalpha and ERbeta, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17beta-estradiol (E2), binds with high affinity to both ERalpha and ERbeta. However, a close analogue. 16alpha-iodo-17beta-estradiol (16alphaIE2) showed about 10-fold selectivity for ERalpha over ERbeta. 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 (ERa Leu384 to ERbeta Met336, and ERalpha Met421 to ERbeta Ile373). To understand the molecular basis for the ERalpha selectivity of 16alphaIE2, mutants and chimeras of ERalpha and ERbeta were generated, and ligand-binding and transactivation functions were studied. The ERalpha Leu384 Met mutant behaved like ERalpha WT in the presence of 16alphaIE2; whereas the profile of the ERalpha Met421 Ile mutant was similar to that of ERbeta WT. The ERbeta mutant Ile 373 Met behaved like ERalpha with16alphaIE2. The results clearly demonstrate the role of ERalpha Met421 in the ERalpha selectivity of 16alphaIE2. (C) 2004 Elsevier Ltd. All rights reserved.