Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1992881 | The Journal of Steroid Biochemistry and Molecular Biology | 2006 | 11 Pages |
Abstract
Estradiol (E2) and tamoxifen exert their effects through two members of the nuclear receptor superfamily, estrogen receptor (ER)-alpha and -beta. We want to identify the key interactions linking ligand-binding and activity of the ERα. Asp-351 and Leu-536 participate in hydrogen bond (Asp-351) and hydrophobic (Leu-536) interactions at the start of helix 12 in the ligand-binding domain (LBD) of the ERα. Mutations at each position alter ER activity, but we do not know which is more important. We mutated these residues in combination and individually and assessed the activity of the mutated ERs in the absence and presence of E2 and 4-OHT on an ERE-driven and an AP-1-driven promoter, as well as their ability to interact with coregulators. On an ERE-driven promoter, the residue at position 351 determined whether E2 stimulated or reduced the activity of the ER, as well as the level of activity in the presence of 4-OHT. Surprisingly, mutation of both residues generally did not produce cumulative deleterious effects, and they exerted counterbalancing effects on the basal activity on both promoters. Our results identify the contributions of specific interactions to the activity of the hERα, and support the concept that this region couples ligand-binding with ER activity.
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Authors
Changqing Zhao, Judith Abrams, Debra F. Skafar,