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J. Biol. Chem., Vol. 278, Issue 14, 12255-12262, April 4, 2003

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Molecular Determinants of the Stereoselectivity of Agonist Activity of Estrogen Receptors (ER)  and ^*

Stefan O. Mueller^§, Julie M. Hall, Deborah L. Swope, Lars C. Pedersen^¶, and Kenneth S. Korach

From the Laboratories of  Reproductive and Developmental Toxicology and ^¶ Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

The two known estrogen receptors, ER and ER, are hormone-inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. Previously, our laboratory demonstrated that ER exhibits stereoselective ligand binding and transactivation for several structural derivatives and metabolites of the synthetic estrogen diethylstilbestrol. We have previously described the properties of indenestrol A (IA) enantiomers on ER. In the study presented here, the estrogenic properties of the S and R enantiomers of IA, IA-S and IA-R, respectively, were expanded to examine the activity in different cell and promoter contexts using ER and ER. Using human cell lines stably expressing either ER or ER, we found that IA-S was a more potent activator of transcription than IA-R through ER in human endometrial Ishikawa and breast MDA-MB 231 (MDA) cells. Interestingly, IA-R was more potent on ER when compared with ER in MDA, but not in Ishikawa cells, and IA-R exhibited equally low binding affinities to ER and ER in vitro in contrast to its cell line-dependent preferential activation of ER. Alignment of the protein structures of the ligand-binding domains of ER and ER revealed one mismatched residue, Leu-384 in ER and Met-283 in ER, which may be responsible for making contact with the methyl substituent at the chiral carbon of IA-S and IA-R. Mutagenesis and exchange of this one residue showed that the binding of IA-R and IA-S was not affected by this mutation in ER and ER. However, in transactivation studies, IA-R showed higher potency in activating L384M-mutated ER and wild-type ER compared with wild-type ER and M283L-mutated ER in all cell and promoter contexts examined. Furthermore, IA-R-bound ER L384M and wild-type ER displayed enhanced interactions with the nuclear receptor interaction domains of the coactivators SRC-1 and GRIP1. These data demonstrate that a single residue in the ligand-binding domain determines the stereoselectivity of ER and ER for indenestrol ligands and that IA-R shows cell type selectivity through ER.

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