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Ligand-Selective Interdomain Conformations of Estrogen Receptor-

Diabetes Center (A.P., L.L., E.M.K., F.S.) and Department of Medicine (F.S), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Fred Schaufele, S-1230, 513 Parnassus, University of California San Francisco, San Francisco, California 94143-0540. E-mail: freds{at}diabetes.ucsf.edu.

Selective estrogen receptor modulators (SERMs) inhibit estrogen activation of the estrogen receptor (ER) in some tissues but activate ER in other tissues. These tissue-selective actions suggest that SERMs may be identified with tissue specificities that would improve the safety of breast cancer and hormone replacement therapies. The identification of an improved SERM would be aided by understanding the effects of each SERM on the structure and interactions of ER. To date, the inability to obtain structures of the full-length ER has limited our structural characterization of SERM action to their antiestrogenic effects on the isolated ER ligand binding domain. We studied the effects of estradiol and the clinically useful SERMs 4-hydroxytamoxifen and fulvestrant on the conformation of the full-length ER dimer complex by comparing, in living human breast cancer cells, the amounts of energy transfer between fluorophores attached to different domains of ER. Estradiol, 4-hydroxytamoxifen, and fulvestrant all promoted the rapid formation of ER dimers with equivalent interaction kinetics. The amino- and carboxyl-terminal ER domains both contain activation functions differentially affected by these ligands, but the positions of only the carboxyl termini differed upon binding with estradiol, 4-hydroxytamoxifen, or fulvestrant. The association of a specific ER dimer conformation with the binding of ligands of different clinical effect will assist the identification of a SERM with optimal tissue-selective estrogenic and antiestrogenic activities. These studies also provide a roadmap for dissecting important structural and kinetic details for any protein complex from the quantitative analysis of energy transfer.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Fulvestrant