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https://hdl.handle.net/2142/87224
Description
Title
Estrogen Receptor Subtype Selective Ligands
Author(s)
Sun, Jun
Issue Date
2002
Doctoral Committee Chair(s)
Katzenellenbogen, Benita S.
Department of Study
Molecular and Integrative Physiology
Discipline
Molecular and Integrative Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Language
eng
Abstract
Estrogen action is mediated through estrogen receptor alpha (ERalpha) and beta (ERbeta). We report on the identification of several groups of non-steroidal ligands that show pronounced subtype-selective differences in ligand binding and transactivation potency or efficacy, the study of the structure-function relationships, and the molecular basis for the subtype-selective action. A 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) is an agonist on ERalpha, but a complete antagonist on ERbeta. Among a series of cis- and trans-dialkyl-THCs, all compounds are agonists on ERbeta, and THCs with small substituents are agonists on both ERalpha and ERbeta. As substituent size was increased, ERbeta-selective antagonism developed first in the (R,R)-cis enantiomer series and finally in the trans diastereomer and (S,S)-cis enatiomer series. Propylpyrazole triol (PPT) has a 410-fold binding affinity preference for ERalpha. It activates gene transcription only through ERalpha and is the first ERalpha-specific agonist identified. Basic side-chains can be added to pyrazole compounds to produce basic side-chain pyrazoles (BSC-pyrazoles), which are high affinity, potent, selective antagonists on ERalpha. To understand the basis of ligand binding and potency selectivity for these ER subtype-selective ligands, we generated a series of ER chimeras using DNA shuffling. We found that the ligand-binding domain (LBD) of ER was the major determinant of the subtype-selective character of the ligands, and that the structural basis of the selectivity for different groups of ER subtype-selective ligands was not identical. For ERbeta potency selective agonist compound DPN, differential interaction of the ligand with ERbeta Met-336 or ERalpha Leu-384 in the ligand-binding pocket is mainly responsible for its character. The different residues at the N-terminus of ERbeta helix 3 in the LBD also contribute to its potency selectivity. One enantiomers of the DPN racemate, SDPN, might be a more ERbeta potency selective ligand. A broader region in the ERalpha LBD is required for the full agonism of PPT. The determinant for its binding/potency selectivity and its efficacy selectivity are largely separable. The binding mode of PPT in the two ER subtypes is likely different.
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