Estrogen Receptor Subtype Selective Ligands

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular and Integrative Physiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Sun, Jun

Contributors dc:contributor

• Katzenellenbogen, Benita S.

• Biology, Molecular

Language dc:language

eng

Identifier

(MiAaPQ)AAI3070450

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/87224