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Katzenellenbogen, Benita S. Sun, Jun 2015-09-28T15:50:06Z 2015-09-28T15:50:06Z 10000-01-01 2002 2002 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. Made available in DSpace on 2015-09-28T15:50:06Z (GMT). No. of bitstreams: 2 license.txt: 4848 bytes, checksum: 96035ab3f5e1c23cc7138a224ce498bd (MD5) 3070450.pdf: 6016853 bytes, checksum: 9c5a2fdc4e0a69e94caa33ebc49d1593 (MD5) Previous issue date: 2002 Embargo set by: Seth Robbins for item 88505 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs U of I Only 119 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2002. http://hdl.handle.net/2142/87224 (MiAaPQ)AAI3070450 eng Biology, Molecular Estrogen Receptor Subtype Selective Ligands text Molecular and Integrative Physiology Molecular and Integrative Physiology University of Illinois at Urbana-Champaign Dissertation Ph.D.