{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/87224"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/87224","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Estrogen Receptor Subtype Selective Ligands","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Sun, Jun"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Molecular and Integrative Physiology","degree_department":null,"school":null,"contributors":["Katzenellenbogen, Benita S."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-09-28T15:50:06Z","date_published":"2015-09-28T15:50:06Z","updated_at":"2026-07-22T22:26:28Z","subjects":["Biology, Molecular"],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(MiAaPQ)AAI3070450"],"render_values":[{"text":"(MiAaPQ)AAI3070450","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/87224","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Katzenellenbogen, Benita S."]},{"key":"dc:creator","label":"Author","values":["Sun, Jun"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015-09-28T15:50:06Z","10000-01-01","2002"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Molecular and Integrative Physiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biology, Molecular"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/87224","(MiAaPQ)AAI3070450"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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). 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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). 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