Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2000-10-2
pubmed:abstractText
Ligands for the estrogen receptor (ER) that have the capacity to selectively bind to or activate the ER subtypes ERalpha or ERbeta would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. In this study, we examine three compounds of novel structure that act as ER subtype-selective ligands. These are a propyl pyrazole triol (PPT), which is a potent agonist on ERalpha but is inactive on ERbeta, and a pair of substituted tetrahydrochrysenes (THC), one enantiomer of which (S,S-THC) is an agonist on both ERalpha and ERbeta, the other (R,R-THC) being an agonist on ERalpha but an antagonist on ERbeta. To investigate the molecular mechanisms underlying the ER subtype-selective actions of these compounds, we have determined the conformational changes induced in ERalpha and ERbeta by these ligands using protease digestion sensitivity, and we have tested the ability of these ligands to promote the recruitment of representatives of the three SRC/p160 coactivator protein family members (SRC-1, GRIP-1, ACTR, respectively) to ERalpha and ERbeta using yeast two-hybrid and glutathione-S-transferase (GST) pull-down assays. We find that the ligand-ER protease digestion pattern is distinctly different for stimulatory and inhibitory ligands, and that this assay, as well as coactivator recruitment, are excellent indicators of their agonist/antagonist character. Interestingly however, compared with estradiol, the novel agonist ligands show some quantitative differences in their ability to recruit SRC-1, -2, and -3. This implies that while generally similar to estradiol, these ligands induce ER conformations that differ somewhat from that induced by estradiol, differences that are illustrative of the nature of their biological character. The application of methods to characterize the conformations induced in ER subtypes by novel ligands, as done in this study, enables a greater understanding of how ligand-receptor conformations relate to estrogen agonist or antagonist behavior.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Acetyltransferases, http://linkedlifedata.com/resource/pubmed/chemical/Estrogen Receptor alpha, http://linkedlifedata.com/resource/pubmed/chemical/Estrogen Receptor beta, http://linkedlifedata.com/resource/pubmed/chemical/Histone Acetyltransferases, http://linkedlifedata.com/resource/pubmed/chemical/Ligands, http://linkedlifedata.com/resource/pubmed/chemical/NCOA1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/NCOA2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/NCOA3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Coactivator 1, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Coactivator 2, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Coactivator 3, http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Peptide Hydrolases, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Estrogen, http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0013-7227
pubmed:author
pubmed:issnType
Print
pubmed:volume
141
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3534-45
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:11014206-Acetyltransferases, pubmed-meshheading:11014206-Estrogen Receptor alpha, pubmed-meshheading:11014206-Estrogen Receptor beta, pubmed-meshheading:11014206-Histone Acetyltransferases, pubmed-meshheading:11014206-Humans, pubmed-meshheading:11014206-Ligands, pubmed-meshheading:11014206-Molecular Conformation, pubmed-meshheading:11014206-Nuclear Receptor Coactivator 1, pubmed-meshheading:11014206-Nuclear Receptor Coactivator 2, pubmed-meshheading:11014206-Nuclear Receptor Coactivator 3, pubmed-meshheading:11014206-Oncogene Proteins, pubmed-meshheading:11014206-Peptide Hydrolases, pubmed-meshheading:11014206-Receptors, Estrogen, pubmed-meshheading:11014206-Trans-Activators, pubmed-meshheading:11014206-Transcription Factors, pubmed-meshheading:11014206-Transcriptional Activation, pubmed-meshheading:11014206-Tumor Cells, Cultured
pubmed:year
2000
pubmed:articleTitle
Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: correlations with biological character and distinct differences among SRC coactivator family members.
pubmed:affiliation
Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine, Urbana 61801, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.