Linked Life Data

16648639

Source:http://linkedlifedata.com/resource/pubmed/id/16648639

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2006-6-26
pubmed:databankReference
pubmed:abstractText
Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
281
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
17909-19
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:16648639-Animals, pubmed-meshheading:16648639-Binding Sites, pubmed-meshheading:16648639-Cell Line, Tumor, pubmed-meshheading:16648639-Crystallography, pubmed-meshheading:16648639-Estrogen Receptor alpha, pubmed-meshheading:16648639-Estrogen Receptor beta, pubmed-meshheading:16648639-Female, pubmed-meshheading:16648639-Genistein, pubmed-meshheading:16648639-Growth Inhibitors, pubmed-meshheading:16648639-Humans, pubmed-meshheading:16648639-Ligands, pubmed-meshheading:16648639-Methionine, pubmed-meshheading:16648639-Osteosarcoma, pubmed-meshheading:16648639-Phenol, pubmed-meshheading:16648639-Protein Structure, Tertiary, pubmed-meshheading:16648639-Rats, pubmed-meshheading:16648639-Rats, Sprague-Dawley, pubmed-meshheading:16648639-Receptors, Androgen, pubmed-meshheading:16648639-Transfection, pubmed-meshheading:16648639-Uterus
pubmed:year
2006
pubmed:articleTitle
Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity.
pubmed:affiliation
Ben May Institute for Cancer Research, University of Chicago W330, 929 E. 57th Street, Chicago, IL 60637, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural