Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens

2006 ◽  
Vol 99 (2-3) ◽  
pp. 108-114 ◽  
Author(s):  
Rocio García-Becerra ◽  
Elizabeth Borja-Cacho ◽  
Austin J. Cooney ◽  
Carolyn L. Smith ◽  
Ana E. Lemus ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Conformational Changes ◽  
Estrogen Receptor Alpha ◽  
Steroid Receptor ◽  
Receptor Alpha ◽  
Steroid Receptor Coactivator ◽  
Natural Estrogens ◽  
Selective Ligands ◽  
Subtype Selective

The nature of the ligand-binding pocket of estrogen receptor alpha and beta: The search for subtype-selective ligands and implications for the prediction of estrogenic activity

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2397-2403 ◽  
Author(s):  
J. A. Katzenellenbogen ◽  
R. Muthyala ◽  
B. S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Binding Pocket ◽  
Receptor Alpha ◽  
Subtype Selectivity ◽  
Selective Ligands ◽  
Binding Pockets ◽  
Subtype Selective

The ligand-binding pockets of estrogen receptor alpha and beta (ERα and ERβ) appear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared compounds of varying size, shape and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERα and ERβ. In this manner, we have identified a number of ligands that show pronounced ER subtype selectivity. These studies also highlight the eclectic structure–activity relationships of estrogens and the challenges inherent in developing computational methods for the prediction of estrogenic activity.

Activities of estrogen receptor alpha- and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression

2003 ◽  
Vol 206 (1-2) ◽  
pp. 13-22 ◽  
Author(s):  
William R. Harrington ◽  
Shubin Sheng ◽  
Daniel H. Barnett ◽  
Larry N. Petz ◽  
John A. Katzenellenbogen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Receptor Alpha ◽  
Selective Ligands ◽  
Estrogen Responsive Gene ◽  
Responsive Gene

scholarly journals Estrogen response element binding induces alterations in estrogen receptor-alpha conformation as revealed by susceptibility to partial proteolysis

2001 ◽  
Vol 27 (3) ◽  
pp. 275-292 ◽  
Author(s):  
TL Ramsey ◽  
CM Klinge
Keyword(s):  
Estrogen Receptor ◽  
Conformational Changes ◽  
Transcriptional Activation ◽  
Estrogen Receptor Alpha ◽  
Single Copy ◽  
Trypsin Digestion ◽  
Western Blots ◽  
Receptor Alpha ◽  
Estrogen Response ◽  
Increased Sensitivity

Genes whose expression is highly induced by estradiol (E(2)) contain multiple estrogen response elements (EREs) in their promoters. Previously we reported that estrogen receptor-alpha (ERalpha) binds cooperatively to and E(2) synergistically activates reporter gene expression from three or four tandem copies of a consensus ERE (EREc38). Here we evaluated how ERalpha binding to one, two, three or four tandem copies of EREc38 affects ERalpha conformation as detected by altered ERalpha trypsin digestion patterns in Western blots. E(2)- or 4hydroxytamoxifen (4-OHT)-occupied ERalpha bound to the pS2 ERE or to a single copy of EREc38 showed enhanced susceptibility to trypsin digestion compared to E(2)- or 4-OHT-ERalpha incubated with DNA lacking an ERE. ERalpha binding to multiple tandem copies of EREc38 further increased sensitivity to trypsin digestion. These results correlate with synergistic transcription and cooperativity of ERalpha binding to multiple tandem copies of EREc38. These observations suggest that EREc38 binding alters the overall conformation of ERalpha and that multiple tandem copies of EREc38 enhance these conformational changes. We hypothesize that ERE-induced alterations in ERalpha conformation modulate interaction with coregulatory proteins, resulting in synergistic transcriptional activation.

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