Document Detail

Nonsteroidal bivalent estrogen ligands: an application of the bivalent concept to the estrogen receptor.
MedLine Citation:
PMID:  23312071     Owner:  NLM     Status:  MEDLINE    
The estrogen receptor (ER) is a hormone-regulated transcription factor that binds, as a dimer, to estrogens and to specific DNA sequences. To explore at a fundamental level the geometric and topological features of bivalent-ligand binding to the ER dimer, dimeric ER crystal structures were used to rationally design nonsteroidal bivalent estrogen ligands. Guided by this structure-based ligand design, we prepared two series of bivalent ligands (agonists and antagonists) tethered by flexible spacers of varying lengths (7-47 Å) and evaluated their ER-binding affinities for the two ER subtypes and their biological activities in cell lines. Bivalent ligands based on the agonist diethylstilbestrol (DES) proved to be poor candidates, but bivalent ligands based on the antagonist hydroxytamoxifen (OHT) were well suited for intensive study. Binding affinities of the OHT-based bivalent ligands were related to spacer length in a distinctive fashion, reaching two maximum values at 14 and 29 Å in both ER subtypes. These results demonstrate that the bivalent concept can operate in determining ER-ligand binding affinity and suggest that two distinct modes operate for the binding of bivalent estrogen ligands to the ER dimers, an intermolecular as well as an intramolecular mode. Our insights, particularly the possibility of intramolecular bivalent binding on a single ER monomer, may provide an alternative strategy for preparing more selective and active ER antagonists for endocrine therapy of breast cancer.
Min Shan; Kathryn E Carlson; Alexander Bujotzek; Anja Wellner; Ronald Gust; Marcus Weber; John A Katzenellenbogen; Rainer Haag
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-30
Journal Detail:
Title:  ACS chemical biology     Volume:  8     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-10-17     Revised Date:  2014-06-06    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  707-15     Citation Subset:  IM    
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MeSH Terms
Cell Line
Computer Simulation
Estrogens / chemistry,  metabolism*
Models, Molecular
Receptors, Estrogen / chemistry,  metabolism*
Grant Support
Reg. No./Substance:
0/Estrogens; 0/Ligands; 0/Receptors, Estrogen

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