scholarly journals Transactivation Function-1-Mediated Partial Agonist Activity of Selective Estrogen Receptor Modulator Requires Homo-Dimerization of the Estrogen Receptor α Ligand Binding Domain

2019 ◽  
Vol 20 (15) ◽  
pp. 3718 ◽  
Author(s):  
Yukitomo Arao ◽  
Kenneth S. Korach
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Partial Agonist ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Agonist Activity ◽  
Partial Agonist Activity

The isolation of estrogen receptor alpha (ERα) cDNA was successful around 30 years ago. The characteristics of ERα protein have been examined from various aspects, primarily through in vitro cell culture studies, but more recently using in vivo experimental models. There remains, however, some uncharacterized ERα functionalities. In particular, the mechanism of partial agonist activity of selective estrogen receptor modulators (SERMs) that involves control of the N-terminal transcription function of ERα, termed AF-1, is still an unsolved ERα functionality. We review the possible mechanism of SERM-dependent regulation of ERα AF-1-mediated transcriptional activity, which includes the role of helix 12 of ERα ligand binding domain (LBD) for SERM-dependent AF-1 regulation. In addition, we describe a specific portion of the LBD that associates with blocking AF-1 activity with an additional role of the F-domain in mediating SERM activity.

scholarly journals Probing the structure and function of the estrogen receptor ligand binding domain by analysis of mutants with altered transactivation characteristics.

1997 ◽  
Vol 17 (8) ◽  
pp. 4644-4653 ◽  
Author(s):  
F C Eng ◽  
H S Lee ◽  
J Ferrara ◽  
T M Willson ◽  
J H White
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Hormonal Regulation ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Hydroxyl Group ◽  
Yeast Saccharomyces Cerevisiae ◽  
Contact Points

We have developed a genetic screen for the yeast Saccharomyces cerevisiae to isolate estrogen receptor (ER) mutants with altered transactivation characteristics. Use of a "reverse" ER, in which the mutagenized ligand binding domain was placed at the N terminus of the receptor, eliminated the isolation of truncated constitutively active mutants. A library was screened with a low-affinity estrogen, 2-methoxyestrone (2ME), at concentrations 50-fold lower than those required for activation of the unmutagenized ER. Several mutants displaying enhanced sensitivity to 2ME were isolated. We further characterized a mutant carrying the substitution L536P, which was located immediately N terminal to the AF-2-activating domain of the receptor. Amino acid 536 corresponds to a ligand contact residue in retinoic acid receptor gamma, suggesting that key contact points are conserved among receptors. Introduction of L536P into the original ER cDNA isolate HE0, which contains the substitution G400V, rendered the receptor more sensitive to a variety of agonists. When introduced into the wild-type ER HEG0, L536P also rendered the receptor more sensitive to agonists, and, in addition, induced high levels of constitutive activity that could be inhibited by antiestrogens. Estrogens containing a keto substitution in the steroid D ring, but not those containing a hydroxyl group, were full agonists of L536P-HEG0. Limited proteolytic analysis suggested that the L536P substitution, which is located immediately N terminal to the AF-2 domain, induces a conformational change in the ER that partially mimics binding by hormone. Both HEG0 and L536P-HEG0 formed complexes with hsp90 in vitro, indicating a lack of correlation between interaction with hsp90 in vitro and hormonal regulation of ER transactivation in vivo. This supports the idea that a factor(s) acting downstream of hsp90 is important for controlling activity of the hormone-free receptor.

scholarly journals Partial agonist activity of R3(BΔ23–27)R/I5 at RXFP3 – Investigation of in vivo and in vitro pharmacology

2015 ◽  
Vol 747 ◽  
pp. 123-131 ◽  
Author(s):  
Lisbeth Kristensson ◽  
Gaëll Mayer ◽  
Karolina Ploj ◽  
Martina Wetterlund ◽  
Susanne Arlbrandt ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Agonist Activity ◽  
Partial Agonist Activity ◽  
In Vitro Pharmacology

scholarly journals Peptide Vaccines and Peptidomimetics of EGFR (HER-1) Ligand Binding Domain Inhibit Cancer Cell Growth In Vitro and In Vivo

2013 ◽  
Vol 191 (1) ◽  
pp. 217-227 ◽  
Author(s):  
Kevin Chu Foy ◽  
Ruthie M. Wygle ◽  
Megan J. Miller ◽  
Jay P. Overholser ◽  
Tanios Bekaii-Saab ◽  
...  
Keyword(s):  
Cell Growth ◽  
Ligand Binding ◽  
Cancer Cell ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Peptide Vaccines ◽  
Cancer Cell Growth

scholarly journals Estrogen Receptor α L543A,L544A Mutation Changes Antagonists to Agonists, Correlating with the Ligand Binding Domain Dimerization Associated with DNA Binding Activity

2013 ◽  
Vol 288 (29) ◽  
pp. 21105-21116 ◽  
Author(s):  
Yukitomo Arao ◽  
Katherine J. Hamilton ◽  
Laurel A. Coons ◽  
Kenneth S. Korach
Keyword(s):  
Ligand Binding ◽  
Partial Agonist ◽  
Estrogen Receptor Α ◽  
Binding Activity ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Transcription Activity ◽  
Dna Binding Activity ◽  
Domain Truncation

A ligand-dependent nuclear transcription factor, ERα has two transactivating functional domains (AF), AF-1 and AF-2. AF-1 is localized in the N-terminal region, and AF-2 is distributed in the C-terminal ligand-binding domain (LBD) of the ERα protein. Helix 12 (H12) in the LBD is a component of the AF-2, and the configuration of H12 is ligand-inducible to an active or inactive form. We demonstrated previously that the ERα mutant (AF2ER) possessing L543A,L544A mutations in H12 disrupts AF-2 function and reverses antagonists such as fulvestrant/ICI182780 (ICI) or 4-hydoxytamoxifen (OHT) into agonists in the AF2ER knock-in mouse. Our previous in vitro studies suggested that the mode of AF2ER activation is similar to the partial agonist activity of OHT for WT-ERα. However, it is still unclear how antagonists activate ERα. To understand the molecular mechanism of antagonist reversal activity, we analyzed the correlation between the ICI-dependent estrogen-responsive element-mediated transcription activity of AF2ER and AF2ER-LBD dimerization activity. We report here that ICI-dependent AF2ER activation correlated with the activity of AF2ER-LBD homodimerization. Prevention of dimerization impaired the ICI-dependent ERE binding and transcription activity of AF2ER. The dislocation of H12 caused ICI-dependent LBD homodimerization involving the F-domain, the adjoining region of H12. Furthermore, F-domain truncation also strongly depressed the dimerization of WT-ERα-LBD with antagonists but not with E2. AF2ER activation levels with ICI, OHT, and raloxifene were parallel with the degree of AF2ER-LBD homodimerization, supporting a mechanism that antagonist-dependent LBD homodimerization involving the F-domain results in antagonist reversal activity of H12-mutated ERα.

Simulations of the Estrogen Receptor Ligand-Binding Domain:  Affinity of Natural Ligands and Xenoestrogens

2000 ◽  
Vol 43 (24) ◽  
pp. 4594-4605 ◽  
Author(s):  
B. Chris Oostenbrink ◽  
Jed W. Pitera ◽  
Marola M. H. van Lipzig ◽  
John H. N. Meerman ◽  
Wilfred F. van Gunsteren
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Receptor Ligand ◽  
Natural Ligands ◽  
Estrogen Receptor Ligand

Differing Species Responsiveness of Estrogenic Contaminants in Fish Is Conferred by the Ligand Binding Domain of the Estrogen Receptor

2014 ◽  
Vol 48 (9) ◽  
pp. 5254-5263 ◽  
Author(s):  
Shinichi Miyagawa ◽  
Anke Lange ◽  
Ikumi Hirakawa ◽  
Saki Tohyama ◽  
Yukiko Ogino ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Estrogenic Contaminants

Solution Structure of the Ligand Binding Domain of the Fibroblast Growth Factor Receptor:  Role of Heparin in the Activation of the Receptor†,‡

Biochemistry ◽  
2005 ◽  
Vol 44 (48) ◽  
pp. 15787-15798 ◽  
Author(s):  
Kuo-Wei Hung ◽  
Thallapuranam Krishnaswamy S. Kumar ◽  
Karuppanan Muthusamy Kathir ◽  
Ping Xu ◽  
Feng Ni ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ligand Binding ◽  
Fibroblast Growth Factor ◽  
Solution Structure ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Fibroblast Growth

Amino acid sequence of the AhR1 ligand-binding domain predicts avian sensitivity to dioxin like compounds: In vivo verification in European starlings

2014 ◽  
Vol 33 (12) ◽  
pp. 2753-2758 ◽  
Author(s):  
Margaret L. Eng ◽  
John E. Elliott ◽  
Stephanie P. Jones ◽  
Tony D. Williams ◽  
Ken G. Drouillard ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
European Starlings
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