The Dynamic Structure of the Estrogen Receptor

Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18510, USA.
Journal of amino acids 07/2011; 2011:812540. DOI: 10.4061/2011/812540
Source: PubMed


The estrogen receptor (ER) mediates most of the biological effects of estrogens at the level of gene regulation by interacting through its site-specific DNA and with other coregulatory proteins. In recent years, new information regarding the dynamic structural nature of ER has emerged. The physiological effects of estrogen are manifested through ER's two isoforms, ER(α) and ER(β). These two isoforms (ER(α) and ER(β)) display distinct regions of sequence homology. The three-dimensional structures of the DNA-binding domain (DBD) and ligand-binding domain (LBD) have been solved, whereas no three-dimensional natively folded structure for the ER N-terminal domain (NTD) is available to date. However, insights about the structural and functional correlations regarding the ER NTD have recently emerged. In this paper, we discuss the knowledge about the structural characteristics of the ER in general and how the structural features of the two isoforms differ, and its subsequent role in gene regulation.

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Available from: Gianluca Toraldo, Jan 01, 2014
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    • "Among the sex steroid receptors, only ERs possess a welldefined F domain (Fig. 1). This region is relatively unstructured with little known function, although some data indicate a role in coactivator recruitment,(2012)Mediator 'Bridges' ER and transcriptionaldimerization and receptor stability (Katzenellenbogen et al. 2000, Koide et al. 2007, Yang et al. 2008, Kumar et al. 2011, Arao et al. 2013).). SRC1 (NCOA1), SRC2 (GRIP1 and TIF2), and SRC3 (pCIP, RAC3, ACTR, TRAM, and A1B1) interact with helix 12 of ERs via 'LXXLL' motifs in their nuclear receptor interacting domains, which are leucine rich regions with 'X' designating any amino acid (Johnson & O'Malley 2012). "
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    ABSTRACT: Estrogen receptor alpha (ERα) is a critical player in development and function of the female reproductive system. Perturbations in ERα response can affect wide-ranging aspects of health in humans as well as in livestock and wildlife. Because of its long-known and broad impact, ERα mechanisms of action continue to be the focus on cutting-edge research efforts. Consequently, novel insights have greatly advanced understanding of every aspect of estrogen signaling. In this review, we attempt to briefly outline the current understanding of ERα mediated mechanisms in the context of the female reproductive system.
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    • "Estrogenicity of hydroxybenzophenones has also become an important issue, because some hydroxylated benzophenones, including BP-3, show estrogenic activity in reporter gene assay using MCF-7 and other cells (Suzuki et al., 2005;Molina-Molina et al., 2008). Estrogenic responses are mediated via two distinct estrogen receptors , estrogen receptor α (ERα) and ERβ, which are members of the nuclear receptor family (Kumar et al., 2011). ERα and ERβ have similar affinity for estrogen, but exhibit distinct tissue distributions and physiological functions (Shanle and Xu, 2011). "
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    ABSTRACT: Benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) is widely used as sunscreen for protection of human skin and hair from damage by ultraviolet (UV) radiation. In this study, we examined the metabolism of BP-3 by rat and human liver microsomes, and the estrogenic and anti-androgenic activities of the metabolites. When BP-3 was incubated with rat liver microsomes in the presence of NADPH, 2,4,5-trihydroxybenzophenone (2,4,5-triOH BP) and 3-hydroxylated BP-3 (3-OH BP-3) were newly identified as metabolites, together with previously detected metabolites 5-hydroxylated BP-3 (5-OH BP-3), a 4-desmethylated metabolite (2,4-diOH BP) and 2,3,4-trihydroxybenzophenone (2,3,4-triOH BP). In studies with recombinant rat cytochrome P450, 3-OH BP-3 and 2,4,5-triOH BP were mainly formed by CYP1A1. BP-3 was also metabolized by human liver microsomes and CYP isoforms. In estrogen reporter (ER) assays using estrogen-responsive CHO cells, 2,4-diOH BP exhibited stronger estrogenic activity, 2,3,4-triOH BP exhibited similar activity, and 5-OH BP-3, 2,4,5-triOH BP and 3-OH BP-3 showed lower activity as compared to BP-3. Structural requirements for activity were investigated in a series of 14 BP-3 derivatives. When BP-3 was incubated with liver microsomes from untreated rats or phenobarbital-, 3-methylcholanthrene-, or acetone-treated rats in the presence of NADPH, estrogenic activity was increased. However, liver microsomes from dexamethasone-treated rats showed decreased estrogenic activity due to formation of inactive 5-OH BP-3 and reduced formation of active 2,4-diOH BP. Anti-androgenic activity of BP-3 was decreased after incubation with liver microsomes. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Dec 2014 · Toxicology and Applied Pharmacology
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    • "The full transcriptional activity of the human estrogen receptor is dependent on synergism between AF-2 and AF-1 (hormone-independent activation function) (Kumar et al., 2011). Taken together, all of the elements are highly conserved in the selected species compared to humans, which demonstrates that this estrogen receptor is highly conserved in mollusks. "
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