The Dynamic Structure of the Estrogen Receptor

Abstract

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, ERα and ERβ. These two isoforms (ERα and ERβ) 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.

Steroid Receptors in the Uterus and Ovary

“…37,38 The greatest structural disparities between ERα and ERβ lie within the A/B domain, which is approximately 30 amino acids shorter in ERβ and exhibits only >20% homology. 8,61,62 This divergence likely accounts for the many functional differences that have been revealed from comparative studies of the two ER forms. 8,17,18,62 In general, ERβ tends to be a less effective transcriptional activator compared with ERα when acting in a classic estrogen response element (ERE)-driven mechanism in vitro.…”

“…8,61,62 This divergence likely accounts for the many functional differences that have been revealed from comparative studies of the two ER forms. 8,17,18,62 In general, ERβ tends to be a less effective transcriptional activator compared with ERα when acting in a classic estrogen response element (ERE)-driven mechanism in vitro. 18 An ERα/ERβ chimera in which the A/B domain of ERβ has been replaced with that of ERα is able to activate transcription much better than the native ERβ.…”

“…2,46,64 The C domains of ERα and ERβ are practically identical (>95% homology) in most species and are therefore expected to exhibit a similar affinity for the same HREs. 62 The functionality of the C domain is provided by a motif of two zinc fingers, each composed of four cysteine residues that chelate a single Zn 2 ion, and are always encoded by separate exons within the gene (Figure 25.3).…”

Hazard assessment through hybrid in vitro / in silico approach: The case of zearalenone

“…ZEN is known to produce an array of toxicological effects with the most critical resulting from estrogenic activity triggered by an activation of the estrogen receptor alpha (ERα) (EFSA, 2011;WHO, 2000;Shen et al, 2013). ERα is a transcriptional factor belonging to the nuclear receptor superfamily that mediates, together with the beta isoform (ERβ), many of the biological effects of estrogens (Kumar et al, 2011).…”

In vitro evaluation of a tetrahydroisoquinoline derivative as a steroid sulfatase inhibitor and a selective estrogen receptor modulator

“…7) likely to form hydrogen bonds with the key residues Glu353, Arg394 and His524 in the ligand binding domain (LBD) of ERα [25]. For 8-EO-14 and 6-EO-14, we calculated the distance between the carbonyl oxygen and either the hydroxyl group hydrogen or one hydrogen of the amino moiety in the sulfamate group.…”