Estrogen-receptor complexes

Bentrem, D.J., Zapf, J.W. and Jordan, V.C. (2000) Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 351. Cancer Research, 60, 5097-5105. 

The triphenylethylene antiestrogens (Fig. 46.9) are structurally related to the stilbene family of estrogens and exhibit high affinity for the ER. They prevent translocation of the estrogen-receptor complex into the nucleus of target cells and interfere with the binding of the receptor-hormone complex to the acceptor site of the chromatin (29,30). 

Describe the zinc finger structure of nuclear hormone receptors and describe how it is involved in the interaction of the estrogen-estrogen receptor complex interaction with estrogen response elements. 

The IRE is a sequence in the 5 -untranslated region of the mRNA that encodes the ferritin molecule. The IRE-binding protein (IRE-BP) binds to the IRE and blocks translation. The ERE is a DNA sequence to which the estrogen-estrogen receptor complex binds to lacilitate trancription. 

Steroids Estrogen Receptor Complexed with 17p-Estradio and Raloxifene... 

We will now turn our attention to another example of the application of FT-IR, this time in the area of hormone-receptor site detection through the detection of organometallic labels [7]. When an estrogen molecule enters a cell from the blood stream it searches for a specific receptor protein and the resultant estrogen-receptor complex ultimately affects new protein... 

Although estrone and estradiol (26) have both been isolated from human urine, it has recently been shown that it is the latter that is the active compound that binds to the so-called estrogen receptor protein. Reduction of estrone with any of a large number of reducing agents (for example, any of the complex metal hydrides) leads cleanly to estradiol. This high degree of stereoselectivity to afford the product of attack at the alpha side of the molecule is characteristic of many reactions of steroids. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Azuma K, Horie K, Inoue S, Ouchi Y, Sakai R (2004) Analysis of estrogen receptor a signalling complex at the plasma membrane. FEBS Lett 577 339-344... 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

Some crucial steps in the biology of CVD have demonstrated sensitivity to estrogen agonists. Some of these actions have shown to be mediated by the classical pathway of estrogen receptors (ERs), though in other cases the involved mechanisms seem more complex and require the consideration of alternative options (Mendelsohn 2002). The available evidence concentrates on actions on lipids or on direct actions on the vascular wall. 

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