Estrogen receptor estradiol binding

N. Miller, J. Whelan, Random mutagenesis of human estrogen receptor ligand binding domain identifies mutations that decrease sensitivity to estradiol and increase sensitivity to a diphenol indene-ol compound basis for a regulatable expression system, J. Steroid. 

Fig. 12.42. Relative binding affinity of estrogen compounds to estrogen receptor. 50% binding achieved by 0.034 ng diethylstilbestrol (DBS), 0.33 ng 17-p-estradiol (EST), 0.6 ng hexestrol (HEX), 1.2 ng zera-nol (ZER), 2.9 ng dienestrol (DIEN). (according to In-gerowski and Stan, 1978)...

WS-7528 [132147-69-4][VI] a nonsteroidal estrogen, is an isoflavone which has been isolated from Streptomjces sp. No. 7528 and is an estrogen agonist. It inhibits [3ff]-estradiol binding to its receptor in rat uterine cytosol at an inhibitor for 50% of the rats tested (IC q) concentration of 5.7 nM. It also induces the growth of estrogen-dependent human breast cancer cell line MCE-7 (7). 

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. 

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

Estradiol. The first neuroactive steroid receptor type to be recognized was that for estradiol [3]. In vivo uptake of [3H] estradiol, and binding to cell nuclei isolated from hypothalamus, pituitary and other brain regions, revealed steroid specificity closely resembling that of the uterus, where steroid receptors were first discovered [3]. Cytosolic estrogen receptors isolated from pituitary and brain tissue closely resemble those found in uterus and mammary tissue. A hallmark of the estrogen receptor is its existence... 

Figure 25.3 Presentation of estradiol to A. endothelial cells affects signaling. (A) Physiological levels of estradiol (E2) complexed with albumin do not elicit the production of nitric oxide when presented to cultured endothelial cells although E2-albumin binds to caveolar SR-B1. (B) Physiological levels of estradiol complexed with HDL elicit the production of nitric oxide by activating AMPK and then eNOS. Although it is depicted in this figure that AMPK is activated by binding of estradiol to the estrogen receptor, B. this mechanism has not been experimentally demonstrated. Other mechanisms of E2-HDL activation of AMPK and eNOS are thus possible (See also color insert).

A secondary screen for compounds that bind non-covalently to estrogen receptor (ER, MW 67 kDa) was evaluated and illustrated for 17yS-estradiol (Ka 1 nM,... 

Fulvestrant is an estrogen receptor competitive antagonist that binds to the estrogen receptor with comparable affinity to that of estradiol. Fulvestrant downregulates the estrogen receptor in human breast cancer cells. It is marketed for treatment of hormone-dependent breast cancer (Figure 8.76). °... 

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