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Estradiol Estrogen Receptor Complex

Estradiol is the natural agonist ligand of the estrogen receptors (ER). There are two isotypes of the estrogen receptor, ER-a and ER-y . There are four structures of the complex between the LED of ER-a and estradiol in the PBD. Expression, purification and crystallization of LEDs can often be problematic. Thus, the first structure solved (PDE entry lERE) [6] used protein in which the free cysteines were carboxymethylated. The refined structure showed at least one of the cysteines was modified. Another structure (PDE entry 1A52) [7] used protein that was refolded. The structure of this protein showed an artifact where two LEDs were connected by an intermolecular disulfide bond. Through much experimentation, conditions were found to express, purify and crystallize ER-a LED without modification or refolding. The protein structure was deposited as PDB entry IQKU [8] and it is this protein structure that will be discussed. [Pg.5]

There are polar interactions at both ends of the ligand the A-ring phenol group interacts with the side chain of Glu-353 of he- [Pg.6]

Estradiol is a pure agonist of estrogen receptor-a and the structure of this complex (PDB entry IQKU) [8] shows how an agonist ligand precisely and productively folds ER-a and stabilizes the unique agonist position of helix-12 (Figs. 1.4 and [Pg.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. [Pg.161]

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). 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 notable substitution product of ruthenocene is ethynyl-ruthenocene, which can be bound to estradiol, a form of estrogen studied for breast cancer treatment. With the rigid alkyne spacer, the steroid s affinity to the estrogen receptor was surprisingly unchanged upon addition of the metallocene. The addition of organometallic complexes to biomolecules may allow for the selective tuning of properties of the molecule. ... [Pg.4158]

Recent studies on the three-dimensional structure of the complex formed by estradiol and the human estrogen receptor-a ligand binding domain have revealed the structural... [Pg.141]

Figure 31.25. Coactivator-Nuclear Hormoue Receptor Interactions. The structure of a complex between the ligand-binding domain of the estrogen receptor with estradiol bound and a peptide from a coactivator reveals that the Leu-X-X-Leu-Leu (LXXLL) sequence forms a helix that binds in a groove on the surface of the ligand-binding domain. Figure 31.25. Coactivator-Nuclear Hormoue Receptor Interactions. The structure of a complex between the ligand-binding domain of the estrogen receptor with estradiol bound and a peptide from a coactivator reveals that the Leu-X-X-Leu-Leu (LXXLL) sequence forms a helix that binds in a groove on the surface of the ligand-binding domain.
Fig. 8.3 Yeast-based screen for agonists or antagonists of the human estrogen receptor. The hormone estrogen (estradiol) binds to the estrogen receptor which is expressed from a gene driven by the PGK promoter. The hormone-receptor complex binds to an estrogen-responsive element (ERE) that controls the expression of the p-galactosidase reporter gene. The assay measures the activity of the enzyme using a substrate that forms a colored product on conversion. Fig. 8.3 Yeast-based screen for agonists or antagonists of the human estrogen receptor. The hormone estrogen (estradiol) binds to the estrogen receptor which is expressed from a gene driven by the PGK promoter. The hormone-receptor complex binds to an estrogen-responsive element (ERE) that controls the expression of the p-galactosidase reporter gene. The assay measures the activity of the enzyme using a substrate that forms a colored product on conversion.

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Estradiol

Estradiol receptors

Estrogen receptor

Estrogen-receptor complexes

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