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Introduction

Estrogen receptors are proteins found on and inside of the cell. When activated by estrogen these receptors are important in sexual maturation and gestation. There are two types of estrogen receptors that exist which include nuclear estrogen receptors (ERa and ERb), which are included in the nuclear receptor family of intracellular receptors, and membrane estrogen receptors.

A series of p-hydroxybenzenesulphonamides ERb receptor agonists discovered along with various compounds listed showed selectivity over the ERa receptor. Overall, they found that compound 11 showed better binding conformation determined by X-ray, and presents a better starting point for the journey to find a more selective ERb agonist.

Looking at the gonadal steroid hormone estradiol,1, action is performed through estrogen subtypes, ERa and ERb. The detrimental effects of ERb in comparison to the proliferative effects ERa are found to inhibit breast and endometrial tissue compared to ERa and could potentially be responsible for the immunomodulatory and neuropharmacalogical behavior of estradiol 1,2. The interest in the therapeutic benefits of selective ERb agonists to combatant various conditions including endometriosis and inflammatory bowel disease.

This is an overall scene with the beta sheets in purple and the alpha helices in ball and stick figures

Here is another scene with a rainbow diagram description of the whole molecule

Overall Structure

- Secondary Structure

- Mostly alpha helices with only two beta strands on the outside of the receptor shown below with the apla helices showing pollar and non-polar parts of the chain. The beta sheets are shown in yellow in the second green scene

- , and

- Tertiary Structure

- Polar- Pink, Hydrophobic- Grey

- Surface groups (orange) vs. Buried groups (blue)

Binding Interactions

- Complexes were originally designed to form an interaction with the His475 through the tertiary hydroxyl group

- Instead, the hydroxyl group acts as a conformational lock which forms an internal hydrogen bond with the sulphonamide oxygen about 2.3 A apart.

- The sulphonamide oxygens pack against Met336 and the benzyl group at top of the pocket comes near His475 but does not form any coulombic interactions but Van der Waals interactions exist near the pocket.

- Complexes make H-bonding interactions not only with Arg346 (yellow) and Glu305 (blue) but also His475 (green). Binding sites are shown

See Also

• [Estrogen Receptor]
• [1yy4]
• [1u3s]
• [1x78]
• [1qkn]

Credits

Introduction - Benjamin Homyak

Overall Structure - Marissa Burgess

Drug Binding Site - Soo Lim Park

References

1. ↑ Roberts LR, Armor D, Barker C, Bent A, Bess K, Brown A, Favor DA, Ellis D, Irving SL, MacKenny M, Phillips C, Pullen N, Stennett A, Strand L, Styles M. Sulfonamides as selective oestrogen receptor beta agonists. Bioorg Med Chem Lett. 2011 Oct 1;21(19):5680-3. Epub 2011 Aug 16. PMID:21885279 doi:10.1016/j.bmcl.2011.08.041