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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 (ERα and ERβ), which are included in the nuclear receptor family of intracellular receptors, and membrane estrogen receptors.

A series of p-hydroxybenzenesulphonamides ERβ receptor agonists discovered along with various compounds listed showed selectivity over the ERα 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 ERβ agonist.

Looking at the gonadal steroid hormone estradiol,1, action is performed through estrogen subtypes, ERα and ERβ. The detrimental effects of ERβ in comparison to the proliferative effects ERα are found to inhibit breast and endometrial tissue compared to ERα and could potentially be responsible for the immunomodulatory and neuropharmacalogical behavior of estradiol 1,2. The interest in the therapeutic benefits of selective ERβ 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

The assembly composition of the 2yly protein is a homodimer. (Quaternary structure)

The DNA Binding domain is located in the C region, which is highly conserved. The ligand binding domain is located at the C terminus in the E and F regions. The ligand binding domain is often called the “three-layered anti-parallel α helical sandwich” because it contains 12 alpha helices along with one beta hairpin. Sites for dimerization and nuclear localization are located in the the D region, which is poorly conserved. Both ERα and ERβ have several splice variants, with ERα having over 20 and ERβ having 5.

The 2yly protein's secondary structure consists of mostly alpha helices (148 residues) and only two beta strands (6 residues) on the outside of the receptor shown below with the alpha helices showing polar 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

Among the series of p-hydroxybenzene sulfonamide ERβ receptor agonists discovered, protein 2yly has been identified for great selectivity over the related ERα receptor. Protein 2yly was originally designed to form an interaction with the His 475 through the tertiary hydroxyl group. However, the hydroxyl group serves as a conformational lock to form an internal hydrogen bond with the about 2.3 Å apart.^[1]

Internally packed against the phenyl group is the cyclopropyl group with large (shown in gray) between Ile 373 and both the benzyl and chiral methyl groups. The sulphonamide oxygens come in close contact with Met 336 and the benzyl group of the ligand comes near His 475 but there are no coulombic interactions formed. Depending on the functional group placed either next to the tertiary hydroxyl group or on the benzyl ring, further Van der Waals interactions can be seen within the lipophilic pocket. In other words, depending on the polarity of the group attached to the sulphonamide, interactions with His 475 will be varied.

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