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==Introduction==
==Introduction==


(Some sections below taken from primary paper) Further introduction for estrogen receptors later and why useful
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.


- "The gonadal steroid hormone estradiol, 1, exerts genomic actions through two oestrogen receptor subtypes, ERa and ERb. Emerging evidence has suggested that the function of ERb in contrast to ERa, potentially counteracts the proliferative effects of ERa on breast and endometrial tissue as well as being potentially responsible for the immunomodulatory as well as neuropharmacological behaviour of estradiol 1,2 There has been significant interest in the potential therapeutic benefit of selective ERb agonists to treat a variety of conditions including endometriosis3 and inflammatory bowel disease."
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.
- A series of p-hydroxybenzenesulphonamides ERb receptor agonists were discovered and several compounds identified had excellent selectivity over the related ERa receptor. One of these, compound 11, had an interesting binding conformation determined by X-ray and represents an excellent starting point in the quest for further selective ERb agonists.
 
- There has been significant interest in the potential therapeutic benefit of selective ERb agonists to treat a variety of conditions including endometriosis3 and inflammatory bowel disease
 
- The amino acid sequence of the ligand binding domains between ERa and ERb is very highly conserved with only minor differences; Leu384 and Met421 in ERa is replaced by Met336 and Ile373 in ERb. The overall molecule is shown here with the <scene name='48/483890/Met336_and_ile373_in_erb/1'>Met336 and Ile373</scene> in ERb in blue to show their location.
 
1. The amines were either purchased commercially or made via addition of a primary amine to an epoxide as shown in Scheme
2. The compounds were tested as racemates and those of interest were separated by chiral HPLC. A wide range of analogues were prepared utilising the approach described.


This is an overall scene with the beta sheets in purple and the alpha helices in ball and stick figures <scene name='48/483890/Ben_homyak_overall_structure/1'>Overall Structure</scene>
This is an overall scene with the beta sheets in purple and the alpha helices in ball and stick figures <scene name='48/483890/Ben_homyak_overall_structure/1'>Overall Structure</scene>
Line 29: Line 21:
Here is another scene with a rainbow diagram description of the whole molecule
Here is another scene with a rainbow diagram description of the whole molecule
<scene name='48/483890/2yly_overall_diagram/3'>Rainbow diagram</scene>
<scene name='48/483890/2yly_overall_diagram/3'>Rainbow diagram</scene>
Further scenes will be put in regarding more in depth focus on the estrogen receptor


==Overall Structure==
==Overall Structure==

Revision as of 21:39, 10 April 2016


This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.


Estrogen receptor beta/p-hydroxybenzene sulfonamide complexes (2yly)[1]

by Benjamin Homyak, Soo Lim Park, Marissa Burgess

Student Projects for UMass Chemistry 423 Spring 2016 <StructureSection load='2yly' size='350' side='right' caption='p-hydroxybenzenesulphonamides ERb receptor (PDB entry 2yly)' scene=>

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 Overall Structure

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

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

- Alpha Helices, and Beta Sheets

- Tertiary Structure

- Polar- Pink, Hydrophobic- Grey Polar and Nonpolar Groups

- Surface groups (orange) vs. Buried groups (blue) Check it out

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 here


See Also

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
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