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The estrogen receptor beta <scene name='48/483891/Initial_view/1'>(initial view)</scene> is one of the two isoforms of the estrogen receptor, a ligand-activated transcription factor, which regulates the biological effects of the steroid hormone 17 beta-estradiol, or estrogen, in both males and females. <scene name='48/483891/Ligand/3'>Genistein</scene> is a phytoestrogen with structural similarity to estrogen and competes for estrogen receptors. This ligand can increase growth rate of estrogen receptor expressing breast cancers and can inhibit immune response to cancer cells allowing them to proliferate depending on its concentration. In this <scene name='48/483891/Rainbow/1'>rainbow representation</scene> the N and C termini are at opposite ends of the structure. | The estrogen receptor beta <scene name='48/483891/Initial_view/1'>(initial view)</scene> is one of the two isoforms of the estrogen receptor, a ligand-activated transcription factor, which regulates the biological effects of the steroid hormone 17 beta-estradiol, or estrogen, in both males and females. <scene name='48/483891/Ligand/3'>Genistein</scene> is a phytoestrogen with structural similarity to estrogen and competes for estrogen receptors. This ligand can increase growth rate of estrogen receptor expressing breast cancers and can inhibit immune response to cancer cells allowing them to proliferate depending on its concentration. In this <scene name='48/483891/Rainbow/1'>rainbow representation</scene> the N and C termini are at opposite ends of the structure. | ||
| + | HeteroTetrameric Assembly: This assembly consists of 4 molecules (2 types): | ||
| + | 2 copies of estrogen receptor beta | ||
| + | 2 copies of steroid receptor coactivator-1 | ||
| + | Ramachandran analysis | ||
| + | Discovered in 1996, estrogen receptor beta (ERβ) has become a target for drug delivery since it was discovered that it could be targeted apart from ERα. | ||
| + | |||
| + | ERβ is widely expressed but is not the primary estrogen receptor in most tissues | ||
| + | can target other tissues while avoiding some estrogenic effects | ||
| + | |||
| + | is a 40-fold ERβ-selective ligand over ERα | ||
| + | ERβ Met336 and ERβ Ile373 may have to do with the enhanced selectivity of GEN | ||
| + | may allow ERβ to accommodate more polar substituents at the distal end of the binding cavity | ||
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Genistein's bicyclic form allows it to hydrogen bond on opposite sides with the hydroxyls of the histidine groups on the receptor. (His475) Its binding to the receptor causes a conformational change and activates the receptor resulting in either up-regulation or down-regulation of gene expression. In order for the estrogen receptor beta genistein to bind to a receptor and activate it there must be stabilization by a coactivator. The coactivator increases the gene expression and with this increase allows it to bind to an activator group consisting of a DNA binding domain. The estrogen receptor is found to be comprised of a dimer attached to a ligand and coactivator peptide which helps to stabilize the structure of each monomer. The conformational state of helix-12 can be modified by the binding of the coactivator. | Genistein's bicyclic form allows it to hydrogen bond on opposite sides with the hydroxyls of the histidine groups on the receptor. (His475) Its binding to the receptor causes a conformational change and activates the receptor resulting in either up-regulation or down-regulation of gene expression. In order for the estrogen receptor beta genistein to bind to a receptor and activate it there must be stabilization by a coactivator. The coactivator increases the gene expression and with this increase allows it to bind to an activator group consisting of a DNA binding domain. The estrogen receptor is found to be comprised of a dimer attached to a ligand and coactivator peptide which helps to stabilize the structure of each monomer. The conformational state of helix-12 can be modified by the binding of the coactivator. | ||
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| - | This <scene name='48/483891/Estrogen_kyle/2'>scene</scene> shows the hydrophobic and hydrophilic residues of the genistein receptor. | ||
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Revision as of 03:12, 1 April 2015
| 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. |
Contents |
Estrogen receptor beta/genistein complex
Introduction
|
The estrogen receptor beta is one of the two isoforms of the estrogen receptor, a ligand-activated transcription factor, which regulates the biological effects of the steroid hormone 17 beta-estradiol, or estrogen, in both males and females. is a phytoestrogen with structural similarity to estrogen and competes for estrogen receptors. This ligand can increase growth rate of estrogen receptor expressing breast cancers and can inhibit immune response to cancer cells allowing them to proliferate depending on its concentration. In this the N and C termini are at opposite ends of the structure.
HeteroTetrameric Assembly: This assembly consists of 4 molecules (2 types): 2 copies of estrogen receptor beta 2 copies of steroid receptor coactivator-1
Ramachandran analysis
Discovered in 1996, estrogen receptor beta (ERβ) has become a target for drug delivery since it was discovered that it could be targeted apart from ERα.
ERβ is widely expressed but is not the primary estrogen receptor in most tissues can target other tissues while avoiding some estrogenic effects
is a 40-fold ERβ-selective ligand over ERα
ERβ Met336 and ERβ Ile373 may have to do with the enhanced selectivity of GEN
may allow ERβ to accommodate more polar substituents at the distal end of the binding cavity
Overall Structure
|
When the protein is colored according to , residues at the ligand site are the most conserved.
Estrogen receptor beta and genistein complex consists of 4 chains. The phytoestrogen, genistein, is completely buried in the hydrophobic core of the protein.
Estrogen receptor beta contains several domains for different functions. Its N-terminal domain (NTD) consists most of random coils and a small portion of helices and sheets. This lack of structure allows it to recruit and bond proper interaction partners. Within the NTD, the A and B domains can transactivate transcription without binding estrogen, and the C domain or the DNA binding domain (DBD) that binds estrogen response elements of DNA. The D domain is a hinge region connecting DBD to the E domain, ligand binding domain (LBD), at the C terminal. LBD binds coregulatory proteins, corepressors and coactivators.
Binding Interactions
|
Genistein's bicyclic form allows it to hydrogen bond on opposite sides with the hydroxyls of the histidine groups on the receptor. (His475) Its binding to the receptor causes a conformational change and activates the receptor resulting in either up-regulation or down-regulation of gene expression. In order for the estrogen receptor beta genistein to bind to a receptor and activate it there must be stabilization by a coactivator. The coactivator increases the gene expression and with this increase allows it to bind to an activator group consisting of a DNA binding domain. The estrogen receptor is found to be comprised of a dimer attached to a ligand and coactivator peptide which helps to stabilize the structure of each monomer. The conformational state of helix-12 can be modified by the binding of the coactivator.
Additional Features
|
Quiz Question 1
First, we can see the of the complex. Upon visualizing the estrogen receptor in an arrow formation, , one can determine the structure of the complex.
a. alpha helix
b. beta sheet, parallel
c. beta sheet, anti-parallel
Quiz Question 2
See Also
- UvrABC
- Androgen receptor
- Estrogen receptor
- Estrogen-related receptor
- Nuclear receptor coactivator
- Hormone
- Glycogen synthase kinase 3
- CREB-binding protein
Credits
Introduction - Brian Cain
Overall Structure - Anna Novikova
Drug Binding Site - Kyle Missaggia
Additional Features - William Doherty
Quiz Question 1 - James Conner
Quiz Question 2 - name of team member
