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| - | <Structure load=' | ||
| - | ==''' | + | =='''Estrogen receptor beta/p-hydroxybenzene sulfonamide complexes (2yly)<ref>PMID: 21885279 </ref>'''== |
| - | + | 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== | ==Introduction== | ||
| - | This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. | ||
| - | + | 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. | |
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| + | 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 <scene name='48/483890/Ben_homyak_overall_structure/1'>Overall Structure</scene> |
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| - | + | Here is another scene with a rainbow diagram description of the whole molecule | |
| + | <scene name='48/483890/2yly_overall_diagram/3'>Rainbow diagram</scene> | ||
| - | + | ==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. | |
| + | - <scene name='48/483890/2yly_alpha_helicies/1'>Alpha Helices</scene>, and <scene name='48/483890/2yly_beta_sheets/1'>Beta Sheets</scene> | ||
| + | - Tertiary Structure | ||
| - | + | - Polar- Pink, Hydrophobic- Grey <scene name='48/483890/2yly_polar_hydrophobic/1'>Polar and Nonpolar Groups</scene> | |
| + | - Surface groups (orange) vs. Buried groups (blue) <scene name='48/483890/2yly_surface_buried/1'>Check it out</scene> | ||
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| - | <scene name='48/483890/1q3d/1'>1q3d structure</scene> | ||
==Binding Interactions== | ==Binding Interactions== | ||
| - | 1)Folding of protein | ||
| - | a) location and description of position of alpha and beta sheets (Show in separate color on green screen) | ||
| - | b) crystal structure data (Table 1, Structural Characterizaiton of the GSK-3B Active Site Using Selective and Non-selective ATP-mimetic Inhibitors) | ||
| - | 2)Substrate binding | ||
| - | a) “phosphate-binding” pocket: describe three crucial basic residues (Show in different color on green screen) | ||
| - | b) GSK-3 substrates and binding specifics- S/TxxxS/T (S=Serine, T=threonine, X= any amino acid) | ||
| - | + | 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 <scene name='48/483890/Soolim_binding/1'>sulphonamide oxygen </scene> about 2.3 Å apart.<sup>[1]</sup> | |
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| - | = | + | Internally packed against the phenyl group is the cyclopropyl group with large <scene name='48/483890/Soolim_hydrophobic/1'>hydrophobic interactions</scene> (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. |
| - | 1. | + | |
| - | 2. Difference that can be observed from GSK-3 beta complexes with Staurosporine and other inhibitors (AMP-PNP, indirubin-3'-monoxime) | ||
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| - | ==Quiz Question 1== | ||
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| - | Which isoform of GSK-3 would work best for ___ function in ___ pathway? | ||
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| - | What kind of bond would GSK-3B form with a staurosporine complex? Picture is shown below. | ||
| - | [[Media:http://upload.wikimedia.org/wikipedia/commons/3/34/Staurosporine1.png]] | ||
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| - | Excerpt from GSK-3: Functional Insights from Cell Biology and Animal Models: | ||
| - | "In certain cell types of the brain, alternative splicing between exon 8 and 9 of GSK-3β leads to the generation of an additional “long” form containing a 13 amino acid insert within the catalytic domain (GSK-3β2; see Figure Figure1).1). This insert is located between residues 303 and 304 of GSK-3β, and is flanked by two proximal α-helices of kinase subdomains X and XI (Hanks and Hunter, 1995; Mukai et al., 2002). This alternatively spliced isoform of GSK-3β in rodents (Mukai et al., 2002; Yao et al., 2002) and in human (Lau et al., 1999; Schaffer et al., 2003; Kwok et al., 2005) has been implicated in neuronal-specific functions. The short form of GSK-3β is ubiquitously expressed in the body, including the developing and adult nervous system (Takahashi et al., 1994; Leroy and Brion, 1999). By contrast, GSK-3β2 is predominantly expressed in the neural tissues, with highest levels in the developing brain and persistence into adulthood (Mukai et al., 2002; Wood-Kaczmar et al., 2009)." | ||
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| - | "From the crystal structure, it has been proposed that unphosphorylated Tyr276/Tyr216 act to block the access of primed substrates (as discussed below). Indeed, the structure of phosphorylated GSK-3β (Bax et al., 2001) shows that phosphorylated Tyr216 undergoes a conformational change that allows substrates to bind the enzyme" | ||
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| - | ==Quiz Question 2== | ||
==See Also== | ==See Also== | ||
| - | *[ | + | *[[http://www.proteopedia.org/wiki/index.php/Estrogen_receptor Estrogen Receptor]] |
| - | + | *[[http://www.proteopedia.org/wiki/index.php/1yy4 1yy4]] | |
| - | *[http://proteopedia.org/wiki/index.php/ | + | *[[http://www.proteopedia.org/wiki/index.php/1u3s 1u3s]] |
| - | *[http://proteopedia.org/wiki/index.php/ | + | *[[http://www.proteopedia.org/wiki/index.php/1x78 1x78]] |
| - | *[http:// | + | *[[http://www.proteopedia.org/wiki/index.php/1qkm 1qkn]] |
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| - | *[http://www.proteopedia.org/wiki/index.php/ | + | |
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==Credits== | ==Credits== | ||
| - | Introduction - | + | Introduction - Benjamin Homyak |
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| - | + | Overall Structure - Marissa Burgess | |
| - | + | Drug Binding Site - Soo Lim Park | |
==References== | ==References== | ||
<references/> | <references/> | ||
Current revision
| 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
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