Peroxisome Proliferator-Activated Receptors: Difference between revisions
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[[Image: 3dzy2.png|420px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]] | [[Image: 3dzy2.png|420px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]] | ||
{{ | {{STRUCTURE_3dzy| right| PDB=3dzy | SCENE=Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1 |CAPTION= Crystal Structure of Human PPARγ, [[3dzy]] }} | ||
The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factor to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases. <ref>PMID:15860251 </ref> | The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factor to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases. <ref>PMID:15860251 </ref> | ||
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==Natural Ligands== | ==Natural Ligands== | ||
[[Image: Linoleic_Acid.png|400px|left|thumb| PPARγ Ligand, Linoleic Acid]] | [[Image: Linoleic_Acid.png|400px|left|thumb| PPARγ Ligand, Linoleic Acid]] | ||
<applet load=" 1i7g2.pdb" size="400" color="white" frame="true" spin="on" Scene ="" caption="Crystal Structure of Human PPAR" align="right"/> | <applet load=" 1i7g2.pdb" size="400" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/1" caption="Crystal Structure of Human PPAR" align="right"/> | ||
PPARγ binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and [http://en.wikipedia.org/wiki/Eicosapentaenoic_acid eicosapentaenoic acid] at affinities that are in line with serum levels. PPARα binds a variety of saturated and unsaturated fatty acids including [http://en.wikipedia.org/wiki/Palmitic_acid palmitic acid], [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], [http://en.wikipedia.org/wiki/Linoleic_acid linoleic acid], and arachidonic acid. <ref> PMID:1316614</ref> PPARδs ligand selectivity is intermediate between that of the other isotypes and is activated by palmitic acid and a number of eicosanoids. <ref> PMID:7836471</ref> | PPARγ binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and [http://en.wikipedia.org/wiki/Eicosapentaenoic_acid eicosapentaenoic acid] at affinities that are in line with serum levels. PPARα binds a variety of saturated and unsaturated fatty acids including [http://en.wikipedia.org/wiki/Palmitic_acid palmitic acid], [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], [http://en.wikipedia.org/wiki/Linoleic_acid linoleic acid], and arachidonic acid. <ref> PMID:1316614</ref> PPARδs ligand selectivity is intermediate between that of the other isotypes and is activated by palmitic acid and a number of eicosanoids. <ref> PMID:7836471</ref> | ||
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===AF-2 Domain: Structure and Function=== | ===AF-2 Domain: Structure and Function=== | ||
<applet load="2prg2.pdb" size="400" color="white" frame="true" spin="on" Scene ="" caption="Crystal Structure of Human PPAR" align="right"/> | <applet load="2prg2.pdb" size="400" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/1" caption="Crystal Structure of Human PPAR" align="right"/> | ||
As briefly mentioned before, the AF-2 domain is essential for ligand binding and PPAR function. Helix H12 of AF-2 closes on the ligand-binding site upon ligand binding, reducing conformational flexibility of the LBD and assuming a structure that is ideal for co-activator binding. Using Molecular Dynamic simulations, it has been determined that residues **Glu324, Arg397, Arg443, and Tyr 447** (in PPARγ) are involved in a hydrogen-bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding. <ref> PMID:7501014</ref> | As briefly mentioned before, the AF-2 domain is essential for ligand binding and PPAR function. Helix H12 of AF-2 closes on the ligand-binding site upon ligand binding, reducing conformational flexibility of the LBD and assuming a structure that is ideal for co-activator binding. Using Molecular Dynamic simulations, it has been determined that residues **Glu324, Arg397, Arg443, and Tyr 447** (in PPARγ) are involved in a hydrogen-bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding. <ref> PMID:7501014</ref> | ||
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==Binding of Synthetic Agonists and Medical Implications== | ==Binding of Synthetic Agonists and Medical Implications== | ||
<applet load=" 3dzy2.pdb" size="400" color="white" frame="true" spin="on" Scene ="" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/> | <applet load=" 3dzy2.pdb" size="400" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/> | ||
A number of synthetic agonists have been developed to bind to PPAR to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([www.avandia.com Avandia)). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a **number of interactions that stabilize the agonist**. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282 and Leu469, and the central benzene ring of the ligand occupies a pocket formed by Cys285 and Met364.<ref>PMID:9744270</ref> | A number of synthetic agonists have been developed to bind to PPAR to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([www.rezulin.com Rezulin]), [http://en.wikipedia.org/wiki/pioglitazone pioglitazone] ([www.actos.com Actos]), and [http://en.wikipedia.org/wiki/Rosiglitazone rosiglitazone] ([www.avandia.com Avandia)). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a **number of interactions that stabilize the agonist**. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its [http://en.wikipedia.org/wiki/Thiazolidinedione TZD] group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282 and Leu469, and the central benzene ring of the ligand occupies a pocket formed by Cys285 and Met364.<ref>PMID:9744270</ref> | ||
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | [[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]] | ||