Peroxisome Proliferator-Activated Receptors: Difference between revisions
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==Natural Ligands== | ==Natural Ligands== | ||
[[Image: Linoleic_Acid.png|350px|left|thumb| PPARγ Ligand, Linoleic Acid]] | [[Image: Linoleic_Acid.png|350px|left|thumb| PPARγ Ligand, Linoleic Acid]] | ||
<applet load=" 1i7g2.pdb" size="450" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2" caption="Crystal Structure of Human PAPR" align="right"/> | <applet load=" 1i7g2.pdb" size="450" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2" caption="Crystal Structure of Human PAPR ([[1i7g]])" align="right"/> | ||
<scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'>PPAR gamma</scene> binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and eicosapentaenoic acid at affinities that are in line with serum levels found in the blood. PPARα binds a variety of saturated and unsaturated fatty acids including palmitic acid, oleic 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> | <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening_2/2'>PPAR gamma</scene> binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and eicosapentaenoic acid at affinities that are in line with serum levels found in the blood. PPARα binds a variety of saturated and unsaturated fatty acids including palmitic acid, oleic 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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==PPAR Structure== | ==PPAR Structure== | ||
===Ligand Binding Domain=== | ===Ligand Binding Domain=== | ||
The structures of the PPARs are very similar over each isotype. All PPAR isotypes have a ligand binding domain (LBD). The LBD, which is located in the C-terminal half of the receptor, is composed of 13 α-helices and a four-stranded ß-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/2'>The ligand binding pocket</scene> is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/4'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>.<ref name="Nolte">PMID:9744270</ref> The ligand binding pocket of PPARs is quite large (about 1400 cubic angstroms) in comparison to that of other nuclear receptors which allows the PPARs to interact with numerous structurally distinct ligands.<ref name="Nolte"/>. Within Arm I, four polar resides are conserved over all PPAR isotypes, <scene name='Peroxisome_Proliferator-Activated_Receptors/4_conserved_residues/1'>namely Ser280, Tyr314, His440, and Tyr464</scene> in the case of PPARα. These residues are part of a hydrogen bonding network that interacts with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/4'>ligand-dependent activation domain (AF-2) helix H12</scene>, whose function is to generate the receptors’ co-activator binding pocket, is located at the C-terminal end of the LBD.<ref>PMID:11027271</ref> The conserved hydrogen bonding network in <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12_in_place/1'>Arm I also helps hold the AF2-helix in the active conformation</scene>, promoting co-activator binding.<ref name="Zoete"/> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/3'>Arm II is highly hydrophobic </scene>and is thus ideal for binding the hydrophobic tail of fatty acids via Van der Waals interactions. | The structures of the PPARs are very similar over each isotype. All PPAR isotypes have a ligand binding domain (LBD). The LBD, which is located in the C-terminal half of the receptor, is composed of 13 α-helices and a four-stranded ß-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/2'>The ligand binding pocket</scene> ([[2f4b]]) is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/4'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>.<ref name="Nolte">PMID:9744270</ref> The ligand binding pocket of PPARs is quite large (about 1400 cubic angstroms) in comparison to that of other nuclear receptors which allows the PPARs to interact with numerous structurally distinct ligands.<ref name="Nolte"/>. Within Arm I, four polar resides are conserved over all PPAR isotypes, <scene name='Peroxisome_Proliferator-Activated_Receptors/4_conserved_residues/1'>namely Ser280, Tyr314, His440, and Tyr464</scene> in the case of PPARα. These residues are part of a hydrogen bonding network that interacts with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/4'>ligand-dependent activation domain (AF-2) helix H12</scene> ([[1kkq]]), whose function is to generate the receptors’ co-activator binding pocket, is located at the C-terminal end of the LBD.<ref>PMID:11027271</ref> The conserved hydrogen bonding network in <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12_in_place/1'>Arm I also helps hold the AF2-helix in the active conformation</scene>, promoting co-activator binding.<ref name="Zoete"/> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/3'>Arm II is highly hydrophobic </scene>and is thus ideal for binding the hydrophobic tail of fatty acids via Van der Waals interactions. | ||
Despite over 80% of the ligand binding cavity residues being conserved over all PPAR isotypes, it is the remaining 20% that creates the ligand specificity seen between isotypes. A few examples illustrate this point. In PPARδ, the cavity is significantly narrower adjacent to the AF-2 helix and Arm I. This prevents PPARδ from being able to accommode large headed TZDs and L-tyrosine based agonsists. In the case of PPARα, PPARα does not bind ligands with large carboxylate head groups because of <scene name='Peroxisome_Proliferator-Activated_Receptors/Tyr_314/4'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref name="Zoete"/> Or in the case of binding some benzenesulfonamide derivatives, the <scene name='Peroxisome_Proliferator-Activated_Receptors/Pi_stacking/2'>pi stacking of Phe363 and the aromatic moiety</scene> in the case of PPARγ is lost in PPARα (Ile354) and PPARδ(Ile 363)<ref name="Zoete"/> | Despite over 80% of the ligand binding cavity residues being conserved over all PPAR isotypes, it is the remaining 20% that creates the ligand specificity seen between isotypes. A few examples illustrate this point. In PPARδ, the cavity is significantly narrower adjacent to the AF-2 helix and Arm I. This prevents PPARδ from being able to accommode large headed TZDs and L-tyrosine based agonsists. In the case of PPARα, PPARα does not bind ligands with large carboxylate head groups because of <scene name='Peroxisome_Proliferator-Activated_Receptors/Tyr_314/4'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref name="Zoete"/> Or in the case of binding some benzenesulfonamide derivatives, the <scene name='Peroxisome_Proliferator-Activated_Receptors/Pi_stacking/2'>pi stacking of Phe363 and the aromatic moiety</scene> ([[2g0g]]) in the case of PPARγ is lost in PPARα (Ile354) and PPARδ(Ile 363)<ref name="Zoete"/> | ||
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[[Image: Binding_site.png|350px|left|thumb| Human PPARγ Ligand Binding Site with Rosiglitazone Bound. [[2prg]]]] | [[Image: Binding_site.png|350px|left|thumb| Human PPARγ Ligand Binding Site with Rosiglitazone Bound. [[2prg]]]] | ||
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===AF-2 Domain: Structure and Function=== | ===AF-2 Domain: Structure and Function=== | ||
<applet load="2prg2.pdb" size="450" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2" caption="Crystal Structure of Human PPAR" align="right"/> | <applet load="2prg2.pdb" size="450" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2" caption="Crystal Structure of Human PPAR, ([[2prg]])" align="right"/> | ||
As briefly mentioned before, the AF-2 domain is essential for ligand binding and <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2'>PPAR</scene> function. Upon ligand binding, helix H12 of AF-2 closes on the ligand-binding site, 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 <scene name='Peroxisome_Proliferator-Activated_Receptors/H_bonding_network/3'>Glu324, Arg397, Arg443, and Tyr 477</scene> (in PPARγ) are involved in a hydrogen bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding.<ref name="Zoete"/> | As briefly mentioned before, the AF-2 domain is essential for ligand binding and <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening3/2'>PPAR</scene> function. Upon ligand binding, helix H12 of AF-2 closes on the ligand-binding site, 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 <scene name='Peroxisome_Proliferator-Activated_Receptors/H_bonding_network/3'>Glu324, Arg397, Arg443, and Tyr 477</scene> (in PPARγ) are involved in a hydrogen bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding.<ref name="Zoete"/> | ||
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===DNA Binding Domain Structure=== | ===DNA Binding Domain Structure=== | ||
[[Image:Rosiglitazone.png|300px|left|thumb| Human PPARγ agonist, Rosiglitazone ([[Avandia]])]] | [[Image:Rosiglitazone.png|300px|left|thumb| Human PPARγ agonist, Rosiglitazone ([[Avandia]])]] | ||
PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene>, one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | PPARs also contain a DNA binding domain (DBD) The <scene name='Peroxisome_Proliferator-Activated_Receptors/Zinc_fingers/1'>DBD consists of two zinc fingers</scene> ([[3dzy]]), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.<ref>PMID:9383428</ref> Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a <scene name='Peroxisome_Proliferator-Activated_Receptors/Dbd_hbonds/1'>head-to-tail interaction between the PPAR DBD and RXR DBD</scene> using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.<ref>PMID:19043829</ref> | ||
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