Peroxisome Proliferator-Activated Receptors: Difference between revisions
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==PPAR Structure== | ==PPAR Structure== | ||
<StructureSection load='1dq8' size='500' side='right' caption='Structure of HMG-CoA reductase (PDB entry [[1dq8]])' scene=''> | |||
===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> ([[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. | 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. | ||
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===AF-2 Domain: Structure and Function=== | ===AF-2 Domain: Structure and Function=== | ||
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> ([[2prg]]) 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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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> | 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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</StructureSection> | |||
==Binding of Synthetic Agonists and Medical Implications== | ==Binding of Synthetic Agonists and Medical Implications== | ||