Peroxisome Proliferator-Activated Receptors: Difference between revisions
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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 δ-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/1'>The ligand binding pocket</scene> is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/2'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>. The ligand binding pocket of PPARs is quite large in comparison to that of other nuclear receptors (about 1400 cubic angstroms) which allows the PPARs to interact with a broad range of structurally distinct ligands.<ref>PMID:9744270</ref>. 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 is formed with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/1'>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>PMID:17317294</ref> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/2'>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 δ-sheet. <scene name='Peroxisome_Proliferator-Activated_Receptors/Ligand_binding_pocket/1'>The ligand binding pocket</scene> is Y-shaped and consists of an <scene name='Peroxisome_Proliferator-Activated_Receptors/Y_shaped/2'>entrance and two pockets, Arm I and Arm II, along with a "charge-clamp"</scene>. The ligand binding pocket of PPARs is quite large in comparison to that of other nuclear receptors (about 1400 cubic angstroms) which allows the PPARs to interact with a broad range of structurally distinct ligands.<ref>PMID:9744270</ref>. 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 is formed with the carboxylate group of fatty acids and other ligands upon binding.<ref>PMID:16405912</ref> The <scene name='Peroxisome_Proliferator-Activated_Receptors/Helix_h12/1'>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>PMID:17317294</ref> <scene name='Peroxisome_Proliferator-Activated_Receptors/Arm_ii_hydrophobic/2'>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 accommodating 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_314/3'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref>PMID:17317294</ref> Or in the case of binding some benzenesulfonamide derivatives, the <scene name='Peroxisome_Proliferator-Activated_Receptors/Pi_stacking/ | 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 accommodating 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_314/3'> Tyrosine 314</scene> as compared to PPARγ which has a smaller equivalent residue in His323.<ref>PMID:17317294</ref> 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>PMID:16640330</ref> | ||
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