Peroxisome Proliferator-Activated Receptors: Difference between revisions

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David Canner, Alexander Berchansky, Michal Harel, Joel L. Sussman

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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 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.
-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>PMID:16640330</ref>
+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"/>
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 [[Image: Binding_site.png|350px|left|thumb| Human PPARγ Ligand Binding Site with Rosiglitazone Bound. [[2prg]]]]