Sandbox Reserved 323: Difference between revisions
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==Structure== | ==Structure== | ||
<Structure load='1k7l' size='300' frame='true' align='left' caption='Human PPARα' /> | <Structure load='1k7l' size='300' frame='true' align='left' caption='Human PPARα' /> | ||
PPAR-alpha structure shares common characteristics with the other isoforms in this nuclear receptor superfamily, as it displays five distinguishable domains designated the A/B, C, D, E and F domains. The A/B domain, on the N-terminus of PPAR-alpha, contains an activation function region (AF-1), which has a low level of basal transcriptional activity and functions independently of ligand-binding. The DNA binding domain (C) contains two very highly conserved zinc finger motifs and architectural elements capable of sequence-specific binding to DNA <ref name="PPAR4">PMID:10529898</ref>. A flexible hinge region (D) connects the DNA binding domain to the ligand-binding domain (E). The ligand-binding domain in the human PPAR alpha protein contains the activation function-2 (AF-2) region composed of two alpha helices flanking one four-sided beta sheet <ref name="PPAR4"/>. Following ligand interaction, the AF-2 domain undergoes a conformational change which promotes the hydrogen bonding between Tyr-314 and Tyr-464, as well as the formation of the “charge clamp” between Glu-462 and Lys-292 <ref name="PPAR5">PMID:11698662</ref>. | PPAR-alpha structure shares common characteristics with the other isoforms in this nuclear receptor superfamily, as it displays five distinguishable domains designated the A/B, C, D, E and F domains. The A/B domain, on the N-terminus of PPAR-alpha, contains an activation function region (AF-1), which has a low level of basal transcriptional activity and functions independently of ligand-binding. The DNA binding domain (C) contains two very highly conserved zinc finger motifs and architectural elements capable of sequence-specific binding to DNA <ref name="PPAR4">PMID:10529898</ref>. A flexible hinge region (D) connects the DNA binding domain to the ligand-binding domain (E). The ligand-binding domain in the human PPAR alpha protein contains the activation function-2 (AF-2) region composed of two alpha helices flanking one four-sided beta sheet <ref name="PPAR4"/>. Following ligand interaction, the AF-2 domain undergoes a conformational change which promotes the hydrogen bonding between Tyr-314 and Tyr-464, as well as the formation of the “charge clamp” between <scene name='Sandbox_Reserved_323/1k7l/2'>Glu-462 and Lys-292 </scene><ref name="PPAR5">PMID:11698662</ref>. | ||
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==Ligand Interactions== | ==Ligand Interactions== | ||
[[Image: PPARa_LBD.jpeg|375px|right|thumb|Figure 1: Three-dimensional crystal structure of PPARα complexed to a chemical agonist and coactivator peptide | [[Image: PPARa_LBD.jpeg|375px|right|thumb|Figure 1: Three-dimensional crystal structure of PPARα complexed to a chemical agonist and coactivator peptide]] | ||
PPAR alpha ligands can consist of either synthetic drugs (exogenous) or biological molecules (endogenous). Most common biological molecules that serve as ligands for human PPAR alpha are fatty acids, fatty acid derivatives <ref name="PPAR1"/><ref name="PPAR2"/>. Several enzymes such as 8-, 12-, 15-, and 5-lipoxygenases, the cyclooxygenases and cytochrome P450 utilize fatty acids as substrates to produce putative PPAR alpha ligands. Leukotriene B4 is a well-known putative PPAR alpha ligand, as well as 19- and 20- hydroxyeicosatetraeonic acid, generated from cytochrome P450 as a conversion of arachidonic acid. Oleylethanolamide, a naturally occurring lipid, has also been identified as a high affinity PPAR alpha ligand regulating PPAR alpha activity and lipid metabolism <ref name="PPAR6">PMID:20414453</ref>. | PPAR alpha ligands can consist of either synthetic drugs (exogenous) or biological molecules (endogenous). Most common biological molecules that serve as ligands for human PPAR alpha are fatty acids, fatty acid derivatives <ref name="PPAR1"/><ref name="PPAR2"/>. Several enzymes such as 8-, 12-, 15-, and 5-lipoxygenases, the cyclooxygenases and cytochrome P450 utilize fatty acids as substrates to produce putative PPAR alpha ligands. Leukotriene B4 is a well-known putative PPAR alpha ligand, as well as 19- and 20- hydroxyeicosatetraeonic acid, generated from cytochrome P450 as a conversion of arachidonic acid. Oleylethanolamide, a naturally occurring lipid, has also been identified as a high affinity PPAR alpha ligand regulating PPAR alpha activity and lipid metabolism <ref name="PPAR6">PMID:20414453</ref>. | ||
