User:Adam Davis/Sandbox 1
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==PPARδ Bound to GW074== | ==PPARδ Bound to GW074== | ||
| - | Peroxisome proliferator activated receptors are transcription factors. | + | == Introduction == |
| + | Peroxisome proliferator activated receptors ([[PPAR]]s) are ligand-activated transcription factors that regulate metabolism. They are divided into three families: α, γ, and δ. PPARδ is activated by endogenous lipids, and plays a role in the regulation of lipid metabolism. Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases. (Note: In the literature, PPARδ is sometimes also called PPARβ). In this structure, PPARδ is bound to a synthetic agonist, GW074, which binds PPARδ 300-fold more tightly than PPARα and PPARγ<ref>DOI 10.1371/journal.pone.0033643</ref>. | ||
<StructureSection load='3tkm' size='340' side='right' caption='PDB ID: 3TKM' scene=''> | <StructureSection load='3tkm' size='340' side='right' caption='PDB ID: 3TKM' scene=''> | ||
| - | This is a default text for your page '''Adam Davis/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs. | ||
| - | You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | ||
== Structural highlights == | == Structural highlights == | ||
| - | This is an X-ray crystallography structure, | + | This is an X-ray crystallography structure, with a resolution of 1.95 Å, which models the region of PPARδ from Gln171 to Tyr441<ref>DOI 10.1371/journal.pone.0033643</ref>. It is composed of <scene name='10/1079455/Helices/1'>twelve alpha helices</scene>, with one small <scene name='10/1079455/Beta_sheet/1'>beta sheet region</scene>. The structure is bound to a synthetic ligand, <scene name='10/1079455/Ligand/2'>GW0742</scene>, which contains a carboxylate group, a thiophenol, a thiazole, and a fluorine substituted phenyl ring. This ligand can be divided into a hydrophilic head group (carboxylate) and a hydrophobic tail (thiophenol, thiazole, phenyl). There is also a glycerol molecule in the structure, which is an artifact of the crystallization process and is not biologically relevant. |
| - | The ligand binding pocket (LBP) is made of <scene name='10/1079455/Armsi_ii_iii/2'>three arms</scene> ( | + | The ligand binding pocket (LBP) is made of <scene name='10/1079455/Armsi_ii_iii/2'>three arms</scene> (Arm I residues are green, Arm II residues are blue, Arm III residues are red), with fifteen residues that contact the ligand. <scene name='10/1079455/Armi/1'>Arm I</scene> interacts with the ligand through Phe246, Cys249, His287, Phe291, Ile327, His413, Leu433, and Tyr437. The <scene name='10/1079455/Hydrophilic_head/2'>hydrophilic head</scene> of the ligand interacts via polar contacts with Arm I residues His287, His413, and Tyr437. <scene name='10/1079455/Arm_ii/1'>Arm II</scene>, includes residues Val245, Val305, Val312, Leu317, and Ile 328, while <scene name='10/1079455/Arm_iii/1'>Arm III</scene> includes Leu249 and Thr252. The <scene name='10/1079455/Hydrophobic_tail/2'>hydrophobic tail</scene> of the ligand interacts via nonpolar contacts with residues from all three arms (Phe246, Phe291, His 413, Ile327, Leu433, Cys249, Val245, Val305, Val312, Leu317, Ile328, Thr252, and Leu294). |
| - | + | Using site-directed mutagenesis to replace LBP amino acids with Met, the authors found that <scene name='10/1079455/Val312_ile328/3'>two LBP residues</scene> from Arm II, Val312 and Ile328, are key to the specificity of this ligand for PPARδ. | |
== Function == | == Function == | ||
| - | + | PPARs are ligand-activated transcription factors. These receptors are activated by a number of endogenous lipids, but synthetic ligands have also been developed for therapeutic use<ref>DOI 10.1016/j.phrs.2004.07.012</ref>. After activation, PPAR forms a heterodimer with the [[Retinoid X receptor]], and the complex binds to DNA, either stimulating or repressing transcription of genes involved in glucose or lipid metabolism. | |
| - | == | + | PPARδ is found in many tissues, but is most highly expressed in the gut, kidney, and heart<ref>DOI 10.1210/edrv.20.5.0380</ref>. It is activated by fatty acids, triglycerides, prostacyclin, and retinoic acid<ref>DOI doi.org/10.1016/j.pharmthera.2009.12.001</ref>. Though it is the least studied PPAR, its known functions include regulating acyl-CoA synthetase 2 expression and mediating embryo implantation<ref>DOI 10.1074/jbc.274.50.35881</ref><ref>DOI 10.1101/gad.13.12.1561</ref>. |
| + | |||
| + | == Disease == | ||
| + | PPARδ agonists are being investigated as treatments for a number of metabolic disorder and cardiovascular disorders, but have not yet been deployed clinically. Current literature suggests that PPARδ agonists could enhance fatty acid oxidation in skeletal muscle, reduce serum triglycerides, increase serum HDL levels, and enhance weight loss<ref>DOI 10.1210/edrv.20.5.0380</ref>. Though there are some health benefits associated with PPARα and γ agonists, these drugs also have undesirable side effects including such as edema and weight gain, and carcinogenicity in rodents<ref>DOI 10.1371/journal.pone.0033643</ref><ref>DOI 10.1038/35013000</ref>. If PPARδ agonists are to be used clinically, it is thus important to develop a ligand that does not also bind to the other PPARs. | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
PPARδ Bound to GW074
Introduction
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that regulate metabolism. They are divided into three families: α, γ, and δ. PPARδ is activated by endogenous lipids, and plays a role in the regulation of lipid metabolism. Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases. (Note: In the literature, PPARδ is sometimes also called PPARβ). In this structure, PPARδ is bound to a synthetic agonist, GW074, which binds PPARδ 300-fold more tightly than PPARα and PPARγ[1].
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References
- ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
- ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
- ↑ doi: https://dx.doi.org/10.1016/j.phrs.2004.07.012
- ↑ doi: https://dx.doi.org/10.1210/edrv.20.5.0380
- ↑ doi: https://dx.doi.org/doi.org/10.1016/j.pharmthera.2009.12.001
- ↑ doi: https://dx.doi.org/10.1074/jbc.274.50.35881
- ↑ doi: https://dx.doi.org/10.1101/gad.13.12.1561
- ↑ doi: https://dx.doi.org/10.1210/edrv.20.5.0380
- ↑ Batista FA, Trivella DB, Bernardes A, Gratieri J, Oliveira PS, Figueira AC, Webb P, Polikarpov I. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One. 2012;7(5):e33643. Epub 2012 May 11. PMID:22606221 doi:10.1371/journal.pone.0033643
- ↑ Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000 May 25;405(6785):421-4. PMID:10839530 doi:10.1038/35013000
