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PPARδ Bound to GW074

Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that regulate metabolism of lipids and glucose. They are divided into three families: α, γ, and δ. Activation of PPARδ by endogenous ligands results in increased insulin sensitivity. (Note: In the literature, PPARδ is sometimes also called PPARβ). Synthetic PPARδ agonists hold significant promise for treatment of metabolic and cardiovascular diseases.

spinqualitylabelsall models PDB ID: 3TKM Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights This is an X-ray crystallography structure, with a resolution of 1.95 Å, which models the region of PPARδ from Gln171 to Tyr441. It is composed of twelve alpha helices, with one small beta sheet region. The structure is bound to a synthetic ligand, GW0742, 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 three arms (Arm I residues are green, Arm II residues are blue, Arm III residues are red), with fifteen residues that contact the ligand. Arm I interacts with the ligand through Phe246, Cys249, His287, Phe291, Ile327, His413, Leu433, and Tyr437. The hydrophilic head of the ligand interacts via polar contacts with Arm I residues His287, His413, and Tyr437. Arm II, includes residues Val245, Val305, Val312, Leu317, and Ile 328, while Arm III includes Leu249 and Thr252. The hydrophobic tail 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 two LBP residues from Arm II, Val312 and Ile328, are key to the specificity of this ligand for PPARδ. Function PPARs are ligand-activated transcription factors. The endogenous activators for these receptors are prostaglandins and fatty acids, but synthetic ligands have also been developed for therapeutic use. 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. It is important for fatty acid metabolism, and is known to increase insulin sensitivity. Its most well-studied functions include regulation of acyl-CoA synthetase 2 expression and mediation of embryo implantation. Disease PPARδ agonists are being investigated as treatments for a number of metabolic disorders, but have not yet been deployed clinically. Though there are some health benefits associates with PPARα and γ agonists, these drugs also have undesirable side effects including such as edema and weight gain for PPARα, and carcinogenicity for PPARγ. 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.

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Adam Davis