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Human PPAR delta ligand binding domain in complex with a synthetic agonist TIPP401Human PPAR delta ligand binding domain in complex with a synthetic agonist TIPP401
Structural highlights
FunctionPPARD_HUMAN Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPeroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARalpha and PPARgamma LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD-ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARdelta LBD in complex with an alpha/delta-selective ligand, TIPP-401, and with a related delta-specific ligand, TIPP-204, were also determined. The comparison between the two PPARdelta complexes revealed how each ligand exhibits either a ;dual selective' or ;single specific' binding mode. Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures.,Oyama T, Toyota K, Waku T, Hirakawa Y, Nagasawa N, Kasuga JI, Hashimoto Y, Miyachi H, Morikawa K Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):786-95. Epub 2009, Jul 10. PMID:19622862[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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