title: Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.
abstract: The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARgamma, and provide an explanation on a molecular basis for their different potency and efficacy against PPARgamma. The more potent S-enantiomer is a dual PPARalpha/PPARgamma agonist which presents a partial agonism profile against PPARgamma. Docking of the S-enantiomer in the PPARalpha-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARgamma-LBD never sampled before by other ligands.
authors.affiliation: Consiglio Nazionale delle Ricerche, Roma 00016, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Montanari
authors.forename: Fulvio
authors.initials: F
authors.lastname: Saccoccia
authors.forename: Elena
authors.initials: E
authors.lastname: Scotti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.forename: Cristina
authors.initials: C
authors.lastname: Godio
authors.forename: Federica
authors.initials: F
authors.lastname: Gilardi
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Fernando
authors.initials: F
authors.lastname: Mazza
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Aschi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pochetti
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D047493:PPAR alpha / Q000737:chemistry / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: C000589034:2-(4-phenylphenoxy)-3-phenylpropanoic acid; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates