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.
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.
Montanari
Roberta
R
Consiglio Nazionale delle Ricerche, Roma 00016, Italy.
Saccoccia
Fulvio
F
Scotti
Elena
E
Crestani
Maurizio
M
Godio
Cristina
C
Gilardi
Federica
F
Loiodice
Fulvio
F
Fracchiolla
Giuseppe
G
Laghezza
Antonio
A
Tortorella
Paolo
P
Lavecchia
Antonio
A
Novellino
Ettore
E
Mazza
Fernando
F
Aschi
Massimiliano
M
Pochetti
Giorgio
G
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
C000589034:2-(4-phenylphenoxy)-3-phenylpropanoic acid; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates