title: Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode.
abstract: The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015 Monterotondo Stazione, Roma, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Capelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli, Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015 Monterotondo Stazione, Roma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Montanari
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E.Orabona 4, 70126 Bari, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E.Orabona 4, 70126 Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E.Orabona 4, 70126 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Università di Roma "La Sapienza", Piazzale A. Moro 5, 00185 Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cervoni
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, 00015 Monterotondo Stazione, Roma, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Pochetti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli, Via Montesano 49, 80131 Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
mesh_terms: D001665:Binding Sites; D002152:Calorimetry, Differential Scanning; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D011487:Protein Conformation; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009281:Naphthalenes; D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; C006253:pirinixic acid