Insights into the Mechanism of Partial Agonism: Crystal Structures of the Peroxisome Proliferator-activated Receptor-gamma Ligand-Binding Domain in the Complex with Two Enantiomeric Ligands
Poster Feb 07, 2007
Giorgio Pochetti, Cristina Godio, Nico Mitro, Donatella Caruso, Samuele Scurati, Andrea Galmozzi, Fulvio Loiodice, Giuseppe Fracchiolla, Paolo Tortorella, Antonio Laghezza, Antonio Lavecchia, Ettore Novellino, Fernando Mazza, Maurizio Crestani
The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also target of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate derivatives. In particular, we show that the R-enantiomer, is a full agonist of PPAR-gamma, whereas the S-enantiomer, is a less potent partial agonist.
These two molecules affect specifically the transcriptional activity of PPAR-alpha and gamma subtypes, whereas the activity of other members of the nuclear receptor gene superfamily is not altered. Most importantly, we report the X-ray crystal structures of the PPAR-gamma ligand binding domain respectively complexed with the R- and the S-enantiomer. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behaviour as full or partial agonist.
Measuring the 2nd Virial Coeffient and Molecular Density of Proteins to Improve CrystallizationPoster
The second virial coefficient of Human Serum Albumin (HSA) was measured using a SEC-MALS 20 detector connected to a Refractive Index concentration detector and an online differential viscometer. Two different buffer conditions, Phosphate buffer pH 7.4 and Citrate buffer pH 4.1 were used, which revealed interesting and contrasting dataREAD MORE
"In-vitro studies on hydroxamic acid- CT DNA binding"Poster
In vitro studies of five the interaction between five different derivatives of hydroxamic acids, N-phenyl 2,4dichloro phenoxybutyro, N-m-tolyl 2,4 dichlorophenoxyglutero, N-m-tolyl-4-chlorophenoxyaceto, N-m-chloro-phenyl-tertiarybutylbenzo and N-p-tolyl-iso-valero hydroxamic acids and calf thymus DNA was investigated under simulated physiological condition.READ MORE
Rapid Quantification of Proteins in Complex Matrices using the DeNovix DS11 Microvolume SpectrophotometerPoster
In this poster, we will introduce the DeNovix DS-11 as the next generation in microvolume spectrophotometry.READ MORE