Structural Insight into PPARγ Ligands Binding

Abstract

Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetic efforts, more particularly PPARgamma. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARgamma.

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…DNA fragmentation assay was carried out treating HT-29 cells with 20 lM cladosporol A and, simultaneously, with 5 lM cladosporol B for different times (12,24,48 and 72 h). After treatment, the cells were harvested and washed with 1 ml of PBS, resuspended in 100 ll of PBS.…”

“…To investigate whether cladosporol B is endowed with antiproliferative activity as cladosporol A, we assessed the growth of colon carcinoma HT-29 cells treated for different time points (24,48 [7]. To confirm these results, we treated HT-29 cells with increasing concentrations of cladosporol B or A for 8, 24, 48 and 72 h and counted the surviving cells.…”

“…PPARc full agonists, such as TZDs, generally engage canonical H-bonds with the three residues H323, H449, and Y473 on the inner surface of helix 12 (H12). These interactions stabilize H12 and are responsible for PPARc transactivation [47,48]. The 5-OH-dihydronaphthalenone moiety of 2A is deeply inserted into a specific pocket of the LBD, previously named ''diphenyl pocket" [35] thereby forming several favorable hydrophobic interactions.…”

Structural insights for the design of new PPARgamma partial agonists with high binding affinity and low transactivation activity

“…Analyses of a large number of crystallographic structures of the PPARc ligand-binding domain (LBD) bound to an agonist have revealed that PPARc has at least two binding modes in a single binding site. These two binding modes correspond to full and partial agonists [9]. The binding pocket of PPARc has a Y-shaped form, consisting of an entrance (arm III) that branches off into two pockets.…”

“…Arm I is the only substantially polar cavity of the PPARc ligand-binding domain, whereas arms II and III are mainly hydrophobic [10]. Full agonists occupy arm I, making a net of hydrogen bonds with the side chains of Ser289, His323, His449 and Tyr473 [9,11]. These interactions stabilize H12 and are responsible for the transactivation activity of PPARc [9,11].…”