Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

Abstract

The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ ligand-binding domain (LBD). A combination of atomic-resolution protein X-ray crystallographic structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineate structure-activity relationships (SARs) for PPARδ-selective targeting and structural modulation. We identify key ligand-induced conformational transitions of a conserved tryptophan side chain in the LBD that trigger reorganization of the H2′-H3 surface segment of PPARδ. The subtype-specific conservation of H2′-H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.nuclear receptors | drug discovery | structure-based design | peroxisome proliferator-activated receptor | cation-π interaction

The Interplay of Genetics and Environmental Factors in the Development of Obesity

“…Fenofibrate is an antilipemic agent that is an agonist for PPARα which results in increased fatty acid oxidation, triglyceride elimination, an upregulation of lipoprotein lipase activity and very low-density lipoprotein (VLDL) catabolism. Also, mice with absent PPARα became obese with age as compared to the mice that had PPARα [ 27 - 28 ]. Medium-chain fatty acids (saturated and unsaturated) are the ligands for PPARα which stimulates the increased expression of genes encoding enzymes for β-oxidation of fatty acids in mitochondria.…”

Rationally designed PPARδ-specific agonists and their therapeutic potential for metabolic syndrome

“…Wu et al (5) rationally designed ligands to occupy both of these arms of PPARδ, focusing on interacting with residues not shared with the α-and γ-types in a successful attempt to improve the specificity of their compounds. Similar to the GW501516 compound, their ligands all have a carboxyl head group, which interacts with the AF-2 region, but their ligands are an order-of-magnitude more selective for PPARδ than previous compounds.…”

“…The loop is so flexible as to be almost disordered in some structures, and is difficult enough to model that it is missing from many available crystal structures of PPAR nuclear receptor LBDs. Through comparing structures of PPARδ bound to conformationally distinct ligands, Wu et al (5) have found a tryptophan residue in this loop region that dramatically changes conformation upon binding of different ligands. The authors posit that the resulting change in conformation because of the bulkiness of the ligand tail is a mechanism of ligand selectivity by which PPAR nuclear receptors may bind to distinct ligands.…”

The Role of PPAR-δ in Metabolism, Inflammation, and Cancer: Many Characters of a Critical Transcription Factor

“…Although PPAR-δ has a narrower LBD relative to PPARs-α and-γ, binding pocket characteristics allow potential interaction with a variety of ligands, albeit many appear to bind at relatively low affinities [ 13 ]. While many potential endogenous ligands have been suggested in the literature, there is still some uncertainty about the physiological significance [ 14 ]. Selective ligands targeting PPAR-δ have also been developed, although none have been approved for clinical use to date [ 14 , 15 ].…”

“…While many potential endogenous ligands have been suggested in the literature, there is still some uncertainty about the physiological significance [ 14 ]. Selective ligands targeting PPAR-δ have also been developed, although none have been approved for clinical use to date [ 14 , 15 ].…”