Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

Abstract

Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.

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

“…3 B and C), and similarly impacted the binding of compounds 1-8 and 10-16 (SI Appendix, Fig. S7), consistent with previous reports (37). V312 resides at the end of arm II in hPPARδ, whereas hPPARα and hPPARγ have methionines at the equivalent positions.…”

Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

“…Introduction of smaller, monocyclic aromatic moieties as acyl substituents such as a 4-tert-butylbenzoyl (22) or a 4-ethylbenzoyl residue (23) strongly diminished the activity on PPARγ while 23 exhibited moderate PPARα agonistic activity. Since PPARγ activity seemed to require large aromatic substituents, we investigated the activity of biphenyl residues (24)(25)(26) as acyl substituents which were all inactive on FXR but showed partial to superagonistic activity on PPARγ. 4-biphenyl derivative 24 activated PPARγ with the lowest EC 50 amongst the biphenyl isomers while moving the phenyl substituent to 3-position in 25 increased maximum relative activation.…”

“…The cterminal arm I is highly conserved over all PPAR subtypes and offer a hydrogen bond network that complexes the carboxylate group of fatty acids and many synthetic ligands. [23][24][25][26] Arm II and arm III are mainly hydrophobic and contain the less conserved amino acids regarding the PPAR subtypes. Subtype selectivity therefore predominantly has to rely on different interactions with these regions of the ligand binding pocket.…”

“…Subtype selectivity therefore predominantly has to rely on different interactions with these regions of the ligand binding pocket. According to Fernanda et al [26], subtype selectivity for PPARδ can be achieved especially via the hydrophobic tail of ligands. They suggest that large and bulky lipophilic substituents with short linkers improve the selectivity for PPARδ since there are two lipophilic amino acids in arm II of the ligand binding pocket that differ from subtype to subtype.…”

New PPARα/γ/δ Optimal Activator Rationally Designed by Computational Methods

“…20 Some PPAR pan agonists have entered clinical trials and show a promising field of research in the development of new drugs to treat metabolic syndrome. [21][22][23] In this study, we aimed to propose new drug candidates for the treatment of the metabolic syndrome originated from type 2 diabetes. For that, we studied available PPARγ ligands in order to determine their pharmacophore groups through PharmaGist Server.…”