Insights into Dynamic Mechanism of Ligand Binding to Peroxisome Proliferator-Activated Receptor γ toward Potential Pharmacological Applications

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, which regulates the transcription of a variety of genes involved in lipid and glucose metabolism, inflammation, and cell proliferation. These functions correlate with the onset of type-2 diabetes, obesity, and immune disorders, which makes PPARγ a promising target for drug development. The majority of PPARγ functions are regulated by binding of small molecule ligands, which cause conformational changes of PPARγ followed by coregulator recruitment. The ligand-binding domain (LBD) of PPARγ contains a large Y-shaped cavity that can be occupied by various classes of compounds such as full agonists, partial agonists, natural lipids, and in some cases, a combination of multiple molecules. Several crystal structure studies have revealed the binding modes of these compounds in the LBD and insight into the resulting conformational changes. Notably, the apo form of the PPARγ LBD contains a highly mobile region that can be stabilized by ligand binding. Furthermore, recent biophysical investigations have shed light on the dynamic mechanism of how ligands induce conformational changes in PPARγ and result in functional output. This information may be useful for the design of new and repurposed structures of ligands that serve a different function from original compounds and more potent pharmacological effects with less undesirable clinical outcomes. This review provides an overview of the peculiar characteristics of the PPARγ LBD by examining a series of structural studies focused on the dynamic mechanism of binding and the potential applications of strategies for ligand screening and chemical labeling.

Valerenic Acid Promotes Adipocyte Differentiation, Adiponectin Production, and Glucose Uptake via Its PPARγ Ligand Activity

“…For example, MRL24 that binds near the Ω loop pocket ameliorated high-fat diet (HFD)-induced diabetes . A synthetic ligand S35 that binds hydrogen to Leu270 and Gln 283 in the Ω loop pocket inhibited the phosphorylation of Ser245 in PPARγ by the cyclin-dependent kinase 5, and the resulting effect is associated with diabetic profiles . Therefore, it is likely that VA harbors similar positive effect on diabetes as a partial agonist by inducing the binding of PPARγ to the Ω loop pocket.…”

“…PPARγ has two large ligand-binding pockets (LBPs) of approximately 1300–1440 Å and can bind to various types of ligands. , PPARγ LBPs are Y-shaped, and each sub-pocket is known as activation function-2 (AF2) (the canonical LBP) pocket adjacent to Helix (H) 12 and the Ω loop pocket located near H2’. Thiazolidinediones (TZDs) are active PPARγ full agonists, which bind to His 323, His 449, and Tyr 473 on the AF2 surface via a hydrogen bond, resulting in the stabilization of the AF2 region in PPARγ. , The stabilization of the AF2 region facilitates the association of co-activators containing LXXLL motif, such as steroid receptor co-activating factor and PPARγ co-activator-1α, thereby activating the transcriptional activity of PPARγ. , However, the transcriptional activation of PPARγ is inhibited by covalent antagonists, such as GW9662 and T0070907, due to the close proximity of their binding sites to Cys285 in H3. In contrast, since partial agonists, including indomethacin and 5-methoxy-indole acetate, can bind near AF2 and the Ω loop without Cys285, their transcriptional activation of PPARγ is not blocked by these covalent antagonists .…”

“… 31 , 32 The stabilization of the AF2 region facilitates the association of co-activators containing LXXLL motif, such as steroid receptor co-activating factor and PPARγ co-activator-1α, thereby activating the transcriptional activity of PPARγ. 28 , 32 However, the transcriptional activation of PPARγ is inhibited by covalent antagonists, such as GW9662 and T0070907, 33 due to the close proximity of their binding sites to Cys285 in H3. In contrast, since partial agonists, including indomethacin and 5-methoxy-indole acetate, can bind near AF2 and the Ω loop without Cys285, their transcriptional activation of PPARγ is not blocked by these covalent antagonists.…”

“…Thiazolidinediones (TZDs) are active PPARγ full agonists, which bind to His 323, His 449, and Tyr 473 on the AF2 surface via a hydrogen bond, resulting in the stabilization of the AF2 region in PPARγ. 31 , 32 The stabilization of the AF2 region facilitates the association of co-activators containing LXXLL motif, such as steroid receptor co-activating factor and PPARγ co-activator-1α, thereby activating the transcriptional activity of PPARγ. 28 , 32 However, the transcriptional activation of PPARγ is inhibited by covalent antagonists, such as GW9662 and T0070907, 33 due to the close proximity of their binding sites to Cys285 in H3.…”

Roles of PPARα and PPARγ As Regulator of Free Fatty Acids in Nonalcoholic Steatohepatitis

“…The A/B domain, which is the least conserved domain among PPARs, harbors a ligand-independent activation function-1 (AF-1) region. The DBD, which is highly conserved and rich in cysteine and basic amino acids, consists of two zinc-finger binding motifs [15]. The domain is responsible for physical interaction with DNA.…”