Structural basis for differential activities of enantiomeric PPARγ agonists: Binding of S35 to the alternate site

Jang, Jun Young; Koh, Minseob; Bae, Hwan; An, Doo Ri; Im, Ha Na; Kim, Hyoun Sook; Yoon, Ji Young; Yoon, Hye‐Jin; Han, Byung Woo; Park, Seung Bum; Suh, Se Won

doi:10.1016/j.bbapap.2017.03.008

Cited by 52 publications

(44 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to these 8 ligands that adopt "canonical" binding modes, Ciglitazone and Mitoglitazone, two of the least potent ligands in the series, show alternate binding modes in the chain A active conformation where their TZD head groups associate near the flexible, solvent accessible Ω-loop and their relatively shorter extended tail groups insert into the orthosteric pocket along side the β-sheet surface. Ligand binding to this alternate site has been observed in several other structural studies (Hughes et al 2014, Bae et al 2016, Hughes et al 2016, Brust et al 2017, Jang et al 2017, Laghezza et al 2018. The alternate binding modes of Ciglitazone and Mitoglitazone may originate from their lower affinity, and in the case of Ciglitazone, a lack of atoms in its shorter tail group capable of forming water-mediated polar interactions with residues in the β-sheet (Mosure et al 2019).…”

Section: Crystal Structures Provide Some Insight Into Tzd Affinity Bumentioning

confidence: 72%

Quantitative Structural Assessment of Graded Receptor Agonism

Shang

Brust

Griffin

et al. 2019

Preprint

View full text Add to dashboard Cite

Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded-efficacy receptor conformations predicted by receptor theory has been limited, but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). For all ligands, agonist efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state towards an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency is also correlated to efficacy and conformation, indicating ligand residence times among related analogs can influence receptor conformation and function. Our results derived from quantitative graded activityconformation correlations provide new experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.

show abstract

Section: Crystal Structures Provide Some Insight Into Tzd Affinity Bumentioning

confidence: 72%

Quantitative Structural Assessment of Graded Receptor Agonism

Shang

Brust

Griffin

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Alternate site binding occurs via a second molar equivalent of ligand, i.e. one bound to the orthosteric pocket and a second to the alternate site (20)(21)(22); when the orthosteric pocket is blocked by a covalent antagonist inhibitor that physically blocks the orthosteric pocket (20,22,24,25); or one equivalent through an alternate binding mode (24,25).…”

Section: Mcfas Cobound In Other Pparγ Crystal Structures Bound To Synmentioning

confidence: 99%

“…However, recent studies have shown that synthetic PPARγ ligands that were originally designed to bind to the orthosteric pocket can also bind to an alternate site (20)(21)(22)(23)(24)(25). The alternate site that partially overlaps with 1 one of the arms of the T/Y-shaped orthosteric pocket near the β-sheet surface (branch II), but it uniquely occupies space in a solvent exposed pocket formed by the flexible omega (Ω)-loop that precedes helix 3 (Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, ligands that either do not form hydrogen bonds in the helix 12/ branch I subpocket, or bind to a combination of branch II and the alternate site, can stabilize the Ω-loop region and a nearby loop. Stabilization of this region near the Ω-loop can inhibit phosphorylation of a serine residue (S273 in PPARγ isoform 1 or S245 in isoform 2) by the Cdk5 kinase and is associated with anti-diabetic efficacy (24,25,27,28).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ

Shang

Brust

Mosure

et al. 2018

Preprint

View full text Add to dashboard Cite

“…4) PPARγ partial agonists and non-agonists have similar insulin-sensitizing effects as full agonists, such as TZDs, but with fewer side effects. 5,6) The antidiabetic effects of these PPARγ ligands are primarily mediated by blocking PPARγ phosphorylation at Ser273 by CDK5, 7,8) suggesting that obesity-mediated Ser273 phosphorylation may be the casual to insulin resistance. Compounds that inhibit Ser273 phosphorylation might be potential antidiabetic drugs that target PPARγ.…”

Section: Introductionmentioning

confidence: 99%

WSF-7 Inhibits Obesity-Mediated PPARγ Phosphorylation and Improves Insulin Sensitivity in 3T3-L1 Adipocytes

Zhang

Wang

et al. 2020

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor γ (PPARγ), the molecular target for antidiabetic thiazolidinediones (TZDs), is a master regulator of preadipocyte differentiation and lipid metabolism. The adverse side effects of TZDs, arising from their potent agonistic activity, can be minimized by PPARγ partial agonists or PPARγ non-agonists without loss of insulin sensitization. In this study, we reported that WSF-7, a synthetic chemical derived from natural monoterpene α-pinene, is a partial PPARγ agonist. We found that WSF-7 binds directly to PPARγ. Activation of PPARγ by WSF-7 promotes adipogenesis, adiponectin oligomerization and insulin-induced glucose uptake. WSF-7 also inhibits obesity-mediated PPARγ phosphorylation at serine (Ser)273 and improves insulin sensitivity of 3T3-L1 adipocytes. Our study suggested that WSF-7 activates PPARγ transcription by a mechanism different from that of rosiglitazone or luteolin. Therefore, WSF-7 might be a potential therapeutic drug to treat type 2 diabetes.

show abstract

Structural basis for differential activities of enantiomeric PPARγ agonists: Binding of S35 to the alternate site

Cited by 52 publications

References 35 publications

Quantitative Structural Assessment of Graded Receptor Agonism

Quantitative Structural Assessment of Graded Receptor Agonism

Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ

WSF-7 Inhibits Obesity-Mediated PPARγ Phosphorylation and Improves Insulin Sensitivity in 3T3-L1 Adipocytes

Contact Info

Product

Resources

About