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

2018 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A. Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Endogenous Ligand ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a “ligand link” to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Cellular Assays ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a ‘ligand link’ to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals Investigations on Binding Pattern of Kinase Inhibitors with PPARγ: Molecular Docking, Molecular Dynamic Simulations, and Free Energy Calculation Studies

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Mohit Mazumder ◽  
Prija Ponnan ◽  
Umashankar Das ◽  
Samudrala Gourinath ◽  
Haseeb Ahmad Khan ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Kinase Inhibitors ◽  
Energy Calculation ◽  
Peroxisome Proliferator ◽  
Dynamic Simulations ◽  
Peroxisome Proliferator Activated Receptor ◽  
Predictive Values ◽  
Dynamics Simulations

Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential target for the treatment of several disorders. In view of several FDA approved kinase inhibitors, in the current study, we have investigated the interaction of selected kinase inhibitors with PPARγusing computational modeling, docking, and molecular dynamics simulations (MDS). The docked conformations and MDS studies suggest that the selected KIs interact with PPARγin the ligand binding domain (LBD) with high positive predictive values. Hence, we have for the first time shown the plausible binding of KIs in the PPARγligand binding site. The results obtained from these in silico investigations warrant further evaluation of kinase inhibitors as PPARγligands in vitro and in vivo.

scholarly journals Mechanisms of Peroxisome Proliferator Activated Receptor γ Regulation by Non-steroidal Anti-inflammatory Drugs

2015 ◽  
Vol 13 (1) ◽  
pp. nrs.13004 ◽  
Author(s):  
Ana C. Puhl ◽  
Flora A. Milton ◽  
Aleksandra Cvoro ◽  
Douglas H. Sieglaff ◽  
Jéssica C.L. Campos ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Target Genes ◽  
Partial Agonist ◽  
High Dose ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sulindac Sulfide ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

scholarly journals A structural mechanism for directing inverse agonism of PPARγ

2018 ◽  
Author(s):  
Richard Brust ◽  
Jinsai Shang ◽  
Jakob Fuhrmann ◽  
Jared Bass ◽  
Andrew Cano ◽  
...  
Keyword(s):  
Bound State ◽  
Inverse Agonist ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Structural Mechanism ◽  
X Ray Crystallography ◽  
Inverse Agonism ◽  
Orthosteric Ligands ◽  
Dynamics Simulations ◽  
Structural Mechanisms

AbstractSmall chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor gamma (PPARγ) converts a transcriptionally neutral antagonist (GW9662) into an inverse agonist (T0070907). X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide new routes for developing PPARγ inverse agonist.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

scholarly journals Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0151412 ◽  
Author(s):  
Rico Schwarz ◽  
Dirk Tänzler ◽  
Christian H. Ihling ◽  
Andrea Sinz
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Solution Structures

scholarly journals The Potential Applications of Peroxisome Proliferator-Activated ReceptorδLigands in Assisted Reproductive Technology

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Jaou-Chen Huang
Keyword(s):  
Assisted Reproductive Technology ◽  
Reproductive Function ◽  
Reproductive Technology ◽  
Embryonic Cell ◽  
Preimplantation Embryos ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Potential Applications ◽  
And Function

Peroxisome proliferator-activated receptorδ(PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδwas first revealed in the uterus at the implantation site. Since then, PPARδand its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδin preimplantation embryos is normally activated by oviduct-derived PPARδligand. PPARδactivation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδand its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδand project its potential applications in assisted reproductive technology.

Abstract 126: Peroxisomal Proliferator Activated Receptor Alpha Overexpression in Hypertrophied Cardiomyocytes Restores Mitochondrial Integrity and Function

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Santanu Rana
Keyword(s):  
Energy Demand ◽  
Cardiac Tissue ◽  
Structural Integrity ◽  
Heart Function ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Production ◽  
Receptor Alpha ◽  
And Function

Cardiac tissue engineering is an interdisciplinary field that engineers modulation of viable molecular milieu to restore, maintain or improve heart function. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux to maintain specialized cellular processes, yet the heart has a limited capacity for substrate storage and utilization during pathophysiological conditions. Damage to heart muscle, acute or chronic, leads to dysregulation of cardiac metabolic processes associated with gradual but progressive decline in mitochondrial respiratory pathways resulting in diminished ATP production. The Peroxisome Proliferator Activated Receptor Alpha ( PPARα ) is known to regulate fatty acid to glucose metabolic balance as well as mitochondrial structural integrity. In this study, a non-canonical pathway of PPARα was analyzed by cardiomyocyte targeted PPARα overexpression during cardiac hypertrophy that showed significant downregulation in p53 acetylation as well as GSK3β activation levels. Targeted PPARα overexpression during hypertrophy resulted in restoration of mitochondrial structure and function along with significantly improved mitochondrial ROS generation and membrane potential. This is the first report of myocyte targeted PPARα overexpression in hypertrophied myocardium that results in an engineered heart with significantly improved function with increased muscle mitochondrial endurance and reduced mitochondrial apoptotic load, thus conferring a greater resistance to pathological stimuli within cardiac microenvironment.

Abstract 12555: The Dual PPAR-α/γ Agonist Aleglitazar Enhances Arteriogenesis, Angiogenesis and Endothelial Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Christian Werner ◽  
Stephan H Schirmer ◽  
Valerie Pavlickova ◽  
Michael Böhm ◽  
Ulrich Laufs
Keyword(s):  
Endothelial Function ◽  
Vascular Function ◽  
Daily Injection ◽  
Peroxisome Proliferator ◽  
Fluorescent Microspheres ◽  
Artery Ligation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
And Function

Objective: Peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists modify lipid and glucose metabolism. The aim of the study was to characterize the effects of the dual PPAR-α/γ agonist aleglitazar on endothelial function, neoangiogenesis and arteriogenesis in mice and on human endothelial progenitor cells (EPC). Methods and Results: Male C57Bl/6 wild-type (WT, normal chow) and apolipoprotein E-deficient (apoE-/-) mice on Western-type diet (WTD) were treated with aleglitazar (10 mg/kg i.p.) or vehicle by daily injection. Hindlimb ischemia was induced by right femoral artery ligation (FAL). ApoE-/- mice on WTD treated with aleglitazar before FAL were characterized by an improvement of endothelial-dependent laser Doppler perfusion (right/left foot ratio 0.40±0.03) 1 week after FAL compared to controls (R/L foot ratio 0.24±0.01; p<0.001). Collateral-dependent perfusion measured under conditions of maximal vasodilatation 1 week after FAL using fluorescent microspheres was impaired in apoE-/- on WTD compared to WT mice (R/L leg ratio in WT 78±13 vs. apoE-/- 56±6; p<0.001) and was normalized by aleglitazar treatment. Neoangiogenesis was measured in-vivo by subcutaneously implanting discs covered with cell-impermeable filters. The vascularized area of the discs was quantified after 14 days by perfusion of the animals with space-filling fluorescent microspheres. Aleglitazar increased neoangiogenesis in WT mice by 178±18% compared to vehicle (p<0.05). Endothelium-dependent relaxation of aortic rings was impaired in apoE-/- mice on WTD for 6 weeks (relaxation to 52±5% of max. contraction) compared to WT animals (relaxation to 18±5% of max. contraction) (p<0.001). Aleglitazar treatment improved endothelial function (relaxation to 39±5% of max. contraction; p<0.05). In parallel, number and function of EPC were improved in mice. Studies in human EPC showed that 1) aleglitazar’s effects were mediated by both PPAR-α and -γ signalling and Akt and 2) migration and colony forming units were up-regulated by aleglitazar in cultivated EPC from CAD patients. Conclusion: The study provides evidence for beneficial effects of the dual PPAR-α/γ agonist aleglitazar on vascular function in addition to or mediated by its metabolic actions.

Sex hormones influence expression and function of peroxisome proliferator-activated receptor γ in adipocytes: pathophysiological aspects

2014 ◽  
Vol 20 (2) ◽  
Author(s):  
Hiromi Sato ◽  
Momoko Ishikawa ◽  
Hana Sugai ◽  
Asami Funaki ◽  
Yuki Kimura ◽  
...  
Keyword(s):  
Sex Hormones ◽  
Metabolic Diseases ◽  
Fat Distribution ◽  
Inflammatory Factors ◽  
Peroxisome Proliferator ◽  
Metabolic Homeostasis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Post Menopausal ◽  
And Function

AbstractAdipose tissue plays important roles not only in storing fat but also in maintaining metabolic homeostasis by regulating hundreds of biological signaling events and the secretion of various cytokines. One of the central regulators of adipocyte differentiation is peroxisome proliferator-activated receptor γ (PPARγ), which promotes downstream transcriptional activities, such as adiponectin. Disruption of homeostasis leads to the onset of metabolic diseases such as type 2 diabetes and other triggers for metabolic syndrome. Males and post-menopausal females are more likely to be affected with metabolic diseases than pre-menopausal females, suggesting that sex hormones might be involved in the pathogenesis and development of metabolic diseases. Indeed, 17β-estradiol, testosterone, dihydrotestosterone, and their receptors clearly play a role in adipose regulation: they can alter fat distribution and can modify the expression and activities of PPARγ and its downstream adipocytokines. Furthermore, sex hormones affect inflammatory factors such as nitric oxygen, nitric oxygen synthase, and their surrounding components. Sex hormones are also suggested to be involved with sex differences in the efficacy of the PPARγ agonist thiazolidinediones. Therefore, thorough investigation of how sex hormone-dependent regulation of metabolic homeostasis occurs is necessary in order to develop individualized clinical therapies optimized with regard to each patient’s biological condition and drug sensitivities.

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