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 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 A Molecular Dynamics Approach to Explore the Intramolecular Signal Transduction of PPAR-α

2019 ◽  
Vol 20 (7) ◽  
pp. 1666 ◽  
Author(s):  
Shaherin Basith ◽  
Balachandran Manavalan ◽  
Tae Shin ◽  
Gwang Lee
Keyword(s):  
Molecular Dynamics ◽  
Bound States ◽  
Structural Information ◽  
Peroxisome Proliferator ◽  
Structural Variations ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Dynamics Analyses ◽  
Signal Transductions

Dynamics and functions of the peroxisome proliferator-activated receptor (PPAR)-α are modulated by the types of ligands that bind to the orthosteric sites. While several X-ray crystal structures of PPAR-α have been determined in their agonist-bound forms, detailed structural information in their apo and antagonist-bound states are still lacking. To address these limitations, we apply unbiased molecular dynamics simulations to three different PPAR-α systems to determine their modulatory mechanisms. Herein, we performed hydrogen bond and essential dynamics analyses to identify the important residues involved in polar interactions and conformational structural variations, respectively. Furthermore, betweenness centrality network analysis was carried out to identify key residues for intramolecular signaling. The differences observed in the intramolecular signal flow between apo, agonist- and antagonist-bound forms of PPAR-α will be useful for calculating maps of information flow and identifying key residues crucial for signal transductions. The predictions derived from our analysis will be of great help to medicinal chemists in the design of effective PPAR-α modulators and additionally in understanding their regulation and signal transductions.

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