Dataset Information

Activation of PPAR?: from computer modelling to biological effects.

ABSTRACT: PPAR? is a ligand-activated receptor that dimerizes with another nuclear receptor of the retinoic acid receptor family. The dimers interact with other co-activator proteins and form active complexes that bind to PPAR response elements and promote transcription of genes involved in lipid metabolism. It appears that various natural fatty acids and their metabolites serve as endogenous activators of PPAR?; however, there is no consensus in the literature on the nature of the prime activators of the receptor. In vitro and cell-based assays of PPAR? activation by fatty acids and their derivatives often produce conflicting results. The search for synthetic and selective PPAR? agonists, which may be pharmacologically useful, is intense. Current rational modelling used to obtain such compounds relies mostly on crystal structures of synthetic PPAR? ligands with the recombinant ligand binding domain (LBD) of the receptor. Here, we introduce an original computational prediction model for ligand binding to PPAR? LBD. The model was built based on EC50 data of 16 ligands with available crystal structures and validated by calculating binding probabilities of 82 different natural and synthetic compounds from the literature. These compounds were independently tested in cell-free and cell-based assays for their capacity to bind or activate PPAR?, leading to prediction accuracy of between 70% and 93% (depending on ligand type). This new computational tool could therefore be used in the search for natural and synthetic agonists of the receptor.

SUBMITTER: Kahremany S

PROVIDER: S-EPMC4301687 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Activation of PPARδ: from computer modelling to biological effects.

Kahremany Shirin S Livne Ariela A Gruzman Arie A Senderowitz Hanoch H Sasson Shlomo S

British journal of pharmacology 20141215 3

PPARδ is a ligand-activated receptor that dimerizes with another nuclear receptor of the retinoic acid receptor family. The dimers interact with other co-activator proteins and form active complexes that bind to PPAR response elements and promote transcription of genes involved in lipid metabolism. It appears that various natural fatty acids and their metabolites serve as endogenous activators of PPARδ; however, there is no consensus in the literature on the nature of the prime activators of the ...[more]

PMID: 25255770

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Project description:Body mass reconstructions of extinct vertebrates are most robust when complete to near-complete skeletons allow the reconstruction of either physical or digital models. Digital models are most efficient in terms of time and cost, and provide the facility to infinitely modify model properties non-destructively, such that sensitivity analyses can be conducted to quantify the effect of the many unknown parameters involved in reconstructions of extinct animals. In this study we use laser scanning (LiDAR) and computer modelling methods to create a range of 3D mass models of five specimens of non-avian dinosaur; two near-complete specimens of Tyrannosaurus rex, the most complete specimens of Acrocanthosaurus atokensis and Strutiomimum sedens, and a near-complete skeleton of a sub-adult Edmontosaurus annectens. LiDAR scanning allows a full mounted skeleton to be imaged resulting in a detailed 3D model in which each bone retains its spatial position and articulation. This provides a high resolution skeletal framework around which the body cavity and internal organs such as lungs and air sacs can be reconstructed. This has allowed calculation of body segment masses, centres of mass and moments or inertia for each animal. However, any soft tissue reconstruction of an extinct taxon inevitably represents a best estimate model with an unknown level of accuracy. We have therefore conducted an extensive sensitivity analysis in which the volumes of body segments and respiratory organs were varied in an attempt to constrain the likely maximum plausible range of mass parameters for each animal. Our results provide wide ranges in actual mass and inertial values, emphasizing the high level of uncertainty inevitable in such reconstructions. However, our sensitivity analysis consistently places the centre of mass well below and in front of hip joint in each animal, regardless of the chosen combination of body and respiratory structure volumes. These results emphasize that future biomechanical assessments of extinct taxa should be preceded by a detailed investigation of the plausible range of mass properties, in which sensitivity analyses are used to identify a suite of possible values to be tested as inputs in analytical models.

Dataset Information

Activation of PPAR?: from computer modelling to biological effects.

Publications

Activation of PPARδ: from computer modelling to biological effects.

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