Molecular modelling of the peroxisome proliferator-activated receptor alpha (PPARalpha) from human, rat and mouse, based on homology with the human PPARypsilon crystal structure
article
The generation of homology models of human, rat and mouse peroxisome proliferator-activated receptor α (PPARα) are reported, based on the recently published crystal structure of the human PPARγ ligand-binding domain (LBD) with bound ligand, rosiglitazone. It is found that a template of peroxisome proliferating fibrate drugs and related compounds can fit within the putative ligand-binding site of rat PPARα, via contacts with amino acid residues which are consistent with their biological potency for peroxisome proliferation, site-directed mutagenesis experiments and with quantitative structure-activity relationship (QSAR) analysis studies. The experimental binding affinity of leukotriene B<sub>4</sub> (LTB<sub>4</sub>) for the mouse PPARα agrees closely with the calculated value based on the modelled interactions, whereas selective PPARα ligands such as clofibric acid are able to fit the human PPARα binding site in agreement with reported site-directed mutagenesis information. © 2002 Elsevier Science Ltd. All rights reserved.
Topics
Clofibric acidLeukotriene B4Peroxisome proliferator activated receptor alphaRosiglitazoneCell receptorLigandPeroxisome proliferatorTranscription factorBinding affinityBinding siteCalculationCrystal structureHumanMolecular interactionMouseMutagenesisNonhumanProtein bindingProtein domainQuantitative structure activity relationRatSequence homologyAmino acid sequenceAnimalChemical structureChemistryClassificationCrystallizationGuinea pigMetabolismMolecular geneticsSite directed mutagenesisSpecies differenceAmino Acid SequenceAnimalBinding SitesCrystallizationGuinea PigsHumanLeukotriene B4LigandsMiceModels, MolecularMolecular Sequence DataMutagenesis, Site-DirectedPeroxisome ProliferatorsQuantitative Structure-Activity RelationshipRatsReceptors, Cytoplasmic and NuclearSequence Homology, Amino AcidSpecies SpecificitySupport, Non-U.S. Gov'tTranscription FactorsAnimalsHumans
TNO Identifier
42167
Source
Toxicology in Vitro, 16, pp. 275-280.
Pages
275-280
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