Molecular Mechanism of Peroxisome Proliferator-Activated Receptor alpha Activation by WY14643: a New Mode of Ligand Recognition and Receptor Stabilization

dc.creatorBernardes, A
dc.creatorSouza, PCT
dc.creatorMuniz, JRC
dc.creatorRicci, CG
dc.creatorAyers, SD
dc.creatorParekh, NM
dc.creatorGodoy, AS
dc.creatorTrivella, DBB
dc.creatorReinach, P
dc.creatorWebb, P
dc.creatorSkaf, MS
dc.creatorPolikarpov, I
dc.date2013
dc.dateAUG 23
dc.date2014-07-30T14:03:44Z
dc.date2015-11-26T17:40:45Z
dc.date2014-07-30T14:03:44Z
dc.date2015-11-26T17:40:45Z
dc.date.accessioned2018-03-29T00:22:29Z
dc.date.available2018-03-29T00:22:29Z
dc.identifierJournal Of Molecular Biology. Academic Press Ltd- Elsevier Science Ltd, v. 425, n. 16, n. 2878, n. 2893, 2013.
dc.identifier0022-2836
dc.identifierWOS:000323094000005
dc.identifier10.1016/j.jmb.2013.05.010
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/57790
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/57790
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1286821
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionPeroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear transcription factors. They are involved in mediating numerous physiological effects in humans, including glucose and lipid metabolism. PPAR alpha ligands effectively treat dyslipidemia and have significant antiinflammatory and anti-atherosclerotic activities. These effects and their ligand-dependent activity make nuclear receptors obvious targets for drug design. Here, we present the structure of the human PPAR alpha in complex with WY14643, a member of fibrate class of drug, and a widely used PPAR activator. The crystal structure of this complex suggests that WY14643 induces activation of PPAR alpha in an unusual bipartite mechanism involving conventional direct helix 12 stabilization and an alternative mode that involves a second ligand in the pocket. We present structural observations, molecular dynamics and activity assays that support the importance of the second site in WY14643 action. The unique binding mode of WY14643 reveals a new pattern of nuclear receptor ligand recognition and suggests a novel basis for ligand design, offering clues for improving the binding affinity and selectivity of ligand. We show that binding of WY14643 to PPAR alpha was associated with antiinflammatory disease in a human corneal cell model, suggesting possible applications for PPAR alpha ligands. (C) 2013 Elsevier Ltd. All rights reserved.
dc.description425
dc.description16
dc.description2878
dc.description2893
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionNational Institutes of Health [DK41482]
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionNational Institutes of Health [DK41482]
dc.languageen
dc.publisherAcademic Press Ltd- Elsevier Science Ltd
dc.publisherLondon
dc.publisherInglaterra
dc.relationJournal Of Molecular Biology
dc.relationJ. Mol. Biol.
dc.rightsfechado
dc.rightshttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.sourceWeb of Science
dc.subjectPPAR alpha
dc.subjectcrystal structure
dc.subjectprotein and ligand interaction
dc.subjectdry eye disease
dc.subjectmolecular dynamics
dc.subjectThyroid-hormone Receptors
dc.subjectPpar-gamma Ligand
dc.subjectRetinoic Acid Receptor
dc.subjectDynamics Simulations
dc.subjectBinding Domain
dc.subjectAlpha/gamma Agonists
dc.subjectInflammation Control
dc.subjectStructural Basis
dc.subjectDual Agonists
dc.subjectSelectivity
dc.titleMolecular Mechanism of Peroxisome Proliferator-Activated Receptor alpha Activation by WY14643: a New Mode of Ligand Recognition and Receptor Stabilization
dc.typeArtículos de revistas


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