4BCR

Structure of PPARalpha in complex with WY14643

Summary for 4BCR

• Entry DOI: 10.2210/pdb4bcr/pdb
• Related: 1I7G 1K7L 1KKQ
• Descriptor: PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA, 1,2-ETHANEDIOL, 2-({4-CHLORO-6-[(2,3-DIMETHYLPHENYL)AMINO]PYRIMIDIN-2-YL}SULFANYL)ACETIC ACID, ... (4 entities in total)
• Functional Keywords: transcription, nuclear receptor, ppar, fibrate
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: Q07869
• Total number of polymer chains: 2
• Total formula weight: 63451.59

Authors

Bernardes, A.,Muniz, J.R.C.,Polikarpov, I. (deposition date: 2012-10-02, release date: 2013-05-29, Last modification date: 2024-05-08)

Primary citation

Bernardes, A.,T Souza, P.C.,Muniz, J.R.C.,Ricci, C.G.,Ayers, S.D.,Parekh, N.M.,Godoy, A.S.,Trivella, D.B.B.,Reinach, P.,Webb, P.,Skaf, M.S.,Polikarpov, I.
Molecular Mechanism of Peroxisome Proliferator-Activated Receptor Alpha Activation by Wy14643: A New Mode of Ligand Recognition and Receptor Stabilization
J.Mol.Biol., 425:2878-, 2013

PubMed Abstract: Peroxisome 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. PPARα 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 PPARα 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 PPARα 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 PPARα was associated with antiinflammatory disease in a human corneal cell model, suggesting possible applications for PPARα ligands.

PubMed: 23707408
DOI: 10.1016/J.JMB.2013.05.010

Experimental method

X-RAY DIFFRACTION (2.497 Å)