Molecular Mechanism of Peroxisome Proliferator-Activated Receptor ¦Á Activation by WY14643: a New Mode of Ligand Recognition and Receptor Stabilization
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- 作者：Am ; a Bernardes ; Paulo C.T. Souza ; Jo?o R.C. Muniz ; Clarisse G. Ricci ; Stephen D. Ayers ; Nili M. Parekh ; Andr¨¦ S. Godoy ; Daniela B.B. Trivella ; Peter Reinach ; Paul Webb ; Munir S. Skaf ; Igor Polikarpov
- 关键词：PPAR ; peroxisome proliferator-activated receptor ; DBD ; DNA-binding domain ; LBD ; ligand-binding domain ; AF-2 ; activation function 2 ; MD ; molecular dynamics ; RMSF ; root-mean-square fluctuation ; PBS ; phosphate-buffered saline ; PCA ; principal component analys
- 刊名：Journal of Molecular Biology
- 出版年：2013
- 出版时间：23 August, 2013
- 年：2013
- 卷：425
- 期：16
- 页码：2878-2893
- 全文大小：2548 K
文摘
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. PPAR¦Á 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¦Á 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¦Á 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¦Á was associated with antiinflammatory disease in a human corneal cell model, suggesting possible applications for PPAR¦Á ligands.