The conserved residue Phe273(282) of PPAR alpha(gamma), beyond the ligand-binding site, functions in binding affinity through solvation effect
文献类型：期刊论文
| 作者 | Yue, LD; Ye, F; Xu, XY; Shen, JH ; Chen, KX; Shen, X; Jiang, HL
|
| 刊名 | BIOCHIMIE
 |
| 出版日期 | 2005-06 |
| 卷号 | 87期号:6页码:539-550 |
| 关键词 | peroxisome proliferator-activated receptor (PPAR) mutation ligand-binding affinity solvation effect molecular dynamics surface plamon resonance (SPR) transcriptional activation |
| ISSN号 | 0300-9084 |
| DOI | 10.1016/j.biochi.2005.02.002 |
| 文献子类 | Article |
| 英文摘要 | Peroxisome proliferator-activated receptors (PPARs) belong to the members of the nuclear receptor superfamily, and play important roles in lipid and glucose homeostasis. Residue Phe282 in PPAR gamma (Phe273 in PPAR alpha), beyond the ligand-binding site, is a conserved amino acid across several nuclear receptors and in all PPAR subfamily. In this work, we firstly investigated the influence of Phe282(273)Ala mutation on the binding affinity of PPAR gamma(alpha) against a series of agonists by use of surface plasmon resonance (SPR) technique and cellular transcriptional activation analysis. Phe282(273)Ala mutation decreases the binding affinities of the ligands to the receptors in certain degrees, from several to 1000-folds. Phe282Ala mutation dramatically reduced the binding affinity of PPAR gamma to GI262570, however, this mutation did not affect PPAR alpha binding to this ligand, thereby suggesting that the Phe282 and Phe273 are associated with the selectivity of GI262570 binding to PPAR gamma and PPAR alpha. The mutation reduced the transcriptional activation activities of the receptors induced by the ligand binding, and the decrease degree is generally in agreement with the binding affinities of the ligands to the receptors. The 5 ns MD simulations for the wild-type and mutated PPAR gamma showed that the mutation did not influence the flexibility of the receptor. There is no repulsion between Phe282 and the proceeding loop of AF2. However, substitution of Phe282 by alanine enlarged the entrance of the binding pocket and abolished the repulsive interaction between solvent water molecules and this hydrophobic residue, thus more water molecules can enter into the binding pocket. It needs more energy to exclude the extra water molecules for a ligand binding to the mutated receptor. In addition, the extra water molecules abolish some of H-bonds between the ligand and receptors. Therefore, solvent effect may be concluded as the major source of the decrease of binding affinity for the mutated receptors to the ligands, and thereby of the decrease of their transcriptional activation activities. (c) 2005 Elsevier SAS. All rights reserved. |
| WOS关键词 | ACTIVATED RECEPTOR-GAMMA ; HUMAN PPAR-GAMMA ; ADIPOCYTE DIFFERENTIATION ; MOLECULAR-DYNAMICS ; SELECTIVITY ; DISCOVERY ; AGONISTS ; DOMAIN ; ALPHA |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000229895700007 |
| 出版者 | EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273861]  |
| 专题 | 药理学第三研究室 药物发现与设计中心 |
| 通讯作者 | Shen, X |
| 作者单位 | Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci,Shanghai Inst Mat Med, Drug Discovery & Design Ctr,State Key Lab Drug Re, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yue, LD,Ye, F,Xu, XY,et al. The conserved residue Phe273(282) of PPAR alpha(gamma), beyond the ligand-binding site, functions in binding affinity through solvation effect[J]. BIOCHIMIE,2005,87(6):539-550. |
| APA | Yue, LD.,Ye, F.,Xu, XY.,Shen, JH.,Chen, KX.,...&Jiang, HL.(2005).The conserved residue Phe273(282) of PPAR alpha(gamma), beyond the ligand-binding site, functions in binding affinity through solvation effect.BIOCHIMIE,87(6),539-550. |
| MLA | Yue, LD,et al."The conserved residue Phe273(282) of PPAR alpha(gamma), beyond the ligand-binding site, functions in binding affinity through solvation effect".BIOCHIMIE 87.6(2005):539-550. |
入库方式： OAI收割
来源：上海药物研究所
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