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	The conserved residue phe273(282) of ppar alpha(gamma), beyond the ligand-binding site, functions in binding affinity through solvation effect
	Yue, LD; Ye, F; Xu, XY; Shen, JH; Chen, KX; Shen, X; Jiang, HL
刊名	Biochimie
	2005-06-01
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
通讯作者	Shen, x()
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
WOS类目	Biochemistry & Molecular Biology
语种	英语
出版者	EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000229895700007
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2377825
专题	中国科学院大学
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.

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