Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode

doi:10.1016/j.jmb.2011.01.032

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	Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode
	Zhang, Haitao 1; Li, Li 2; Chen, Lili1 ; Hu, Lihong 1; Jiang, Hualiang1 ; Shen, Xu1
刊名	JOURNAL OF MOLECULAR BIOLOGY
	2011-03-18
卷号	407 期号:1 页码:13-20
关键词	RXR agonist bigelovin crystal structure cancer
ISSN号	0022-2836
DOI	10.1016/j.jmb.2011.01.032
文献子类	Article
英文摘要	The nuclear receptor retinoid X receptor (RXR) functions potently in the regulation of homeostasis and cell development, while rexinoids as RXR agonists have proved their therapeutic potential in the treatment of metabolic diseases and cancer. Here, the natural product bigelovin was identified as a selective RXR alpha agonist. Interestingly, this compound could not transactivate RXR alpha:RXR alpha homodimer but could enhance the transactivation of RXR alpha:peroxisome proliferator-activated receptor gamma heterodimer and repress that of RXR alpha:liver X receptor (LXR) alpha heterodimer, while it had no effects on RXR alpha:farnesoid X receptor heterodimer. Considering that the effective role of LXR response element involved transactivation of sterol regulatory element-binding protein-1c mediated by RXR alpha:LXR alpha in triglyceride elevation, such LXR response element repressing by bigelovin has obviously addressed its potency for further research. Moreover, our determined crystal structure of the bigelovin-activated RXR alpha ligand-binding domain with the coactivator human steroid receptor coactivator-1 peptide revealed that bigelovin adopted a distinct binding mode. Compared with the known RXR ligands, bigelovin lacks the acidic moiety in structure, which indicated that the acidic moiety rendered little effects on RXR activation. Our results have thereby provided new insights into the structure-based selective rexinoids design with bigelovin as a potential lead compound. (C) 2011 Elsevier Ltd. All rights reserved.
资助项目	State Key Program of Basic Research of China[2010CB912501] ; State Key Program of Basic Research of China[2007CB914304] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[30925040] ; National Natural Science Foundation of China[30890044] ; National Natural Science Foundation of China[10979072] ; Science Foundation of Shanghai[08431902900] ; Foundation of Chinese Academy of Sciences[KSCX2-YW-R-168] ; Foundation of Chinese Academy of Sciences[SCX1-YW-02-2]
WOS关键词	RETINOID-X-RECEPTOR ; UNION-OF-PHARMACOLOGY ; NUCLEAR RECEPTOR ; PPAR-GAMMA ; CRYSTAL-STRUCTURE ; CELL-LINES ; ACTIVATION ; CANCER ; BEXAROTENE ; MECHANISMS
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS记录号	WOS:000288725500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278580]
专题	上海中药现代化研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第三研究室
通讯作者	Hu, Lihong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.E China Univ Sci & Technol, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Haitao,Li, Li,Chen, Lili,et al. Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode[J]. JOURNAL OF MOLECULAR BIOLOGY,2011,407(1):13-20.
APA	Zhang, Haitao,Li, Li,Chen, Lili,Hu, Lihong,Jiang, Hualiang,&Shen, Xu.(2011).Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode.JOURNAL OF MOLECULAR BIOLOGY,407(1),13-20.
MLA	Zhang, Haitao,et al."Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode".JOURNAL OF MOLECULAR BIOLOGY 407.1(2011):13-20.