Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha) in Stabilizing the Homodimerization of the Receptor

doi:10.1074/jbc.M114.630475

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	Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha) in Stabilizing the Homodimerization of the Receptor
	Xu, Xing 1,2; Xu, Xin 1; Liu, Peng 1; Zhu, Zhi-yuan 1; Chen, Jing1 ; Fu, Hai-an 3; Chen, Li-li1 ; Hu, Li-hong 1; Shen, Xu1
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2015-08-07
卷号	290 期号:32 页码:19888-19899
ISSN号	0021-9258
DOI	10.1074/jbc.M114.630475
文献子类	Article
英文摘要	Farnesoid X receptor alpha (FXR alpha) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXR alpha (hFXR alpha), and the crystal structure of hFXR alpha ligand binding domain (hFXR alpha-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXR alpha-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXR alpha target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDBto db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXR alpha-LBD.NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research.
资助项目	National Natural Science Foundation of China[91413102] ; National Natural Science Foundation of China[81373462] ; National Natural Science Foundation of China[81173105]
WOS关键词	ORPHAN NUCLEAR RECEPTOR ; BILE-ACID RECEPTOR ; NATURAL PRODUCT ; IDENTIFICATION ; LIGAND ; AGONIST ; OBESITY ; CHOLESTEROL ; HOMEOSTASIS ; METABOLISM
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000359364600044
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276438]
专题	生物技术药物研发中心（筹）药理学第三研究室
通讯作者	Chen, Li-li
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Shanghai Jiao Tong Univ, Shanghai Key Lab Bone & Joint Dis, Shanghai Inst Traumatol & Orthopaed, Shanghai Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China; 3.Emory Univ, Dept Pharmacol, Sch Med, Atlanta, GA 30322 USA
推荐引用方式 GB/T 7714	Xu, Xing,Xu, Xin,Liu, Peng,et al. Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha) in Stabilizing the Homodimerization of the Receptor[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2015,290(32):19888-19899.
APA	Xu, Xing.,Xu, Xin.,Liu, Peng.,Zhu, Zhi-yuan.,Chen, Jing.,...&Shen, Xu.(2015).Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha) in Stabilizing the Homodimerization of the Receptor.JOURNAL OF BIOLOGICAL CHEMISTRY,290(32),19888-19899.
MLA	Xu, Xing,et al."Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXR alpha) in Stabilizing the Homodimerization of the Receptor".JOURNAL OF BIOLOGICAL CHEMISTRY 290.32(2015):19888-19899.