Molecular Determinants of Magnolol Targeting Both RXR alpha and PPAR gamma

doi:10.1371/journal.pone.0028253

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 上海中药现代化研究中心

	Molecular Determinants of Magnolol Targeting Both RXR alpha and PPAR gamma
	Zhang, Haitao; Xu, Xing; Chen, Lili; Chen, Jing; Hu, Lihong; Jiang, Hualiang; Shen, Xu
刊名	PLOS ONE
	2011-11-29
卷号	6 期号:11
ISSN号	1932-6203
DOI	10.1371/journal.pone.0028253
文献子类	Article
英文摘要	Nuclear receptors retinoic X receptor alpha (RXR alpha) and peroxisome proliferator activated receptor gamma (PPAR gamma) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXR alpha and PPAR gamma is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXR alpha and PPAR gamma. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXR alpha:PPAR gamma heterodimer, instead of RXR-response element (RXRE) mediated by RXR alpha:RXRa homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXR alpha and PPAR gamma ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXR alpha L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPAR gamma Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXR alpha and PPAR gamma are determined. As the first report on the dual agonist targeting RXR alpha and PPAR gamma with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design.
资助项目	State Key Program of Basic Research of China[2010CB912501] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[90713046] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[10979072] ; National Natural Science Foundation of China[30890044] ; National Natural Science Foundation of China[30801415] ; Science Foundation of Shanghai[11XD1406100]
WOS关键词	ACTIVATED RECEPTOR-GAMMA ; RETINOID-X-RECEPTOR ; TYPE-2 DIABETES-MELLITUS ; UNION-OF-PHARMACOLOGY ; METABOLIC SYNDROME ; CRYSTAL-STRUCTURE ; CELLS ; RAR ; MODULATORS ; AGONISTS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000298166300043
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278330]
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	Zhang, Haitao
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Haitao,Xu, Xing,Chen, Lili,et al. Molecular Determinants of Magnolol Targeting Both RXR alpha and PPAR gamma[J]. PLOS ONE,2011,6(11).
APA	Zhang, Haitao.,Xu, Xing.,Chen, Lili.,Chen, Jing.,Hu, Lihong.,...&Shen, Xu.(2011).Molecular Determinants of Magnolol Targeting Both RXR alpha and PPAR gamma.PLOS ONE,6(11).
MLA	Zhang, Haitao,et al."Molecular Determinants of Magnolol Targeting Both RXR alpha and PPAR gamma".PLOS ONE 6.11(2011).