文献类型：期刊文献

英文题名：Structure Basis of Bigelovin as a Selective RXR Agonist with a Distinct Binding Mode

作者：Zhang, Haitao[1];Li, Li[2];Chen, Lili[1];Hu, Lihong[1];Jiang, Hualiang[1];Shen, Xu[1]

机构：[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

年份：2011

卷号：407

期号：1

起止页码：13

外文期刊名：JOURNAL OF MOLECULAR BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000288725500002)】；

基金：This work was supported by the State Key Program of Basic Research of China (grants 2010CB912501, 2007CB914304, and 2009CB918502), the National Natural Science Foundation of China (grants 30925040, 30890044, and 10979072), Science Foundation of Shanghai (grant 08431902900), and Foundation of Chinese Academy of Sciences (grants KSCX2-YW-R-168 and SCX1-YW-02-2).

语种：英文

外文关键词：RXR; agonist; bigelovin; crystal structure; cancer

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.