title: Danthron functions as a retinoic X receptor antagonist by stabilizing tetramers of the receptor.
abstract: Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here, we identified a specific RXRα antagonist, danthron, from the traditional Chinese medicine rhubarb. Danthron repressed all tested RXRα-involved response element transcription, including the RXRE, PPRE, FXRE, and LXRE. Results from native PAGE and isothermal titration calorimetry (ITC)-based assays indicated that danthron bound to the tetrameric RXRα-LBD in a specific stoichimetric ratio, and such a binding could influence the corepressor SMRT affinity to the receptor. Additionally, a unique tetrameric structure of the apo-RXRα ligand-binding domain (LBD) was determined, which exhibited a larger tetramer interface and different ligand-binding pocket size compared with the one previously reported. Together with the biochemical and biophysical results, the determined crystal structure of danthron-soaked RXRα-LBD suggested a new mechanism for danthron antagonism to tetrameric RXRα. Moreover, the in vivo efficient improvement of insulin sensitivity by danthron was observed in diet-induced obese (DIO) mice. Thus, our findings were expected to supply new insights into the structural basis of RXRα antagonist for its further potential therapeutic application.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Chenjing
authors.initials: C
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D020218:Response Elements; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012250:Rheum / Q000737:chemistry*
chemical_list: D000880:Anthraquinones; D004365:Drugs, Chinese Herbal; D009153:Mutagens; D047490:Retinoid X Receptor alpha; C004315:danthron