Molecular determinants of magnolol targeting both RXR? and PPAR?.

ABSTRACT: Nuclear receptors retinoic X receptor ? (RXR?) and peroxisome proliferator activated receptor ? (PPAR?) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXR? and PPAR? 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? and PPAR?. 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?:PPAR? heterodimer, instead of RXR-response element (RXRE) mediated by RXR?:RXR? homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXR? and PPAR? 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? L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPAR? Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXR? and PPAR? are determined. As the first report on the dual agonist targeting RXR? and PPAR? 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.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC3226690 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature