Molecular Determinants of Magnolol Targeting Both RXRα and PPARγ

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.