3R5N

Crystal structure of PPARgammaLBD complexed with the agonist magnolol

Summary for 3R5N

• Entry DOI: 10.2210/pdb3r5n/pdb
• Related: 3R5M
• Descriptor: Peroxisome proliferator-activated receptor gamma, 5,5'-di(prop-2-en-1-yl)biphenyl-2,2'-diol (3 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, transcription-transcription agonist complex, transcription/transcription agonist
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 1
• Total formula weight: 31854.06

Authors

Zhang, H.,Chen, L.,Chen, J.,Hu, L.,Jiang, H.,Shen, X. (deposition date: 2011-03-18, release date: 2012-02-08, Last modification date: 2023-09-13)

Primary citation

Zhang, H.,Xu, X.,Chen, L.,Chen, J.,Hu, L.,Jiang, H.,Shen, X.
Molecular determinants of magnolol targeting both RXR(alpha) and PPAR(gamma).
Plos One, 6:e28253-e28253, 2011

PubMed Abstract: Nuclear receptors retinoic X receptor α (RXRα) and peroxisome proliferator activated receptor γ (PPARγ) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRα and PPARγ is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRα and PPARγ. 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 RXRα:PPARγ heterodimer, instead of RXR-response element (RXRE) mediated by RXRα:RXRα homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRα and PPARγ 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 RXRα L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARγ Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRα and PPARγ are determined. As the first report on the dual agonist targeting RXRα and PPARγ 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.

PubMed: 22140563
DOI: 10.1371/journal.pone.0028253

Experimental method

X-RAY DIFFRACTION (2 Å)