Molecular determinants of magnolol targeting both RXRα and PPARγ.

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 metaboli...

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Autores principales:	Haitao Zhang, Xing Xu, Lili Chen, Jing Chen, Lihong Hu, Hualiang Jiang, Xu Shen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/17a2f9d2aa8e4466b8798141fe897eb7
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spelling	oai:doaj.org-article:17a2f9d2aa8e4466b8798141fe897eb72021-11-18T07:33:26ZMolecular determinants of magnolol targeting both RXRα and PPARγ.1932-620310.1371/journal.pone.0028253https://doaj.org/article/17a2f9d2aa8e4466b8798141fe897eb72011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22140563/?tool=EBIhttps://doaj.org/toc/1932-6203Nuclear 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.Haitao ZhangXing XuLili ChenJing ChenLihong HuHualiang JiangXu ShenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e28253 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Haitao Zhang Xing Xu Lili Chen Jing Chen Lihong Hu Hualiang Jiang Xu Shen Molecular determinants of magnolol targeting both RXRα and PPARγ.
description	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.
format	article
author	Haitao Zhang Xing Xu Lili Chen Jing Chen Lihong Hu Hualiang Jiang Xu Shen
author_facet	Haitao Zhang Xing Xu Lili Chen Jing Chen Lihong Hu Hualiang Jiang Xu Shen
author_sort	Haitao Zhang
title	Molecular determinants of magnolol targeting both RXRα and PPARγ.
title_short	Molecular determinants of magnolol targeting both RXRα and PPARγ.
title_full	Molecular determinants of magnolol targeting both RXRα and PPARγ.
title_fullStr	Molecular determinants of magnolol targeting both RXRα and PPARγ.
title_full_unstemmed	Molecular determinants of magnolol targeting both RXRα and PPARγ.
title_sort	molecular determinants of magnolol targeting both rxrα and pparγ.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/17a2f9d2aa8e4466b8798141fe897eb7
work_keys_str_mv	AT haitaozhang moleculardeterminantsofmagnololtargetingbothrxraandpparg AT xingxu moleculardeterminantsofmagnololtargetingbothrxraandpparg AT lilichen moleculardeterminantsofmagnololtargetingbothrxraandpparg AT jingchen moleculardeterminantsofmagnololtargetingbothrxraandpparg AT lihonghu moleculardeterminantsofmagnololtargetingbothrxraandpparg AT hualiangjiang moleculardeterminantsofmagnololtargetingbothrxraandpparg AT xushen moleculardeterminantsofmagnololtargetingbothrxraandpparg
_version_	1718423270968000512

Molecular determinants of magnolol targeting both RXRα and PPARγ.

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