气候变化领域集成服务门户(CCPortal): Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures

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DOI	10.1073/PNAS.2020551118
	Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures
	Delfosse V.; Huet T.; Harrus D.; Granell M.; Bourguet M.; Gardia-Parège C.; Chiavarina B.; Grimaldi M.; Le Mével S.; Blanc P.; Huang D.; Gruszczyk J.; Demeneix B.; Cianférani S.; Fini J.-B.; Balaguer P.; Bourguet W.
发表日期	2021
ISSN	00278424
卷号	118 期号:1
英文摘要	Humans are chronically exposed to mixtures of xenobiotics referred to as endocrine-disrupting chemicals (EDCs). A vast body of literature links exposure to these chemicals with increased incidences of reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, chemicals have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form with the retinoid X receptor (RXR), the pregnane X receptor (PXR) plays an essential role in controlling the mammalian xenobiotic response and mediates both beneficial and detrimental effects. Our previous work shed light on a mechanism by which a binary mixture of xenobiotics activates PXR in a synergistic fashion. Structural analysis revealed that mutual stabilization of the compounds within the ligand-binding pocket of PXR accounts for the enhancement of their binding affinity. In order to identify and characterize additional active mixtures, we combined a set of cell-based, biophysical, structural, and in vivo approaches. Our study reveals features that confirm the binding promiscuity of this receptor and its ability to accommodate bipartite ligands. We reveal previously unidentified binding mechanisms involving dynamic structural transitions and covalent coupling and report four binary mixtures eliciting graded synergistic activities. Last, we demonstrate that the robust activity obtained with two synergizing PXR ligands can be enhanced further in the presence of RXR environmental ligands. Our study reveals insights as to how low-dose EDC mixtures may alter physiology through interaction with RXR–PXR and potentially several other nuclear receptor heterodimers. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cocktail effect; Endocrine disruptor; Low dose; Mixture; Synergy
语种	英语
scopus关键词	endocrine disruptor; pregnane X receptor; retinoid X receptor; Article; binding affinity; biochemistry; controlled study; human; human cell; ligand binding; priority journal; protein analysis; protein binding; protein stability; protein structure; signal transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181130
作者单位	Centre de Biologie Structurale, INSERM, CNRS, Université de Montpellier, Montpellier, France; Laboratoire de Spectrométrie de Masse BioOrganique, Université de Strasbourg, CNRS, Institut Pluridisciplinaire Hubert Curien, Unité Mixte de Recherche 7178, Strasbourg, 67000, France; Institut de Recherche en Cancérologie de Montpellier, INSERM, Institut Régional du Cancer de Montpellier, Université de Montpellier, Montpellier, France; Muséum National d’Histoire Naturelle, Laboratoire Physiologie Moléculaire et Adaptation, CNRS Unité Mixte de Recherche 7221, Paris, France
推荐引用方式 GB/T 7714	Delfosse V.,Huet T.,Harrus D.,等. Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures[J],2021,118(1).
APA	Delfosse V..,Huet T..,Harrus D..,Granell M..,Bourguet M..,...&Bourguet W..(2021).Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures.Proceedings of the National Academy of Sciences of the United States of America,118(1).
MLA	Delfosse V.,et al."Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures".Proceedings of the National Academy of Sciences of the United States of America 118.1(2021).