Mechanistic insights into the synergistic activation of the RXR–PXR heterodimer by endocrine disruptor mixtures

• DOI: 10.1073/pnas.2020551118
• Publication Date: 2020-12-23T22:41:11Z
• Authors: Vanessa Delfosse; Tiphaine Huet; Deborah Harrus; Meritxell Granell; Maxime Bourguet; Caroline Gardia-P...; Barbara Chiavarina; Marina Grimaldi; Sébastien Le Mével; Pauline Blanc; David Huang; Jakub Gruszczyk; Barbara Demeneix; Sarah Cianférani; Jean-Baptiste Fini; Patrick Balaguer; William Bourguet
• Keywords: Pregnane X receptor; Retinoid X receptor; Xenobiotic; Endocrine disruptor; Constitutive androstane receptor

Humans are chronically exposed to mixtures of xenobiotics referred as endocrine-disrupting chemicals (EDCs). A vast body literature links exposure these with increased incidences reproductive, metabolic, or neurological disorders. Moreover, recent data demonstrate that, when used in combination, have outcomes that cannot be predicted from their individual behavior. In its heterodimeric form the retinoid X receptor (RXR), pregnane (PXR) plays an essential role controlling mammalian xenobiotic response and mediates both beneficial detrimental effects. Our previous work shed light on a mechanism by which binary mixture activates PXR synergistic fashion. Structural analysis revealed mutual stabilization compounds within ligand-binding pocket accounts for enhancement binding affinity. order identify characterize additional active mixtures, we combined set cell-based, biophysical, structural, vivo approaches. study reveals features confirm promiscuity this ability accommodate bipartite ligands. We reveal previously unidentified mechanisms involving dynamic structural transitions covalent coupling report four eliciting graded activities. Last, robust activity obtained two synergizing ligands can enhanced further presence RXR environmental insights how low-dose EDC may alter physiology through interaction RXR-PXR potentially several other nuclear heterodimers.