So-called endocrine disruptors — environmental pollutants that can cause reproductive, metabolic, or neurological disorders — target the pregnane X receptor (PXR), a nuclear receptor unique for its sensitivity to a wide range of compounds. Recent studies have demonstrated that PXR, in its heterodimeric form with the retinoid X receptor (RXR), can mediate both harmful effects in response to xenobiotics, although the mechanisms by which pollutants activate PXR are still being investigated. Vanessa Delfosse, Tiphaine Huet, Deborah Harrus, Meritxell Granell, Maxime Bourguet, et al. utilize cell-based, biophysical, structural, and in vivo approaches to identify novel mixtures of chemicals, whose constituents have low individual affinity for PXR but combine synergistically to robustly activate the receptor. As an extension of their previous work, which showed that binary cocktails of xenobiotics synergistically activate RXR–PXR, the authors describe previously unreported binding mechanisms, substantiating the versatility of PXR's ligand binding domain and the receptor's role in sensing a diverse array of chemicals. Furthermore, the study shows that environmental compounds targeting RXR can boost the activity of two synergizing PXR ligands. The findings suggest that certain chemicals such as endocrine disruptors or pharmaceuticals, at levels deemed individually safe, can potentially interact synergistically and disrupt critical cell signaling.
Link to the article: https://www.pnas.org/content/118/1/e2020551118