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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 JB, Balaguer P, Bourguet W
Proc Natl Acad Sci U S A 118 (2021)
Related entries: 7ax8, 7ax9, 7axa, 7axb, 7axc, 7axd, 7axf, 7axg, 7axh, 7axi, 7axj, 7axk, 7axl

Cited: 19 times
EuropePMC logo PMID: 33361153

Abstract

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.

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  1. Expanding the Library of 1,2,4-Oxadiazole Derivatives: Discovery of New Farnesoid X Receptor (FXR) Antagonists/Pregnane X Receptor (PXR) Agonists. Finamore C, Festa C, Fiorillo B, Leva FSD, Roselli R, Marchianò S, Biagioli M, Spinelli L, Fiorucci S, Limongelli V, Zampella A, De Marino S. Molecules 28 2840 (2023)


Reviews citing this publication (7)

  1. Obesity II: Establishing causal links between chemical exposures and obesity. Heindel JJ, Howard S, Agay-Shay K, Arrebola JP, Audouze K, Babin PJ, Barouki R, Bansal A, Blanc E, Cave MC, Chatterjee S, Chevalier N, Choudhury M, Collier D, Connolly L, Coumoul X, Garruti G, Gilbertson M, Hoepner LA, Holloway AC, Howell G, Kassotis CD, Kay MK, Kim MJ, Lagadic-Gossmann D, Langouet S, Legrand A, Li Z, Le Mentec H, Lind L, Monica Lind P, Lustig RH, Martin-Chouly C, Munic Kos V, Podechard N, Roepke TA, Sargis RM, Starling A, Tomlinson CR, Touma C, Vondracek J, Vom Saal F, Blumberg B. Biochem Pharmacol 199 115015 (2022)
  2. Approaches to Heterogeneity in Native Mass Spectrometry. Rolland AD, Prell JS. Chem Rev 122 7909-7951 (2022)
  3. Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond. Poudel S, Huber AD, Chen T. Drug Metab Dispos 51 228-236 (2023)
  4. A concise review on hPXR ligand-recognizing residues and structure-based strategies to alleviate hPXR transactivation risk. Liu T, Beck JP, Hao J. RSC Med Chem 13 129-137 (2022)
  5. Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future. Dvořák Z, Li H, Mani S. Drug Metab Dispos 51 219-227 (2023)
  6. Allosteric Antagonism of the Pregnane X Receptor (PXR): Current-State-of-the-Art and Prediction of Novel Allosteric Sites. Kamaraj R, Drastik M, Maixnerova J, Pavek P. Cells 11 2974 (2022)
  7. Basic concepts of mixture toxicity and relevance for risk evaluation and regulation. Bloch D, Diel P, Epe B, Hellwig M, Lampen A, Mally A, Marko D, Villar Fernández MA, Guth S, Roth A, Marchan R, Ghallab A, Cadenas C, Nell P, Vartak N, van Thriel C, Luch A, Schmeisser S, Herzler M, Landsiedel R, Leist M, Marx-Stoelting P, Tralau T, Hengstler JG. Arch Toxicol 97 3005-3017 (2023)

Articles citing this publication (11)

  1. Helix 12 stabilization contributes to basal transcriptional activity of PXR. Shizu R, Nishiguchi H, Tashiro S, Sato T, Sugawara A, Kanno Y, Hosaka T, Sasaki T, Yoshinari K. J Biol Chem 297 100978 (2021)
  2. A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays. Creusot N, Garoche C, Grimaldi M, Boulahtouf A, Chiavarina B, Bourguet W, Balaguer P. Front Endocrinol (Lausanne) 12 665521 (2021)
  3. Cooperative Interaction of Phenolic Acids and Flavonoids Contained in Activated Charcoal with Herb Extracts, Involving Cholesterol, Bile Acid, and FXR/PXR Activation in Broilers Fed with Mycotoxin-Containing Diets. Zhang Y, Lin Z, Wang L, Guo X, Hao Z, Li Z, Johnston LJ, Dong B. Antioxidants (Basel) 11 2200 (2022)
  4. Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist. Rashidian A, Mustonen EK, Kronenberger T, Schwab M, Burk O, Laufer SA, Pantsar T. Comput Struct Biotechnol J 20 3004-3018 (2022)
  5. IM MiXie, an Online Tool for Better Health Assessment of Workers Exposed to Multiple Chemicals. La Rocca B, Sarazin P. Int J Environ Res Public Health 19 951 (2022)
  6. Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions. Fan S, Yan Y, Xia Y, Zhou Z, Luo L, Zhu M, Han Y, Yao D, Zhang L, Fang M, Peng L, Yu J, Liu Y, Gao X, Guan H, Li H, Wang C, Wu X, Zhu H, Cao Y, Huang C. Nat Commun 14 3368 (2023)
  7. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs. Li F, Song C, Zhang Y, Wu D. Acta Biochim Biophys Sin (Shanghai) 54 12-24 (2022)
  8. Development of new approach methods for the identification and characterization of endocrine metabolic disruptors-a PARC project. Braeuning A, Balaguer P, Bourguet W, Carreras-Puigvert J, Feiertag K, Kamstra JH, Knapen D, Lichtenstein D, Marx-Stoelting P, Rietdijk J, Schubert K, Spjuth O, Stinckens E, Thedieck K, van den Boom R, Vergauwen L, von Bergen M, Wewer N, Zalko D. Front Toxicol 5 1212509 (2023)
  9. Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides. Dauwe Y, Mary L, Oliviero F, Grimaldi M, Balaguer P, Gayrard V, Mselli-Lakhal L. Cells 12 1201 (2023)
  10. Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein. Lin W, Huber AD, Poudel S, Li Y, Seetharaman J, Miller DJ, Chen T. Proc Natl Acad Sci U S A 120 e2217804120 (2023)
  11. The Novel RXR Agonist MSU-42011 Differentially Regulates Gene Expression in Mammary Tumors of MMTV-Neu Mice. Reich LA, Leal AS, Ellsworth E, Liby KT. Int J Mol Sci 24 4298 (2023)


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