New structural insights into the control of the retinoic acid receptors RAR/RXR by DNA, ligands, and transcriptional coregulators
Year: 2025
Type: article
Abstract: Retinoic acid receptors (RARs) are ligand-dependent transcription factors essential for various biological processes, including embryogenesis, differentiation, and apoptosis. RARs function as heterodimers with retinoid X receptors (RXRs) and regulate gene expression via retinoic acid response elements (RAREs). Their transcriptional activity is modulated by coregulators, with corepressors maintaining repression in the absence of ligand and coactivators enabling transcription upon ligand binding. Structural studies reveal that DNA binding induces conformational changes affecting coregulator interactions. However, the precise structural organization of RAR/RXR-coregulator complexes and the allosteric influence of DNA on receptor function remain incompletely understood. Our study presents an integrative analysis of the RAR/RXR heterodimer bound to four distinct and relevant RAREs (DR0, DR1, DR5, and IR0) in complex with either a corepressor (NCoR) or a coactivator (TIF-2) nuclear receptor interaction domain. By combining small-angle X-ray scattering, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we revealed that the heterodimer adopts distinct conformations depending on the DNA sequence, influencing interdomain distances and receptor interactions. Additionally, we uncovered the dynamic interplay between ligand, DNA, and coregulator binding. This study provides new insights into the structural features of coregulator proteins and highlights the allosteric influence of RAREs on receptor function.
Source: Nucleic Acids Research
DOI: 10.1093/nar/gkaf967
Institutions: Centre National de la Recherche Scientifique, Inserm, Université de Montpellier, Centre de Biologie Structurale, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Biotechnology, Czech Academy of Sciences, Institute of Microbiology, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,992
Funders: European Proteomics Infrastructure Consortium providing access, Agence Nationale de la Recherche, Ministerstvo Školství, Mládeže a Tělovýchovy, Centre National de la Recherche Scientifique, Institut National Du Cancer, Grand Équipement National De Calcul Intensif, French Infrastructure for Integrated Structural Biology, Horizon 2020 Framework Programme, National Cancer Institute, Vermont Agency of Natural Resources
Awards: G1492093572, CBH-EUR-GS, Deciphering the molecular causation of human acute promyelocytic leukemia (APL), an innovative approach to improve treatment of retinoid-sensitive malignancies, G1935710221, G2447855386, G256544642, G2659019386, G3850027771, G4399195447, G4460985483, G4957650857, G5007093561, G5107653209, G6044710921, G678225801, G6803667113, G7240651115, G7259097847, G7351664618, G8140083606, Czech Infrastructure for Integrative Structural Biology, Infrastructure Française pour la Biologie Structurale Intégrée, G8783424967, G8851755006
OpenAlex ID: W4414764966