Nuclear receptors (NRs) are conditional transcription factors with common multidomain organization that bind diverse DNA elements. How DNA sequences influence NR conformation is poorly understood. Here we report the crystal structure of the human retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on its cognate element, an AGGTCA direct repeat spaced by 4 nt. The complex has an extended X-shaped arrangement, with DNA- and ligand-binding domains crossed, in contrast to the parallel domain arrangement of other NRs that bind an AGGTCA direct repeat spaced by 1 nt. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element. Comparisons of RXRα-LXRβs in the crystal asymmetric unit and with previous NR structures reveal flexibility in NR organization and suggest a role for RXRα in adaptation of heterodimeric complexes to DNA.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1038/nsmb.2778 | DOI Listing |
Dermatol Ther (Heidelb)
January 2025
Dermatological Centre in Milan, Milan, Italy.
Acne and acne sequelae can have an important impact on patients' quality of life, affecting interpersonal relationships and social functioning. Acne-induced scars (AIS) and acne-induced macular hyperpigmentation (AIH), in particular, are a major concern for patients with acne, as their management is challenging and often unsatisfactory. Retinoids are considered the mainstay of acne treatment because of their action on multiple pathogenetic factors, and there is increasing evidence that they can also improve AIS and AIH.
View Article and Find Full Text PDFBackground: Treatment with the RXR-specific agonist Bexarotene exerts neuroprotective effects in Alzheimer's disease (AD) mouse models by improving cognition and increasing Aβ clearance. At the transcriptional level, ligand-activated RXR receptors regulate gene networks linked to neural development, neuroinflammation, and metabolism. This study aimed to reveal the association between changes in chromatin architecture and transcriptional activity in the brain of Bexarotene-treated APP/PS1 mice.
View Article and Find Full Text PDFFASEB J
January 2025
Department of Obstetrics, Gynecology and Reproductive Health, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
At the maternal-fetal interface, tightly regulated levels of retinoic acid (RA), the physiologically active metabolite of vitamin A, are required for embryo implantation and pregnancy success. Herein, we utilize mouse models, primary human cells, and pharmacological tools to demonstrate how depletion of RA signaling via RA receptor (RAR) disrupts implantation and progression of early pregnancy. To inhibit RAR signaling during early pregnancy, BMS493, an inverse pan-RAR agonist that prevents RA-induced differentiation, was administered to pregnant mice during the peri-implantation period.
View Article and Find Full Text PDFViruses
December 2024
Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USA.
During virus infection, the activation of the antiviral endoribonuclease, ribonuclease L (RNase L), by a unique ligand 2'-5'-oilgoadenylate (2-5A) causes the cleavage of single-stranded viral and cellular RNA targets, restricting protein synthesis, activating stress response pathways, and promoting cell death to establish broad antiviral effects. The immunostimulatory dsRNA cleavage products of RNase L activity (RL RNAs) recruit diverse dsRNA sensors to activate signaling pathways to amplify interferon (IFN) production and activate inflammasome, but the sensors that promote cell death are not known. In this study, we found that DEAH-box polypeptide 15 (DHX15) and retinoic acid-inducible gene I (Rig-I) are essential for apoptosis induced by RL RNAs and require mitochondrial antiviral signaling (MAVS), c-Jun amino terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) for caspase-3-mediated intrinsic apoptosis.
View Article and Find Full Text PDFCells
December 2024
Targeted Therapy Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.
Metastasis is a leading cause of lung adenocarcinoma (LUAD)-related mortality and presents significant challenges for treatment. The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptor (GPCR) family, has an unclear role in LUAD progression. This study aimed to investigate the function and underlying mechanisms of GRPR in LUAD metastasis.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!