9o45
Crystal structure of the L411W mutant of pregnane X receptor ligand binding domain in complex with SJPYT-328
Structural highlights
DiseaseNCOA1_HUMAN Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. FunctionNCOA1_HUMAN Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4] [5] [6] [7] NR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[8] [9] [10] [11] [12] [13] Publication Abstract from PubMedNuclear receptor antagonists are used to treat various diseases, but the precise antagonist mechanisms differ among receptors and compounds. Understanding the interplay between ligand-receptor interactions and transcriptional outcomes is critical. The nuclear receptor pregnane X receptor (PXR) is activated by many medicinal compounds and upregulates drug metabolism genes in response, decreasing efficacy and/or increasing toxicity of drugs. Co-administered PXR antagonists could reduce these effects, but such compounds have only recently been identified, and molecular elements governing their actions remain largely unknown. Here, we show chemically similar PXR ligands with three distinct activities (agonist, antagonist, and inverse agonist) that are altered by PXR mutations. These diverging activities are linked to ligand-induced changes at the intersection of ligand, receptor ligand-binding pocket, and receptor surface where transcriptional coregulators are recruited. We also find that antagonists can act by multiple mechanisms regarding coregulator recruitment, highlighting the complexity of ligand-receptor interactions that influence transcriptional activity. Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.,Huber AD, Garcia-Maldonado E, Lin W, Poudel S, Wu J, Miller DJ, Chen T Structure. 2025 Oct 24:S0969-2126(25)00386-7. doi: 10.1016/j.str.2025.09.011. PMID:41138720[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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