9O45

Crystal structure of the L411W mutant of pregnane X receptor ligand binding domain in complex with SJPYT-328

Summary for 9O45

• Entry DOI: 10.2210/pdb9o45/pdb
• Descriptor: Pregnane X receptor ligand binding domain tethered to steroid receptor coactivator-1 peptide, (1P)-N-(5-tert-butyl-2-{[(3S)-hexan-3-yl]oxy}phenyl)-1-(2,4-dimethoxy-5-methylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide (3 entities in total)
• Functional Keywords: pregnane x receptor, pxr, nr1i2, transcription factor, nuclear receptor, drug metabolism, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 81847.90

Authors

Huber, A.D.,Garcia-Maldonado, E.,Miller, D.J.,Chen, T. (deposition date: 2025-04-08, release date: 2025-11-05)

Primary citation

Huber, A.D.,Garcia-Maldonado, E.,Lin, W.,Poudel, S.,Wu, J.,Miller, D.J.,Chen, T.
Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.
Structure, 2025

PubMed Abstract: Nuclear 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.

PubMed: 41138720
DOI: 10.1016/j.str.2025.09.011

Experimental method

X-RAY DIFFRACTION (2.56 Å)