Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.

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.