ArticleCellular and molecular life sciences : CMLS2021
Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning.
Article in Cellular and molecular life sciences : CMLS, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 31 citations in OpenAlex.
- Rifamycin Structural Modifications Attenuate PXR Binding and CYP3A4 Induction.Journal of medicinal chemistry · 2026Article
- Subtle changes in ligand-receptor interactions dramatically alter transcriptional outcomes of pregnane X receptor modulators.Structure (London, England : 1993) · 2026Article
- Patchouli alcohol suppressesFrontiers in pharmacology · 2026Article
- PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.Nature communications · 2025Article
- Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation.Journal of medicinal chemistry · 2025Article
- Recent advances in gut microbiota metabolite regulation of hepatic pregnane X receptor.Frontiers in immunology · 2025Review
- PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.Structure (London, England : 1993) · 2024Article
- First-in-Class Small Molecule Degrader of Pregnane X Receptor Enhances Chemotherapy Efficacy.Journal of medicinal chemistry · 2024Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Design and Optimization of 1Journal of medicinal chemistry · 2022Article
- Review
- SJPYT-195: A Designed Nuclear Receptor Degrader That Functions as a Molecular Glue Degrader of GSPT1.ACS medicinal chemistry letters · 2022Article
- Probing PXR activation and modulation of CYP3A4 by Tinospora crispa and Tinospora sinensis.Journal of ethnopharmacology · 2022Article
- Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation.Nucleic acids research · 2022Article
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist.Computational and structural biotechnology journal · 2022Article
- Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning.Cells · 2021Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Pregnane X receptor (PXR) is activated by chemicals to transcriptionally regulate drug disposition and possibly decrease drug efficacy and increase resistance, suggesting therapeutic value for PXR antagonists. We previously reported the antagonist SPA70 and its analog SJB7, which unexpectedly is an agonist. Here, we describe another unexpected observation: mutating a single residue (W299A) within the PXR ligand-binding domain converts SPA70 to an agonist. After characterizing wild-type and W299A PXR activity profiles, we used molecular dynamics simulations to reveal that in wild-type PXR, agonists stabilize the activation function 2 (AF-2) helix in an "inward" position, but SPA70 displaces the AF-2. In W299A, however, SPA70 stabilizes the AF-2 "inward", like agonists. We validated our model by predicting the antagonist SJC2 to be a W299A agonist, which was confirmed experimentally. Our work correlates previously unobserved ligand-induced conformational changes to PXR cellular activity and, for the first time, reveals how PXR antagonists work.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.