ArticleProceedings of the National Academy of Sciences of the United States of America2023
Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 17 citations in OpenAlex.
- Development of Membrane Transport-Inspired Biomimetic System to Degrade Plasticizers.Chemistry, an Asian journal · 2026Article
- 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
- PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors.Nature communications · 2025Article
- Targeting pregnane X receptor with a potent agonist-based PROTAC to delay colon cancer relapse.Oncogenesis · 2025Article
- Discovery of PXR Antagonist MI891 and PXR Degrader MI1013 and Their Roles in Hepatic Gene Regulation.Journal of medicinal chemistry · 2025Article
- A two-in-one expression construct for biophysical and structural studies of the human pregnane X receptor ligand-binding domain, a pharmaceutical and environmental target.Acta crystallographica. Section F, Structural biology communications · 2025Article
- An abundant ginger compound furanodienone alleviates gut inflammation via the xenobiotic nuclear receptor PXR in mice.Nature communications · 2025Article
- Targeting a distinct binding pocket in the pregnane X receptor with natural agonist TRLW-2 ameliorates murine ulcerative colitis.Frontiers in pharmacology · 2025Article
- 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
- Dose-dependent induction of CYP3A activity by St. John's wort alone and in combination with rifampin.Clinical and translational science · 2024Article
- Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR.Nature communications · 2024Article
- Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.Structure (London, England : 1993) · 2023Article
- Regulation of PXR in drug metabolism: chemical and structural perspectives.Expert opinion on drug metabolism & toxicologyReview
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Ligand-binding promiscuity in detoxification systems protects the body from toxicological harm but is a roadblock to drug development due to the difficulty in optimizing small molecules to both retain target potency and avoid metabolic events. Immense effort is invested in evaluating metabolism of molecules to develop safer, more effective treatments, but engineering specificity into or out of promiscuous proteins and their ligands is a challenging task. To better understand the promiscuous nature of detoxification networks, we have used X-ray crystallography to characterize a structural feature of pregnane X receptor (PXR), a nuclear receptor that is activated by diverse molecules (with different structures and sizes) to up-regulate transcription of drug metabolism genes. We found that large ligands expand PXR's ligand-binding pocket, and the ligand-induced expansion occurs through a specific unfavorable compound-protein clash that likely contributes to reduced binding affinity. Removing the clash by compound modification resulted in more favorable binding modes with significantly enhanced binding affinity. We then engineered the unfavorable ligand-protein clash into a potent, small PXR ligand, resulting in marked reduction in PXR binding and activation. Structural analysis showed that PXR is remodeled, and the modified ligands reposition in the binding pocket to avoid clashes, but the conformational changes result in less favorable binding modes. Thus, ligand-induced binding pocket expansion increases ligand-binding potential of PXR but is an unfavorable event; therefore, drug candidates can be engineered to expand PXR's ligand-binding pocket and reduce their safety liability due to PXR binding.
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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.