ArticleBiochemistry2009
The structural basis of pregnane X receptor binding promiscuity.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 81 citations in OpenAlex.
- Bridging between Structure-Based and Data-Driven Affinity Prediction.Journal of chemical information and modeling · 2026Article
- Herbal Medicines and Drugs Interactions: Cytochrome P450 Responsibility.Current medicinal chemistry · 2026Review
- Exploring Adverse Event Associations of Predicted PXR Agonists Using the FAERS Database.International journal of molecular sciences · 2025Article
- The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model.Nature communications · 2025Article
- Moldable Plastics (Polycaprolactone) can be Acutely Toxic to Developing Zebrafish and Activate Nuclear Receptors in Mammalian Cells.ACS biomaterials science & engineering · 2024Article
- Dose-dependent induction of CYP3A activity by St. John's wort alone and in combination with rifampin.Clinical and translational science · 2024Article
- Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors.International journal of molecular sciences · 2024Article
- Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.Journal of chemical information and modeling · 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
- Antifouling Marine Coatings with a Potentially Safer and Sustainable Synthetic Polyphenolic Derivative.Marine drugs · 2022Article
- Pregnane X Receptor and the Gut-Liver Axis: A Recent Update.Drug metabolism and disposition: the biological fate of chemicals · 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
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- Mutation of a single amino acid of pregnane X receptor switches an antagonist to agonist by altering AF-2 helix positioning.Cellular and molecular life sciences : CMLS · 2021Article
- Potential for pharmacokinetic interactions between Schisandra sphenanthera and bosutinib, but not imatinib: in vitro metabolism study combined with a physiologically-based pharmacokinetic modelling approach.British journal of clinical pharmacology · 2020Article
- Sequence Variations in pxr (nr1i2) From Zebrafish (Danio rerio) Strains Affect Nuclear Receptor Function.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- Probing Ligand Structure-Activity Relationships in Pregnane X Receptor (PXR): Efavirenz and 8-Hydroxyefavirenz Exhibit Divergence in Activation.ChemMedChem · 2018Article
- Epigenetic impact of endocrine disrupting chemicals on lipid homeostasis and atherosclerosis: a pregnane X receptor-centric view.Environmental epigenetics · 2017Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The steroid and xenobiotic-responsive human pregnane X receptor (PXR) binds a broad range of structurally diverse compounds. The structures of the apo and ligand-bound forms of PXR are very similar, in contrast to most promiscuous proteins that generally adapt their shape to different ligands. We investigated the structural origins of PXR's recognition promiscuity using computational solvent mapping, a technique developed for the identification and characterization of hot spots, i.e., regions of the protein surface that are major contributors to the binding free energy. Results reveal that the smooth and nearly spherical binding site of PXR has a well-defined hot spot structure, with four hot spots located on four different sides of the pocket and a fifth close to its center. Three of these hot spots are already present in the ligand-free protein. The most important hot spot is defined by three structurally and sequentially conserved residues, W299, F288, and Y306. This largely hydrophobic site is not very specific and interacts with all known PXR ligands. Depending on their sizes and shapes, individual PXR ligands extend into two, three, or four more hot spot regions. The large number of potential arrangements within the binding site explains why PXR is able to accommodate a large variety of compounds. All five hot spots include at least one important residue, which is conserved in all mammalian PXRs, suggesting that the hot spot locations have remained largely invariant during mammalian evolution. The same side chains also show a high level of structural conservation across hPXR structures. However, each of the hPXR hot spots also includes residues with moveable side chains, further increasing the size variation in ligands that PXR can bind. Results also suggest a unique signal transduction mechanism between the PXR homodimerization interface and its coactivator binding site.
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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.