ArticleBiochemical pharmacology2016
Tryptophan 299 is a conserved residue of human pregnane X receptor critical for the functional consequence of ligand binding.
Article in Biochemical pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- Article
- Probing PXR activation and modulation of CYP3A4 by Tinospora crispa and Tinospora sinensis.Journal of ethnopharmacology · 2022Article
- Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning.Cells · 2021Review
- Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction.ACS medicinal chemistry letters · 2021Article
- 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
- CITCO Directly Binds to and Activates Human Pregnane X Receptor.Molecular pharmacology · 2020Article
- Mechanistic Insights of Phenobarbital-Mediated Activation of Human but Not Mouse Pregnane X Receptor.Molecular pharmacology · 2019Article
- Drug discovery technologies to identify and characterize modulators of the pregnane X receptor and the constitutive androstane receptor.Drug discovery today · 2019Review
- RNA interference screen identifies NAA10 as a regulator of PXR transcription.Biochemical pharmacology · 2019Article
- CINPA1 binds directly to constitutive androstane receptor and inhibits its activity.Biochemical pharmacology · 2018Article
- SPA70 is a potent antagonist of human pregnane X receptor.Nature communications · 2017Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
PXR is a xenobiotic receptor that regulates drug metabolism by regulating the expression of drug-metabolizing enzymes including CYP3A4. It can be modulated by chemicals with different structures, functional groups and sizes. X-ray crystal structures of the ligand binding domain of human PXR (hPXR) alone or bound with agonists reveal a highly hydrophobic ligand binding pocket where the aromatic amino acid residue W299 appears to play a critical role in ligand binding. Here, we have investigated the role of W299 on the functional consequence of hPXR ligand binding. We first found that substitution of W299 with a hydrophobic residue retained its response to rifampicin, but substitution with a charged residue altered such agonist response in activating the transcription of CYP3A4. The activity of hPXR mutants on CYP3A4 expression correlates with the ability of hPXR mutants to interact with co-activator SRC-1. We further demonstrated that the effect of replacing W299 by residues with different side chains on hPXR's function varied depending on the specific agonist used. Finally we interpreted the cellular activity of the hPXR mutants by analyzing reported crystallographic data and proposing a model. Our findings reveal the essential role of W299 in the transactivation of hPXR in response to agonist binding, and provide useful information for designing modulators of hPXR.
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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.