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The structural coordinates of the tethered hPXR, linker, steroid receptor coactivator 1 (PXR/ SRC-1) were retrieved from the RSCB Protein Data Bank entry 3HVL (RSCB Protein Data Bank 2012; Wang et al.
We first tested the ability of BPA to activate hPXR or mPXR using transfection assays.
To determine whether BPA acts specifically on hPXR, we evaluated the ability of BPA to activate a number of other nuclear receptors, including rPXR, human retinoid acid receptor (RAR)a, retinoid X receptor (RXR), farnesoid X receptor (FXR), liver X receptor (LXR)a, peroxisome proliferator-activated receptor (PPAR)a, PPARy, vitamin D receptor (VDR), and ERa (Figure ID).
Unliganded hPXR was able to interact with the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone (SMRT; Figure IF).
After 50 independent docking exercises, a single orientation was identified for BPA in the ligand-binding pocket of hPXR. BPA forms a hydrogen bond with one PXR side chain and additional interactions with 10 other residues (Figure 2).
Ihese indirect interactions between BPA and the AF-2 surface may stabilize the active AF-2 conformation of the receptor and contribute to the agonistic activity of BPA on hPXR (Figure 2B,C).
Several previous studies have constructed ligand-based computational models for hPXR agonists employing pharmacophores (Bachmann et al.
Both FlexX and GOLD had mixed success in predicting a large set of structurally diverse hPXR agonists (Khandelwal et al.
In this study we initially used docking and scoring approaches to classify the hPXR agonist activity of these ToxCast compounds and prioritized them for in vitro screening prior to release of U.S.
EPA 2009); these structures were docked into the five crystal structures of hPXR (1M13, 1NRL, 1SKX, 2O9I, and 2QNV) using the docking program GOLD (version 4) as described by Jones et al.
We generated a Bayesian classification model using Discovery Studio 2.1 with the Laplacian-corrected Bayesian classifier and molecular descriptors, as previously described for 115 steroidal compounds (namely, androstanes, estratrienes, pregnanes, and bile salts), with hPXR activation determined by a luciferase-based reporter assay (Ekins et al.
We determined hPXR activation in HepG2 cells using a luciferase-based reporter assay, as previously described (Ekins et al.
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