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Species Differences in Pregnane X Receptor Activation: Examination of common laboratory animal species

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INTRODUCTION

Nuclear receptors (NRs) are ligand-dependent transcription factors found in many species that regulate the expression of important target genes involved in a spectrum of developmental and physiological processes. In addition to ligand binding, the transcriptional activities of NRs are also modulated through a range of protein-protein interactions with coregulatory proteins, either with coactivator or with corepressor functions (1-4). The ligand binding domain (LBD) of NRs is responsible for both ligand recognition and regulation of protein-protein interactions, notably with coregulatory factors. Upon agonist binding, conformational changes are induced within the LBD, particularly the activation function-2 (AF-2) region, which leads to the dissociation of corepressors and recruitment of the coactivator complex, ultimately leading to transcriptional activation from specific DNA response elements. NRs represent important targets for therapeutic interventions for diseases including cancer, inflammation and metabolic diseases. Understanding xenobiotic interactions with NRs is also important in the context of endocrine disruptors and environmental toxicity assessment. One NR with the ability to associate with a wide range of xenobiotics, including pharmaceutical agents, natural products and environmental chemicals is pregnane X receptor (PXR).

[Full Version]

Date of publication: 2016
Author: Jack Vanden Heuvel, PhD; INDIGO Biosciences, Inc.

Filed Under: Whitepapers Tagged With: ortholog, PXR

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