Structure and Function of the Human Nuclear Xenobiotic Receptor PXR

V.   E.   Carnahan; M.   R.   Redinbo

doi:10.2174/1389200054633844

Abstract

The pregnane X receptor (PXR) is a member of the nuclear receptor family of ligand-regulated transcription factors. Like many former orphan nuclear receptors, it contains both DNA and ligand binding domains and binds to response elements in the regulatory regions of target genes as a heterodimer with RXRα. Unlike the vast majority of nuclear receptors, however, PXR responds to a wide variety of chemically distinct xenobiotics and endobiotics, regulating the expression of genes central to both drug and bile acid metabolism. We review the structural basis of PXRs promiscuity in ligand binding, its recruitment of transcriptional coregulators, its potential formation of higher-order nuclear receptor complexes, and its control of target gene expression. Structural flexibility appears to be central to the receptors ability to conform to ligands that differ both in size and shape. We also discuss the clinical implications of PXRs role in the drugdrug interactions, cancer, and cholestatic liver disease.

Keywords: promiscuity, structural flexibility, drug metabolism, polymorphism, cancer, drug interactions, cholestasis, transcription