RESUMEN
The human nuclear receptor pregnane X receptor (PXR) responds to a wide variety of potentially harmful chemicals and coordinates the expression of genes central to xenobiotic and endobiotic metabolism. Structural studies reveal that the PXR ligand binding domain (LBD) uses a novel sequence insert to form a homodimer unique to the nuclear receptor superfamily. Terminal beta-strands from each monomeric LBD interact in an ideal antiparallel fashion to bury potentially exposed surface beta-strands, generating a 10-stranded intermolecular beta-sheet. Conserved tryptophan and tyrosine residues lock across the dimer interface and provide the first tryptophan-zipper (Trp-Zip) interaction observed in a native protein. We show using analytical ultracentrifugation that the PXR LBD forms a homodimer in solution. We further find that removal of the interlocking aromatic residues eliminates dimer formation but does not affect PXR's ability to interact with DNA, RXRalpha, or ligands. Disruption of the homodimer significantly reduces receptor activity in transient transfection experiments, however, and effectively eliminates the receptor's recruitment of the transcriptional coactivator SRC-1 both in vitro and in vivo. Taken together, these results suggest that the unique Trp-Zip-mediated PXR homodimer plays a role in the function of this nuclear xenobiotic receptor.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/química , Receptores de Esteroides/química , Triptófano/química , ADN/química , ADN/metabolismo , Dimerización , Histona Acetiltransferasas , Humanos , Ligandos , Coactivador 1 de Receptor Nuclear , Receptor X de Pregnano , Estructura Terciaria de Proteína , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptor alfa X Retinoide/química , Receptor alfa X Retinoide/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , UltracentrifugaciónRESUMEN
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 RXRalpha. 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 PXR's 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 receptor's ability to conform to ligands that differ both in size and shape. We also discuss the clinical implications of PXR's role in the drug-drug interactions, cancer, and cholestatic liver disease.