The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity

The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A e xpression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 a ngstroms, respectively. The hydrophobic ligand-binding cavity of hPXR conta ins a small number of polar residues, permitting SR12813 to bind in three d istinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detec ts xenobiotics and may prove useful in predicting and avoiding drug-drug in teractions.