title: The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
abstract: The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression 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 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct 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 detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Watkins
authors.forename: G B
authors.initials: GB
authors.lastname: Wisely
authors.forename: L B
authors.initials: LB
authors.lastname: Moore
authors.forename: J L
authors.initials: JL
authors.lastname: Collins
authors.forename: M H
authors.initials: MH
authors.lastname: Lambert
authors.forename: S P
authors.initials: SP
authors.lastname: Williams
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
authors.forename: S A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: M R
authors.initials: MR
authors.lastname: Redinbo
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry* / Q000378:metabolism*; D012293:Rifampin / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D004164:Diphosphonates; D008024:Ligands; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C100355:SR 12813; D015262:Xenobiotics; D012293:Rifampin