毒理学相关资料,第四章内容参考文献5.docVIP

窗体顶端 Copyright ? 2001 by the American Association for the Advancement of Science Volume 292(5525)? ? ? ? ? ? ?22 June 2001? ? ? ? ? ? ?pp 2329-2333 The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity [Research: Reports] Watkins, Ryan E.1; Wisely, G. Bruce3; Moore, Linda B.3; Collins, Jon L.3; Lambert, Millard H.3; Williams, Shawn P.3; Willson, Timothy M.3; Kliewer, Steven A.3; Redinbo, Matthew R.2* 1Department of Biochemistry and Biophysics, School of Medicine, 2Department of Chemistry and Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC 27599, USA. 3Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. *To whom correspondence should be addressed. E-mail: redinbo@ 16 March 2001; accepted 11 May 2001 Published online 14 June 2001; 10.1126/science. 1060762 Include this information when citing this paper. Outline Abstract References and Notes Graphics Table 1 Fig. 1 Fig. 2 Fig. 3 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.  The pregnane X receptor (PXR; also known as NR1I2), a member of the nuclear receptor family of ligand-activated transcription