Publication Date:
2001-06-16
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watkins, R E -- Wisely, G B -- Moore, L B -- Collins, J L -- Lambert, M H -- Williams, S P -- Willson, T M -- Kliewer, S A -- Redinbo, M R -- New York, N.Y. -- Science. 2001 Jun 22;292(5525):2329-33. Epub 2001 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11408620" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Binding Sites
;
Crystallography, X-Ray
;
Diphosphonates/chemistry/*metabolism
;
Humans
;
Ligands
;
Models, Molecular
;
Molecular Sequence Data
;
Protein Conformation
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Receptors, Cytoplasmic and Nuclear/*chemistry/*metabolism
;
Receptors, Steroid/*chemistry/*metabolism
;
Rifampin/metabolism
;
Xenobiotics/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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