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

R. E. Watkins, G. B. Wisely, L. B. Moore, J. L. Collins, M. H. Lambert, S. P. Williams, T. M. Willson, S. A. Kliewer, M. R. Redinbo

Research output: Contribution to journalArticle

659 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2329-2333
Number of pages5
JournalScience
Volume292
Issue number5525
DOIs
StatePublished - Jun 22 2001

ASJC Scopus subject areas

  • General

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    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. (2001). The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity. Science, 292(5525), 2329-2333. https://doi.org/10.1126/science.1060762