E0019

Crystal Structure of Human PXR in Complex with the Hormone. Yu Xue, Sompop Bencharit, Matthew Redinbo, Dept. of Chemistry, Univ. of North Carolina at Chapel Hill, CB 3290#, Chapel Hill, NC 27599-3290.

The nuclear pregnane X receptor (PXR; NR1I2) is an important component of the bodyís adaptive defense against toxic substances including foreign chemicals. It is activated by a wide variety of clinically used drugs and serves as a master regulator of the expression of the CYP3A gene, which encodes for the most abundant and promiscuous drug-metabolizing enzyme in humans. Elucidation of the crystal structure of the PXR ligand binding domain revealed that it has a large spherical ligand binding cavity that allows it to interact with a wide range of hydrophobic chemicals. Here we present the crystal structures of the ligand binding domain of hPXR with breast cancer drug tamoxifen, an estrogen estradiol, and also, with coactivator SRC1 at resolutions of 2.3, 2.8 and 2.1 angstroms, respectively. The hydrophobic ligand ñbinding cavity of hPXR contains small amount of polar residues, which are 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.