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Submitted on September 3, 2004
Accepted on January 14, 2005
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709; Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Biochemistry & Biophysics, Program in Molecular Biology and Biotechnology, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
* To whom correspondence should be addressed. E-mail: redinbo{at}unc.edu.
The human nuclear xenobiotic receptor PXR detects a variety of structurally-distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 Å crystal structure of the ligand binding domain (LBD) of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the "directed promiscuity" exhibited by the PXRs across species. Three structurally-flexible loops adjacent to the ligand binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics.
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