![[logo] US EPA](http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
2007 CompTox Forum
Abstract - Motion and Antagonism of the Human Xenobiotic Receptor PXR
Matthew R. Redinbo, Ph.D.
Professor of Chemistry & Biochemistry
University of North Carolina at Chapel Hill
Department of Chemistry (CB#3290), Chapel Hill, NC 27599-3290
Phone: 919-843-8910
E-mail: redinbo@unc.edu
The nuclear receptor PXR is a primary drug and xenobiotic receptor in human tissues and regulates the expression of key drug metabolism enzymes and efflux pumps. The receptor functions as both a heterodimer with RXR, another member of the nuclear receptor superfamily of transcription factors, and as a PXR homodimer via a unique b-strand-mediated interface. Analysis by molecular dynamics trajectories indicate that long-range motions from this b-strand homodimer interface are essential for producing a functional receptor AF-2 surface that can interact with members of the p160 family of transcriptional coactivators. Antagonism of PXR can also be achieved by disrupting protein-protein interactions at the AF-2 surface using specific small molecules, which represses the activation of drug metabolism pathways in a PXR-dependent fashion in mice. These results suggest that the short-term modulation of drug metabolism pathways using PXR antagonists may successfully improve the therapeutic treatment of human disease.