The PXR ligand-binding domain: how to be picky and promiscuous at the same time

Abstract

The pregnane-X receptor (PXR) – or should that be ‘promiscuous xenobiotic receptor’ – has hit the headlines again. The PXR is the nuclear receptor that upregulates the body's primary chemical defense system in response to challenge. In particular, PXR induces CYP3A4, a cytochrome P450 that has exceptional versatility in the substrates it can metabolize, and therefore potentially detoxify. Unfortunately, PXR-mediated induction of CYP3A4 leads to many adverse drug interactions, where one drug enhances the metabolism of another. PXR can be activated by a range of ligands that is almost as diverse as the substrates of CYP3A4, including many drugs [e.g. steroids (dexamethasone) and macrolide antibiotics (rifampicin)]; however, PXR can also display considerable discretion. Watkins et al.1 Watkins R.E. et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science. 2001; 292: 2329-2333 Crossref PubMed Scopus (704) Google Scholar have now helped to rationalize this selective promiscuity by solving the structure of the ligand-binding domain (LBD) of the PXR in the presence and absence of a prototypical inducer, SR12813.