The human
pregnane X receptor (PXR) is a member of the
nuclear receptor superfamily of
ligand-regulated
transcription factors. PXR responds to a structurally diverse variety of endogenous and
xenobiotic compounds, and coordinates the expression of genes central to the metabolism and excretion of potentially harmful chemicals, including human
therapeutics. The
reverse transcriptase inhibitor PNU-142721 has been designed to treat human immunodeficiency virus (
HIV) infection. Although this compound has anti-HIV activity, it was established using cell-based assays that
PNU-142721 is an efficacious PXR agonist. We present here the 2.8 Å resolution crystal structure of the human PXR
ligand-binding domain in complex with
PNU-142721. PXR employs one hydrogen bond and fourteen van der Waals contacts to interact with the
ligand, but allows two loops adjacent to the
ligand-binding pocket to remain disordered in the structure. These observations highlight the role structural flexibility plays in PXR's promiscuous responses to
xenobiotics. The crystal structure also explains why PNU-173575, a thiomethyl metabolite of
PNU-142721, exhibits enhanced PXR activation relative to the unmodified compound and why
PNU-142721 can also activate rat PXR. Taken together, the results presented here elucidate the structural basis for PXR activation by
PNU-142721 and related chemicals.