PXR plays an important role in recognizing drugs and other harmful chemicals in the human body. PXR is unique in the family of nuclear receptors in its ability to be activated by a wide variety of structurally distinct chemicals (from endogenous to xenobiotic), and in its sequence divergence across species. Thus, a crystal structure of the ligand binding domain of PXR, which is largely what we presented in this paper, allowed the first views of how PXR achieves both promiscuity and specificity in ligand binding.

The structural results we present in this paper could be used to screen drug leads for the potential to activate PXR, something you’d ideally like to avoid in a clinical drug. Indeed, PXR has been linked to dangerous drug-drug interactions in humans. For example, components of the herbal remedy St. John’s wort activate PXR well, which in turn activates numerous drug metabolism pathways that eliminate other drugs present in a patient, including oral contraceptives and anti-HIV drugs.

We presented the first detailed, structural views of a key, front-line drug receptor at work in the human liver and intestine. PXR recognizes many of the drugs we take as foreign, and initiates the process of drug breakdown and removal.

This work was a collaboration between my laboratory and scientists at GlaxoSmithKline, including Bruce Wisely, Steven Kliewer, and Tim Willson.