In the human liver, nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A in response to a wide variety of drugs and plays a critical role in mediating drug-drug interactions. In June 14 Sciencexpress Ryan Watkins and colleagues from the University of North Carolina at Chapel Hill, and GlaxoSmithKline US, report the three-dimensional structure and mechanism of binding of hPXR. These discoveries help to explain its ability to interact with so many different drug molecules.

Watkins et al. used X-ray crystallography to evaluate the structure of hPXR alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 Å. They found that hPXR has a hydrophobic ligand-binding cavity that contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues are critical for establishing the precise pharmacologic activation profile of hPXR (Sciencexpress...

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