Docking for fragment inhibitors of AmpC beta-lactamase.

Fragment screens for new ligands have had wide success, notwithstanding their constraint to libraries of 1,000-10,000 molecules. Larger libraries would be addressable were molecular docking reliable for fragment screens, but this has not been widely accepted. To investigate docking's ability to prioritize fragments, a library of >137,000 such molecules were docked against the structure of beta-lactamase.

Structural basis of human pregnane X receptor activation by the hops constituent colupulone.

Hops extracts are used to alleviate menopausal symptoms and as an alternative to hormone replacement therapy, but they can produce potentially harmful drug-drug interactions. The nuclear xenobiotic receptor pregnane X receptor (PXR) is promiscuously activated by a range of structurally distinct chemicals. It has a key role in the transcriptional regulation of genes that encode xenobiotic metabolism enzymes.

Active nuclear receptors exhibit highly correlated AF-2 domain motions.

Nuclear receptor ligand binding domains (LBDs) convert ligand binding events into changes in gene expression by recruiting transcriptional coregulators to a conserved activation function-2 (AF-2) surface. While most nuclear receptor LBDs form homo- or heterodimers, the human nuclear receptor pregnane X receptor (PXR) forms a unique and essential homodimer and is proposed to assemble into a functional heterotetramer with the retinoid X receptor (RXR). How the homodimer interface, which is located 30 A from the AF-2, would affect function at this critical surface has remained unclear.

Activated pregnenolone X-receptor is a target for ketoconazole and its analogs.

Purpose: Variations in biotransformation and elimination of microtubule-binding drugs are a major cause of unpredictable side effects during cancer therapy. Because the orphan receptor, pregnenolone X-receptor (PXR), coordinately regulates the expression of paclitaxel metabolizing and transport enzymes, controlling this process could improve therapeutic outcome.

Experimental Design: In vitro RNA-, protein-, and transcription-based assays in multiple cell lines derived from hepatocytes and PXR wild-type and null mouse studies were employed to show the effects of ketoconazole and its analogues on ligand-activated PXR-mediated gene transcription and translation.

The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges.

The nuclear receptor pregnane X receptor (PXR) plays a key but structurally enigmatic role in human biology. This ligand-regulated transcription factor responds to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs, and regulates the expression of a critical set of protective gene products involved in xenobiotic and endobiotic metabolism. The structural basis of this receptor's remarkable and unique promiscuity is just now coming into focus.