Abstract
The Pregnane X Receptor (PXR) is a ligand-activated transcription factor belonging to the nuclear receptor family. PXR can bind diverse drugs and environmental toxicants with different binding modes, making it an intriguing target for drug discovery. Here we investigated the binding mechanism of the SR12813 ligand to elucidate the significant steps, from the ligand entrance pathway into the binding cavity, to the ligand-induced conformational changes, and to the exploration of its alternative binding geometries. We used the advanced Molecular Dynamics-based methods implemented in the BiKi suite and developed specific methodological approaches to overcome the complexity induced by the buried and flexible binding cavity. The adopted methods provided a full dynamic description of the binding event and allowed rationalization of the observed multiple binding modes. These results suggest that the same approach could be exploited for the study of other binding processes with similar characteristics.
Highlights
The Pregnane X Receptor (PXR or NR1I2) is a nuclear receptor (NR) that has important roles in drug metabolism and drug-drug interactions
It has been suggested that the human PXR acts as a gene silencer, i.e. it is constitutively bound to DNA as heterodimer with the Retinoid X receptor (RXR) and in this form it silences transcription of target genes[7]
The two protein partners bind in different regions: RXR dimerizes with the α9/α10 PXR helices, while SRC-1 binds to the αAF helix
Summary
The Pregnane X Receptor (PXR or NR1I2) is a nuclear receptor (NR) that has important roles in drug metabolism and drug-drug interactions It regulates the expression of genes encoding drug-metabolizing enzymes (CYPs), which enhancement may lead to an undesired decrease in the bioavailability of many prescribed drugs[1]. For this reason, elucidation of the exact molecular mechanism that underlies PXR activation has important implications for drug development processes[2]. The ligand binding domain (LBD) is located at the C-term of the receptor and forms a heterodimer with RXR8,9. The interaction with an agonist within the binding cavity leads to the exposure of the hydrophobic surface of αAF and promotes co-activator binding[4]
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