RT Journal Article
SR Electronic
T1 Structural Model Reveals Key Interactions in the Assembly of the Pregnane X Receptor/Corepressor Complex
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1513
OP 1517
DO 10.1124/mol.106.022368
VO 69
IS 5
A1 Ching Y. Wang
A1 Chia W. Li
A1 J. Don Chen
A1 William J. Welsh
YR 2006
UL http://molpharm.aspetjournals.org/content/69/5/1513.abstract
AB The human pregnane X receptor (PXR), also known as steroid and xenobiotic receptor, is a member of the orphan nuclear receptors and mediates the mammalian xenobiotic response with broad specificity and implications for drug clearance. The mouse pregnane X receptor is highly similar to the human ortholog in structure but with subtle species differentiation in the ligand binding domain (LBD). The C-terminal helix named αAF or AF-2 helix in other nuclear receptors is responsible for transcription activation by recruiting coactivators through conformational change. In the absence of ligands, PXR can also repress gene expression by interacting with transcriptional corepressors, such as the silencing mediator for retinoid and thyroid hormone receptor (SMRT). We first constructed homology models of the complete LBD with two SMRT nuclear receptor (NR)-interacting domains (ID1 and ID2), respectively. We then performed energy minimization and molecular dynamics simulations on these systems to study the specific interactions between the interacting domains and LBD. Further experimental results supported and validated the observed preference of SMRT toward ID2 over ID1. Our modeling results revealed the key interactions that account for the binding preference. Here, we propose structural models of the PXR-LBD/SMRT-ID1 and PXR-LBD/SMRT-ID2 complexes to understand their molecular interactions and potential inhibitory mechanism.