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Accelerated Communication

Structural Model Reveals Key Interactions in the Assembly of the Pregnane X Receptor/Corepressor Complex

Department of Pharmacology, University of Medicine & Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School and UMDNJ Informatics Institute, Piscataway, New Jersey

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 AF 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.

Address correspondence to: Dr. William J. Welsh, Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. E-mail: welshwj{at}umdnj.edu

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