Vol. 30, Issue 9, 951-956, September 2002

Insights from a Three-Dimensional Model into Ligand Binding to Constitutive Active Receptor

Li Xiao, Xiaoming Cui, Vincent Madison, Ronald E. White, and K.-C. Cheng

Department of Structural Chemistry (L.X., V.M.) and Department of Exploratory Drug Metabolism (X.C., R.E.W., K.-C.C), Schering-Plough Research Institute, Kenilworth, New Jersey

Two orphan nuclear receptors, constitutive active (or androstane) receptor (CAR) and pregnane X receptor (PXR), are among the most important mediators of ligand-activated transcriptional induction of liver microsomal cytochrome P450 drug-metabolizing enzymes. CAR and PXR belong to the same NR1I receptor subfamily and show high sequence homology to each other. The vitamin D receptor (VDR) also belongs to the NR1I subfamily and has the second highest homology to CAR in the ligand binding domain. A 3D model of the ligand binding domain of human CAR (hCAR) was constructed based on the available X-ray structures of human PXR (hPXR) and VDR (hVDR). The model shows that the size of the ligand binding cavities of hCAR and hPXR are similar, but larger than that of hVDR. hPXR's capability of binding to extremely large ligands, such as rifampicin, implies that its binding cavity may be able to expand further through the flexibility of a surface loop. In contrast, hCAR does not have this loop so that its cavity cannot expand, suggesting that hCAR would not bind to the largest hPXR ligands. Docking calculations of selected ligands to hCAR, based on the structural model, are consistent with previously reported receptor binding data. The results from this study indicate that structural modeling will be a useful tool for understanding ligand binding to hCAR and for design of drugs free of hCAR-mediated enzyme induction.