Insights from a Three-Dimensional Model into Ligand Binding to Constitutive Active Receptor
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 rece...
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Published in | Drug metabolism and disposition Vol. 30; no. 9; pp. 951 - 956 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.09.2002
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.30.9.951 |