Murine CAR nuclear receptor/inverse agonist androstenol complex
Mus musculus (house mouse)
Various small, hydrophobic signal molecules function by directly entering cells and binding to various receptors. These receptors then bind to DNA at specific sequences and regulate the transcription of the genes in that region. These genes further regulate the transcription of other genes resulting in a complex pattern of change in gene expression. Steroid hormones, thyroid hormones, retinoids and vitamin D are such molecules. The receptors of all these molecules are structurally related and form a large family called the nuclear receptor superfamily. All nuclear receptors have a DNA binding domain (DBD) with which they bind to specific sequences of DNA, and a ligand binding domain (LBD) where the signal molecules bind. Some nuclear receptors are primarily found in the cytosol and translocate to the nucleus on ligand binding. Others are already bound to specific DNA sequences and are activated on ligand binding. Almost all of the nuclear receptors are bound to inhibitory protein complexes when inactive. Ligand binding changes the conformation of the receptor to free it from the inhibitory protein complex and expose the binding site for transcriptional coactivator proteins. Coactivator proteins bind these sites on the nuclear receptor and induce gene transcription.
The structure shown here is that of two molecules of constitutive androstane receptor (CAR), a nuclear receptor, with a bound androstenol molecule. CAR plays an important role in the clearance of xenobiotics (drugs, carcinogens and other compounds that have been introduced in the environment by artificial means) and toxins found in the body. CAR is also known to promote the toxicity of acetaminophen and cocaine. Though CAR is a member of the nuclear receptor superfamily, it functions in a manner that is reverse to the other nuclear receptors. In its apo (unbound) form, it forms a heterodimer with the retinoid X receptor (RXR) and is constitutively or always active, though its activity may be partially enhanced by agonists. This constitutive activity of CAR can be reversed by the binding of a class of compounds called inverse agonists. Androstenol is one such molecule. In CAR, a small helix forms the domain where the transcriptional coactivator binds, called the transactivation domain. In the apo state, the conformation of CAR is such that this helix is stabilized, allowing the coactivator to bind and induce gene transcription. On binding of androstenol to CAR, the helix is moved away from the rest of the CAR receptor allowing corepressors (proteins repressing gene transcription) to bind thus preventing gene transcription.
Protein Data Bank (PDB)
author: Ashwini Patil