The structural basis of pregnane X receptor binding promiscuity.

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• The human pregnane X receptor (PXR) is a nuclear receptor that regulates genes involved in the metabolism of steroids and xenobiotics.
• PXR is known for its ability to bind a wide array of structurally diverse compounds, making it a promiscuous protein.
• Unlike many other promiscuous proteins, PXR's structure remains largely unchanged upon ligand binding.

Purpose of the Study:

• To investigate the structural basis for the broad ligand-binding promiscuity of the human pregnane X receptor (PXR).
• To identify and characterize the "hot spots" within the PXR binding site that contribute significantly to ligand binding free energy.

Main Methods:

• Computational solvent mapping was employed to identify and characterize hot spots in the PXR binding site.
• Analysis of conserved residues and side chain flexibility within the identified hot spots.

Main Results:

• PXR possesses a smooth, nearly spherical binding site with a well-defined hot spot structure comprising five key regions.
• Three hot spots are present even in the ligand-free PXR, with the most significant one formed by conserved residues W299, F288, and Y306.
• Ligand binding is accommodated by extending into multiple hot spots, explaining PXR's ability to bind diverse compounds.
• Hot spot locations are conserved across mammalian PXRs, and movable side chains further enhance ligand size accommodation.

Conclusions:

• The structural features of the PXR binding site, including multiple conserved and flexible hot spots, explain its remarkable ligand promiscuity.
• These findings suggest conserved evolutionary mechanisms for PXR ligand recognition and potential implications for drug development.
• A unique signal transduction pathway between the PXR homodimerization interface and coactivator binding site was also suggested.