Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Ligand-binding promiscuity in detoxification systems aids the body but hinders drug development.
• Developing safer drugs requires understanding and engineering specificity into promiscuous proteins like pregnane X receptor (PXR).

Purpose of the Study:

• To investigate the structural basis of pregnane X receptor's (PXR) ligand-binding promiscuity.
• To understand how ligand-induced pocket expansion affects PXR binding affinity and activation.

Main Methods:

• X-ray crystallography was used to characterize the structural features of PXR.
• Ligand modifications were engineered to alter compound-protein interactions within the PXR binding pocket.

Main Results:

• Large ligands expand PXR's binding pocket via an unfavorable compound-protein clash, reducing binding affinity.
• Modifying ligands to remove this clash significantly enhanced binding affinity.
• Engineering the clash into a potent PXR ligand reduced its binding and activation, showing PXR remodeling.

Conclusions:

• Ligand-induced binding pocket expansion in PXR is an unfavorable event that can be engineered.
• Drug candidates can be designed to exploit this mechanism, expanding the PXR pocket to reduce safety liabilities.