Abstract
Nuclear receptors are targets for a wide range of ligands, both natural and synthetic, which regulate their activity and provide a means to pharmacologically modulate the receptor. Recent emphasis in the nuclear receptor field has focused on selective nuclear receptor modulators, which can display graded transcriptonal responses and tissue selective pharmacological responses that deviate from the prototypical agonist or antagonist. Understanding the molecular mechanism of action of these selective modulators will provide significant insight towards the development of the next generation of modulators. Although most nuclear receptor structural studies have primarily focused on obtaining ligand-receptor co-crystal structures, recent studies implicate an important role for protein dynamics in the mechanism of action of nuclear receptor ligands. Here we review nuclear receptor studies reporting how ligands modulate the conformational dynamics of the nuclear receptor ligand-binding domain (LBD). A particular emphasis is placed on protein NMR and hydrogen/deuterium exchange (HDX) techniques, and how they provide complimentary information that, when combined with crystallography, provides detailed insight into the function of nuclear receptors.
- PPARs
- Vitamin D
- Structure-activity relationships and modeling
- Mass Spectroscopy
- NMR
- Nuclear Magnetic Resonance
- Receptor binding studies
- X-ray crystallography
- Received April 12, 2012.
- Revision received July 10, 2012.
- Accepted August 6, 2012.
- The American Society for Pharmacology and Experimental Therapeutics