Regulation of nuclear receptors by agonists and antagonists

Abstract

The nuclear receptor superfamily presents an exceptional spectrum of targets for pharmacologic developments. Different members of the superfamily mediate the biological activities of the steroid and thyroid hormones and the vitamins A and D, among others. The pharmacologic potential of the nuclear receptors rests in part on the ability of synthetic derivatives of these hormones and vitamins to completely block, or partially imitate, the activities of the authentic ligand. The activities of these synthetic ligands pose two questions. How do some of them block the action of their cognate receptor? How do others elicit a subset of cognate receptor responses? The recent determination of crystal structures of three nuclear receptor ligand-binding domains presents structural answers to these questions. Ligand-binding domains bind ligand by burying them into the hydrophobic core of the domain. From this position, ligands can remodel the ligand-binding domain conformation. Different ligand-binding domain conformations that reflect differences in the bound ligand can explain the different biological activities elicited. This proposition is related to recent progress in the biology of ligand regulation of nuclear receptor ligand-binding domain activities.