Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation

Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action.