Steroid nuclear hormone receptors: The allosteric conversation

Abstract

Nuclear hormone receptors (NHRs) regulate gene expression by forming complexes with small molecule ligands, other proteins, and DNA. Specific ligands, which include steroids, thyroids, and retinoids, are responsible for the regulation of complex processes in cellular differentiation, homeostasis, reproduction, and development. NHRs responding to steroid ligands (e.g., androgens, estrogens, glucocorticoids, mineralocorticoids, and progesterones) are the focus of this review, in particular, highlighting the subtle relationships between ligand structure and receptor function. In the light of x-ray crystallographic information obtained in recent years, the structural organization of the ligand-and DNAbinding domains of steroid nuclear hormone receptors is well understood. Less clear is the means by which a steroid ligand affects the three-dimensional structure of a receptor, and how subtle differences in ligand structure can lead to major differences in functional activity (agonism, partial agonism, antagonism). Potential mechanisms by which ligands elicit such effects, statistical and mutational techniques used to identify key protein residues likely involved in the transmission of structural information, and novel sites of ligand-protein interaction are discussed in this review. Drug Dev Res 68: 95-106, 2007.

Azaxanthene Based Selective Glucocorticoid Receptor Modulators: Design, Synthesis, and Pharmacological Evaluation of (S)-4-(5-(1-((1,3,4-Thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and Its Methylene Homologue (BMS-791826)

“…However, the para-substituted benzamide portion of this class of ligands protrudes into the previously identified “meta channel”. It has been noted that perturbation of the homologous region of the estrogen receptor (ERα), through binding of a peptide ligand or residue mutation, leads to altered TIF-2 binding despite its remoteness from the coactivator binding (AF-2) site . The effects of azaxanthene ligand binding on GR coactivator recruitment will be reported at a later date.…”

Ligand-Induced Allosteric Effects Governing SR Signaling

“…ligand binding, mutations) induce effects at a distal site. Mechanisms of allostery in NRs have been heavily reviewed [41][42][43][44][45][46][47] (ii) DNA-coregulator allosteric coupling. NR DBD binding to DNA response elements propagates conformational changes across protein domains, extending to the AF-2 surface and allosterically regulating coregulator association [46,54] ( Figure 3C).…”

Genetically Encoded Bioluminescent Indicators for Stress Hormones

“…In addition, it is interesting to consider the reason that CP-ctrl1 and -ctrl2 weakly respond to cortisol. GR LBD exposes a hydrophobic region to the cytosol upon agonist binding . This may aggregate nonspecifically with the remaining components, GLuc-N and -C, increasing the encounter chance between the split-GLuc fragments.…”