Abstract
The human genome contains numerous single nucleotide variations, and the human glucocorticoid receptor (GR) gene harbors ∼450 of these genetic changes. Among them, extremely rare, nonsynonymous variants, known as pathologic GR gene mutations, develop a characteristic pathologic condition, familial/sporadic generalized glucocorticoid resistance syndrome, by replacing the amino acids critical for GR protein structure and functions, whereas others, known as pathologic polymorphisms, develop mild manifestations recognized mainly at population bases by changing the GR activities slightly. Recent progress on the structural analysis to the GR protein and subsequent computer-based structural simulation revealed details of the molecular defects caused by such pathologic GR gene mutations, including their impact on the receptor interaction to ligands, nuclear receptor coactivators (NCoAs) or DNA glucocorticoid response elements (GREs). Indeed, those found in the GR ligand-binding domain significantly damage protein structure of the ligand-binding pocket and/or the activation function-2 transactivation domain and change their molecular interaction to glucocorticoids or the LxxLL signature motif of NCoAs. Two mutations found in GR DNA-binding domain also affect interaction of the mutant receptors to GRE DNA by affecting the critical amino acid for the interaction or changing local hydrophobic circumstance. In this review, I discuss recent findings on the structural simulation of the pathologic GR mutants in connection to their functional and clinical impacts, along with a brief explanation to recent research achievement on the GR polymorphisms.
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