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  • Title: Agonist versus antagonist induce distinct thermodynamic modes of co-factor binding to the glucocorticoid receptor.
    Author: Kroe RR, Baker MA, Brown MP, Farrow NA, Gautschi E, Hopkins JL, LaFrance RR, Kronkaitis A, Freeman D, Thomson D, Nabozny G, Grygon CA, Labadia ME.
    Journal: Biophys Chem; 2007 Jul; 128(2-3):156-64. PubMed ID: 17466438.
    Abstract:
    The glucocorticoid receptor (GR) is involved in the transcriptional regulation of genes associated with inflammation, glucose homeostasis, and bone turnover through the association with ligands, such as corticosteroids. GR-mediated gene transcription is regulated or fine-tuned via the recruitment of co-factors including coactivators and corepressors. Current therapeutic approaches to targeting GR aim to retain the beneficial anti-inflammatory activity of the corticosteroids while eliminating negative side effects. Towards achieving this goal the experiments discussed here reveal a mechanism of co-factor binding in the presence of either bound agonist or antagonist. The GR ligand binding domain (GR-LBD(F602S)), in the presence of agonist or antagonist, utilizes different modes of binding for coactivator versus corepressor. Coactivator binding to the co-effector binding pocket of GR-LBD(F602S) is driven both by favorable enthalpic and entropic interactions whereas corepressor binding to the same pocket is entropically driven. These data support the hypothesis that ligand-induced conformational changes dictate co-factor binding and subsequent trans-activation or trans-repression.
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