title: Agonist versus antagonist induce distinct thermodynamic modes of co-factor binding to the glucocorticoid receptor.
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.
authors.affiliation: Department of Biologics and Biomolecular Sciences, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Kroe
authors.forename: Martha A
authors.initials: MA
authors.lastname: Baker
authors.forename: Martha P
authors.initials: MP
authors.lastname: Brown
authors.forename: Neil A
authors.initials: NA
authors.lastname: Farrow
authors.forename: Elda
authors.initials: E
authors.lastname: Gautschi
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Hopkins
authors.forename: Roger R
authors.initials: RR
authors.lastname: LaFrance
authors.forename: Anthony
authors.initials: A
authors.lastname: Kronkaitis
authors.forename: Dorothy
authors.initials: D
authors.lastname: Freeman
authors.forename: David
authors.initials: D
authors.lastname: Thomson
authors.forename: Gerald
authors.initials: G
authors.lastname: Nabozny
authors.forename: Christine A
authors.initials: CA
authors.lastname: Grygon
authors.forename: Mark E
authors.initials: ME
authors.lastname: Labadia
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D003907:Dexamethasone / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D015735:Mifepristone / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D010455:Peptides; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D015735:Mifepristone; D003907:Dexamethasone