Agonist versus antagonist induce distinct thermodynamic modes of co-factor binding to the glucocorticoid receptor.
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.
Kroe
Rachel R
RR
Department of Biologics and Biomolecular Sciences, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA.
Baker
Martha A
MA
Brown
Martha P
MP
Farrow
Neil A
NA
Gautschi
Elda
E
Hopkins
Jerry L
JL
LaFrance
Roger R
RR
Kronkaitis
Anthony
A
Freeman
Dorothy
D
Thomson
David
D
Nabozny
Gerald
G
Grygon
Christine A
CA
Labadia
Mark E
ME
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
D008024:Ligands; D010455:Peptides; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D015735:Mifepristone; D003907:Dexamethasone