Probing Dominant Negative Behavior of Glucocorticoid Receptor ? through a Hybrid Structural and Biochemical Approach.

ABSTRACT: Glucocorticoid receptor ? (GR?) is associated with glucocorticoid resistance via dominant negative regulation of GR?. To better understand how GR? functions as a dominant negative inhibitor of GR? at a molecular level, we determined the crystal structure of the ligand binding domain of GR? complexed with the antagonist RU-486. The structure reveals that GR? binds RU-486 in the same ligand binding pocket as GR?, and the unique C-terminal amino acids of GR? are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GR? do not contribute to RU-486 binding. Intriguingly, the GR?/RU-486 complex binds corepressor peptide with affinity similar to that of a GR?/RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analyses reveal that in the presence of RU-486, GR? is found in a conformation that favors corepressor binding, potentially antagonizing GR? function. This study thus presents an unexpected molecular mechanism by which GR? could repress transcription.

SUBMITTER: Min J 

PROVIDER: S-EPMC5879464 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature