5uc1

Publication Abstract from PubMed

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

Probing Dominant Negative Behavior of Glucocorticoid Receptor beta through a Hybrid Structural and Biochemical Approach.,Min J, Perera L, Krahn JM, Jewell CM, Moon AF, Cidlowski JA, Pedersen LC Mol Cell Biol. 2018 Feb 5. pii: MCB.00453-17. doi: 10.1128/MCB.00453-17. PMID:29437838^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.