5UC1

Structural Analysis of Glucocorticoid Receptor beta Ligand Binding Domain Complexed with Glucocorticoid Antagonist RU-486: Implication of Helix 12 in Antagonism

Summary for 5UC1

• Entry DOI: 10.2210/pdb5uc1/pdb
• Related: 5UC3
• Descriptor: Glucocorticoid receptor, 11-(4-DIMETHYLAMINO-PHENYL)-17-HYDROXY-13-METHYL-17-PROP-1-YNYL-1,2,6,7,8,11,12,13,14,15,16,17-DODEC AHYDRO-CYCLOPENTA[A]PHENANTHREN-3-ONE, 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE, ... (7 entities in total)
• Functional Keywords: nuclear receptor, hormone receptor
• Biological source: Heterocephalus glaber (Naked mole rat)
• Total number of polymer chains: 2
• Total formula weight: 55276.61

Authors

Pedersen, L.C.,Min, J. (deposition date: 2016-12-21, release date: 2017-12-27, Last modification date: 2023-10-04)

Primary citation

Min, J.,Perera, L.,Krahn, J.M.,Jewell, C.M.,Moon, A.F.,Cidlowski, J.A.,Pedersen, L.C.
Probing Dominant Negative Behavior of Glucocorticoid Receptor beta through a Hybrid Structural and Biochemical Approach.
Mol. Cell. Biol., 2018

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

PubMed: 29437838
DOI: 10.1128/MCB.00453-17

Experimental method

X-RAY DIFFRACTION (2.351 Å)