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Title: Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach

Abstract

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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1435832
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular and Cellular Biology; Journal Volume: 38; Journal Issue: 8
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Min, Jungki, Perera, Lalith, Krahn, Juno M., Jewell, Christine M., Moon, Andrea F., Cidlowski, John A., and Pedersen, Lars C. Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach. United States: N. p., 2018. Web. doi:10.1128/MCB.00453-17.
Min, Jungki, Perera, Lalith, Krahn, Juno M., Jewell, Christine M., Moon, Andrea F., Cidlowski, John A., & Pedersen, Lars C. Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach. United States. doi:10.1128/MCB.00453-17.
Min, Jungki, Perera, Lalith, Krahn, Juno M., Jewell, Christine M., Moon, Andrea F., Cidlowski, John A., and Pedersen, Lars C. Mon . "Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach". United States. doi:10.1128/MCB.00453-17.
@article{osti_1435832,
title = {Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach},
author = {Min, Jungki and Perera, Lalith and Krahn, Juno M. and Jewell, Christine M. and Moon, Andrea F. and Cidlowski, John A. and Pedersen, Lars C.},
abstractNote = {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.},
doi = {10.1128/MCB.00453-17},
journal = {Molecular and Cellular Biology},
number = 8,
volume = 38,
place = {United States},
year = {Mon Feb 05 00:00:00 EST 2018},
month = {Mon Feb 05 00:00:00 EST 2018}
}