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

Abstract

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

Authors:
 [1];  [1];  [1];  [2];  [1];  [2]; ORCiD logo [1]
  1. National Inst. of Health (NIH), Research Triangle Park, NC (United States). National Inst. of Environmental Health Sciences, Genome Integrity and Structural Biology Lab.
  2. National Inst. of Health (NIH), Research Triangle Park, NC (United States). National Inst. of Environmental Health Sciences, Signal Transduction Lab.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH), National Institute of Environmental Health Sciences; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1435832
Grant/Contract Number:  
ZIA ES102645; Z01 ES043010; Z01 ES090057; W-31-109-Eng-38
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecular and Cellular Biology
Additional Journal Information:
Journal Volume: 38; Journal Issue: 8; Journal ID: ISSN 0270-7306
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; glucocorticoid receptor beta (GRβ), RU-486; dominant negative; glucocorticoid resistance; transrepression

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. https://www.osti.gov/servlets/purl/1435832.
@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 = {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 furthermore, 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},
issn = {0270-7306},
number = 8,
volume = 38,
place = {United States},
year = {2018},
month = {2}
}

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