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

Min, Jungki; Perera, Lalith; Krahn, Juno M.; Jewell, Christine M.; Moon, Andrea F.; Cidlowski, John A.; Pedersen, Lars C.

doi:10.1128/MCB.00453-17

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

Journal Article · Mon Feb 05 00:00:00 EST 2018 · Molecular and Cellular Biology

DOI:https://doi.org/10.1128/MCB.00453-17· OSTI ID:1435832

Min, Jungki ^[1]; Perera, Lalith ^[1]; Krahn, Juno M. ^[1]; Jewell, Christine M. ^[2]; Moon, Andrea F. ^[1]; Cidlowski, John A. ^[2];

^[1]

National Inst. of Health (NIH), Research Triangle Park, NC (United States). National Inst. of Environmental Health Sciences, Genome Integrity and Structural Biology Lab.
National Inst. of Health (NIH), Research Triangle Park, NC (United States). National Inst. of Environmental Health Sciences, Signal Transduction Lab.

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH), National Institute of Environmental Health Sciences; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: ZIA ES102645; Z01 ES043010; Z01 ES090057; W-31-109-Eng-38

OSTI ID:: 1435832

Journal Information:: Molecular and Cellular Biology, Vol. 38, Issue 8; ISSN 0270-7306

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 5 works

Citation information provided by
Web of Science

References (50)

Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Reveals a Novel Mode of Receptor Dimerization and Coactivator Recognition Bledsoe, Randy K.; Montana, Valerie G.; Stanley, Thomas B. Cell, Vol. 110, Issue 1 https://doi.org/10.1016/S0092-8674(02)00817-6	journal	July 2002
Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs Rhen, Turk; Cidlowski, John A. New England Journal of Medicine, Vol. 353, Issue 16 https://doi.org/10.1056/NEJMra050541	journal	October 2005
The Human Glucocorticoid Receptor Isoform: EXPRESSION, BIOCHEMICAL PROPERTIES, AND PUTATIVE FUNCTION Oakley, Robert H.; Sar, Madhabananda; Cidlowski, John A. Journal of Biological Chemistry, Vol. 271, Issue 16 https://doi.org/10.1074/jbc.271.16.9550	journal	April 1996
Gene regulation by steroid hormones Beato, Miguel Cell, Vol. 56, Issue 3 https://doi.org/10.1016/0092-8674(89)90237-7	journal	February 1989
The Physiology of Human Glucocorticoid Receptor beta (hGRbeta) and Glucocorticoid Resistance Lewis-Tuffin, L. J. Annals of the New York Academy of Sciences, Vol. 1069, Issue 1 https://doi.org/10.1196/annals.1351.001	journal	June 2006
Ligand-selective transactivation and transrepression via the glucocorticoid receptor: Role of cofactor interaction Ronacher, Katharina; Hadley, Katie; Avenant, Chanel Molecular and Cellular Endocrinology, Vol. 299, Issue 2 https://doi.org/10.1016/j.mce.2008.10.008	journal	February 2009
Increased number of glucocorticoid receptor-β–expressing cells in the airways in fatal asthma Christodoulopoulos, Pota; Leung, Donald Y. M.; Elliott, Mark W. Journal of Allergy and Clinical Immunology, Vol. 106, Issue 3 https://doi.org/10.1067/mai.2000.109054	journal	September 2000
GRβ expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone☆ Hamilos, Daniel L.; Leung, Donald Y. M.; Muro, Shegio Journal of Allergy and Clinical Immunology, Vol. 108, Issue 1 https://doi.org/10.1067/mai.2001.116428	journal	July 2001
Isolation of a cDNA Encoding Human Rev-ErbAα: Transcription from the Noncoding DNA Strand of a Thyroid Hormone Receptor Gene Results in a Related Protein That Does Not Bind Thyroid Hormone Lazar, Mitchell A.; Jones, Karen E.; Chin, William W. DNA and Cell Biology, Vol. 9, Issue 2 https://doi.org/10.1089/dna.1990.9.77	journal	March 1990
Comparative Protein Structure Modeling Using Modeller Eswar, Narayanan; Webb, Ben; Marti-Renom, Marc A. Current Protocols in Bioinformatics, Vol. 15, Issue 1 https://doi.org/10.1002/0471250953.bi0506s15	journal	September 2006
DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity Meijsing, S. H.; Pufall, M. A.; So, A. Y. Science, Vol. 324, Issue 5925 https://doi.org/10.1126/science.1164265	journal	April 2009
Imbalanced Expression of the Glucocorticoid Receptor Isoforms in Cultured Lymphocytes from a Patient with Systemic Glucocorticoid Resistance and Chronic Lymphocytic Leukemia Shahidi, Homayoun; Vottero, Alessandra; Stratakis, Constantine A. Biochemical and Biophysical Research Communications, Vol. 254, Issue 3 https://doi.org/10.1006/bbrc.1998.9980	journal	January 1999
Significance of glucocorticoid receptor expression in colonic mucosal cells of patients with ulcerative colitis Zhang, Hu World Journal of Gastroenterology, Vol. 11, Issue 12 https://doi.org/10.3748/wjg.v11.i12.1775	journal	January 2005
Widespread Negative Response Elements Mediate Direct Repression by Agonist- Liganded Glucocorticoid Receptor Surjit, Milan; Ganti, Krishna Priya; Mukherji, Atish Cell, Vol. 145, Issue 2 https://doi.org/10.1016/j.cell.2011.03.027	journal	April 2011
Expression of glucocorticoid receptor β in lymphocytes of patients with glucocorticoid-resistant ulcerative colitis Honda, Mitsunori; Orii, Fumika; Ayabe, Tokiyoshi Gastroenterology, Vol. 118, Issue 5 https://doi.org/10.1016/S0016-5085(00)70172-7	journal	May 2000
Nuclear Receptor Coregulators: Cellular and Molecular Biology* McKenna, Neil J.; Lanz, Rainer B.; O’Malley, Bert W. Endocrine Reviews, Vol. 20, Issue 3 https://doi.org/10.1210/edrv.20.3.0366	journal	June 1999
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Molecular Switch in the Glucocorticoid Receptor: Active and Passive Antagonist Conformations Schoch, Guillaume A.; D'Arcy, Brigitte; Stihle, Martine Journal of Molecular Biology, Vol. 395, Issue 3 https://doi.org/10.1016/j.jmb.2009.11.011	journal	January 2010
Gene regulation by the glucocorticoid receptor: Structure:function relationship Kumar, Raj; Thompson, E. Brad The Journal of Steroid Biochemistry and Molecular Biology, Vol. 94, Issue 5 https://doi.org/10.1016/j.jsbmb.2004.12.046	journal	April 2005
Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. Bamberger, C. M.; Bamberger, A. M.; de Castro, M. Journal of Clinical Investigation, Vol. 95, Issue 6 https://doi.org/10.1172/JCI117943	journal	June 1995
The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease Oakley, Robert H.; Cidlowski, John A. Journal of Allergy and Clinical Immunology, Vol. 132, Issue 5 https://doi.org/10.1016/j.jaci.2013.09.007	journal	November 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor Leung, D. Y. M.; Hamid, Q.; Vottero, A. Journal of Experimental Medicine, Vol. 186, Issue 9 https://doi.org/10.1084/jem.186.9.1567	journal	November 1997
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions Krissinel, E.; Henrick, K. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12 https://doi.org/10.1107/S0907444904026460	journal	November 2004
Translational Regulatory Mechanisms Generate N-Terminal Glucocorticoid Receptor Isoforms with Unique Transcriptional Target Genes Lu, Nick Z.; Cidlowski, John A. Molecular Cell, Vol. 18, Issue 3 https://doi.org/10.1016/j.molcel.2005.03.025	journal	April 2005
Increased Glucocorticoid Receptor β in Airway Cells of Glucocorticoid-insensitive Asthma Hamid, Qutayba A.; Wenzel, Sally E.; Hauk, Pia J. American Journal of Respiratory and Critical Care Medicine, Vol. 159, Issue 5 https://doi.org/10.1164/ajrccm.159.5.9804131	journal	May 1999
Mechanisms involved in the side effects of glucocorticoids Schacke, H. Pharmacology & Therapeutics, Vol. 96, Issue 1 https://doi.org/10.1016/S0163-7258(02)00297-8	journal	October 2002
Low Glucocorticoid Receptor α/β Ratio in T-cell Lymphoblastic Leukemia Longui, C.; Vottero, A.; Adamson, P. Hormone and Metabolic Research, Vol. 32, Issue 10 https://doi.org/10.1055/s-2007-978661	journal	October 2000
Quantitative analysis for human glucocorticoid receptor α/β mRNA in IBD Orii, Fumika; Ashida, Toshifumi; Nomura, Masafumi Biochemical and Biophysical Research Communications, Vol. 296, Issue 5 https://doi.org/10.1016/S0006-291X(02)02030-2	journal	September 2002
Mifepristone Inhibits GRβ Coupled Prostate Cancer Cell Proliferation Ligr, Martin; Li, Yirong; Logan, Susan K. Journal of Urology, Vol. 188, Issue 3 https://doi.org/10.1016/j.juro.2012.04.102	journal	September 2012
Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta Yudt, M. R.; Jewell, C. M.; Bienstock, R. J. Molecular and Cellular Biology, Vol. 23, Issue 12 https://doi.org/10.1128/MCB.23.12.4319-4330.2003	journal	June 2003
Structure of Rev-erbα bound to N-CoR reveals a unique mechanism of nuclear receptor–co-repressor interaction Phelan, Caroline A.; Gampe, Robert T.; Lambert, Millard H. Nature Structural & Molecular Biology, Vol. 17, Issue 7 https://doi.org/10.1038/nsmb.1860	journal	June 2010
Expression and Subcellular Distribution of the β-Isoform of the Human Glucocorticoid Receptor ¹ Oakley, Robert H.; Webster, Jeffrey C.; Sar, Madhabananda Endocrinology, Vol. 138, Issue 11 https://doi.org/10.1210/endo.138.11.5501	journal	November 1997
RU486-induced Glucocorticoid Receptor Agonism Is Controlled by the Receptor N Terminus and by Corepressor Binding Schulz, Martin; Eggert, Martin; Baniahmad, Aria Journal of Biological Chemistry, Vol. 277, Issue 29 https://doi.org/10.1074/jbc.M203268200	journal	May 2002
Primary structure and expression of a functional human glucocorticoid receptor cDNA Hollenberg, Stanley M.; Weinberger, Cary; Ong, Estelita S. Nature, Vol. 318, Issue 6047 https://doi.org/10.1038/318635a0	journal	December 1985
Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver He, Bo; Cruz-Topete, Diana; Oakley, Robert H. Molecular and Cellular Biology, Vol. 36, Issue 5 https://doi.org/10.1128/MCB.00908-15	journal	December 2015
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Human Glucocorticoid Receptor β Binds RU-486 and Is Transcriptionally Active Lewis-Tuffin, Laura J.; Jewell, Christine M.; Bienstock, Rachelle J. Molecular and Cellular Biology, Vol. 27, Issue 6 https://doi.org/10.1128/MCB.01439-06	journal	January 2007
Conformational changes of the glucocorticoid receptor ligand binding domain induced by ligand and cofactor binding, and the location of cofactor binding sites determined by hydrogen/deuterium exchange mass spectrometry Frego, L. Protein Science, Vol. 15, Issue 4 https://doi.org/10.1110/ps.051781406	journal	March 2006
Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative isoform: A mechanism for the generation of glucocorticoid resistance Webster, J. C.; Oakley, R. H.; Jewell, C. M. Proceedings of the National Academy of Sciences, Vol. 98, Issue 12 https://doi.org/10.1073/pnas.121455098	journal	May 2001
Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia–implications for treatment of infants Pieters, R.; den Boer, Ml; Durian, M. Leukemia, Vol. 12, Issue 9 https://doi.org/10.1038/sj.leu.2401129	journal	September 1998
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
The Orphan Nuclear Receptor Rev-erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene Yin, Lei; Lazar, Mitchell A. Molecular Endocrinology, Vol. 19, Issue 6 https://doi.org/10.1210/me.2005-0057	journal	June 2005
Mechanisms of Corticosteroid Resistance in Rheumatoid Arthritis Chikanza, Ian C. Annals of the New York Academy of Sciences, Vol. 966, Issue 1 https://doi.org/10.1111/j.1749-6632.2002.tb04200.x	journal	June 2002
FRED Pose Prediction and Virtual Screening Accuracy McGann, Mark Journal of Chemical Information and Modeling, Vol. 51, Issue 3 https://doi.org/10.1021/ci100436p	journal	February 2011
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6 https://doi.org/10.1007/s00775-020-01814-y	journal	August 2020
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver A., Cidlowski, John; H., Oakley, Robert; Xiao, Xiao, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/cg62-p583	text	January 2016
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

Cited By (1)

Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age Ferrara, Giovanna; Petrillo, Maria; Giani, Teresa International Journal of Molecular Sciences, Vol. 20, Issue 2 https://doi.org/10.3390/ijms20020444	journal	January 2019

Similar Records

Glucocorticoid receptor (GR) {beta} has intrinsic, GR{alpha}-independent transcriptional activity

Journal Article · Fri Apr 17 00:00:00 EDT 2009 · Biochemical and Biophysical Research Communications · OSTI ID:1435832

Kino, Tomoshige; Manoli, Irini; Kelkar, Sujata; +3 more

Xenobiotics and the Glucocorticoid Receptor

Journal Article · Wed Mar 15 00:00:00 EDT 2017 · Toxicology and Applied Pharmacology · OSTI ID:1435832

Characterization of a novel non-steroidal glucocorticoid receptor antagonist

Journal Article · Fri Jan 15 00:00:00 EST 2010 · Biochemical and Biophysical Research Communications · OSTI ID:1435832

Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; +5 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
glucocorticoid receptor beta (GRβ)
RU-486
dominant negative
glucocorticoid resistance
transrepression

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

Citation Formats

References (50)

Cited By (1)

Similar Records

Related Subjects