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| Status |
Public on Jan 11, 2023 |
| Title |
The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor (FL-GR), which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR’s LBD and suggest many dimeric conformations can coexist within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design.
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| Overall design |
Comparative gene expression profiling analyses of RNA-seq data of dexamethasone treated mammary adenocarcinoma 3617-derived GRKO cells stably expressing GFP-tagged versions of mouse GR (WT, Y551A, Y551A-Dim, D647V, D647V-Tetra).
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| Contributor(s) |
Jiménez-Panizo A, Alegre-Martí A, Tettey TT, Fettweis G, Abella M, Antón R, Johnson TA, Schiltz RL, Kim S, Nuñez-Barrios I, Font-Díaz J, Caelles C, Valledor AF, Pérez P, Rojas AM, Fernández-Recio J, Presman DM, Hager GL, Fuentes-Prior P, Estébanez-Perpiñá E |
| Citation(s) |
36464162 |
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| Submission date |
Sep 08, 2022 |
| Last update date |
Jan 12, 2023 |
| Contact name |
Gordon Hager |
| Organization name |
NIH
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| Department |
NCI
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| Lab |
LRBGE
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| Street address |
41 Center Dr
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (34)
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| Relations |
| BioProject |
PRJNA878538 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE212973_RAW.tar |
126.4 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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