|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Glucocorticoid receptor DNA binding domain - IL8 NF-kB response element complex== | | ==Glucocorticoid receptor DNA binding domain - IL8 NF-kB response element complex== |
| - | <StructureSection load='5e69' size='340' side='right' caption='[[5e69]], [[Resolution|resolution]] 1.85Å' scene=''> | + | <StructureSection load='5e69' size='340' side='right'caption='[[5e69]], [[Resolution|resolution]] 1.85Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5e69]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5E69 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5e69]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5E69 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5E69 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5e6a|5e6a]], [[5e6b|5e6b]], [[5e6c|5e6c]], [[5e6d|5e6d]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR3C1, GRL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5e69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e69 OCA], [https://pdbe.org/5e69 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5e69 RCSB], [https://www.ebi.ac.uk/pdbsum/5e69 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5e69 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5e69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5e69 OCA], [http://pdbe.org/5e69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5e69 RCSB], [http://www.ebi.ac.uk/pdbsum/5e69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5e69 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[http://omim.org/entry/138040 138040]]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[https://omim.org/entry/138040 138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 24: |
Line 23: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Glucocorticoid receptor|Glucocorticoid receptor]] | + | *[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Herbst, A G]] | + | [[Category: Large Structures]] |
| - | [[Category: Hudson, W H]] | + | [[Category: Herbst AG]] |
| - | [[Category: Ortlund, E A]] | + | [[Category: Hudson WH]] |
| - | [[Category: Rye, E A]] | + | [[Category: Ortlund EA]] |
| - | [[Category: Dna binding protein-dna complex]] | + | [[Category: Rye EA]] |
| - | [[Category: Dna binding protein]]
| + | |
| Structural highlights
Disease
GCR_HUMAN Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5]
Function
GCR_HUMAN Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6]
Publication Abstract from PubMed
Glucocorticoids (GCs) are potent repressors of NF-kappaB activity, making them a preferred choice for treatment of inflammation-driven conditions. Despite the widespread use of GCs in the clinic, current models are inadequate to explain the role of the glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly to NF-kappaB itself-tethering in a DNA binding-independent manner-represents the standing model of how GCs inhibit NF-kappaB-driven transcription. We demonstrate that direct binding of GR to genomic NF-kappaB response elements (kappaBREs) mediates GR-driven repression of inflammatory gene expression. We report five crystal structures and solution NMR data of GR DBD-kappaBRE complexes, which reveal that GR recognizes a cryptic response element between the binding footprints of NF-kappaB subunits within kappaBREs. These cryptic sequences exhibit high sequence and functional conservation, suggesting that GR binding to kappaBREs is an evolutionarily conserved mechanism of controlling the inflammatory response.
Cryptic glucocorticoid receptor-binding sites pervade genomic NF-kappaB response elements.,Hudson WH, Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q, Bain DL, Nettles KW, Kojetin DJ, Ortlund EA Nat Commun. 2018 Apr 6;9(1):1337. doi: 10.1038/s41467-018-03780-1. PMID:29626214[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230
- ↑ Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:http://dx.doi.org/10.1172/JCI115046
- ↑ Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:http://dx.doi.org/10.1172/JCI116410
- ↑ Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680
- ↑ Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741
- ↑ Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014
- ↑ Hudson WH, Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q, Bain DL, Nettles KW, Kojetin DJ, Ortlund EA. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-kappaB response elements. Nat Commun. 2018 Apr 6;9(1):1337. doi: 10.1038/s41467-018-03780-1. PMID:29626214 doi:http://dx.doi.org/10.1038/s41467-018-03780-1
|
