|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='3h52' size='340' side='right'caption='[[3h52]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='3h52' size='340' side='right'caption='[[3h52]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3h52]] is a 6 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=3H52 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3H52 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3h52]] is a 6 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=3H52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H52 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=486:11-(4-DIMETHYLAMINO-PHENYL)-17-HYDROXY-13-METHYL-17-PROP-1-YNYL-1,2,6,7,8,11,12,13,14,15,16,17-DODEC+AHYDRO-CYCLOPENTA[A]PHENANTHREN-3-ONE'>486</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.8Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3h52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h52 OCA], [http://pdbe.org/3h52 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3h52 RCSB], [http://www.ebi.ac.uk/pdbsum/3h52 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3h52 ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=486:11-(4-DIMETHYLAMINO-PHENYL)-17-HYDROXY-13-METHYL-17-PROP-1-YNYL-1,2,6,7,8,11,12,13,14,15,16,17-DODEC+AHYDRO-CYCLOPENTA[A]PHENANTHREN-3-ONE'>486</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=3h52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h52 OCA], [https://pdbe.org/3h52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h52 RCSB], [https://www.ebi.ac.uk/pdbsum/3h52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h52 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> [[http://www.uniprot.org/uniprot/NCOR1_HUMAN NCOR1_HUMAN]] Mediates transcriptional repression by certain nuclear receptors. Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.<ref>PMID:14527417</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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 38: |
Line 39: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arcy, B D]] | + | [[Category: Benz J]] |
| - | [[Category: Benz, J]] | + | [[Category: Burger D]] |
| - | [[Category: Burger, D]] | + | [[Category: D'Arcy B]] |
| - | [[Category: Ruf, A]] | + | [[Category: Ruf A]] |
| - | [[Category: Schoch, G A]] | + | [[Category: Schoch GA]] |
| - | [[Category: Stihle, M]] | + | [[Category: Stihle M]] |
| - | [[Category: Thoma, R]] | + | [[Category: Thoma R]] |
| - | [[Category: Hormone receptor]]
| + | |
| - | [[Category: Hormone receptor 3]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Peptide complex]]
| + | |
| - | [[Category: Protein-ligand complex]]
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mifepristone is known to induce mixed passive antagonist, active antagonist, and agonist effects via the glucocorticoid receptor (GR) pathway. Part of the antagonist effects of mifepristone are due to the repression of gene transcription mediated by the nuclear receptor corepressor (NCoR). Here, we report the crystal structure of a ternary complex of the GR ligand binding domain (GR-LBD) with mifepristone and a receptor-interacting motif of NCoR. The structures of three different conformations of the GR-LBD mifepristone complex show in the oxosteroid hormone receptor family how helix 12 modulates LBD corepressor and coactivator binding. Differences in NCoR binding and in helix 12 conformation reveal how the 11beta substituent in mifepristone triggers the helix 12 molecular switch to reshape the coactivator site into the corepressor site. Two observed conformations exemplify the active antagonist state of GR with NCoR bound. In another conformation, helix 12 completely blocks the coregulator binding site and explains the passive antagonistic effect of mifepristone on GR.
Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations.,Schoch GA, D'Arcy B, Stihle M, Burger D, Bar D, Benz J, Thoma R, Ruf A J Mol Biol. 2010 Jan 22;395(3):568-77. Epub 2009 Nov 11. PMID:19913032[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
- ↑ Schoch GA, D'Arcy B, Stihle M, Burger D, Bar D, Benz J, Thoma R, Ruf A. Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations. J Mol Biol. 2010 Jan 22;395(3):568-77. Epub 2009 Nov 11. PMID:19913032 doi:10.1016/j.jmb.2009.11.011
|
