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| | ==Glucocorticoid Receptor in complex with Compound 11== | | ==Glucocorticoid Receptor in complex with Compound 11== |
| - | <StructureSection load='6dxk' size='340' side='right' caption='[[6dxk]], [[Resolution|resolution]] 3.05Å' scene=''> | + | <StructureSection load='6dxk' size='340' side='right'caption='[[6dxk]], [[Resolution|resolution]] 3.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dxk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DXK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DXK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dxk]] is a 2 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=6DXK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DXK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HJ4:(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one+(non-preferred+name)'>HJ4</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]] 3.05Å</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=6dxk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dxk OCA], [http://pdbe.org/6dxk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dxk RCSB], [http://www.ebi.ac.uk/pdbsum/6dxk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dxk ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HJ4:(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one+(non-preferred+name)'>HJ4</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=6dxk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dxk OCA], [https://pdbe.org/6dxk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dxk RCSB], [https://www.ebi.ac.uk/pdbsum/6dxk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dxk 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 == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6dxk" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6dxk" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chen, C]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Daqing, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Du, X]] | + | [[Category: Chen C]] |
| - | [[Category: Eksterowicz, J]] | + | [[Category: Daqing S]] |
| - | [[Category: Fantin, V R]] | + | [[Category: Du X]] |
| - | [[Category: Huang, E]] | + | [[Category: Eksterowicz J]] |
| - | [[Category: Huang, T]] | + | [[Category: Fantin VR]] |
| - | [[Category: Jackson, E]] | + | [[Category: Huang E]] |
| - | [[Category: Jahchan, N]] | + | [[Category: Huang T]] |
| - | [[Category: Kawai, H]] | + | [[Category: Jackson E]] |
| - | [[Category: McGee, L R]] | + | [[Category: Jahchan N]] |
| - | [[Category: Medina, J C]] | + | [[Category: Kawai H]] |
| - | [[Category: Rew, Y]] | + | [[Category: McGee LR]] |
| - | [[Category: Sutimantanapi, D]] | + | [[Category: Medina JC]] |
| - | [[Category: Waszczuk, J]] | + | [[Category: Rew Y]] |
| - | [[Category: Yan, X]] | + | [[Category: Sutimantanapi D]] |
| - | [[Category: Ye, Q]] | + | [[Category: Waszczuk J]] |
| - | [[Category: Zavorotinskaya, T]] | + | [[Category: Yan X]] |
| - | [[Category: Zhou, H]] | + | [[Category: Ye Q]] |
| - | [[Category: Zhu, L]] | + | [[Category: Zavorotinskaya T]] |
| - | [[Category: Ligand complex]]
| + | [[Category: Zhou H]] |
| - | [[Category: Nuclear hormone receptor]]
| + | [[Category: Zhu L]] |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Transcription]]
| + | |
| 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
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR(+) OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).,Rew Y, Du X, Eksterowicz J, Zhou H, Jahchan N, Zhu L, Yan X, Kawai H, McGee LR, Medina JC, Huang T, Chen C, Zavorotinskaya T, Sutimantanapi D, Waszczuk J, Jackson E, Huang E, Ye Q, Fantin VR, Sun D J Med Chem. 2018 Sep 13;61(17):7767-7784. doi: 10.1021/acs.jmedchem.8b00743. Epub, 2018 Aug 23. PMID:30091920[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
- ↑ Rew Y, Du X, Eksterowicz J, Zhou H, Jahchan N, Zhu L, Yan X, Kawai H, McGee LR, Medina JC, Huang T, Chen C, Zavorotinskaya T, Sutimantanapi D, Waszczuk J, Jackson E, Huang E, Ye Q, Fantin VR, Sun D. Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101). J Med Chem. 2018 Sep 13;61(17):7767-7784. doi: 10.1021/acs.jmedchem.8b00743. Epub, 2018 Aug 23. PMID:30091920 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00743
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