View source for 6dxk


==Glucocorticoid Receptor in complex with Compound 11==
<StructureSection load='6dxk' size='340' side='right'caption='[[6dxk]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
== Structural highlights ==
<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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.05&#8491;</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>
== Disease ==
[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 ==
[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;">
== 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<ref>PMID:30091920</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6dxk" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen C]]
[[Category: Daqing S]]
[[Category: Du X]]
[[Category: Eksterowicz J]]
[[Category: Fantin VR]]
[[Category: Huang E]]
[[Category: Huang T]]
[[Category: Jackson E]]
[[Category: Jahchan N]]
[[Category: Kawai H]]
[[Category: McGee LR]]
[[Category: Medina JC]]
[[Category: Rew Y]]
[[Category: Sutimantanapi D]]
[[Category: Waszczuk J]]
[[Category: Yan X]]
[[Category: Ye Q]]
[[Category: Zavorotinskaya T]]
[[Category: Zhou H]]
[[Category: Zhu L]]