View source for 4csj


==The discovery of potent selective glucocorticoid receptor modulators, suitable for inhalation==
<StructureSection load='4csj' size='340' side='right'caption='[[4csj]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4csj]] 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=4CSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CSJ 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NN7:N-[(2S)-1-[[1-(4-FLUOROPHENYL)INDAZOL-4-YL]AMINO]PROPAN-2-YL]-2,4,6-TRIMETHYL-BENZENESULFONAMIDE'>NN7</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=4csj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4csj OCA], [https://pdbe.org/4csj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4csj RCSB], [https://www.ebi.ac.uk/pdbsum/4csj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4csj 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 ==
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.

The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation.,Edman K, Ahlgren R, Bengtsson M, Bladh H, Backstrom S, Dahmen J, Henriksson K, Hillertz P, Hulikal V, Jerre A, Kinchin L, Kase C, Lepisto M, Mile I, Nilsson S, Smailagic A, Taylor J, Tjornebo A, Wissler L, Hansson T Bioorg Med Chem Lett. 2014 Apr 2. pii: S0960-894X(14)00297-2. doi:, 10.1016/j.bmcl.2014.03.070. PMID:24755427<ref>PMID:24755427</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4csj" 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: Ahlgren R]]
[[Category: Backstrom S]]
[[Category: Bengtsson M]]
[[Category: Bladh H]]
[[Category: Dahmen J]]
[[Category: Edman K]]
[[Category: Hansson T]]
[[Category: Henriksson K]]
[[Category: Hillertz P]]
[[Category: Hulikal V]]
[[Category: Jerre A]]
[[Category: Kase C]]
[[Category: Kinchin L]]
[[Category: Lepisto M]]
[[Category: Mile I]]
[[Category: Nilsson S]]
[[Category: Smailagic A]]
[[Category: Taylor J]]
[[Category: Tjornebo A]]
[[Category: Wissler L]]