5nft
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Glucocorticoid Receptor in complex with AZD5423== | |
| + | <StructureSection load='5nft' size='340' side='right' caption='[[5nft]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5nft]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NFT FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8W8:2,2,2-tris(fluoranyl)-~{N}-[(1~{R},2~{S})-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-(3-methoxyphenyl)propan-2-yl]ethanamide'>8W8</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=5nft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nft OCA], [http://pdbe.org/5nft PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nft RCSB], [http://www.ebi.ac.uk/pdbsum/5nft PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nft ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == 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> [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. | ||
| + | == 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/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A class of potent, non-steroidal, selective indazole ether based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft drug strategy was implemented to ensure rapid elimination of drug candidates and minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate 15m (AZD7594) that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged inhibition of lung edema, indicating potential for once-daily treatment. | ||
| - | + | Selective Non-steroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases.,Hemmerling M, Nilsson S, Edman K, Eirefelt S, Russell W, Hendrickx R, Johnsson E, Karrman-Mardh C, Berger M, Rehwinkel H, Abrahamsson A, Dahm Eacute N J, Eriksson AR, Gabos B, Henriksson K, Hossain N, Ivanova S, Jansson AH, Jensen TJ, Jerre A, Johansson H, Klingstedt T, Lepisto M, Lindsjo M, Mile I, Nikitidis G, Steele J, Tehler U, Wissler L, Hansson T J Med Chem. 2017 Sep 22. doi: 10.1021/acs.jmedchem.7b01215. PMID:28937774<ref>PMID:28937774</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 5nft" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Edman, K]] | [[Category: Edman, K]] | ||
[[Category: Wissler, L]] | [[Category: Wissler, L]] | ||
| + | [[Category: Glucocorticoid receptor]] | ||
| + | [[Category: Hormone]] | ||
| + | [[Category: Ligand complex]] | ||
| + | [[Category: Nuclear hormone receptor]] | ||
| + | [[Category: Peptide complex]] | ||
| + | [[Category: Steroid receptor]] | ||
Revision as of 09:29, 4 October 2017
Glucocorticoid Receptor in complex with AZD5423
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