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New page: left|200px<br /> <applet load="1nhz" size="450" color="white" frame="true" align="right" spinBox="true" caption="1nhz, resolution 2.30Å" /> '''Crystal Structure o...
 
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[[Image:1nhz.gif|left|200px]]<br />
<applet load="1nhz" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1nhz, resolution 2.30&Aring;" />
'''Crystal Structure of the Antagonist Form of Glucocorticoid Receptor'''<br />


==Overview==
==Crystal Structure of the Antagonist Form of Glucocorticoid Receptor==
Here we describe the three-dimensional crystal structures of human, glucocorticoid receptor ligand-binding domain (GR-LBD) in complex with the, antagonist RU-486 at 2.3 A resolution and with the agonist dexamethasone, ligand together with a coactivator peptide at 2.8 A. The RU-486 structure, was solved in several different crystal forms, two with helix 12 intact, (GR1 and GR3) and one with a protease-digested C terminus (GR2). In GR1, part of helix 12 is in a position that covers the co-activator pocket, whereas in the GR3, domain swapping is seen between the, crystallographically identical subunits in the GR dimer. An arm consisting, of the end of helix 11 and beyond stretches out from one molecule, and, helix 12 binds to the other LBD, partly blocking the coactivator pocket of, that molecule. This type of GR-LBD dimer has not been described before but, might be an artifact from crystallization. Furthermore, the subunits of, the GR3 dimers are covalently connected via a disulfide bond between the, Cys-736 residues in the two molecules. All three RU-486 GR-LBD structures, show that GR has a very flexible region between the end of helix 11 and, the end of helix 12.
<StructureSection load='1nhz' size='340' side='right'caption='[[1nhz]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1nhz]] is a 1 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=1NHZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1NHZ 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=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=HEZ:HEXANE-1,6-DIOL'>HEZ</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=1nhz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1nhz OCA], [https://pdbe.org/1nhz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1nhz RCSB], [https://www.ebi.ac.uk/pdbsum/1nhz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1nhz 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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/nh/1nhz_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1nhz ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Cortisol resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=138040 138040]]
*[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]]
 
== References ==
==About this Structure==
<references/>
1NHZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 486 and HEZ as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NHZ OCA].
__TOC__
 
</StructureSection>
==Reference==
The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism., Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K, Engstrom O, Harlan J, Muchmore S, Ramqvist AK, Thorell S, Ohman L, Greer J, Gustafsson JA, Carlstedt-Duke J, Carlquist M, J Biol Chem. 2003 Jun 20;278(25):22748-54. Epub 2003 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12686538 12686538]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Ahola, H.]]
[[Category: Ahola H]]
[[Category: Alarcon, M.]]
[[Category: Alarcon M]]
[[Category: Calles, K.]]
[[Category: Calles K]]
[[Category: Carlquist, M.]]
[[Category: Carlquist M]]
[[Category: Carlstedt-Duke, J.]]
[[Category: Carlstedt-Duke J]]
[[Category: Engstrom, O.]]
[[Category: Engstrom O]]
[[Category: Farnegardh, M.]]
[[Category: Farnegardh M]]
[[Category: Greer, J.]]
[[Category: Greer J]]
[[Category: Gustafsson, J.A.]]
[[Category: Gustafsson J-A]]
[[Category: Harlan, J.]]
[[Category: Harlan J]]
[[Category: Jakob, C.]]
[[Category: Jakob C]]
[[Category: Kauppi, B.]]
[[Category: Kauppi B]]
[[Category: Muchmore, S.]]
[[Category: Muchmore S]]
[[Category: Ohman, L.]]
[[Category: Ohman L]]
[[Category: Ramqvist, A.K.]]
[[Category: Ramqvist A-K]]
[[Category: Thorell, S.]]
[[Category: Thorell S]]
[[Category: Yang, J.]]
[[Category: Yang J]]
[[Category: 486]]
[[Category: HEZ]]
[[Category: anti parallel alpha helix sandwich]]
[[Category: protien-ligand complex]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:21:41 2007''

Latest revision as of 07:56, 14 February 2024

Crystal Structure of the Antagonist Form of Glucocorticoid Receptor

1nhz, resolution 2.30Å

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