2oax: Difference between revisions

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-{{Seed}}
-[[Image:2oax.png|left|200px]]
-<!--
+==Crystal structure of the S810L mutant mineralocorticoid receptor associated with SC9420==
-The line below this paragraph, containing "STRUCTURE_2oax", creates the "Structure Box" on the page.
+<StructureSection load='2oax' size='340' side='right'caption='[[2oax]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[2oax]] is a 6 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=2OAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OAX FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SNL:SPIRONOLACTONE'>SNL</scene></td></tr>
-{{STRUCTURE_2oax|  PDB=2oax  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2oax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oax OCA], [https://pdbe.org/2oax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2oax RCSB], [https://www.ebi.ac.uk/pdbsum/2oax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2oax ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/MCR_HUMAN MCR_HUMAN] Defects in NR3C2 are a cause of pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:[https://omim.org/entry/177735 177735]. A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment.<ref>PMID:9662404</ref> <ref>PMID:11134129</ref> <ref>PMID:12788847</ref> <ref>PMID:16954160</ref> <ref>PMID:16972228</ref>   Defects in NR3C2 are a cause of early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:[https://omim.org/entry/605115 605115]. Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion.<ref>PMID:9662404</ref> <ref>PMID:15967794</ref> <ref>PMID:15908963</ref> <ref>PMID:10884226</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/MCR_HUMAN MCR_HUMAN] Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.<ref>PMID:3037703</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/oa/2oax_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=2oax ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Spirolactones are potent antagonists of the mineralocorticoid receptor (MR), a ligand-induced transcription factor belonging to the nuclear receptor superfamily. Spirolactones are synthetic molecules characterized by the presence of a C17 gamma-lactone, which is responsible for their antagonist character. They harbor various substituents at several positions of the steroid skeleton that modulate their potency in ways that remain to be determined. This is particularly obvious for C7 substituents. The instability of antagonist-MR complexes makes them difficult to crystallize. We took advantage of the S810L activating mutation in MR (MR(S810L)), which increases the stability of ligand-MR complexes to crystallize the ligand-binding domain (LBD) of MR(S810L) associated with 7alpha-acetylthio-17beta-hydroxy-3-oxopregn-4-en-21-carboxylic acid gamma-lactone (SC9420), a spirolactone with a C7 thioacetyl group. The crystal structure makes it possible to identify the contacts between SC9420 and MR and to elucidate the role of Met852 in the mode of accommodation of the C7 substituent of SC9420. The transactivation activities of MR(S810L/Q776A), MR(S810L/R817A), and MR(S810L/N770A) reveal that the contacts between SC9420 and the Gln776 and Arg817 residues are crucial to maintaining MR(S810L) in its active state, whereas the contact between SC9420 and the Asn770 residue contributes only to the high affinity of SC9420 for MR. Moreover, docking experiments with other C7-substituted spirolactones revealed that the MR(S810L)-activating potency of spirolactones is linked to the ability of their C7 substituent to be accommodated in LBD. It is remarkable that the MR(S810L)-activating and MR(WT)-inactivating potencies of the C7-substituted spirolactones follow the same order, suggesting that the C7 substituent is accommodated in the same way in MR(S810L) and MR(WT). Thus, the MR(S810L) structure may provide a powerful tool for designing new, more effective, MR antagonists.
-===Crystal structure of the S810L mutant mineralocorticoid receptor associated with SC9420===
+Structural basis of spirolactone recognition by the mineralocorticoid receptor.,Huyet J, Pinon GM, Fay MR, Fagart J, Rafestin-Oblin ME Mol Pharmacol. 2007 Sep;72(3):563-71. Epub 2007 Jun 14. PMID:17569793<ref>PMID:17569793</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2oax" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_17569793}}, adds the Publication Abstract to the page
+*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
-(as it appears on PubMed at http://www.pubmed.gov), where 17569793 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_17569793}}
+__TOC__
+</StructureSection>
-==About this Structure==
-OAX is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OAX OCA].
-==Reference==
-Structural basis of spirolactone recognition by the mineralocorticoid receptor., Huyet J, Pinon GM, Fay MR, Fagart J, Rafestin-Oblin ME, Mol Pharmacol. 2007 Sep;72(3):563-71. Epub 2007 Jun 14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17569793 17569793]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Fagart, J.]]
+[[Category: Fagart J]]
-[[Category: Fay, M R.]]
+[[Category: Fay MR]]
-[[Category: Huyet, J.]]
+[[Category: Huyet J]]
-[[Category: Pinon, G M.]]
+[[Category: Pinon GM]]
-[[Category: Rafestin-Oblin, M E.]]
+[[Category: Rafestin-Oblin ME]]
-[[Category: Activating mutation]]
-[[Category: Aldosterone]]
-[[Category: Antagonist]]
-[[Category: Hypertension]]
-[[Category: Nuclear receptor]]
-[[Category: Spironolactone]]
-[[Category: Steroid receptor]]
-[[Category: Transcription factor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 09:00:41 2008''