View source for 3vhu


==Mineralocorticoid receptor ligand-binding domain with spironolactone==
<StructureSection load='3vhu' size='340' side='right'caption='[[3vhu]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3vhu]] 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=3VHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VHU 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]] 2.11&#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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vhu OCA], [https://pdbe.org/3vhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vhu RCSB], [https://www.ebi.ac.uk/pdbsum/3vhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vhu 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H )-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4 -benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.

Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists.,Hasui T, Matsunaga N, Ora T, Ohyabu N, Nishigaki N, Imura Y, Igata Y, Matsui H, Motoyaji T, Tanaka T, Habuka N, Sogabe S, Ono M, Siedem CS, Tang TP, Gauthier C, De Meese LA, Boyd SA, Fukumoto S J Med Chem. 2011 Dec 22;54(24):8616-31. Epub 2011 Nov 29. PMID:22074142<ref>PMID:22074142</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3vhu" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Habuka N]]
[[Category: Sogabe S]]