3vhv

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[[Image:3vhv.jpg|left|200px]]
 
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==Mineralocorticoid receptor ligand-binding domain with non-steroidal antagonist==
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The line below this paragraph, containing "STRUCTURE_3vhv", creates the "Structure Box" on the page.
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<StructureSection load='3vhv' size='340' side='right'caption='[[3vhv]], [[Resolution|resolution]] 1.35&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3vhv]] 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=3VHV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VHV FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.35&#8491;</td></tr>
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<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=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=LD1:6-[(7S)-7-PHENYL-7H-[1,2,4]TRIAZOLO[3,4-B][1,3,4]THIADIAZIN-6-YL]-2H-1,4-BENZOXAZIN-3(4H)-ONE'>LD1</scene>, <scene name='pdbligand=LD2:6-[(1E)-2-PHENYL-N-(3-SULFANYL-4H-1,2,4-TRIAZOL-4-YL)ETHANIMIDOYL]-2H-1,4-BENZOXAZIN-3(4H)-ONE'>LD2</scene></td></tr>
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{{STRUCTURE_3vhv| PDB=3vhv | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vhv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vhv OCA], [https://pdbe.org/3vhv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vhv RCSB], [https://www.ebi.ac.uk/pdbsum/3vhv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vhv ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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===Mineralocorticoid receptor ligand-binding domain with non-steroidal antagonist===
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3vhv" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_22074142}}, adds the Publication Abstract to the page
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*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
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(as it appears on PubMed at http://www.pubmed.gov), where 22074142 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_22074142}}
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__TOC__
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</StructureSection>
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==About this Structure==
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[[3vhv]] is a 1 chain structure with 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=3VHV OCA].
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==Reference==
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<ref group="xtra">PMID:022074142</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Habuka, N.]]
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[[Category: Large Structures]]
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[[Category: Sogabe, S.]]
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[[Category: Habuka N]]
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[[Category: Activating mutation]]
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[[Category: Sogabe S]]
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[[Category: Hypertension]]
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[[Category: Non-steroidal antagonist]]
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[[Category: Nuclear receptor]]
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[[Category: Transcription factor]]
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[[Category: Transcription-inhibitor complex]]
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Current revision

Mineralocorticoid receptor ligand-binding domain with non-steroidal antagonist

PDB ID 3vhv

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