View source for 5hcv


==Identification of Spirooxindole and Dibenzoxazepine Motifs as Potent Mineralocorticoid Receptor Antagonists==
<StructureSection load='5hcv' size='340' side='right'caption='[[5hcv]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hcv]] is a 3 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=5HCV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HCV 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=60R:6-[(~{E})-(3-FLUORANYL-6~{H}-BENZO[C][1]BENZOXEPIN-11-YLIDENE)METHYL]-4~{H}-1,4-BENZOXAZIN-3-ONE'>60R</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=5hcv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hcv OCA], [https://pdbe.org/5hcv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hcv RCSB], [https://www.ebi.ac.uk/pdbsum/5hcv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hcv 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) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.,Lotesta SD, Marcus AP, Zheng Y, Leftheris K, Noto PB, Meng S, Kandpal G, Chen G, Zhou J, McKeever B, Bukhtiyarov Y, Zhao Y, Lala DS, Singh SB, McGeehan GM Bioorg Med Chem. 2016 Mar 15;24(6):1384-91. doi: 10.1016/j.bmc.2016.02.014. Epub , 2016 Feb 9. PMID:26897089<ref>PMID:26897089</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5hcv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen G]]
[[Category: McKeever BM]]