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4pf3

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Revision as of 08:05, 17 April 2019

Mineralocorticoid receptor ligand-binding domain with compuond 37a

Structural highlights

4pf3 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	NR3C2, MCR, MLR (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[MCR_HUMAN] Defects in NR3C2 are a cause of pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM: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.^[1] ^[2] ^[3] ^[4] ^[5] Defects in NR3C2 are a cause of early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM: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.^[6] ^[7] ^[8] ^[9]

Function

[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.^[10]

Publication Abstract from PubMed

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]- 2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.,Hasui T, Ohyabu N, Ohra T, Fuji K, Sugimoto T, Fujimoto J, Asano K, Oosawa M, Shiotani S, Nishigaki N, Kusumoto K, Matsui H, Mizukami A, Habuka N, Sogabe S, Endo S, Ono M, Siedem CS, Tang TP, Gauthier C, De Meese LA, Boyd SA, Fukumoto S Bioorg Med Chem. 2014 Oct 1;22(19):5428-45. doi: 10.1016/j.bmc.2014.07.038. Epub , 2014 Aug 12. PMID:25187277^[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet. 1998 Jul;19(3):279-81. PMID:9662404 doi:10.1038/966
↑ Tajima T, Kitagawa H, Yokoya S, Tachibana K, Adachi M, Nakae J, Suwa S, Katoh S, Fujieda K. A novel missense mutation of mineralocorticoid receptor gene in one Japanese family with a renal form of pseudohypoaldosteronism type 1. J Clin Endocrinol Metab. 2000 Dec;85(12):4690-4. PMID:11134129
↑ Sartorato P, Lapeyraque AL, Armanini D, Kuhnle U, Khaldi Y, Salomon R, Abadie V, Di Battista E, Naselli A, Racine A, Bosio M, Caprio M, Poulet-Young V, Chabrolle JP, Niaudet P, De Gennes C, Lecornec MH, Poisson E, Fusco AM, Loli P, Lombes M, Zennaro MC. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism. J Clin Endocrinol Metab. 2003 Jun;88(6):2508-17. PMID:12788847
↑ Riepe FG, Finkeldei J, de Sanctis L, Einaudi S, Testa A, Karges B, Peter M, Viemann M, Grotzinger J, Sippell WG, Fejes-Toth G, Krone N. Elucidating the underlying molecular pathogenesis of NR3C2 mutants causing autosomal dominant pseudohypoaldosteronism type 1. J Clin Endocrinol Metab. 2006 Nov;91(11):4552-61. Epub 2006 Sep 5. PMID:16954160 doi:jc.2006-1161
↑ Pujo L, Fagart J, Gary F, Papadimitriou DT, Claes A, Jeunemaitre X, Zennaro MC. Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. Hum Mutat. 2007 Jan;28(1):33-40. PMID:16972228 doi:10.1002/humu.20371
↑ Geller DS, Rodriguez-Soriano J, Vallo Boado A, Schifter S, Bayer M, Chang SS, Lifton RP. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet. 1998 Jul;19(3):279-81. PMID:9662404 doi:10.1038/966
↑ Bledsoe RK, Madauss KP, Holt JA, Apolito CJ, Lambert MH, Pearce KH, Stanley TB, Stewart EL, Trump RP, Willson TM, Williams SP. A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor. J Biol Chem. 2005 Sep 2;280(35):31283-93. Epub 2005 Jun 20. PMID:15967794 doi:http://dx.doi.org/10.1074/jbc.M504098200
↑ Fagart J, Huyet J, Pinon GM, Rochel M, Mayer C, Rafestin-Oblin ME. Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension. Nat Struct Mol Biol. 2005 Jun;12(6):554-5. Epub 2005 May 22. PMID:15908963 doi:10.1038/nsmb939
↑ Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000 Jul 7;289(5476):119-23. PMID:10884226
↑ Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science. 1987 Jul 17;237(4812):268-75. PMID:3037703
↑ Hasui T, Ohyabu N, Ohra T, Fuji K, Sugimoto T, Fujimoto J, Asano K, Oosawa M, Shiotani S, Nishigaki N, Kusumoto K, Matsui H, Mizukami A, Habuka N, Sogabe S, Endo S, Ono M, Siedem CS, Tang TP, Gauthier C, De Meese LA, Boyd SA, Fukumoto S. Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists. Bioorg Med Chem. 2014 Oct 1;22(19):5428-45. doi: 10.1016/j.bmc.2014.07.038. Epub , 2014 Aug 12. PMID:25187277 doi:http://dx.doi.org/10.1016/j.bmc.2014.07.038

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4pf3"

@@ Line 1: / Line 1: @@
 ==Mineralocorticoid receptor ligand-binding domain with compuond 37a==
-<StructureSection load='4pf3' size='340' side='right' caption='[[4pf3]], [[Resolution|resolution]] 1.10&Aring;' scene=''>
+<StructureSection load='4pf3' size='340' side='right'caption='[[4pf3]], [[Resolution|resolution]] 1.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4pf3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PF3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PF3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4pf3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PF3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PF3 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=HFN:6-[1-(2,2-DIFLUORO-3-HYDROXYPROPYL)-5-(4-FLUOROPHENYL)-3-METHYL-1H-PYRAZOL-4-YL]-2H-1,4-BENZOXAZIN-3(4H)-ONE'>HFN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR3C2, MCR, MLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4pf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pf3 OCA], [http://pdbe.org/4pf3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pf3 RCSB], [http://www.ebi.ac.uk/pdbsum/4pf3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pf3 ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 4pf3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Habuka, N]]
 [[Category: Sogabe, S]]
@@ Line 31: / Line 37: @@
 [[Category: Nuclear receptor]]
 [[Category: Transcription factor]]
+[[Category: Transcription-transcription inhibitor complex]]

4pf3

From Proteopedia

Revision as of 08:05, 17 April 2019

Mineralocorticoid receptor ligand-binding domain with compuond 37a

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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