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5l7e

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Revision as of 06:26, 16 October 2019

MCR IN COMPLEX WITH ligand

Structural highlights

5l7e is a 2 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

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of non-steroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with a pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X-ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced fit hypothesis that required movement of the Met852 side-chain. An improvement in MR selectivity of 11-79 fold over PR and 23-234 fold over GR was obtained. Given the U-shaped binding conformation, macrocyclizations were explored yielding a macrocycle that bound to MR with a pKi=7.3. Two protein-ligand X-ray structures were determined confirming the hypothesized binding mode for the designed compounds.

Structure-based drug design of mineralocorticoid receptor antagonists to explore oxosteroid receptor selectivity.,Nordqvist A, O'Mahony G, Friden-Saxin M, Fredenwall M, Hogner A, Granberg KL, Aagaard A, Backstrom S, Gunnarsson A, Kaminski T, Xue Y, Dellsen A, Hansson E, Hansson P, Ivarsson I, Karlsson U, Bamberg K, Hermansson M, Georgsson J, Lindmark B, Edman K ChemMedChem. 2016 Nov 29. doi: 10.1002/cmdc.201600529. PMID:27897427^[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
↑ Nordqvist A, O'Mahony G, Friden-Saxin M, Fredenwall M, Hogner A, Granberg KL, Aagaard A, Backstrom S, Gunnarsson A, Kaminski T, Xue Y, Dellsen A, Hansson E, Hansson P, Ivarsson I, Karlsson U, Bamberg K, Hermansson M, Georgsson J, Lindmark B, Edman K. Structure-based drug design of mineralocorticoid receptor antagonists to explore oxosteroid receptor selectivity. ChemMedChem. 2016 Nov 29. doi: 10.1002/cmdc.201600529. PMID:27897427 doi:http://dx.doi.org/10.1002/cmdc.201600529

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/5l7e"

@@ Line 1: / Line 1: @@
 ==MCR IN COMPLEX WITH ligand==
-<StructureSection load='5l7e' size='340' side='right' caption='[[5l7e]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
+<StructureSection load='5l7e' size='340' side='right'caption='[[5l7e]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5l7e]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L7E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L7E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5l7e]] is a 2 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=5L7E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L7E FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6Q0:~{N}-[[4-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)PHENYL]METHYL]BENZENESULFONAMIDE'>6Q0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5l7e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l7e OCA], [http://pdbe.org/5l7e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l7e RCSB], [http://www.ebi.ac.uk/pdbsum/5l7e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l7e ProSAT]</span></td></tr>
 </table>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5l7e" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Mineralocorticoid receptor|Mineralocorticoid receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Aagaard, A]]
 [[Category: Backstrom, S]]

5l7e

From Proteopedia

Revision as of 06:26, 16 October 2019

MCR IN COMPLEX WITH ligand

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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