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==Structure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide==
==Structure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide==
<StructureSection load='4zgx' size='340' side='right' caption='[[4zgx]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
<StructureSection load='4zgx' size='340' side='right'caption='[[4zgx]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4zgx]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZGX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZGX FirstGlance]. <br>
<table><tr><td colspan='2'>[[4zgx]] is a 12 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=4ZGX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZGX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=QHC:N-[(8R)-4-(4-CHLORO-3-FLUOROPHENYL)-5,6,7,8-TETRAHYDROISOQUINOLIN-8-YL]PROPANAMIDE'>QHC</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</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=4zgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zgx OCA], [http://pdbe.org/4zgx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zgx RCSB], [http://www.ebi.ac.uk/pdbsum/4zgx PDBsum]</span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=QHC:N-[(8R)-4-(4-CHLORO-3-FLUOROPHENYL)-5,6,7,8-TETRAHYDROISOQUINOLIN-8-YL]PROPANAMIDE'>QHC</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=4zgx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zgx OCA], [https://pdbe.org/4zgx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zgx RCSB], [https://www.ebi.ac.uk/pdbsum/4zgx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zgx ProSAT]</span></td></tr>
</table>
</table>
{{Large structure}}
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/C11B2_HUMAN C11B2_HUMAN]] Familial hyperreninemic hypoaldosteronism type 1;Familial hyperaldosteronism type I. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2.  
[https://www.uniprot.org/uniprot/C11B2_HUMAN C11B2_HUMAN] Familial hyperreninemic hypoaldosteronism type 1;Familial hyperaldosteronism type I. The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry.  The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/C11B2_HUMAN C11B2_HUMAN]] Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.<ref>PMID:23322723</ref> 
[https://www.uniprot.org/uniprot/C11B2_HUMAN C11B2_HUMAN] Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.<ref>PMID:23322723</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg-1. This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.
 
Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.,Martin RE, Aebi JD, Hornsperger B, Krebs HJ, Kuhn B, Kuglstatter A, Alker AM, Marki HP, Muller S, Burger D, Ottaviani G, Riboulet W, Verry P, Tan X, Amrein K, Mayweg AV J Med Chem. 2015 Oct 2. PMID:26403853<ref>PMID:26403853</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
<div class="pdbe-citations 4zgx" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Joseph, C]]
[[Category: Homo sapiens]]
[[Category: Kuglstatter, A]]
[[Category: Large Structures]]
[[Category: Aldosterone synthase]]
[[Category: Joseph C]]
[[Category: Cyp11b2]]
[[Category: Kuglstatter A]]
[[Category: Cytochrome p450]]
[[Category: Oxidoreductase]]

Latest revision as of 10:20, 1 May 2024

Structure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamideStructure of aldosterone synthase (CYP11B2) in complex with (+)-(R)-N-(4-(4-chloro-3-fluorophenyl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

Structural highlights

4zgx is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.2Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

C11B2_HUMAN Familial hyperreninemic hypoaldosteronism type 1;Familial hyperaldosteronism type I. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2.

Function

C11B2_HUMAN Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.[1]

See Also

References

  1. ↑ Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol Endocrinol. 2013 Feb;27(2):315-24. doi: 10.1210/me.2012-1287. Epub 2013 Jan, 15. PMID:23322723 doi:http://dx.doi.org/10.1210/me.2012-1287

4zgx, resolution 3.20Å

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