6xz8

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==Structure of aldosterone synthase (CYP11B2) in complex with N-[(1R)-1-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]ethyl]methanesulfonamide==
==Structure of aldosterone synthase (CYP11B2) in complex with N-[(1R)-1-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]ethyl]methanesulfonamide==
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<StructureSection load='6xz8' size='340' side='right'caption='[[6xz8]]' scene=''>
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<StructureSection load='6xz8' size='340' side='right'caption='[[6xz8]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XZ8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6xz8]] is a 3 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=6XZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XZ8 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xz8 OCA], [http://pdbe.org/6xz8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xz8 RCSB], [http://www.ebi.ac.uk/pdbsum/6xz8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xz8 ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=O4T:~{N}-[(1~{R})-1-[5-(6-chloranyl-1,1-dimethyl-3-oxidanylidene-isoindol-2-yl)pyridin-3-yl]ethyl]methanesulfonamide'>O4T</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP11B2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xz8 OCA], [http://pdbe.org/6xz8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xz8 RCSB], [http://www.ebi.ac.uk/pdbsum/6xz8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xz8 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[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.
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Aldosterone synthase (CYP11B2) inhibitors were explored in recent years as an alternative therapeutic option to MR antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including heart, vasculature, kidney, and CNS. A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound 44, in an in vivo cynomolgus monkey acute ACTH challenge model and demonstrated a superior 100-fold in vivo selectivity against CYP11B1.
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Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors.,Liu Y, Wu J, Zhou M, Chen W, Li D, Wang ZG, Hornsperger B, Aebi JD, Marki HP, Kuhn B, Wang L, Kuglstatter A, Benz J, Muller S, Hochstrasser R, Ottaviani G, Xin J, Kirchner S, Mohr S, Verry P, Riboulet W, Shen HC, Mayweg AV, Amrein K, Tan X J Med Chem. 2020 Jun 12. doi: 10.1021/acs.jmedchem.0c00233. PMID:32530624<ref>PMID:32530624</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 6xz8" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Benz J]]
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[[Category: Benz, J]]
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[[Category: Joseph C]]
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[[Category: Joseph, C]]
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[[Category: Kuglstatter A]]
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[[Category: Kuglstatter, A]]
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[[Category: Aldosterone synthase]]
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[[Category: Cyp11b2]]
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[[Category: Cytochrome p450]]
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[[Category: Oxidoreductase]]

Revision as of 11:47, 22 July 2020

Structure of aldosterone synthase (CYP11B2) in complex with N-[(1R)-1-[5-(6-chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]ethyl]methanesulfonamide

PDB ID 6xz8

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