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| | <StructureSection load='7m8i' size='340' side='right'caption='[[7m8i]], [[Resolution|resolution]] 2.94Å' scene=''> | | <StructureSection load='7m8i' size='340' side='right'caption='[[7m8i]], [[Resolution|resolution]] 2.94Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7m8i]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7M8I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M8I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7m8i]] 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=7M8I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M8I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0T3:4-[(5R)-5,6,7,8-TETRAHYDROIMIDAZO[1,5-A]PYRIDIN-5-YL]BENZONITRILE'>0T3</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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]] 2.94Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP11B2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0T3:4-[(5R)-5,6,7,8-TETRAHYDROIMIDAZO[1,5-A]PYRIDIN-5-YL]BENZONITRILE'>0T3</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</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=7m8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m8i OCA], [https://pdbe.org/7m8i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m8i RCSB], [https://www.ebi.ac.uk/pdbsum/7m8i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m8i ProSAT]</span></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=7m8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m8i OCA], [https://pdbe.org/7m8i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m8i RCSB], [https://www.ebi.ac.uk/pdbsum/7m8i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m8i ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [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 == |
| - | [[https://www.uniprot.org/uniprot/ADX_HUMAN ADX_HUMAN]] Participates in the synthesis of thyroid hormones. Essential for the synthesis of various steroid hormones, participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage.<ref>PMID:20547883</ref> <ref>PMID:21636783</ref>
| + | [https://www.uniprot.org/uniprot/ADX_HUMAN ADX_HUMAN] Participates in the synthesis of thyroid hormones. Essential for the synthesis of various steroid hormones, participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage.<ref>PMID:20547883</ref> <ref>PMID:21636783</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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 7m8i" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7m8i" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ferredoxin 3D structures|Ferredoxin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brixius-Anderko, S]] | + | [[Category: Brixius-Anderko S]] |
| - | [[Category: Scott, E E]] | + | [[Category: Scott EE]] |
| - | [[Category: Aldosterone synthase]]
| + | |
| - | [[Category: Cyp11b2]]
| + | |
| - | [[Category: Electron transfer]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
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
ADX_HUMAN Participates in the synthesis of thyroid hormones. Essential for the synthesis of various steroid hormones, participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage.[1] [2] C11B2_HUMAN Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.[3]
Publication Abstract from PubMed
Aldosterone is the major mineralocorticoid in the human body controlling blood pressure and salt homeostasis. Overproduction of aldosterone leads to primary aldosteronism which is the most common form of secondary hypertension with limited treatment options. Production of aldosterone by cytochrome P450 11B2 (CYP11B2, aldosterone synthase) requires two reduction events with the electrons delivered by the iron/sulfur protein adrenodoxin. Very limited information is available about the structural and functional basis of adrenodoxin/CYP11B2 interaction which impedes the development of new treatment options for primary aldosteronism. A systematic study was carried out to determine if adrenodoxin interaction with CYP11B2 might also have an allosteric component in addition to electron transfer. Indeed, local increases in adrenodoxin concentration promote binding of the substrate 11-deoxycorticosterone and the inhibitor osilodrostat (LCI699) in the active site-over 17 A away-as well as enhancing the inhibitory effect of this latter drug. CYP11B2 structure in complex with adrenodoxin identified specific residues at the protein-protein interface interacting via five salt bridges and four hydrogen bonds. Comparisons with cholesterol-metabolizing CYP11A1 and cortisol-producing CYP11B1, which also bind adrenodoxin, revealed substantial structural differences in these regions. The structural and functional differences between different P450 interactions with adrenodoxin may provide valuable clues for an orthogonal treatment approach for primary aldosteronism by specifically targeting the interaction between CYP11B2 and adrenodoxin.
Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin.,Brixius-Anderko S, Scott EE J Biol Chem. 2021 May 17:100794. doi: 10.1016/j.jbc.2021.100794. PMID:34015331[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sheftel AD, Stehling O, Pierik AJ, Elsasser HP, Muhlenhoff U, Webert H, Hobler A, Hannemann F, Bernhardt R, Lill R. Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11775-80. doi:, 10.1073/pnas.1004250107. Epub 2010 Jun 14. PMID:20547883 doi:http://dx.doi.org/10.1073/pnas.1004250107
- ↑ Strushkevich N, Mackenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci U S A. 2011 Jun 2. PMID:21636783 doi:10.1073/pnas.1019441108
- ↑ 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
- ↑ Brixius-Anderko S, Scott EE. Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin. J Biol Chem. 2021 May 17:100794. doi: 10.1016/j.jbc.2021.100794. PMID:34015331 doi:http://dx.doi.org/10.1016/j.jbc.2021.100794
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