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| | ==Crystal structure of human CYP11A1 in complex with cholesterol== | | ==Crystal structure of human CYP11A1 in complex with cholesterol== |
| - | <StructureSection load='3n9y' size='340' side='right' caption='[[3n9y]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='3n9y' size='340' side='right'caption='[[3n9y]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3n9y]] is a 4 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=3N9Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3N9Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3n9y]] is a 4 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=3N9Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N9Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3n9z|3n9z]], [[3na0|3na0]], [[3na1|3na1]]</td></tr> | + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3n9z|3n9z]], [[3na0|3na0]], [[3na1|3na1]]</div></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP11A, CYP11A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), adrenodoxin, ADX, FDX1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP11A, CYP11A1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), adrenodoxin, ADX, FDX1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cholesterol_monooxygenase_(side-chain-cleaving) Cholesterol monooxygenase (side-chain-cleaving)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.15.6 1.14.15.6] </span></td></tr> | + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Cholesterol_monooxygenase_(side-chain-cleaving) Cholesterol monooxygenase (side-chain-cleaving)], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.15.6 1.14.15.6] </span></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=3n9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n9y OCA], [http://pdbe.org/3n9y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3n9y RCSB], [http://www.ebi.ac.uk/pdbsum/3n9y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3n9y 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=3n9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n9y OCA], [https://pdbe.org/3n9y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n9y RCSB], [https://www.ebi.ac.uk/pdbsum/3n9y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n9y ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CP11A_HUMAN CP11A_HUMAN]] Inherited isolated adrenal insufficiency due to CYP11A1 deficiency;46,XY disorder of sex development - adrenal insufficiency due to CYP11A1 deficiency. The disease is caused by mutations affecting the gene represented in this entry. | + | [[https://www.uniprot.org/uniprot/CP11A_HUMAN CP11A_HUMAN]] Inherited isolated adrenal insufficiency due to CYP11A1 deficiency;46,XY disorder of sex development - adrenal insufficiency due to CYP11A1 deficiency. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP11A_HUMAN CP11A_HUMAN]] Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.<ref>PMID:21636783</ref> [[http://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/CP11A_HUMAN CP11A_HUMAN]] Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.<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> |
| | <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 3n9y" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3n9y" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ferredoxin 3D structures|Ferredoxin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Arrowsmith, C H]] | | [[Category: Arrowsmith, C H]] |
| | [[Category: Botchkarev, A]] | | [[Category: Botchkarev, A]] |
| Structural highlights
3n9y is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | |
| Gene: | CYP11A, CYP11A1 (HUMAN), adrenodoxin, ADX, FDX1 (HUMAN) |
| Activity: | Cholesterol monooxygenase (side-chain-cleaving), with EC number 1.14.15.6 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[CP11A_HUMAN] Inherited isolated adrenal insufficiency due to CYP11A1 deficiency;46,XY disorder of sex development - adrenal insufficiency due to CYP11A1 deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
[CP11A_HUMAN] Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.[1] [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.[2] [3]
Publication Abstract from PubMed
In humans, the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1). This complex not only plays a key role in steroidogenesis, but also has long been a model to study electron transfer, multistep catalysis, and C-C bond cleavage performed by monooxygenases. Detailed mechanistic understanding of these processes has been hindered by a lack of structural information. Here we present the crystal structure of the complex of human Adx and CYP11A1-the first of a complex between a eukaryotic CYP and its redox partner. The structures with substrate and a series of reaction intermediates allow us to define the mechanism underlying sequential hydroxylations of the cholesterol and suggest the mechanism of C-C bond cleavage. In the complex the [2Fe-2S] cluster of Adx is positioned 17.4 A away from the heme iron of CYP11A1. This structure suggests that after an initial protein-protein association driven by electrostatic forces, the complex adopts an optimized geometry between the redox centers. Conservation of the interaction interface suggests that this mechanism is common for all mitochondrial P450s.
Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.,Strushkevich N, Mackenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW Proc Natl Acad Sci U S A. 2011 Jun 2. PMID:21636783[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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, 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
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