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| | ==Human steroidogenic cytochrome P450 17A1 mutant A105L with substrate 17alpha-hydroxyprogesterone== | | ==Human steroidogenic cytochrome P450 17A1 mutant A105L with substrate 17alpha-hydroxyprogesterone== |
| - | <StructureSection load='4nky' size='340' side='right' caption='[[4nky]], [[Resolution|resolution]] 2.55Å' scene=''> | + | <StructureSection load='4nky' size='340' side='right'caption='[[4nky]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4nky]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NKY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NKY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4nky]] is a 4 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=4NKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NKY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3QZ:(9BETA)-17-HYDROXYPREGN-4-ENE-3,20-DIONE'>3QZ</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]] 2.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ruk|3ruk]], [[3swz|3swz]], [[4nkv|4nkv]], [[4nkw|4nkw]], [[4nkx|4nkx]], [[4nkz|4nkz]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QZ:(9BETA)-17-HYDROXYPREGN-4-ENE-3,20-DIONE'>3QZ</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nky OCA], [http://pdbe.org/4nky PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nky RCSB], [http://www.ebi.ac.uk/pdbsum/4nky PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nky 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=4nky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nky OCA], [https://pdbe.org/4nky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nky RCSB], [https://www.ebi.ac.uk/pdbsum/4nky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nky ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CP17A_HUMAN CP17A_HUMAN]] Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency;46,XY disorder of sex development due to isolated 17, 20 lyase deficiency. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/CP17A_HUMAN CP17A_HUMAN] Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency;46,XY disorder of sex development due to isolated 17, 20 lyase deficiency. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP17A_HUMAN CP17A_HUMAN]] Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.<ref>PMID:22266943</ref> | + | [https://www.uniprot.org/uniprot/CP17A_HUMAN CP17A_HUMAN] Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.<ref>PMID:22266943</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 4nky" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4nky" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Petrunak, E M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Scott, E E]] | + | [[Category: Large Structures]] |
| - | [[Category: 20 lyase]] | + | [[Category: Petrunak EM]] |
| - | [[Category: Cytochrome b5]] | + | [[Category: Scott EE]] |
| - | [[Category: Endoplasmic reticulum membrane]]
| + | |
| - | [[Category: Heme protein]]
| + | |
| - | [[Category: Lyase]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Nadph-cytochrome p450 reductase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Steroid 17alpha-hydroxylase]]
| + | |
| - | [[Category: Steroid c17]]
| + | |
| Structural highlights
Disease
CP17A_HUMAN Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency;46,XY disorder of sex development due to isolated 17, 20 lyase deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
CP17A_HUMAN Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.[1]
Publication Abstract from PubMed
The human cytochrome P450 17A1 (CYP17A1) enzyme operates at a key juncture of human steroidogenesis, controlling the levels of mineralocorticoids influencing blood pressure, glucocorticoids involved in immune and stress responses, and androgens and estrogens involved in development and homeostasis of reproductive tissues. Understanding CYP17A1 multi-functional biochemistry is thus integral to treating prostate and breast cancer, subfertility, blood pressure, and other diseases. CYP17A1 structures with all four physiologically-relevant steroid substrates suggest answers to four fundamental aspects of CYP17A1 function. First, all substrates bind in a similar overall orientation, rising ~60 degrees with respect to the heme. Second, both hydroxylase substrates pregnenolone and progesterone hydrogen bond to Asn202 in orientations consistent with production of 17alpha-hydroxy major metabolites, but functional and structural evidence for an A105L mutation suggest a minor conformation may yield the minor 16alpha-hydroxyprogesterone metabolite. Third, substrate specificity of the subsequent 17,20-lyase reaction may be explained by variation in substrate height above the heme. While 17alpha-hydroxyprogesterone is only observed farther from the catalytic iron, 17alpha-hydroxypregnenolone is also observed closer to the heme. In conjunction with spectroscopic evidence, this suggests that only 17alpha-hydroxypregnenolone approaches and interacts with the proximal oxygen of the catalytic iron-peroxy intermediate, yielding efficient production of dehydroepiandrosterone as the key intermediate in human testosterone and estrogen synthesis. Fourth, differential positioning of 17alpha-hydroxypregnenolone offers a mechanism whereby allosteric binding of cytochrome b5 might selectively enhance the lyase reaction. In aggregate, these structures provide a structural basis for understanding multiple key reactions at the heart of human steroidogenesis.
Structures of Human Steroidogenic Cytochrome P450 17A1 with Substrates.,Petrunak EM, DeVore NM, Porubsky PR, Scott EE J Biol Chem. 2014 Oct 9. pii: jbc.M114.610998. PMID:25301938[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Devore NM, Scott EE. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature. 2012 Jan 22. doi: 10.1038/nature10743. PMID:22266943 doi:10.1038/nature10743
- ↑ Petrunak EM, DeVore NM, Porubsky PR, Scott EE. Structures of Human Steroidogenic Cytochrome P450 17A1 with Substrates. J Biol Chem. 2014 Oct 9. pii: jbc.M114.610998. PMID:25301938 doi:http://dx.doi.org/10.1074/jbc.M114.610998
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