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| | ==Crystal Structure of Human CYP46A1 P450 with bicalutamide Bound== | | ==Crystal Structure of Human CYP46A1 P450 with bicalutamide Bound== |
| - | <StructureSection load='4fia' size='340' side='right' caption='[[4fia]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4fia' size='340' side='right'caption='[[4fia]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fia]] is a 1 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=4FIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FIA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fia]] is a 1 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=4FIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FIA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0U9:S-BICALUTAMIDE'>0U9</scene>, <scene name='pdbligand=198:R-BICALUTAMIDE'>198</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=0U9:S-BICALUTAMIDE'>0U9</scene>, <scene name='pdbligand=198:R-BICALUTAMIDE'>198</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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">[[2q9f|2q9f]]</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=4fia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fia OCA], [https://pdbe.org/4fia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fia RCSB], [https://www.ebi.ac.uk/pdbsum/4fia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fia ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP46, CYP46A1 ([http://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_24-hydroxylase Cholesterol 24-hydroxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.98 1.14.13.98] </span></td></tr>
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| - | <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=4fia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fia OCA], [http://pdbe.org/4fia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fia RCSB], [http://www.ebi.ac.uk/pdbsum/4fia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fia ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP46A_HUMAN CP46A_HUMAN]] Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol. | + | [https://www.uniprot.org/uniprot/CP46A_HUMAN CP46A_HUMAN] Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cholesterol 24-hydroxylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Mast, N]] | + | [[Category: Mast N]] |
| - | [[Category: Pikuleva, I A]] | + | [[Category: Pikuleva IA]] |
| - | [[Category: Stout, C D]] | + | [[Category: Stout CD]] |
| - | [[Category: Bicalutamide complex]]
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| - | [[Category: Cyp46a1]]
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| - | [[Category: Cytochrome p450]]
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| - | [[Category: Oxidoreductase]]
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| Structural highlights
Function
CP46A_HUMAN Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol.
Publication Abstract from PubMed
Cytochrome P450 46A1 (CYP46A1) is the cholesterol 24-hydroxylase initiating the major pathways of cholesterol removal from the brain, and bicalutamide (BIC) is a drug of choice for the treatment of progressive androgen-dependent prostate cancer. We evaluated the interactions of BIC with CYP46A1 by x-ray crystallography and by conducting solution and mutagenesis studies. Because BIC is administered to patients as a racemic mixture of the S and R isomers, we studied all three, racemic BIC as well as the S and R isomers. Co-crystallization of CYP46A1 with racemic BIC led to structure determinations at 2.1 A resolution with the drug complexes exhibiting novel properties. Both BIC isomers bind to the CYP46A1 active site in very similar single orientation and adopt an energetically unfavorable folded conformation. This folded BIC conformation is correlated with drug-induced localized shifts of amino acid side chains in CYP46A1 and unusual interactions in the CYP46A1-BIC complex. One of these interactions involves a water molecule that is coordinated to the P450 heme iron and also hydrogen-bonded to the BIC nitrile. Due to polarization of the water in this environment, the heme elicits previously unreported types of P450 spectral responses. We also observed that access to the P450 active site was affected by differential recognition of S versus R isomers at the CYP46A1 surface arising from BIC conformational polymorphism.
Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response.,Mast N, Zheng W, Stout CD, Pikuleva IA J Biol Chem. 2013 Feb 15;288(7):4613-24. doi: 10.1074/jbc.M112.438754. Epub 2013 , Jan 3. PMID:23288837[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mast N, Zheng W, Stout CD, Pikuleva IA. Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response. J Biol Chem. 2013 Feb 15;288(7):4613-24. doi: 10.1074/jbc.M112.438754. Epub 2013 , Jan 3. PMID:23288837 doi:10.1074/jbc.M112.438754
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