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| | ==Thioperamide complex of Cytochrome P450 46A1== | | ==Thioperamide complex of Cytochrome P450 46A1== |
| - | <StructureSection load='3mdm' size='340' side='right' caption='[[3mdm]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='3mdm' size='340' side='right'caption='[[3mdm]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3mdm]] 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=3MDM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MDM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3mdm]] 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=3MDM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MDM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FJZ:N-CYCLOHEXYL-4-(1H-IMIDAZOL-5-YL)PIPERIDINE-1-CARBOTHIOAMIDE'>FJZ</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]] 1.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2q9f|2q9f]], [[2q9g|2q9g]], [[3mdr|3mdr]], [[3mdt|3mdt]], [[3mdv|3mdv]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FJZ:N-CYCLOHEXYL-4-(1H-IMIDAZOL-5-YL)PIPERIDINE-1-CARBOTHIOAMIDE'>FJZ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3mdm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mdm OCA], [https://pdbe.org/3mdm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mdm RCSB], [https://www.ebi.ac.uk/pdbsum/3mdm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mdm ProSAT]</span></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>
| + | |
| - | <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=3mdm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mdm OCA], [http://pdbe.org/3mdm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3mdm RCSB], [http://www.ebi.ac.uk/pdbsum/3mdm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3mdm 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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/md/3mdm_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/md/3mdm_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cholesterol 24-hydroxylase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Charvet, C]] | + | [[Category: Charvet C]] |
| - | [[Category: Mast, N]] | + | [[Category: Mast N]] |
| - | [[Category: Pikuleva, I]] | + | [[Category: Pikuleva I]] |
| - | [[Category: Stout, C D]] | + | [[Category: Stout CD]] |
| - | [[Category: Cholesterol metabolism]]
| + | |
| - | [[Category: Cyp46a1]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Iron]]
| + | |
| - | [[Category: Lipid metabolism]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Metabolic enzyme]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Microsome]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Nadp]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: P450]]
| + | |
| - | [[Category: P450 46a1]]
| + | |
| - | [[Category: Steroid metabolism]]
| + | |
| - | [[Category: Thioperamide]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| Structural highlights
Function
CP46A_HUMAN Involved in the turnover of cholesterol. It converts cholesterol into 24S-hydroxycholesterol and, to a lesser extent, 25-hydroxycholesterol.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Cytochrome P450 46A1 (CYP46A1) initiates the major pathway of cholesterol elimination from the brain and thereby controls cholesterol turnover in this organ. We determined x-ray crystal structures of CYP46A1 in complex with four structurally distinct pharmaceuticals; antidepressant tranylcypromine (2.15 A), anticonvulsant thioperamide (1.65 A), antifungal voriconazole (2.35 A), and antifungal clotrimazole (2.50 A). All four drugs are nitrogen-containing compounds that have nanomolar affinity for CYP46A1 in vitro yet differ in size, shape, hydrophobicity, and type of the nitrogen ligand. Structures of the co-complexes demonstrate that each drug binds in a single orientation to the active site with tranylcypromine, thioperamide, and voriconazole coordinating the heme iron via their nitrogen atoms and clotrimazole being at a 4 A distance from the heme iron. We show here that clotrimazole is also a substrate for CYP46A1. High affinity for CYP46A1 is determined by a set of specific interactions, some of which were further investigated by solution studies using structural analogs of the drugs and the T306A CYP46A1 mutant. Collectively, our results reveal how diverse inhibitors can be accommodated in the CYP46A1 active site and provide an explanation for the observed differences in the drug-induced spectral response. Co-complexes with tranylcypromine, thioperamide, and voriconazole represent the first structural characterization of the drug binding to a P450 enzyme.
Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain.,Mast N, Charvet C, Pikuleva IA, Stout CD J Biol Chem. 2010 Oct 8;285(41):31783-95. Epub 2010 Jul 28. PMID:20667828[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mast N, Charvet C, Pikuleva IA, Stout CD. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem. 2010 Oct 8;285(41):31783-95. Epub 2010 Jul 28. PMID:20667828 doi:10.1074/jbc.M110.143313
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