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4enh

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==Crystal Structure of Human Cytochrome P450 CYP46A1 with Fluvoxamine Bound==
==Crystal Structure of Human Cytochrome P450 CYP46A1 with Fluvoxamine Bound==
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<StructureSection load='4enh' size='340' side='right' caption='[[4enh]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='4enh' size='340' side='right'caption='[[4enh]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4enh]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ENH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ENH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4enh]] 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=4ENH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ENH FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FVX:FLUVOXAMINE'>FVX</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2q9f|2q9f]], [[2q9g|2q9g]], [[3mdm|3mdm]], [[3mdr|3mdr]], [[3mdt|3mdt]], [[3mdv|3mdv]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FVX:FLUVOXAMINE'>FVX</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP46A1, CYP46 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4enh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4enh OCA], [https://pdbe.org/4enh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4enh RCSB], [https://www.ebi.ac.uk/pdbsum/4enh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4enh ProSAT]</span></td></tr>
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<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=4enh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4enh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4enh RCSB], [http://www.ebi.ac.uk/pdbsum/4enh PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[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.
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Cytochrome P450 46A1 (CYP46A1), or cholesterol 24-hydroxylase, is an important brain enzyme which may be inhibited by structurally distinct pharmaceuticals both in vitro and in vivo. To identify additional inhibitors of CYP46A1 among FDA-approved therapeutic agents, we used in silico and intuitive predictions and evaluated some of the predicted binders in the enzyme and spectral binding assays. We tested a total of 298 marketed drugs for the inhibition of CYP46A1-mediated cholesterol hydroxylation in vitro, and found that 13 of them reduce CYP46A1 activity by &gt;50%. Of these 13 inhibitors, 7 elicited a spectral response in CYP46A1 with apparent spectral K(d) values in a low micromolar range. One of the identified tight binders, the widely used antidepressant fluvoxamine, was co-crystallized with CYP46A1. The structure of this complex was determined at a 2.5 A resolution and revealed the details of drug binding to the CYP46A1 active site. The NH(2)-containing arm of the Y-shaped fluvoxamine coordinates the CYP46A1 heme iron, whereas the methoxy-containing arm points away from the heme group and has multiple hydrophobic interactions with aliphatic amino acid residues. The CF(3)-phenyl ring faces the entrance to the substrate access channel and has contacts with the aromatic side chains. The crystal structure suggests that only certain drug conformers can enter the P450 substrate access channel and reach the active site. Once inside the active site, the conformer likely further adjusts its configuration and elicits the movement of the protein side chains.
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In Silico and Intuitive Predictions of CYP46A1 Inhibition by Marketed Drugs with Subsequent Enzyme Crystallization in Complex with Fluvoxamine.,Mast N, Linger M, Clark M, Wiseman J, Stout CD, Pikuleva IA Mol Pharmacol. 2012 Aug 2. PMID:22859721<ref>PMID:22859721</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Cholesterol 24-hydroxylase]]
 
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Mast, N]]
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[[Category: Large Structures]]
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[[Category: Pikuleva, I A]]
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[[Category: Mast N]]
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[[Category: Stout, C D]]
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[[Category: Pikuleva IA]]
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[[Category: Endoplasmic reticulum]]
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[[Category: Stout CD]]
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[[Category: Enzyme]]
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[[Category: Fluvoxamine]]
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[[Category: Oxidoreductase]]
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[[Category: P450]]
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Current revision

Crystal Structure of Human Cytochrome P450 CYP46A1 with Fluvoxamine Bound

PDB ID 4enh

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