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| | ==Human Cytochrome P450 2A6 in complex with Pilocarpine== | | ==Human Cytochrome P450 2A6 in complex with Pilocarpine== |
| - | <StructureSection load='3t3r' size='340' side='right' caption='[[3t3r]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='3t3r' size='340' side='right'caption='[[3t3r]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3t3r]] 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=3T3R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T3R FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3t3r]] 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=3T3R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T3R FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9PL:(3S,4R)-3-ETHYL-4-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]DIHYDROFURAN-2(3H)-ONE'>9PL</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ebs|3ebs]], [[2fdy|2fdy]], [[1z11|1z11]], [[1z10|1z10]], [[2fdu|2fdu]], [[2fdv|2fdv]], [[2pg7|2pg7]], [[2pg6|2pg6]], [[2pg5|2pg5]], [[2fdw|2fdw]], [[3t3q|3t3q]], [[3t3s|3t3s]], [[3t3z|3t3z]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9PL:(3S,4R)-3-ETHYL-4-[(1-METHYL-1H-IMIDAZOL-5-YL)METHYL]DIHYDROFURAN-2(3H)-ONE'>9PL</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">CYP2A3, CYP2A6 ([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=3t3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3r OCA], [https://pdbe.org/3t3r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t3r RCSB], [https://www.ebi.ac.uk/pdbsum/3t3r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t3r 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/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </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=3t3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t3r OCA], [http://pdbe.org/3t3r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3t3r RCSB], [http://www.ebi.ac.uk/pdbsum/3t3r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3t3r ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN]] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref> | + | [https://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
| + | |
| - | Human xenobiotic-metabolizing cytochrome P450 (CYP) enzymes can each bind and monooxygenate a diverse set of substrates, including drugs, often producing a variety of metabolites. Additionally, a single ligand can interact with multiple CYP enzymes, but often the protein structural similarities and differences that mediate such overlapping selectivity are not well understood. Even though the CYP superfamily has a highly canonical global protein fold, there are large variations in the active site size, topology, and conformational flexibility. We have determined how a related set of three human CYP enzymes bind and interact with a common inhibitor, the muscarinic receptor agonist drug pilocarpine. Pilocarpine binds and inhibits the hepatic CYP2A6 and respiratory CYP2A13 enzymes much more efficiently than the hepatic CYP2E1 enzyme. To elucidate key residues involved in pilocarpine binding, crystal structures of CYP2A6 (2.4 A), CYP2A13 (3.0 A), CYP2E1 (2.35 A), and the CYP2A6 mutant enzyme, CYP2A6 I208S/I300F/G301A/S369G (2.1 A) have been determined with pilocarpine in the active site. In all four structures, pilocarpine coordinates to the heme iron, but comparisons reveal how individual residues lining the active sites of these three distinct human enzymes interact differently with the inhibitor pilocarpine. Database Structural data are available in the Protein Data Bank database under the accession numbers 3T3Q (CYP2A6 I208S/I300F/G301A/S369G with pilocarpine), 3T3R (CYP2A6 with pilocarpine), 3T3S (CYP2A13 with pilocarpine), and 3T3Z (CYP2E1 with pilocarpine).
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| - | Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.,Devore NM, Meneely KM, Bart AG, Stephens ES, Battaile KP, Scott EE FEBS J. 2011 Nov 3. doi: 10.1111/j.1742-4658.2011.08412.x. PMID:22051186<ref>PMID:22051186</ref>
| + | ==See Also== |
| - | | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 3t3r" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Unspecific monooxygenase]] | + | [[Category: Large Structures]] |
| - | [[Category: DeVore, N M]] | + | [[Category: DeVore NM]] |
| - | [[Category: Scott, E E]] | + | [[Category: Scott EE]] |
| - | [[Category: Cyp2a6]]
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| - | [[Category: Cytochrome p450 2a6]]
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| - | [[Category: Drug metabolism]]
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| - | [[Category: Endoplasmic reticulum]]
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| - | [[Category: Heme protein]]
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| - | [[Category: Membrane]]
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| - | [[Category: Monooxygenase]]
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| - | [[Category: Oxidoreductase]]
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| - | [[Category: P450 2a6]]
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| - | [[Category: Xenobiotic metabolism]]
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