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| | <StructureSection load='4wnw' size='340' side='right'caption='[[4wnw]], [[Resolution|resolution]] 3.30Å' scene=''> | | <StructureSection load='4wnw' size='340' side='right'caption='[[4wnw]], [[Resolution|resolution]] 3.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wnw]] is a 2 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=4WNW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WNW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wnw]] is a 2 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=4WNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WNW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=RTZ:10-{2-[(2R)-1-METHYLPIPERIDIN-2-YL]ETHYL}-2-(METHYLSULFANYL)-10H-PHENOTHIAZINE'>RTZ</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]] 3.299Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qm4|3qm4]], [[3tbg|3tbg]], [[3tda|3tda]], [[2f9q|2f9q]], [[4wnv|4wnv]], [[4wnu|4wnu]], [[4wnt|4wnt]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=RTZ:10-{2-[(2R)-1-METHYLPIPERIDIN-2-YL]ETHYL}-2-(METHYLSULFANYL)-10H-PHENOTHIAZINE'>RTZ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2D6, CYP2DL1 ([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=4wnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wnw OCA], [https://pdbe.org/4wnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wnw RCSB], [https://www.ebi.ac.uk/pdbsum/4wnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wnw 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=4wnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wnw OCA], [http://pdbe.org/4wnw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wnw RCSB], [http://www.ebi.ac.uk/pdbsum/4wnw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wnw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CP2D6_HUMAN CP2D6_HUMAN]] Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.<ref>PMID:16352597</ref> | + | [https://www.uniprot.org/uniprot/CP2D6_HUMAN CP2D6_HUMAN] Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.<ref>PMID:16352597</ref> |
| | <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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Unspecific monooxygenase]]
| + | [[Category: Johnson EF]] |
| - | [[Category: Johnson, E F]] | + | [[Category: Stout CD]] |
| - | [[Category: Stout, C D]] | + | [[Category: Wang A]] |
| - | [[Category: Wang, A]] | + | |
| - | [[Category: Cyp2d6]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: P450]]
| + | |
| - | [[Category: P450 2d6]]
| + | |
| Structural highlights
Function
CP2D6_HUMAN Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.[1]
Publication Abstract from PubMed
P450 2D6 contributes significantly to the metabolism of > 15% of the 200 most marketed drugs. Open and closed crystal structures of P450 2D6 thioridazine complexes were obtained using different crystallization conditions. The protonated piperadine moiety of thioridazine forms a charge stabilized hydrogen bond with Asp301 in the active sites of both complexes. The more open conformation exhibits a second molecule of thioridazine bound in an expanded substrate access channel antechamber with its piperidine moiety forming a charge stabilized hydrogen bond with Glu222. Incubation of the crystalline open thioridazine complex with alternative ligands, prinomastat, quinidine, quinine or ajmalicine displaced thioridazine. Quinine and ajmalicine formed charge stabilized hydrogen bonds with Glu216, whereas the protonated nitrogen of quinidine is equidistant from Asp301 and Glu216 with protonated nitrogen H-bonded to a water molecule in the access channel. Prinomastat is not ionized. Adaptations of active site side chain rotamers and polypeptide conformations were evident between the complexes, with the binding of ajmalicine eliciting a closure of the open structure reflecting in part the inward movement of Glu216 to form a hydrogen bond with ajmalicine as well as sparse lattice restraints that would hinder adaptations. These results indicate that P450 2D6 exhibits sufficient elasticity within the crystal lattice to allow the passage of compounds between the active site and bulk solvent and to adopt a more closed form that adapts for binding alternative ligands with different degrees of closure. These crystals provide a means to characterize substrate and inhibitor binding to the enzyme following replacement of thioridazine with alternative compounds.
Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6)Substrate and Inhibitor Binding.,Wang A, Stout CD, Zhang Q, Johnson EF J Biol Chem. 2015 Jan 1. pii: jbc.M114.627661. PMID:25555909[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rowland P, Blaney FE, Smyth MG, Jones JJ, Leydon VR, Oxbrow AK, Lewis CJ, Tennant MG, Modi S, Eggleston DS, Chenery RJ, Bridges AM. Crystal structure of human cytochrome P450 2D6. J Biol Chem. 2006 Mar 17;281(11):7614-22. Epub 2005 Dec 13. PMID:16352597 doi:http://dx.doi.org/10.1074/jbc.M511232200
- ↑ Wang A, Stout CD, Zhang Q, Johnson EF. Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6)Substrate and Inhibitor Binding. J Biol Chem. 2015 Jan 1. pii: jbc.M114.627661. PMID:25555909 doi:http://dx.doi.org/10.1074/jbc.M114.627661
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