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3tda

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Competitive replacement of thioridazine by prinomastat in crystals of cytochrome P450 2D6

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OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3tda"

Categories: Homo sapiens | Large Structures | Johnson EF | Stout CD | Wang A

@@ Line 3: / Line 3: @@
 <StructureSection load='3tda' size='340' side='right'caption='[[3tda]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3tda]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TDA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TDA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3tda]] 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=3TDA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TDA FirstGlance]. <br>
-</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=PN0:PRINOMASTAT'>PN0</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.67&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qm4|3qm4]]</div></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=PN0:PRINOMASTAT'>PN0</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP2D6, CYP2DL1 ([https://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'>[https://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3tda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tda OCA], [https://pdbe.org/3tda PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tda RCSB], [https://www.ebi.ac.uk/pdbsum/3tda PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tda ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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;">
-== Publication Abstract from PubMed ==
-P450 2D6 contributes significantly to the metabolism of &gt; 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<ref>PMID:25555909</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 3tda" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 28: / Line 17: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[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: Heme]]
-[[Category: Monooxygenase]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
-[[Category: Prinomastat]]

3tda

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Competitive replacement of thioridazine by prinomastat in crystals of cytochrome P450 2D6

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