3ua1

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<StructureSection load='3ua1' size='340' side='right'caption='[[3ua1]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
<StructureSection load='3ua1' size='340' side='right'caption='[[3ua1]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3ua1]] is a 1 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=3UA1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UA1 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3ua1]] 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=3UA1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UA1 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=08Y:BROMOERGOCRYPTINE'>08Y</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]] 2.15&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1tqn|1tqn]], [[3nxu|3nxu]], [[2jod|2jod]], [[2vom|2vom]]</div></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=08Y:BROMOERGOCRYPTINE'>08Y</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">CYP3A4, CYP3A3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3ua1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ua1 OCA], [https://pdbe.org/3ua1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ua1 RCSB], [https://www.ebi.ac.uk/pdbsum/3ua1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ua1 ProSAT]</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=3ua1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ua1 OCA], [https://pdbe.org/3ua1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ua1 RCSB], [https://www.ebi.ac.uk/pdbsum/3ua1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ua1 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_HUMAN]] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>
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[https://www.uniprot.org/uniprot/CP3A4_HUMAN CP3A4_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.<ref>PMID:11159812</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Cytochrome P4503A4 (CYP3A4), a major human drug-metabolizing enzyme, is responsible for the oxidation and clearance of the majority of administered drugs. One of the CYP3A4 substrates is bromoergocryptine (BEC), a dopamine receptor agonist prescribed for the inhibition of prolactin secretion and treatment of Parkinson disease, type 2 diabetes and several other pathological conditions. Here we present a 2.15 Angstrom crystal structure of the CYP3A4-BEC complex where the drug, a type I heme ligand, is bound in a productive mode. The manner of BEC binding is consistent with the in vivo metabolite analysis and identifies the 8 and 9 carbons of the proline ring as the primary sites of oxidation. The crystal structure predicts the importance of Arg212 and Thr224 for binding of the tripeptide and lysergic moieties of BEC, respectively, which we experimentally confirmed. Our data support a three-step BEC binding model, according to which the drug binds first at a peripheral site without perturbing the heme spectrum and then translocates into the active site cavity, where formation of a hydrogen bond between Thr224 and the N1 atom of the lysergic moiety is followed by a slower conformational readjustment of the tripeptide group modulated by Arg212.
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Structural and mechanistic insights into the interaction of cytochrome P4503A4 with Bromoergocryptine, a type I ligand.,Sevrioukova IF, Poulos TL J Biol Chem. 2011 Dec 7. PMID:22157006<ref>PMID:22157006</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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<div class="pdbe-citations 3ua1" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Poulos, T L]]
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[[Category: Poulos TL]]
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[[Category: Sevrioukova, I F]]
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[[Category: Sevrioukova IF]]
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[[Category: Cytochrome b5]]
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[[Category: Cytochrome p450 reductase]]
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[[Category: Membrane]]
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[[Category: Monooxygenase]]
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[[Category: Oxidoreductase]]
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[[Category: Protein-substrate complex]]
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Current revision

Crystal structure of the cytochrome P4503A4-bromoergocryptine complex

PDB ID 3ua1

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