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| | ==Crystal structure of human CYP3A4 coordinated to a water molecule== | | ==Crystal structure of human CYP3A4 coordinated to a water molecule== |
| - | <StructureSection load='4i3q' size='340' side='right' caption='[[4i3q]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='4i3q' size='340' side='right'caption='[[4i3q]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4i3q]] 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=4I3Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I3Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4i3q]] 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=4I3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I3Q 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></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]] 2.602Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tqn|1tqn]], [[1woe|1woe]]</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></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4i3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i3q OCA], [https://pdbe.org/4i3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i3q RCSB], [https://www.ebi.ac.uk/pdbsum/4i3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i3q ProSAT]</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=4i3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i3q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i3q RCSB], [http://www.ebi.ac.uk/pdbsum/4i3q PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| - | | + | <div class="pdbe-citations 4i3q" style="background-color:#fffaf0;"></div> |
| - | ==See Also== | + | |
| - | *[[Cytochrome P450|Cytochrome P450]]
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Poulos, T L]] | + | [[Category: Large Structures]] |
| - | [[Category: Sevrioukova, I F]] | + | [[Category: Poulos TL]] |
| - | [[Category: Cytochrome b5]] | + | [[Category: Sevrioukova IF]] |
| - | [[Category: Cytochrome p450]]
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| - | [[Category: Cytochrome p450 reductase]]
| + | |
| - | [[Category: Endoplasmic reticulum]]
| + | |
| - | [[Category: Hemoprotein]]
| + | |
| - | [[Category: Monooxygenase]]
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| - | [[Category: Oxidoreductase]]
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| Structural highlights
Function
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.[1]
Publication Abstract from PubMed
Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.
Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir.,Sevrioukova IF, Poulos TL J Med Chem. 2013 Apr 26. PMID:23586711[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Miyazawa M, Shindo M, Shimada T. Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metab Dispos. 2001 Feb;29(2):200-5. PMID:11159812
- ↑ Sevrioukova IF, Poulos TL. Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir. J Med Chem. 2013 Apr 26. PMID:23586711 doi:10.1021/jm400288z
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