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| | <StructureSection load='4ny4' size='340' side='right'caption='[[4ny4]], [[Resolution|resolution]] 2.95Å' scene=''> | | <StructureSection load='4ny4' size='340' side='right'caption='[[4ny4]], [[Resolution|resolution]] 2.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ny4]] is a 1 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=4NY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NY4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ny4]] 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=4NY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NY4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2QH:(8R)-3,3-DIFLUORO-8-[4-FLUORO-3-(PYRIDIN-3-YL)PHENYL]-8-(4-METHOXY-3-METHYLPHENYL)-2,3,4,8-TETRAHYDROIMIDAZO[1,5-A]PYRIMIDIN-6-AMINE'>2QH</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2QH:(8R)-3,3-DIFLUORO-8-[4-FLUORO-3-(PYRIDIN-3-YL)PHENYL]-8-(4-METHOXY-3-METHYLPHENYL)-2,3,4,8-TETRAHYDROIMIDAZO[1,5-A]PYRIMIDIN-6-AMINE'>2QH</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nz2|4nz2]]</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=4ny4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ny4 OCA], [https://pdbe.org/4ny4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ny4 RCSB], [https://www.ebi.ac.uk/pdbsum/4ny4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ny4 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A3, CYP3A4, CYP3A4 CYP3A3 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ny4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ny4 OCA], [http://pdbe.org/4ny4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ny4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ny4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ny4 ProSAT]</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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| | ==See Also== | | ==See Also== |
| | *[[CYP3A4|CYP3A4]] | | *[[CYP3A4|CYP3A4]] |
| - | *[[Cytochrome P450|Cytochrome P450]] | + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Branden, G]] | + | [[Category: Branden G]] |
| - | [[Category: Sjogren, T]] | + | [[Category: Sjogren T]] |
| - | [[Category: Xue, Y]] | + | [[Category: Xue Y]] |
| - | [[Category: Cyp3a4]]
| + | |
| - | [[Category: Cytochrome p-450]]
| + | |
| - | [[Category: Drug metabolism]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Monooxygenase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Structure-based drug design]]
| + | |
| 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
Cytochrome P450 (CYP) enzymes are key players in xenobiotic metabolism, and inhibition of CYPs can therefore result in unwanted drug-drug interactions. Within drug discovery, CYP inhibition can cause delays in the progression of candidate drugs, or even premature closure of projects. During the past decade, a massive effort in the pharmaceutical industry and academic research has produced a wealth of structural information in the CYP field. In this short review, we will describe how structure-based approaches can be used in the pharmaceutical industry to work away from CYP inhibition, with a focus on the opportunities and challenges. We will show two examples from our own work where structural information on CYP2C9 and CYP3A4 inhibitor complexes have been successfully exploited in ongoing drug discovery projects.
Structure-based ligand design to overcome CYP inhibition in drug discovery projects.,Branden G, Sjogren T, Schnecke V, Xue Y Drug Discov Today. 2014 Jul;19(7):905-911. doi: 10.1016/j.drudis.2014.03.012., Epub 2014 Mar 16. PMID:24642031[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Branden G, Sjogren T, Schnecke V, Xue Y. Structure-based ligand design to overcome CYP inhibition in drug discovery projects. Drug Discov Today. 2014 Jul;19(7):905-911. doi: 10.1016/j.drudis.2014.03.012., Epub 2014 Mar 16. PMID:24642031 doi:http://dx.doi.org/10.1016/j.drudis.2014.03.012
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