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4i4h
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 4i4h is ON HOLD Authors: Sevrioukova, I. F., Poulos, T. L.. Description: Crystal structure of CYP3A4 ligated to pyridine-substituted desoxyritonavi...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of CYP3A4 ligated to pyridine-substituted desoxyritonavir== | |
| + | <StructureSection load='4i4h' size='340' side='right'caption='[[4i4h]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4i4h]] 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=4I4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I4H FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</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=Z9Z:PYRIDIN-3-YLMETHYL+[(2R,5S)-5-{[N-(METHYL{[2-(PROPAN-2-YL)-1,3-THIAZOL-4-YL]METHYL}CARBAMOYL)-D-VALYL]AMINO}-1,6-DIPHENYLHEXAN-2-YL]CARBAMATE'>Z9Z</scene></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=4i4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i4h OCA], [https://pdbe.org/4i4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i4h RCSB], [https://www.ebi.ac.uk/pdbsum/4i4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i4h ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [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;"> | ||
| + | == 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<ref>PMID:23586711</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 4i4h" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Poulos TL]] | ||
| + | [[Category: Sevrioukova IF]] | ||
Current revision
Crystal structure of CYP3A4 ligated to pyridine-substituted desoxyritonavir
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