4d78: Difference between revisions
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<StructureSection load='4d78' size='340' side='right' caption='[[4d78]], [[Resolution|resolution]] 2.80Å' scene=''> | <StructureSection load='4d78' size='340' side='right' caption='[[4d78]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4d78]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D78 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D78 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4d78]] 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=4D78 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D78 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=J9K:TERT-BUTYL+[(2S)-1-({3-OXO-3-[(PYRIDIN-3-YLMETHYL)AMINO]PROPYL}SULFANYL)-3-PHENYLPROPAN-2-YL]CARBAMATE'>J9K</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=J9K:TERT-BUTYL+[(2S)-1-({3-OXO-3-[(PYRIDIN-3-YLMETHYL)AMINO]PROPYL}SULFANYL)-3-PHENYLPROPAN-2-YL]CARBAMATE'>J9K</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d6z|4d6z]], [[4d75|4d75]], [[4d7d|4d7d]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d6z|4d6z]], [[4d75|4d75]], [[4d7d|4d7d]]</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=4d78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d78 OCA], [http://pdbe.org/4d78 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d78 RCSB], [http://www.ebi.ac.uk/pdbsum/4d78 PDBsum]</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=4d78 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d78 OCA], [http://pdbe.org/4d78 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d78 RCSB], [http://www.ebi.ac.uk/pdbsum/4d78 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d78 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Poulos, T]] | [[Category: Poulos, T]] | ||
[[Category: Sevrioukova, I]] | [[Category: Sevrioukova, I]] | ||
Revision as of 18:10, 16 November 2017
Cytochrome P450 3A4 bound to an inhibitorCytochrome P450 3A4 bound to an inhibitor
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 PubMedHuman cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of co-administered pharmaceuticals that are metabolized by CYP3A4. Based on our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety and aromaticity of the side group analogous to Phe-2 of ritonavir, and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable sub-micromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model. Structure-based inhibitor design for evaluation of a CYP3A4 pharmacophore model.,Kaur P, Chamberlin R, Poulos TL, Sevrioukova IF J Med Chem. 2015 Sep 29. PMID:26371436[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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