7uaz: Difference between revisions
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==Crystal structure of human CYP3A4 with the caged inhibitor== | ==Crystal structure of human CYP3A4 with the caged inhibitor== | ||
<StructureSection load='7uaz' size='340' side='right'caption='[[7uaz]]' scene=''> | <StructureSection load='7uaz' size='340' side='right'caption='[[7uaz]], [[Resolution|resolution]] 2.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UAZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UAZ FirstGlance]. <br> | <table><tr><td colspan='2'>[[7uaz]] 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=7UAZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UAZ FirstGlance]. <br> | ||
</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=7uaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uaz OCA], [https://pdbe.org/7uaz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uaz RCSB], [https://www.ebi.ac.uk/pdbsum/7uaz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uaz ProSAT]</span></td></tr> | </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=O3L:(N-[([2,2-bipyridin]-5-yl-kappa~2~N~1~,N~1~)methyl]-3-{[(pyridin-3-yl)methyl]sulfanyl}propanamide)bis[2-(pyridin-2-yl-kappaN)phenyl-kappaC~1~]iridium'>O3L</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=7uaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uaz OCA], [https://pdbe.org/7uaz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uaz RCSB], [https://www.ebi.ac.uk/pdbsum/7uaz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uaz ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Cytochromes P450 (CYPs) are a superfamily of enzymes responsible for biosynthesis and drug metabolism. Monitoring the activity of CYP3A4, the major human drug-metabolizing enzyme, is vital for assessing the metabolism of pharmaceuticals and identifying harmful drug-drug interactions. Existing probes for CYP3A4 are irreversible turn-on substrates that monitor activity at specific time points in end-point assays. To provide a more dynamic approach, we designed, synthesized, and characterized emissive Ir(III) and Ru(II) complexes that allow monitoring of the CYP3A4 active-site occupancy in real time. In the bound state, probe emission is quenched by the active-site heme. Upon displacement from the active site by CYP3A4-specific inhibitors or substrates, these probes show high emission turn-on. Direct probe binding to the CYP3A4 active site was confirmed by X-ray crystallography. The lead Ir(III)-based probe has nanomolar Kd and high selectivity for CYP3A4, efficient cellular uptake, and low toxicity in CYP3A4-overexpressing HepG2 cells. | |||
Ir(III)-Based Agents for Monitoring the Cytochrome P450 3A4 Active Site Occupancy.,Denison M, Steinke SJ, Majeed A, Turro C, Kocarek TA, Sevrioukova IF, Kodanko JJ Inorg Chem. 2022 Aug 22. doi: 10.1021/acs.inorgchem.2c02587. PMID:35994607<ref>PMID:35994607</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7uaz" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Sevrioukova IF]] | [[Category: Sevrioukova IF]] | ||
Revision as of 22:27, 7 September 2022
Crystal structure of human CYP3A4 with the caged inhibitorCrystal structure of human CYP3A4 with the caged 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 PubMedCytochromes P450 (CYPs) are a superfamily of enzymes responsible for biosynthesis and drug metabolism. Monitoring the activity of CYP3A4, the major human drug-metabolizing enzyme, is vital for assessing the metabolism of pharmaceuticals and identifying harmful drug-drug interactions. Existing probes for CYP3A4 are irreversible turn-on substrates that monitor activity at specific time points in end-point assays. To provide a more dynamic approach, we designed, synthesized, and characterized emissive Ir(III) and Ru(II) complexes that allow monitoring of the CYP3A4 active-site occupancy in real time. In the bound state, probe emission is quenched by the active-site heme. Upon displacement from the active site by CYP3A4-specific inhibitors or substrates, these probes show high emission turn-on. Direct probe binding to the CYP3A4 active site was confirmed by X-ray crystallography. The lead Ir(III)-based probe has nanomolar Kd and high selectivity for CYP3A4, efficient cellular uptake, and low toxicity in CYP3A4-overexpressing HepG2 cells. Ir(III)-Based Agents for Monitoring the Cytochrome P450 3A4 Active Site Occupancy.,Denison M, Steinke SJ, Majeed A, Turro C, Kocarek TA, Sevrioukova IF, Kodanko JJ Inorg Chem. 2022 Aug 22. doi: 10.1021/acs.inorgchem.2c02587. PMID:35994607[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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