3tjs: Difference between revisions
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==Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir== | ==Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir== | ||
<StructureSection load='3tjs' size='340' side='right' caption='[[3tjs]], [[Resolution|resolution]] 2.25Å' scene=''> | <StructureSection load='3tjs' size='340' side='right'caption='[[3tjs]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3tjs]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3tjs]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TJS FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D0R:N-[(2S,4S,5S)-5-AMINO-4-HYDROXY-1,6-DIPHENYLHEXAN-2-YL]-N~2~-(METHYL{[2-(PROPAN-2-YL)-1,3-THIAZOL-4-YL]METHYL}CARBAMOYL)-L-VALINAMIDE'>D0R</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=D0R:N-[(2S,4S,5S)-5-AMINO-4-HYDROXY-1,6-DIPHENYLHEXAN-2-YL]-N~2~-(METHYL{[2-(PROPAN-2-YL)-1,3-THIAZOL-4-YL]METHYL}CARBAMOYL)-L-VALINAMIDE'>D0R</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">[[3nxu|3nxu]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3nxu|3nxu]]</div></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A4, CYP3A3 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Albendazole_monooxygenase Albendazole monooxygenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.32 1.14.13.32] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjs OCA], [https://pdbe.org/3tjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tjs RCSB], [https://www.ebi.ac.uk/pdbsum/3tjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tjs ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 3tjs" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 3tjs" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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[[Category: Albendazole monooxygenase]] | [[Category: Albendazole monooxygenase]] | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Poulos, T L]] | [[Category: Poulos, T L]] | ||
[[Category: Sevrioukova, I F]] | [[Category: Sevrioukova, I F]] | ||
Revision as of 20:01, 6 July 2022
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 PubMedRitonavir is a HIV protease inhibitor that also potently inactivates cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme. To better understand the mechanism of ligand binding and to find strategies for improvement of the inhibitory potency of ritonavir, currently administered to enhance pharmacokinetics of other anti-HIV drugs that are quickly metabolized by CYP3A4, we compared the manner of CYP3A4 interaction with the drug and two analogs lacking either the heme-ligating thiazole nitrogen or the entire thiazole group. Based on the kinetic, mutagenesis and structural data, we conclude that: (i) the active site residue Arg212 assists binding of all investigated compounds and, thus, may play a more prominent role in metabolic transformation of xenobiotics than previously thought, (ii) peripheral binding of ritonavir limits the heme coordination rate and complicates the binding kinetics, (iii) association of ritonavir-like type II ligands is driven by heme coordination whereas hydrophobic forces define the binding mode, and (iv) substitution of one phenyl group in ritonavir with a smaller hydrophobic moiety could prevent steric clashing and, hence, increase the affinity and inhibitory potency of the drug. Interaction of human cytochrome P4503A4 with ritonavir analogs.,Sevrioukova IF, Poulos TL Arch Biochem Biophys. 2012 Apr 15;520(2):108-16. Epub 2012 Mar 5. PMID:22410611[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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