3tjs: Difference between revisions

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[[Image:3tjs.jpg|left|200px]]


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==Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir==
The line below this paragraph, containing "STRUCTURE_3tjs", creates the "Structure Box" on the page.
<StructureSection load='3tjs' size='340' side='right'caption='[[3tjs]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[3tjs]] 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=3TJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TJS FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25&#8491;</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>
{{STRUCTURE_3tjs|  PDB=3tjs  |  SCENE=  }}
<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>
== 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 ==
Ritonavir 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.


===Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir===
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<ref>PMID:22410611</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3tjs" style="background-color:#fffaf0;"></div>


==About this Structure==
==See Also==
[[3tjs]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TJS OCA].
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
[[Category: Albendazole monooxygenase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Poulos, T L.]]
[[Category: Large Structures]]
[[Category: Sevrioukova, I F.]]
[[Category: Poulos TL]]
[[Category: Cytochrome p450]]
[[Category: Sevrioukova IF]]
[[Category: Endoplasmic reticulum]]
[[Category: Monooxygenase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

Latest revision as of 10:19, 13 August 2026

Crystal Structure of the complex between human cytochrome P450 3A4 and desthiazolylmethyloxycarbonyl ritonavir

3tjs, resolution 2.25Å

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