3tjs: Difference between revisions
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The | ==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=''> | |||
== Structural highlights == | |||
<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> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25Å</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='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. | |||
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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3tjs" 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]] | |||
