This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

3tjs

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 10:45, 3 August 2017

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

Structural highlights

3tjs is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	3nxu
Activity:	Albendazole monooxygenase, with EC number 1.14.13.32
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Miyazawa M, Shindo M, Shimada T. Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metab Dispos. 2001 Feb;29(2):200-5. PMID:11159812
↑ Sevrioukova IF, Poulos TL. Interaction of human cytochrome P4503A4 with ritonavir analogs. Arch Biochem Biophys. 2012 Apr 15;520(2):108-16. Epub 2012 Mar 5. PMID:22410611 doi:10.1016/j.abb.2012.02.018

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3tjs"

@@ Line 3: / Line 3: @@
 <StructureSection load='3tjs' size='340' side='right' caption='[[3tjs]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3tjs]] 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=3TJS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TJS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3tjs]] is a 1 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nxu|3nxu]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CYP3A3, CYP3A4 ([http://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'>[http://en.wikipedia.org/wiki/Albendazole_monooxygenase Albendazole monooxygenase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjs OCA], [http://pdbe.org/3tjs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3tjs RCSB], [http://www.ebi.ac.uk/pdbsum/3tjs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3tjs ProSAT]</span></td></tr>
@@ Line 29: / Line 28: @@
 </StructureSection>
 [[Category: Albendazole monooxygenase]]
-[[Category: Human]]
 [[Category: Poulos, T L]]
 [[Category: Sevrioukova, I F]]

3tjs

From Proteopedia

Revision as of 10:45, 3 August 2017

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox