1z10: Difference between revisions

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[[Image:1z10.png|left|200px]]


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==Crystal Structure of Human Microsomal P450 2A6 with Coumarin Bound==
The line below this paragraph, containing "STRUCTURE_1z10", creates the "Structure Box" on the page.
<StructureSection load='1z10' size='340' side='right'caption='[[1z10]], [[Resolution|resolution]] 1.90&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'>[[1z10]] is a 4 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=1Z10 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Z10 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]] 1.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=COU:COUMARIN'>COU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr>
{{STRUCTURE_1z10|  PDB=1z10  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1z10 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1z10 OCA], [https://pdbe.org/1z10 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1z10 RCSB], [https://www.ebi.ac.uk/pdbsum/1z10 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1z10 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CP2A6_HUMAN CP2A6_HUMAN] Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.<ref>PMID:1889415</ref> <ref>PMID:1944238</ref> <ref>PMID:11695850</ref> <ref>PMID:16086027</ref> <ref>PMID:17125252</ref> <ref>PMID:18779312</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/z1/1z10_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1z10 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human microsomal cytochrome P450 2A6 (CYP2A6) contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. The CYP2A6 structure shows a compact, hydrophobic active site with one hydrogen bond donor, Asn297, that orients coumarin for regioselective oxidation. The inhibitor methoxsalen effectively fills the active site cavity without substantially perturbing the structure. The structure should aid the design of inhibitors to reduce smoking and tobacco-related cancers.


===Crystal Structure of Human Microsomal P450 2A6 with Coumarin Bound===
Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.,Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:16086027<ref>PMID:16086027</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1z10" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_16086027}}, adds the Publication Abstract to the page
*[[Cytochrome P450 3D structures|Cytochrome P450 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 16086027 is the PubMed ID number.
== References ==
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<references/>
{{ABSTRACT_PUBMED_16086027}}
__TOC__
 
</StructureSection>
==About this Structure==
1Z10 is a 4 chains structure of sequences 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=1Z10 OCA].
 
==Reference==
Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen., Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF, Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16086027 16086027]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Unspecific monooxygenase]]
[[Category: Large Structures]]
[[Category: Griffin, K J.]]
[[Category: Griffin KJ]]
[[Category: Hsu, M H.]]
[[Category: Hsu MH]]
[[Category: Johnson, E F.]]
[[Category: Johnson EF]]
[[Category: Stout, C D.]]
[[Category: Stout CD]]
[[Category: Yano, J K.]]
[[Category: Yano JK]]
[[Category: Coumarin 7-hydroxylase]]
[[Category: Cyp2a6]]
[[Category: Drug metabolizing enzyme]]
[[Category: Heme]]
[[Category: Monooxygenase]]
[[Category: Nicotine oxidase]]
[[Category: Oxidoreductase]]
[[Category: P450]]
[[Category: P450 2a6]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Dec 10 15:12:59 2008''

Latest revision as of 10:02, 23 August 2023

Crystal Structure of Human Microsomal P450 2A6 with Coumarin BoundCrystal Structure of Human Microsomal P450 2A6 with Coumarin Bound

Structural highlights

1z10 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CP2A6_HUMAN Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase. Acts as a 1,4-cineole 2-exo-monooxygenase. Possesses low phenacetin O-deethylation activity.[1] [2] [3] [4] [5] [6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Human microsomal cytochrome P450 2A6 (CYP2A6) contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. The CYP2A6 structure shows a compact, hydrophobic active site with one hydrogen bond donor, Asn297, that orients coumarin for regioselective oxidation. The inhibitor methoxsalen effectively fills the active site cavity without substantially perturbing the structure. The structure should aid the design of inhibitors to reduce smoking and tobacco-related cancers.

Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.,Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:16086027[7]

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

See Also

References

  1. ↑ Maurice M, Emiliani S, Dalet-Beluche I, Derancourt J, Lange R. Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes. Eur J Biochem. 1991 Sep 1;200(2):511-7. PMID:1889415
  2. ↑ Yun CH, Shimada T, Guengerich FP. Purification and characterization of human liver microsomal cytochrome P-450 2A6. Mol Pharmacol. 1991 Nov;40(5):679-85. PMID:1944238
  3. ↑ Miyazawa M, Shindo M, Shimada T. Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1,4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes. Xenobiotica. 2001 Oct;31(10):713-23. PMID:11695850 doi:10.1080/00498250110065595
  4. ↑ Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:16086027 doi:http://dx.doi.org/10.1038/nsmb971
  5. ↑ Yano JK, Denton TT, Cerny MA, Zhang X, Johnson EF, Cashman JR. Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem. 2006 Nov 30;49(24):6987-7001. PMID:17125252 doi:http://dx.doi.org/10.1021/jm060519r
  6. ↑ DeVore NM, Smith BD, Urban MJ, Scott EE. Key residues controlling phenacetin metabolism by human cytochrome P450 2A enzymes. Drug Metab Dispos. 2008 Dec;36(12):2582-90. Epub 2008 Sep 8. PMID:18779312 doi:10.1124/dmd.108.023770
  7. ↑ Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol. 2005 Sep;12(9):822-3. Epub 2005 Aug 7. PMID:16086027 doi:http://dx.doi.org/10.1038/nsmb971

1z10, resolution 1.90Å

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