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[[Image:1m0e.gif|left|200px]]


{{Structure
==ZEBULARINE: A NOVEL DNA METHYLATION INHIBITOR THAT FORMS A COVALENT COMPLEX WITH DNA METHYLTRANSFERASE==
|PDB= 1m0e |SIZE=350|CAPTION= <scene name='initialview01'>1m0e</scene>, resolution 2.50&Aring;
<StructureSection load='1m0e' size='340' side='right'caption='[[1m0e]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=DA:2&#39;-DEOXYADENOSINE-5&#39;-MONOPHOSPHATE'>DA</scene>, <scene name='pdbligand=DC:2&#39;-DEOXYCYTIDINE-5&#39;-MONOPHOSPHATE'>DC</scene>, <scene name='pdbligand=DG:2&#39;-DEOXYGUANOSINE-5&#39;-MONOPHOSPHATE'>DG</scene>, <scene name='pdbligand=DT:THYMIDINE-5&#39;-MONOPHOSPHATE'>DT</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=Z:ZEBULARINE'>Z</scene>
<table><tr><td colspan='2'>[[1m0e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_haemolyticus Haemophilus haemolyticus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M0E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M0E FirstGlance]. <br>
|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Deleted_entry Deleted entry], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.73 2.1.1.73] </span>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
|GENE=
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=Z:1-(2-DEOXY-5-O-PHOSPHONO-BETA-D-ERYTHRO-PENTOFURANOSYL)PYRIMIDIN-2(1H)-ONE'>Z</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1m0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m0e OCA], [https://pdbe.org/1m0e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m0e RCSB], [https://www.ebi.ac.uk/pdbsum/1m0e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m0e ProSAT]</span></td></tr>
|RELATEDENTRY=[[9mht|9MHT]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1m0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m0e OCA], [http://www.ebi.ac.uk/pdbsum/1m0e PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1m0e RCSB]</span>
== Function ==
}}
[https://www.uniprot.org/uniprot/MTH1_HAEPH MTH1_HAEPH] This methylase recognizes the double-stranded sequence GCGC, causes specific methylation on C-2 on both strands, and protects the DNA from cleavage by the HhaI endonuclease.
== 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/m0/1m0e_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=1m0e ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mechanism-based inhibitors of enzymes, which mimic reactive intermediates in the reaction pathway, have been deployed extensively in the analysis of metabolic pathways and as candidate drugs. The inhibition of cytosine-[C5]-specific DNA methyltransferases (C5 MTases) by oligodeoxynucleotides containing 5-azadeoxycytidine (AzadC) and 5-fluorodeoxycytidine (FdC) provides a well-documented example of mechanism-based inhibition of enzymes central to nucleic acid metabolism. Here, we describe the interaction between the C5 MTase from Haemophilus haemolyticus (M.HhaI) and an oligodeoxynucleotide duplex containing 2-H pyrimidinone, an analogue often referred to as zebularine and known to give rise to high-affinity complexes with MTases. X-ray crystallography has demonstrated the formation of a covalent bond between M.HhaI and the 2-H pyrimidinone-containing oligodeoxynucleotide. This observation enables a comparison between the mechanisms of action of 2-H pyrimidinone with other mechanism-based inhibitors such as FdC. This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine.


'''ZEBULARINE: A NOVEL DNA METHYLATION INHIBITOR THAT FORMS A COVALENT COMPLEX WITH DNA METHYLTRANSFERASE'''
Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases.,Zhou L, Cheng X, Connolly BA, Dickman MJ, Hurd PJ, Hornby DP J Mol Biol. 2002 Aug 23;321(4):591-9. PMID:12206775<ref>PMID:12206775</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1m0e" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
Mechanism-based inhibitors of enzymes, which mimic reactive intermediates in the reaction pathway, have been deployed extensively in the analysis of metabolic pathways and as candidate drugs. The inhibition of cytosine-[C5]-specific DNA methyltransferases (C5 MTases) by oligodeoxynucleotides containing 5-azadeoxycytidine (AzadC) and 5-fluorodeoxycytidine (FdC) provides a well-documented example of mechanism-based inhibition of enzymes central to nucleic acid metabolism. Here, we describe the interaction between the C5 MTase from Haemophilus haemolyticus (M.HhaI) and an oligodeoxynucleotide duplex containing 2-H pyrimidinone, an analogue often referred to as zebularine and known to give rise to high-affinity complexes with MTases. X-ray crystallography has demonstrated the formation of a covalent bond between M.HhaI and the 2-H pyrimidinone-containing oligodeoxynucleotide. This observation enables a comparison between the mechanisms of action of 2-H pyrimidinone with other mechanism-based inhibitors such as FdC. This novel complex provides a molecular explanation for the mechanism of action of the anti-cancer drug zebularine.
*[[DNA methyltransferase 3D structures|DNA methyltransferase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1M0E is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Haemophilus_haemolyticus Haemophilus haemolyticus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M0E OCA].
__TOC__
 
</StructureSection>
==Reference==
Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases., Zhou L, Cheng X, Connolly BA, Dickman MJ, Hurd PJ, Hornby DP, J Mol Biol. 2002 Aug 23;321(4):591-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12206775 12206775]
[[Category: Deleted entry]]
[[Category: Haemophilus haemolyticus]]
[[Category: Haemophilus haemolyticus]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Cheng, X.]]
[[Category: Cheng X]]
[[Category: Connolly, B A.]]
[[Category: Connolly BA]]
[[Category: Dickman, M J.]]
[[Category: Dickman MJ]]
[[Category: Hornby, D P.]]
[[Category: Hornby DP]]
[[Category: Hurd, P J.]]
[[Category: Hurd PJ]]
[[Category: Zhou, L.]]
[[Category: Zhou L]]
[[Category: mechanism based dna methylation inhibitor]]
[[Category: protein-dna covalent complex]]
[[Category: zebularine]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:09:36 2008''

Latest revision as of 06:59, 30 October 2024

ZEBULARINE: A NOVEL DNA METHYLATION INHIBITOR THAT FORMS A COVALENT COMPLEX WITH DNA METHYLTRANSFERASE

1m0e, resolution 2.50Å

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