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| | <StructureSection load='4rfr' size='340' side='right'caption='[[4rfr]], [[Resolution|resolution]] 1.50Å' scene=''> | | <StructureSection load='4rfr' size='340' side='right'caption='[[4rfr]], [[Resolution|resolution]] 1.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rfr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RFR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rfr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RFR FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=RHN:4,5-DIHYDROXY-9,10-DIOXO-9,10-DIHYDROANTHRACENE-2-CARBOXYLIC+ACID'>RHN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=RHN:4,5-DIHYDROXY-9,10-DIOXO-9,10-DIHYDROANTHRACENE-2-CARBOXYLIC+ACID'>RHN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3t4h|3t4h]]</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=4rfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfr OCA], [https://pdbe.org/4rfr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rfr RCSB], [https://www.ebi.ac.uk/pdbsum/4rfr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfr ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">alkB, aidD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_oxidative_demethylase DNA oxidative demethylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.11.33 1.14.11.33] </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=4rfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rfr OCA], [http://pdbe.org/4rfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rfr RCSB], [http://www.ebi.ac.uk/pdbsum/4rfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rfr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ALKB_ECOLI ALKB_ECOLI]] Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).<ref>PMID:12226668</ref> <ref>PMID:12594517</ref> <ref>PMID:16482161</ref> <ref>PMID:19706517</ref> <ref>PMID:21068844</ref> <ref>PMID:20084272</ref> | + | [https://www.uniprot.org/uniprot/ALKB_ECOLI ALKB_ECOLI] Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).<ref>PMID:12226668</ref> <ref>PMID:12594517</ref> <ref>PMID:16482161</ref> <ref>PMID:19706517</ref> <ref>PMID:21068844</ref> <ref>PMID:20084272</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Dioxygenase|Dioxygenase]] | + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Escherichia coli]] |
| - | [[Category: DNA oxidative demethylase]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Huang, Y]] | + | [[Category: Huang Y]] |
| - | [[Category: Li, J F]] | + | [[Category: Li JF]] |
| - | [[Category: Li, Q]] | + | [[Category: Li Q]] |
| - | [[Category: Yang, C G]] | + | [[Category: Yang C-G]] |
| - | [[Category: Alkb family]]
| + | |
| - | [[Category: Demethylase]]
| + | |
| - | [[Category: Demethylation]]
| + | |
| - | [[Category: Jellyroll fold]]
| + | |
| - | [[Category: Nucleic acid binding]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Oxidoreductase-inhibitor complex]]
| + | |
| - | [[Category: Protein-inhibitor complex]]
| + | |
| Structural highlights
Function
ALKB_ECOLI Dioxygenase that repairs alkylated DNA and RNA containing 3-methylcytosine or 1-methyladenine by oxidative demethylation. Has highest activity towards 3-methylcytosine. Has lower activity towards alkylated DNA containing ethenoadenine, and no detectable activity towards 1-methylguanine or 3-methylthymine. Accepts double-stranded and single-stranded substrates. Requires molecular oxygen, alpha-ketoglutarate and iron. Provides extensive resistance to alkylating agents such as MMS and DMS (SN2 agents), but not to MMNG and MNU (SN1 agents).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N(1)-methyladenine and N(3)-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N(1)-methyladenine and N(3)-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.
Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage.,Li Q, Huang Y, Liu X, Gan J, Chen H, Yang CG J Biol Chem. 2016 May 20;291(21):11083-93. doi: 10.1074/jbc.M115.711895. Epub, 2016 Mar 25. PMID:27015802[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Falnes PO, Johansen RF, Seeberg E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature. 2002 Sep 12;419(6903):178-82. PMID:12226668 doi:10.1038/nature01048
- ↑ Aas PA, Otterlei M, Falnes PO, Vagbo CB, Skorpen F, Akbari M, Sundheim O, Bjoras M, Slupphaug G, Seeberg E, Krokan HE. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA. Nature. 2003 Feb 20;421(6925):859-63. PMID:12594517 doi:10.1038/nature01363
- ↑ Yu B, Edstrom WC, Benach J, Hamuro Y, Weber PC, Gibney BR, Hunt JF. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature. 2006 Feb 16;439(7078):879-84. PMID:16482161 doi:10.1038/nature04561
- ↑ Yu B, Hunt JF. Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14315-20. Epub 2009 Aug 11. PMID:19706517
- ↑ Yi C, Jia G, Hou G, Dai Q, Zhang W, Zheng G, Jian X, Yang CG, Cui Q, He C. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase. Nature. 2010 Nov 11;468(7321):330-3. PMID:21068844 doi:10.1038/nature09497
- ↑ Holland PJ, Hollis T. Structural and mutational analysis of Escherichia coli AlkB provides insight into substrate specificity and DNA damage searching. PLoS One. 2010 Jan 13;5(1):e8680. PMID:20084272 doi:10.1371/journal.pone.0008680
- ↑ Li Q, Huang Y, Liu X, Gan J, Chen H, Yang CG. Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage. J Biol Chem. 2016 May 20;291(21):11083-93. doi: 10.1074/jbc.M115.711895. Epub, 2016 Mar 25. PMID:27015802 doi:http://dx.doi.org/10.1074/jbc.M115.711895
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