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| | <StructureSection load='7nro' size='340' side='right'caption='[[7nro]], [[Resolution|resolution]] 1.25Å' scene=''> | | <StructureSection load='7nro' size='340' side='right'caption='[[7nro]], [[Resolution|resolution]] 1.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7nro]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7nro]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRO FirstGlance]. <br> |
| - | </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=UPW:2-[[6-[(4-nitrophenyl)amino]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic+acid'>UPW</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3t3y|3t3y]]</div></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=UPW:2-[[6-[(4-nitrophenyl)amino]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic+acid'>UPW</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/DNA_oxidative_demethylase DNA oxidative demethylase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nro OCA], [https://pdbe.org/7nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nro RCSB], [https://www.ebi.ac.uk/pdbsum/7nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nro ProSAT]</span></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=7nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nro OCA], [https://pdbe.org/7nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nro RCSB], [https://www.ebi.ac.uk/pdbsum/7nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nro ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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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| | </div> | | </div> |
| | <div class="pdbe-citations 7nro" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7nro" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dioxygenase 3D structures|Dioxygenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA oxidative demethylase]] | + | [[Category: Escherichia coli K-12]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Aik, W S]] | + | [[Category: Aik WS]] |
| - | [[Category: Leissing, T]] | + | [[Category: Leissing T]] |
| - | [[Category: Maheswaran, P]] | + | [[Category: Maheswaran P]] |
| - | [[Category: McDonough, M A]] | + | [[Category: McDonough MA]] |
| - | [[Category: Schofield, C J]] | + | [[Category: Schofield CJ]] |
| - | [[Category: Shishodia, S]] | + | [[Category: Shishodia S]] |
| - | [[Category: Alpha ketoglutarate and iron dependent oxygenase]]
| + | |
| - | [[Category: Dna demethylase]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| 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
FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of N(6)-methyladenosine (m(6)A) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use in vivo.
Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.,Shishodia S, Demetriades M, Zhang D, Tam NY, Maheswaran P, Clunie-O'Connor C, Tumber A, Leung IKH, Ng YM, Leissing TM, El-Sagheer AH, Salah E, Brown T, Aik WS, McDonough MA, Schofield CJ J Med Chem. 2021 Nov 11. doi: 10.1021/acs.jmedchem.1c01204. PMID:34762429[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
- ↑ Shishodia S, Demetriades M, Zhang D, Tam NY, Maheswaran P, Clunie-O'Connor C, Tumber A, Leung IKH, Ng YM, Leissing TM, El-Sagheer AH, Salah E, Brown T, Aik WS, McDonough MA, Schofield CJ. Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors. J Med Chem. 2021 Nov 11. doi: 10.1021/acs.jmedchem.1c01204. PMID:34762429 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01204
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