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| ==Structure of the glycoslyase domain of MBD4 bound to a 5hmU containing DNA== | | ==Structure of the glycoslyase domain of MBD4 bound to a 5hmU containing DNA== |
| <StructureSection load='4ea5' size='340' side='right' caption='[[4ea5]], [[Resolution|resolution]] 2.14Å' scene=''> | | <StructureSection load='4ea5' size='340' side='right'caption='[[4ea5]], [[Resolution|resolution]] 2.14Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4ea5]] is a 3 chain structure with sequence 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=4EA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EA5 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4ea5]] is a 3 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=4EA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EA5 FirstGlance]. <br> |
| </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=5HU:5-HYDROXYMETHYLURIDINE-2-DEOXY-5-MONOPHOSPHATE'>5HU</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]] 2.14Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4e9e|4e9e]], [[4e9f|4e9f]], [[4e9g|4e9g]], [[4e9h|4e9h]], [[4ea4|4ea4]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5HU:5-HYDROXYMETHYLURIDINE-2-DEOXY-5-MONOPHOSPHATE'>5HU</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MBD4, MED1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4ea5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ea5 OCA], [https://pdbe.org/4ea5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ea5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ea5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ea5 ProSAT]</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=4ea5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ea5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ea5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ea5 PDBsum]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/MBD4_HUMAN MBD4_HUMAN]] Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.<ref>PMID:10097147</ref> <ref>PMID:10930409</ref> | | [https://www.uniprot.org/uniprot/MBD4_HUMAN MBD4_HUMAN] Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.<ref>PMID:10097147</ref> <ref>PMID:10930409</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Active DNA demethylation in mammals occurs via hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation family of proteins (TETs). 5hmC residues in DNA can be further oxidized by TETs to 5-carboxylcytosines and/or deaminated by the Activation Induced Deaminase/Apolipoprotein B mRNA-editing enzyme complex family proteins to 5-hydromethyluracil (5hmU). Excision and replacement of these intermediates is initiated by DNA glycosylases such as thymine-DNA glycosylase (TDG), methyl-binding domain protein 4 (MBD4) and single-strand specific monofunctional uracil-DNA glycosylase 1 in the base excision repair pathway. Here, we report detailed biochemical and structural characterization of human MBD4 which contains mismatch-specific TDG activity. Full-length as well as catalytic domain (residues 426-580) of human MBD4 (MBD4(cat)) can remove 5hmU when opposite to G with good efficiency. Here, we also report six crystal structures of human MBD4(cat): an unliganded form and five binary complexes with duplex DNA containing a T*G, 5hmU*G or AP*G (apurinic/apyrimidinic) mismatch at the target base pair. These structures reveal that MBD4(cat) uses a base flipping mechanism to specifically recognize thymine and 5hmU. The recognition mechanism of flipped-out 5hmU bases in MBD4(cat) active site supports the potential role of MBD4, together with TDG, in maintenance of genome stability and active DNA demethylation in mammals.
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| Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA.,Morera S, Grin I, Vigouroux A, Couve S, Henriot V, Saparbaev M, Ishchenko AA Nucleic Acids Res. 2012 Jul 30. PMID:22848106<ref>PMID:22848106</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Methyl CpG binding protein|Methyl CpG binding protein]] | | *[[Methyl CpG binding protein 3D structures|Methyl CpG binding protein 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
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| </StructureSection> | | </StructureSection> |
| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| [[Category: Morera, S]] | | [[Category: Large Structures]] |
| [[Category: Vigouroux, A]] | | [[Category: Morera S]] |
| [[Category: Hhh dna glycosylase family]] | | [[Category: Vigouroux A]] |
| [[Category: Hydrolase-dna complex]]
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