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| | ==Crystal Structure of MBD4 Catalytic Domain Bound to Abasic DNA== | | ==Crystal Structure of MBD4 Catalytic Domain Bound to Abasic DNA== |
| - | <StructureSection load='4dk9' size='340' side='right' caption='[[4dk9]], [[Resolution|resolution]] 2.76Å' scene=''> | + | <StructureSection load='4dk9' size='340' side='right'caption='[[4dk9]], [[Resolution|resolution]] 2.76Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dk9]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DK9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DK9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dk9]] 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=4DK9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DK9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene></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=4dk9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dk9 OCA], [https://pdbe.org/4dk9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dk9 RCSB], [https://www.ebi.ac.uk/pdbsum/4dk9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dk9 ProSAT]</span></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 HUMAN])</td></tr>
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| - | <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=4dk9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dk9 OCA], [http://pdbe.org/4dk9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dk9 RCSB], [http://www.ebi.ac.uk/pdbsum/4dk9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dk9 ProSAT]</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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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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/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Drohat, A C]] | + | [[Category: Large Structures]] |
| - | [[Category: Manvilla, B A]] | + | [[Category: Drohat AC]] |
| - | [[Category: Toth, E A]] | + | [[Category: Manvilla BA]] |
| - | [[Category: Hydrolase-dna complex]] | + | [[Category: Toth EA]] |
| - | [[Category: Protein-dna complex]]
| + | |
| Structural highlights
Function
[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.[1] [2]
Publication Abstract from PubMed
The mammalian repair protein MBD4 (methyl-CpG-binding domain IV) excises thymine from mutagenic G.T mispairs generated by deamination of 5-methylcytosine (mC), and downstream base excision repair proteins restore a G.C pair. MBD4 is also implicated in active DNA demethylation by initiating base excision repair of G.T mispairs generated by a deaminase enzyme. The question of how mismatch glycosylases attain specificity for excising thymine from G.T, but not A.T, pairs remains largely unresolved. Here, we report a crystal structure of the glycosylase domain of human MBD4 (residues 427-580) bound to DNA containing an abasic nucleotide paired with guanine, providing a glimpse of the enzyme-product complex. The mismatched guanine remains intrahelical, nestled into a recognition pocket. MBD4 provides selective interactions with the mismatched guanine (N1H, N2H(2)) that are not compatible with adenine, which likely confer mismatch specificity. The structure reveals no interactions that would be expected to provide the MBD4 glycosylase domain with specificity for acting at CpG sites. Accordingly, we find modest 1.5- to 2.7-fold reductions in G.T activity upon altering the CpG context. In contrast, 37- to 580-fold effects were observed previously for thymine DNA glycosylase. These findings suggest that specificity of MBD4 for acting at CpG sites depends largely on its methyl-CpG-binding domain, which binds preferably to G.T mispairs in a methylated CpG site. MBD4 glycosylase cannot excise 5-formylcytosine (fC) or 5-carboxylcytosine (caC), intermediates in a Tet (ten eleven translocation)-initiated DNA demethylation pathway. Our structure suggests that MBD4 does not provide the electrostatic interactions needed to excise these oxidized forms of mC.
Crystal Structure of Human Methyl-Binding Domain IV Glycosylase Bound to Abasic DNA.,Manvilla BA, Maiti A, Begley MC, Toth EA, Drohat AC J Mol Biol. 2012 May 2. PMID:22560993[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M, Neri G. MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3969-74. PMID:10097147
- ↑ Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Stoerker J, Genuardi M, Yeung AT, Matsumoto Y, Bellacosa A. Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J Biol Chem. 2000 Oct 20;275(42):32422-9. PMID:10930409 doi:10.1074/jbc.M004535200
- ↑ Manvilla BA, Maiti A, Begley MC, Toth EA, Drohat AC. Crystal Structure of Human Methyl-Binding Domain IV Glycosylase Bound to Abasic DNA. J Mol Biol. 2012 May 2. PMID:22560993 doi:10.1016/j.jmb.2012.04.028
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