View source for 6vjw


==Crystal structure of WT hMBD4 complexed with T:G mismatch DNA==
<StructureSection load='6vjw' size='340' side='right'caption='[[6vjw]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6vjw]] 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=6VJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VJW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.02&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ORP:2-DEOXY-5-PHOSPHONO-RIBOSE'>ORP</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=6vjw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vjw OCA], [https://pdbe.org/6vjw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vjw RCSB], [https://www.ebi.ac.uk/pdbsum/6vjw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vjw ProSAT]</span></td></tr>
</table>
== Function ==
[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;">
== Publication Abstract from PubMed ==
Thymine:guanine base pairs are major promutagenic mismatches occurring in DNA metabolism. If left unrepaired, these mispairs can cause C to T transition mutations. In humans, T:G mismatches are repaired in part by mismatch-specific DNA glycosylases such as methyl-CpG-binding domain 4 (hMBD4) and thymine-DNA glycosylase. Unlike lesion-specific DNA glycosylases, T:G-mismatch-specific DNA glycosylases specifically recognize both bases of the mismatch and remove the thymine but only from mispairs with guanine. Despite the advances in biochemical and structural characterizations of hMBD4, the catalytic mechanism of hMBD4 remains elusive. Herein, we report two structures of hMBD4 processing T:G-mismatched DNA. A high-resolution crystal structure of Asp560Asn hMBD4-T:G complex suggests that hMBD4-mediated glycosidic bond cleavage occurs via a general base catalysis mechanism assisted by Asp560. A structure of wild-type hMBD4 encountering T:G-containing DNA shows the generation of an apurinic/apyrimidinic (AP) site bearing the C1'-(S)-OH. The inversion of the stereochemistry at the C1' of the AP-site indicates that a nucleophilic water molecule approaches from the back of the thymine substrate, suggesting a bimolecular displacement mechanism (SN2) for hMBD4-catalyzed thymine excision. The AP-site is stabilized by an extensive hydrogen bond network in the MBD4 catalytic site, highlighting the role of MBD4 in protecting the genotoxic AP-site.

Catalytic mechanism of the mismatch-specific DNA glycosylase methyl-CpG-binding domain 4.,Ouzon-Shubeita H, Jung H, Lee MH, Koag MC, Lee S Biochem J. 2020 May 15;477(9):1601-1612. doi: 10.1042/BCJ20200125. PMID:32297632<ref>PMID:32297632</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vjw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Methyl CpG binding protein 3D structures|Methyl CpG binding protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Jung H]]
[[Category: Lee S]]