6vjw | pdb_00006vjw

Crystal structure of WT hMBD4 complexed with T:G mismatch DNA

spinqualitylabelsall models 6vjw, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vjw is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.02Å Ligands: ORP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Methyl CpG binding protein 3D structures

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