8c58 | pdb_00008c58

CpG specific M.MpeI methyltransferase crystallized in the presence of 5-hydroxycytosine and 5-methylcytosine containing dsDNA

spinqualitylabelsall models 8c58, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c58 is a 3 chain structure with sequence from Malacoplasma penetrans HF-2 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: 5CM, 5OC, CO3, GOL, SAM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8EVR5_MALP2 Publication Abstract from PubMed DNA methyltransferases are drug targets for myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia (AML) and possibly beta-hemoglobinopathies. We characterize the interaction of nucleoside analogues in DNA with a prokaryotic CpG-specific DNA methyltransferase (M.MpeI) as a model for mammalian DNMT1 methyltransferases. We tested DNA containing 5-hydroxymethylcytosine (5hmC), 5-hydroxycytosine (5OHC), 5-methyl-2-pyrimidinone (in the ribosylated form known as 5-methylzebularine, 5mZ), 5,6-dihydro-5-azacytosine (dhaC), 5-fluorocytosine (5FC), 5-chlorocytosine (5ClC), 5-bromocytosine (5BrC) and 5-iodocytosine (5IC). Covalent complex formation was by far most efficient for 5FC. Non-covalent complexes were most abundant for dhaC and 5mZ. Surprisingly, we observed methylation of 5IC and 5BrC, and to a lesser extent 5ClC and 5FC, in the presence, but not the absence of small molecule thiol nucleophiles. For 5IC and 5BrC, we demonstrated by mass spectrometry that the reactions were due to methyltransferase driven dehalogenation, followed by methylation. Crystal structures of M.MpeI-DNA complexes capture the 'in' conformation of the active site loop for analogues with small or rotatable (5mZ) 5-substituents and its 'out' form for bulky 5-substituents. Since very similar 'in' and 'out' loop conformations were also observed for DNMT1, it is likely that our conclusions generalize to other DNA methyltransferases. Cytosine analogues as DNA methyltransferase substrates.,Wojciechowski M, Czapinska H, Krwawicz J, Rafalski D, Bochtler M Nucleic Acids Res. 2024 Jul 5:gkae568. doi: 10.1093/nar/gkae568. PMID:38966999 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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