2j2s
SOLUTION STRUCTURE OF THE NONMETHYL-CPG-BINDING CXXC DOMAIN OF THE LEUKAEMIA-ASSOCIATED MLL HISTONE METHYLTRANSFERASE
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OverviewOverview
Methylation of CpG dinucleotides is the major epigenetic modification of, mammalian genomes, critical for regulating chromatin structure and gene, activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds, nonmethyl-CpG DNA, and is required for transformation by MLL fusion, proteins that commonly arise from recurrent chromosomal translocations in, infant and secondary treatment-related acute leukaemias. To elucidate the, molecular basis of nonmethyl-CpG DNA recognition, we determined the, structure of the human MLL CXXC domain by multidimensional NMR, spectroscopy. The CXXC domain has a novel fold in which two zinc ions are, each coordinated tetrahedrally by four conserved cysteine ligands provided, by two CGXCXXC motifs and two distal cysteine residues. We have identified, the CXXC domain DNA binding interface by means of chemical shift, perturbation analysis, cross-saturation transfer and site-directed, mutagenesis. In particular, we have shown that residues in an extended, surface loop are in close contact with the DNA. These data provide a, template for the design of specifically targeted therapeutics for poor, prognosis MLL-associated leukaemias.
DiseaseDisease
Known diseases associated with this structure: Leukemia, myeloid/lymphoid or mixed-lineage OMIM:[159555]
About this StructureAbout this Structure
2J2S is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase., Allen MD, Grummitt CG, Hilcenko C, Min SY, Tonkin LM, Johnson CM, Freund SM, Bycroft M, Warren AJ, EMBO J. 2006 Oct 4;25(19):4503-12. Epub 2006 Sep 21. PMID:16990798
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