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PDBsum entry 2j2s
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Transcription regulation
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PDB id
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2j2s
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References listed in PDB file
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Key reference
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Title
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Solution structure of the nonmethyl-Cpg-Binding cxxc domain of the leukaemia-Associated mll histone methyltransferase.
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Authors
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M.D.Allen,
C.G.Grummitt,
C.Hilcenko,
S.Y.Min,
L.M.Tonkin,
C.M.Johnson,
S.M.Freund,
M.Bycroft,
A.J.Warren.
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Ref.
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EMBO J, 2006,
25,
4503-4512.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1 Solution structure of the MLL CXXC domain. (A) An
overlay of the backbone atoms of the 20 lowest energy structures
in stereo. (B) A ribbon representation of the lowest energy
structure (same orientation as in (A)), prepared using the
program PyMOL (http://www.pymol.org). Zn ions are shown as
spheres. (C) A ribbon representation of the Zn coordination
sites in MLL (PyMOL).
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Figure 2.
Figure 2 Ribbon representation of the elaborate turn in the CXXC
domain of MLL showing the side chains of the residues from the
KFGG motif and the second Zn coordination site (PyMOL). An
extended loop is formed between residues G1181 and C1189.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2006,
25,
4503-4512)
copyright 2006.
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