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PDBsum entry 4esg
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Transcription/transferase
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PDB id
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4esg
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References listed in PDB file
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Key reference
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Title
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Structural basis for wdr5 interaction (win) motif recognition in human set1 family histone methyltransferases.
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Authors
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V.Dharmarajan,
J.H.Lee,
A.Patel,
D.G.Skalnik,
M.S.Cosgrove.
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Ref.
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J Biol Chem, 2012,
287,
27275-27289.
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Translocations and amplifications of the mixed lineage leukemia-1 (MLL1) gene
are associated with aggressive myeloid and lymphocytic leukemias in humans. MLL1
is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases,
which are required for transcription of genes involved in hematopoiesis and
development. MLL1 associates with a subcomplex containing WDR5, RbBP5, Ash2L,
and DPY-30 (WRAD), which together form the MLL1 core complex that is required
for sequential mono- and dimethylation of H3K4. We previously demonstrated that
WDR5 binds the conserved WDR5 interaction (Win) motif of MLL1 in vitro, an
interaction that is required for the H3K4 dimethylation activity of the MLL1
core complex. In this investigation, we demonstrate that arginine 3765 of the
MLL1 Win motif is required to co-immunoprecipitate WRAD from mammalian cells,
suggesting that the WDR5-Win motif interaction is important for the assembly of
the MLL1 core complex in vivo. We also demonstrate that peptides that mimic SET1
family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex
with varying degrees of efficiency. To understand the structural basis for these
differences, we determined structures of WDR5 bound to six different naturally
occurring Win motif sequences at resolutions ranging from 1.9 to 1.2 Å. Our
results reveal that binding energy differences result from interactions between
non-conserved residues C-terminal to the Win motif and to a lesser extent from
subtle variation of residues within the Win motif. These results highlight a new
class of methylation inhibitors that may be useful for the treatment of
MLL1-related malignancies.
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