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PDBsum entry 3eg6
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Protein binding
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PDB id
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3eg6
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References listed in PDB file
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Key reference
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Title
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Structure of wdr5 bound to mixed lineage leukemia protein-1 peptide.
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Authors
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A.Patel,
V.Dharmarajan,
M.S.Cosgrove.
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Ref.
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J Biol Chem, 2008,
283,
32158-32161.
[DOI no: ]
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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 were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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The mixed lineage leukemia protein-1 (MLL1) catalyzes histone H3 lysine 4
methylation and is regulated by interaction with WDR5 (WD-repeat protein-5),
RbBP5 (retinoblastoma-binding protein-5), and the Ash2L (absent, small, homeotic
discs-2-like) oncoprotein. In the accompanying investigation, we describe the
identification of a conserved arginine containing motif, called the "Win" or
WDR5 interaction motif, that is essential for the assembly and H3K4
dimethylation activity of the MLL1 core complex. Here we present a 1.7-A crystal
structure of WDR5 bound to a peptide derived from the MLL1 Win motif. Our
results show that Arg-3765 of MLL1 is bound in the same arginine binding pocket
on WDR5 that was previously suggested to bind histone H3. Thermodynamic binding
experiments show that the MLL1 Win peptide is preferentially recognized by WDR5.
These results are consistent with a model in which WDR5 recognizes Arg-3765 of
MLL1, which is essential for the assembly and enzymatic activity of the MLL1
core complex.
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Figure 1.
Crystal structure of WDR5 in complex with the MLL1 Win
peptide. a, surface representation of WDR5 (magenta) showing the
location of MLL1 Win peptide (yellow) bound to the smaller
opening at the top of WDR5. b, cutaway view of WDR5 in complex
with MLL1 Win peptide showing the location of the 3[10]-helix
(yellow ribbon) and the insertion of the Arg-3765 side chain
into the central tunnel.
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Figure 4.
Superposition of WDR5 bound to the MLL1 Win peptide (yellow)
with that of WDR5 bound to an unmodified histone H3 peptide
(white) (PDB code 2CO0, Ref. 17), showing only the bound
peptides. Residue names for the MLL1 Win peptide are shown in
red, and residue names for the histone H3 peptide are shown in
blue. The superposition minimizes the differences between Cα
atoms of WDR5 residues between structures.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
32158-32161)
copyright 2008.
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Secondary reference #1
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Title
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A conserved arginine-Containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex.
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Authors
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A.Patel,
V.E.Vought,
V.Dharmarajan,
M.S.Cosgrove.
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Ref.
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J Biol Chem, 2008,
283,
32162-32175.
[DOI no: ]
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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 were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
92%.
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Figure 4.
Arginine 3765 of MLL1 is critical for the interaction of WDR5
with MLL1. a–c, sedimentation velocity analyses (c(s)) of
wild-type (WT) WDR5 with mutant MLL^3745 constructs: S3763A (a),
R3765A (b), and E3767A (c). Each protein was run at a
concentration of 7 μm. d, circular dichroism spectra of
wild-type and mutant MLL^3745 constructs at 0.2 mg/ml.
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Figure 10.
Schematic models for the role of WDR5 in the MLL1 core
complex. Nucleosomes are shown in yellow with the histone H3
N-terminal tail indicated. a, histone binding model where WDR5
recognizes Arg-2 of histone H3 and facilitates H3 methylation by
presenting the Lys-4 side chain to the SET domain of MLL1. b, a
new model based on the present data in which WDR5's recognition
of Arg-3765 of the MLL1 Win motif is required for the assembly
and H3K4 dimethylation activity of the MLL1 core complex.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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