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PDBsum entry 2vnf
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References listed in PDB file
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Key reference
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Title
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Molecular basis of histone h3k4me3 recognition by ing4.
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Authors
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A.Palacios,
I.G.Muñoz,
D.Pantoja-Uceda,
M.J.Marcaida,
D.Torres,
J.M.Martín-García,
I.Luque,
G.Montoya,
F.J.Blanco.
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Ref.
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J Biol Chem, 2008,
283,
15956-15964.
[DOI no: ]
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PubMed id
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Abstract
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The inhibitors of growth (ING) family of tumor suppressors consists of five
homologous proteins involved in chromatin remodeling. They form part of
different acetylation and deacetylation complexes and are thought to direct them
to specific regions of the chromatin, through the recognition of H3K4me3
(trimethylated K4 in the histone 3 tail) by their conserved plant homeodomain
(PHD). We have determined the crystal structure of ING4-PHD bound to H3K4me3,
which reveals a tight complex stabilized by numerous interactions. NMR shows
that there is a reduction in the backbone mobility on the regions of the PHD
that participate in the peptide binding, and binding affinities differ depending
on histone tail lengths Thermodynamic analysis reveals that the discrimination
in favor of methylated lysine is entropy-driven, contrary to what has been
described for chromodomains. The molecular basis of H3K4me3 recognition by ING4
differs from that of ING2, which is consistent with their different affinities
for methylated histone tails. These differences suggest a distinct role in
transcriptional regulation for these two ING family members because of the
antagonistic effect of the complexes that they recruit onto chromatin. Our
results illustrate the versatility of PHD fingers as readers of the histone code.
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Figure 1.
FIGURE 1. Three-dimensional crystal structure of the
complex of ING4-PHD bound to H3[10]K4me3. A, overall structure
with ING4-PHD shown in gray and H3[10]K4me3 shown in yellow
stick representation. The location of the ING4 residues lining
the binding grooves for histone 3 residues Ala^1, Arg^2, Thr^3,
Lys^4, and Ser^10 is indicated with black labels. B, view of a
2(|F[o]| - |F[c]|) omit map at 1.76 Å contoured at 1  as a
blue mesh. The omit map was calculated with the program OMIT in
the CCP4 package (45). C, details of the β-sheet structure
formed by H3 residues Arg^2–Thr^6 and ING4 residues
Gly^207–Gly^211 with backbone hydrogen bonds in green. D,
details of side chain interactions with hydrogen bonds and water
molecules in green.
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Figure 3.
FIGURE 3. Comparison of the structures of H3K4me3 peptides
bound to ING4 and ING2 PHD. A, the crystal structure of ING4-PHD
is shown as a gray surface with the bound H3[10]K4me3 in yellow
and the superimposed H3[12]K4me3 from the corresponding ING2-PHD
complex structure in green. Only H3 residues Ala^1 to Arg^8 are
seen in the crystal of the ING2 complex (Protein Data Bank entry
2G6Q). Black labels indicate the C  atoms of the peptide
residues, whose positions are very similar in both peptides up
to H3 Thr^6. B, surface representations of the PHD fingers of
ING2 and ING4 bound to the histone peptides where the
electrostatic potential is indicated by a gradient of red
(negative charge) and blue (positive charge) colors. The
positions of the homologous tyrosine residues 198 and 215 are
indicated in ING4 and ING2, respectively.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
15956-15964)
copyright 2008.
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