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PDBsum entry 2f6n
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Transcription
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PDB id
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2f6n
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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 for site-Specific read-Out of histone h3k4me3 by the bptf phd finger of nurf.
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Authors
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H.Li,
S.Ilin,
W.Wang,
E.M.Duncan,
J.Wysocka,
C.D.Allis,
D.J.Patel.
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Ref.
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Nature, 2006,
442,
91-95.
[DOI no: ]
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PubMed id
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Abstract
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Mono-, di- and trimethylated states of particular histone lysine residues are
selectively found in different regions of chromatin, thereby implying
specialized biological functions for these marks ranging from heterochromatin
formation to X-chromosome inactivation and transcriptional regulation. A major
challenge in chromatin biology has centred on efforts to define the connection
between specific methylation states and distinct biological read-outs impacting
on function. For example, histone H3 trimethylated at lysine 4 (H3K4me3) is
associated with transcription start sites of active genes, but the molecular
'effectors' involved in specific recognition of H3K4me3 tails remain poorly
understood. Here we demonstrate the molecular basis for specific recognition of
H3(1-15)K4me3 (residues 1-15 of histone H3 trimethylated at K4) by a plant
homeodomain (PHD) finger of human BPTF (bromodomain and PHD domain transcription
factor), the largest subunit of the ATP-dependent chromatin-remodelling complex,
NURF (nucleosome remodelling factor). We report on crystallographic and NMR
structures of the bromodomain-proximal PHD finger of BPTF in free and
H3(1-15)K4me3-bound states. H3(1-15)K4me3 interacts through anti-parallel
beta-sheet formation on the surface of the PHD finger, with the long side chains
of arginine 2 (R2) and K4me3 fitting snugly in adjacent pre-formed surface
pockets, and bracketing an invariant tryptophan. The observed stapling role by
non-adjacent R2 and K4me3 provides a molecular explanation for H3K4me3 site
specificity. Binding studies establish that the BPTF PHD finger exhibits a
modest preference for K4me3- over K4me2-containing H3 peptides, and
discriminates against monomethylated and unmodified counterparts. Furthermore,
we identified key specificity-determining residues from binding studies of
H3(1-15)K4me3 with PHD finger point mutants. Our findings call attention to the
PHD finger as a previously uncharacterized chromatin-binding module found in a
large number of chromatin-associated proteins.
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Figure 2.
Figure 2: Crystal structures of human BPTF PHD
finger-linker-bromodomain in the free state and bound to
H3(1–15)K4me3. a, Domain architecture of BPTF bromodomain
and proximal PHD finger. b, Ribbon representation of the crystal
structure of the BPTF PHD finger-linker-bromodomain in the free
state. Two bound Zn ions within the PHD fold are shown as balls.
c, Crystal structure of the H3(1–15)K4me3-bound complex, with
bound peptide shown in a space-filling representation. d,
Structure of the PHD finger complex with the 2F[o] - F[c] omit
electron density (0.8  level)
highlighted for the bound H3(1–15)K4me3 peptide. e,
Positioning of the H3(1–15)K4me3 peptide (space-filling
representation) on the surface of the PHD finger portion
(electrostatic surface representation with red as negatively
charged and blue as positively charged surface) of the complex.
f, Different view emphasizing the positioning of R2 and K4me3 in
adjacent channels.
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Figure 3.
Figure 3: Details of the intermolecular contacts in the
H3(1–15)K4me3 peptide–BPTF PHD finger complex and comparison
with its H3(1–15)K4me2-bound counterpart. a, Intermolecular
backbone interactions between the A1–T6 segment of bound
H3(1–15)K4me3 peptide and the PHD finger in the complex. b,
Intermolecular hydrogen-bonding interactions involving the
guanidinium group of R2 in the complex. c, Superposition of free
(coloured green) and H3(1–15)K4me3-bound complex (coloured
yellow) of the BPTF PHD finger. d, e, Positioning of the
trimethylated lysine of the H3(1–15)K4me3 peptide (d) and the
dimethylated lysine of the H3(1–15)K4me2 peptide (e) within a
four-aromatic-amino-acid cage of the BPTF PHD finger. Two
bridging water molecules link the NH of K4me2 to the carboxylate
of D6, as indicated by dashed lines.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2006,
442,
91-95)
copyright 2006.
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