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PDBsum entry 2ri7
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Transcription/nuclear protein
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PDB id
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2ri7
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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 lower lysine methylation state-Specific readout by mbt repeats of l3mbtl1 and an engineered phd finger.
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Authors
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H.Li,
W.Fischle,
W.Wang,
E.M.Duncan,
L.Liang,
S.Murakami-Ishibe,
C.D.Allis,
D.J.Patel.
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Ref.
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Mol Cell, 2007,
28,
677-691.
[DOI no: ]
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PubMed id
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Abstract
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Human L3MBTL1, which contains three malignant brain tumor (MBT) repeats, binds
monomethylated and dimethylated lysines, but not trimethylated lysines, in
several histone sequence contexts. In crystal structures of L3MBTL1 complexes,
the monomethyl- and dimethyllysines insert into a narrow and deep cavity of
aromatic residue-lined pocket 2, while a proline ring inserts into shallower
pocket 1. We have also engineered a single Y to E substitution within the
aromatic cage of the BPTF PHD finger, resulting in a reversal of binding
preference from trimethyl- to dimethyllysine in an H3K4 sequence context. In
both the "cavity insertion" (L3MBTL1) and "surface groove"
(PHD finger) modes of methyllysine recognition, a carboxylate group both
hydrogen bonds and ion pairs to the methylammonium proton. Our structural and
binding studies of these two modules provide insights into the molecular
principles governing the decoding of lysine methylation states, thereby
highlighting a methylation state-specific layer of histone mark readout
impacting on epigenetic regulation.
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Figure 2.
Figure 2. Pro-Ser Step-Containing Peptide Binding by L3MBTL1
Pocket 1
(A) Domain architecture of the L3MBTL1 constructs
used for structural and functional study in this figure. For the
L3MBTL1-H3.3 construct, a Gly-Gly-Gly linker was used to
separate L3MBTL1 and the covalently attached histone
3.3[28–34] segment.
(B) Insertion of proline into a
shallow cavity of symmetry-related L3MBTL1 pocket 1 in the
Kme2-L3MBTL1 complex is shown. The Pro ring is sandwiched within
the narrow walls at the base of the pocket. The interior parts
of the surface are colored in gray, and exterior parts are
colored by their electrostatic potential as described for Figure
1C. The Pro ligand is shown in the dotted van der Waals radius
representation. The “EPS” peptide segment is shown, with
part of the Ser omitted from the drawing for clarity.
(C)
Relative positioning of PS step containing C-terminal L3MBTL1
segment in pocket 1 and Kme2 in pocket 2 on the same L3MBTL1
surface in the Kme2-L3MBTL1 complex.
(D) Stereo view of the
PS step containing H3.3 SAPSTGG segment with its Pro ring
inserted into pocket 1 of the Kme2-L3MBTL1-H3.3[28–34]
complex. Key residues participating in pocket formation are
shown in stick representation (cyan) with main-chain atoms
omitted for clarity. Water molecules are shown as small red
spheres and hydrogen bonds indicated by dashed red lines.
(E) Stereo view of the relative positioning of PS step
containing H3.3 SAPSTGG segment in pocket 1 and Kme2 in pocket 2
on the same L3MBTL1 surface in the Kme2- L3MBTL1-H3.3[28–34]
complex. Note that the type II β-turn formed at the “APST”
motif in pocket 1 helps to direct the C-terminal GG segment of
H3.3 toward the Kme2-bound pocket 2. Water molecules are shown
as small red spheres and hydrogen bonds indicated by dashed red
lines.
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Figure 4.
Figure 4. Stereo Views of Pocket 2 Comparing Superpositioned
Kme2-Bound Wild-Type and Mutant L3MBTL1 Complexes
(A–D)
The wild-type L3MBTL1 complex with bound Kme2 is shown in beige
(A–D). The D355N mutant complex is shown in light blue (A),
the D355A mutant is shown in dark blue (B), the N358Q mutant is
shown in light green (C), and the N358A mutant is shown in dark
green (D). Kme2 was not detected in pocket 2 for complexes with
D355N (A), D355A (B), N358Q (C), and N358A (D).
Superpositioning is based on least-squares fitting of Cα atoms
within the second MBT module (349–416) of L3MBTL1.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2007,
28,
677-691)
copyright 2007.
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