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PDBsum entry 2v1d
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Oxidoreductase/repressor
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PDB id
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2v1d
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Contents |
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666 a.a.
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133 a.a.
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16 a.a.
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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 of lsd1-Corest selectivity in histone h3 recognition.
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Authors
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F.Forneris,
C.Binda,
A.Adamo,
E.Battaglioli,
A.Mattevi.
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Ref.
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J Biol Chem, 2007,
282,
20070-20074.
[DOI no: ]
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PubMed id
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Abstract
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Histone demethylase LSD1 regulates transcription by demethylating Lys(4) of
histone H3. The crystal structure of the enzyme in complex with CoREST and a
substrate-like peptide inhibitor highlights an intricate network of interactions
and a folded conformation of the bound peptide. The core of the peptide
structure is formed by Arg(2), Gln(5), and Ser(10), which are engaged in
specific intramolecular H-bonds. Several charged side chains on the surface of
the substrate-binding pocket establish electrostatic interactions with the
peptide. The three-dimensional structure predicts that methylated Lys(4) binds
in a solvent inaccessible position in front of the flavin cofactor. This
geometry is fully consistent with the demethylation reaction being catalyzed
through a flavin-mediated oxidation of the substrate amino-methyl group. These
features dictate the exquisite substrate specificity of LSD1 and provide a
structural framework to explain the fine tuning of its catalytic activity and
the active role of CoREST in substrate recognition.
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Figure 1.
FIGURE 1. Crystal structure of LSD1-CoREST in complex with
pLys4Met H3 peptide. A, ribbon diagram of the structure. LSD1 is
in blue, CoREST in red, and the peptide in green. The FAD
cofactor is shown as a yellow ball-and-stick. The final model
consists of residues 171–836 of LSD1, residues 308–440 of
CoREST, and residues 1–16 of pLys4Met peptide. B, fitting of
the refined pLys4Met peptide in the unbiased electron density
calculated with weighted 2F[o] – F[c] coefficients. The map
was calculated prior inclusion of the peptide atoms in the
refinement calculations. The contour level is 1.2  , and
the resolution is 3.1 Å. The sequence of the histone H3
peptide used for the x-ray analysis is
^1ARTMQTARKSTGGKAPRKQLA^21.
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Figure 2.
FIGURE 2. Recognition of H3 peptide by LSD1. A, surface
view of the peptide-binding pocket. The peptide is shown in
green and the LSD1 surface in gray. Nitrogens are blue, oxygens
red, sulfurs yellow, and carbons green. The positions of
negatively charged residues lining the peptide-binding site are
labeled. The C  trace of CoREST
residues 308–314 is shown in red, highlighting their proximity
to the LSD1 372–395 -helix that is integral
part of the peptide-binding site. The orientation is the same as
in Fig. 1A. B, three-dimensional view of the peptide-binding
mode. Nitrogens are blue, oxygens red, and sulfurs yellow.
Carbons of peptide and protein residues are in green and gray,
respectively. The flavin cofactor is yellow. With respect to
Fig. 1A, the structure is rotated by  180° about the
vertical axis in the plane of the drawing. C, schematic
representation of the peptide-protein interactions. D, model of
dimethyl Lys^4 peptide substrate bound in the active site.
Orientation and atom colors are the same as described in B. The
modeling was carried out assuming that the C  -C  -C  atoms of dimethyl Lys^4
adopt the same conformation of the C -C -S atoms of pMet^4 in the
crystal structure. In this way, the predicted position of the
N-bound CH[3] group of dimethyl Lys^4 falls exactly in front of
the N-5 atom of the flavin. This type of substrate-binding
geometry is similar to that found in other flavin-dependent
oxidases and is fully consistent with an oxidative attack of the
flavin on the N–CH[3] group of the substrate leading to the
formation of an NH=CH[2] imine that is then hydrolyzed to
generate the demethylated Lys^4 and formaldehyde.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
20070-20074)
copyright 2007.
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