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PDBsum entry 2uxn
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Oxidoreductase/transcription regulator
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PDB id
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2uxn
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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 histone demethylation by lsd1 revealed by suicide inactivation.
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Authors
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M.Yang,
J.C.Culhane,
L.M.Szewczuk,
C.B.Gocke,
C.A.Brautigam,
D.R.Tomchick,
M.Machius,
P.A.Cole,
H.Yu.
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Ref.
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Nat Struct Biol, 2007,
14,
535-539.
[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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Histone methylation regulates diverse chromatin-templated processes, including
transcription. The recent discovery of the first histone lysine-specific
demethylase (LSD1) has changed the long-held view that histone methylation is a
permanent epigenetic mark. LSD1 is a flavin adenine dinucleotide (FAD)-dependent
amine oxidase that demethylates histone H3 Lys4 (H3-K4). However, the mechanism
by which LSD1 achieves its substrate specificity is unclear. We report the
crystal structure of human LSD1 with a propargylamine-derivatized H3 peptide
covalently tethered to FAD. H3 adopts three consecutive gamma-turns, enabling an
ideal side chain spacing that places its N terminus into an anionic pocket and
positions methyl-Lys4 near FAD for catalysis. The LSD1 active site cannot
productively accommodate more than three residues on the N-terminal side of the
methyllysine, explaining its H3-K4 specificity. The unusual backbone
conformation of LSD1-bound H3 suggests a strategy for designing potent LSD1
inhibitors with therapeutic potential.
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Figure 1.
(a) Chemical structures of N-methylpropargyl-K4 H3[1–21],
its covalent adduct with FAD, and the NaBH[4]-reduced adduct.
(b) Stereo view of the structure of the N-methylpropargyl-K4
H3[1–21]–FAD adduct in stick representation, overlaid with a
simulated-annealing composite-omit map contoured at 1.2  .
(c) Overall structure of LSD1–CoREST–H3. The FAD-H3 adduct
is shown in stick representation. All structural figures were
generated with PyMOL (http://pymol.sourceforge.net).
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Figure 2.
(a) Residues 1–7 of the H3 peptide (yellow tube) interact
with the active site cavity of LSD1. Molecular surface of LSD1
AOD and SWIRM is colored by electrostatic potential: red,
negative; blue, positive. Dashed yellow line represents
C-terminal portion of H3, which might bind at a surface groove
between AOD and SWIRM, according to existing biochemical
evidence^8, ^9. (b) Binding of H3 at the active site of LSD1.
Yellow, H3; purple, LSD1. (c) Binding of an H3K4me3 peptide to
the PHD finger of BPTF (PDB 2FUU). Color scheme is as in b. (d)
Stereo view of an H3K4me3 peptide bound to the PHD finger of
ING2 (PDB 2G6Q). The distance between the C  atoms
of Arg2 and Thr6 is 13.1 Å. (e) Stereo view of the
derivatized H3 peptide bound to LSD1 (same scale as e). Dashed
red lines represent the hydrogen bonds of the three  -turns.
The distance between the C atoms
of Arg2 and Thr6 is 9.2 Å. (f) Schematic drawing of
interactions between LSD1 and the H3 peptide, highlighting the
anionic pocket and the serpentine H3 backbone conformation that
results from the three -turns.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2007,
14,
535-539)
copyright 2007.
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Secondary reference #1
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Title
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Structural basis for corest-Dependent demethylation of nucleosomes by the human lsd1 histone demethylase.
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Authors
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M.Yang,
C.B.Gocke,
X.Luo,
D.Borek,
D.R.Tomchick,
M.Machius,
Z.Otwinowski,
H.Yu.
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Ref.
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Mol Cell, 2006,
23,
377-387.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. Structure of LSD1-CoREST
(A) Mechanism of
LSD1-catalyzed demethylation of H3-K4. The carbon atom that is
oxidized to form formaldehyde is shown in red.
(B) Domain
structures of human LSD1 (AAH48134) and CoREST. The boundaries
of proteins used in crystallization are indicated.
(C)
Overall structure of LSD1-CoREST. The color scheme for this and
subsequent figures is similar to that used in (B): SWIRM, blue;
AOD_N, yellow; AOD_C, gold; LSD1 insert, green; CoREST linker,
pink; and CoREST SANT2, red. The FAD is shown in stick
representation in this and subsequent figures. The red arrow
indicates the active site. All structural figures were generated
with PyMOL.
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Figure 2.
Figure 2. Structure of the Amine Oxidase Domain of LSD1
(A) Ribbon drawing of the structure of LSD1 amine oxidase domain
(AOD) and a portion of the CoREST linker. The structural
elements lining the rim of the active site are colored blue. The
location of the LSD1 insert is indicated.
(B) Ribbon
drawing of the structure of maize PAO. The regions in mPAO that
correspond to AOD_N and AOD_C in LSD1 are colored yellow and
gold, respectively. The structural elements lining the rim of
the active site are colored blue.
(C) Overlay of the active
site residues of mPAO and LSD1. The ribbons of mPAO and LSD1 are
colored cyan and gray, respectively. The active site residues of
mPAO and LSD1 are shown as cyan and yellow sticks, respectively.
Only FAD in LSD1 is shown for clarity.
(D) Molecular
surface of the active site of LSD1 AOD in similar orientation as
in (A) with the positive and negative electrostatic potentials
colored blue and red, respectively.
(E) Molecular surface
of the active site of mPAO in similar orientation as in (B) with
superimposed positive and negative electrostatic potentials
colored blue and red, respectively. The two openings of the long
active site tunnel are indicated.
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The above figures are
reproduced from the cited reference
with permission from Cell Press
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