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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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