over productive mode, in agreement with the lack of activity [43]. Similar Kme3
interactions are observed in KDM6A, whereby the H3K27me3 tri-methyl group points
towards the active site metal (Fig. 4d). The tri-methyl group is stabilised by Y1135, and
G1128 forming H-bonded interactions with methyl groups, and E1148 forms electrostatic interaction with methylammonium group to stabilise the orientation of methyl
group for demethylation [49]. From the peptide co-crystal structures available, the Tyr
which stabilises the methyl group of Kme3 is conserved across all trimethyllysine
demethylases (Y177(KDM4A)/Y1135(KDM6A)/Y1380(KDM6B)), but it is absent in
a
b
c
H276
H188
E190
D191
N290
Y177
S288
T289
Y175
D135
a c
H276
H188
E190
D191
N290
Y177
S288
T289
Y175
D135
a
H276
H188
E190
D191
N290
Y177
S288
T289
Y175
D135
C
B
A
NOG
NOG
NOG
w3
w3
w3 w1
K9me3
K9me2
K9me1
H1226
H1146
E1148
NOG
w
Y1135
G1128
K27me3
Q1133
A1238
D
KDM4A.Ni(II).NOG.H3K9me3
E
H319
H247
D249
w
K9me2
Y234
L236
N333
KDM4A.Ni(II).NOG.H3K9me2
KDM4A.Ni(II).NOG.H3K9me1
KDM6A.Ni(II).NOG.H3K27me3
KDM7B.Fe(II).NOG.H3K4me3K9me2
H284
H212
D214
w
NOG
K36me2
Y222
Y199
I144
H284
H212
D214
2OG
K36me2
Y222
Y199
I144
F
G
KDM2A.Ni(II).NOG.H3K36me2
KDM2A.Ni(II).2OG.H3K36me2
Fig. 4 Crystal structures of JmjC-KDMs in complex with NOG/2OG and histone H3 substrates.
(a–c) Different orientations of methyl groups are observed for KDM4A complexed with (a)
H3K9me3 (PDB 2OQ6), (b) H3K9me2 (PDB 2OT7) and (c) H3K9me1 (PDB 2OTQ). (d)
KDM6A in complex with H3K27me3 and (e) KDM7B in complex with H3K9me2 in the JmjCdomain active sites. (f, g) KDM2A in complex with H3K36me2 with NOG (f) and 2OG (g). NOG
adopts an equatorial binding mode to H212, whereas 2OG co-crystal structures can also adopt axial
binding mode relative to H212. Two different conformers are observed for Y222 with H3K36me1/2
but only axial for H3K36me3. Histone methyllysines, NOG/2OG, metal and water molecules are in
green, yellow, orange and red (sphere), respectively
230
M. Wright et al.