2.1.2 Histone Substrate Binding
Despite the high conservation in the active site of JmjC-KDMs, the individual
subfamilies have distinct substrate specificities (Table 1). Structural information is
available for some JmjC-KDMs complexed with histone substrates, which provide
some insight into the unique features of these family of proteins (Table 3).
Recognition of Methylated Lysines Structures of KDM4A in complex with
H3K9me3/2/1 revealed that the size of the active site region can, to some degree,
confer methylation state selectivity in KDM4A [43] (Fig. 4a–c). The tri-Nε-methylated
lysine (Kme3) fits tightly in the active site pocket composed of Y177, E190, S288 and
N290 and one methyl group projects towards the catalytic metal (position b), whereas
the other two point towards Y177 (position c) and N290 (position a). In di-Nε-methylated lysine (Kme2) structures, the methyl group can either occupy a productive conformation pointing towards the metal or a nonproductive conformation towards
Y177 and N290. In the case of mono Nε-methylated lysine, the water molecules are
positioned to direct the methyl group away from the metal, stabilising the unproductive
Table 3 Structures of JmjC-KDMs in complex with histone peptides
KDM(JmjC)
Ligands
PDB
References
Kdm2A
H3K36me1, Ni(II), NOG
4QXH
[42]
H3K36me1, Ni(II), 2OG
4QWN
[42]
H3K36me2, Ni(II), NOG
4QXC
[42]
H3K36me2, Ni(II), 2OG
4QX7
[42]
H3K36me, Ni(II), NOG
4QXB
[42]
H3K36me3, Ni(II), 2OG
4QX8
[42]
KDM4A
H3K9me3, Ni(II), 2OG
2OQ6
[43]
2Q8C
[44]
H3K9me2, Ni(II), 2OG
2OX0
[43]
H3K9me1, Ni(II), 2OG
2OT7
[43]
H3K36me2, Ni(II), succinate
2Q8D
[44]
H3K36me3, Ni(II), 2OG
2OS2
[43]
H3K36me3, Ni(II), 2OG
2P5B
[44]
H3K36me3, Ni(II), 2OG
2Q8E
[45]
H3K36me1, Fe(II), 2OG
2PXJ
[45]
H4R3me2s, Ni(II), 2OG
5FWE
[7]
H3K27me3, Ni(II), 2OG
4V2W
[46]
KDM4B
H3K9me3, Ni(II), 24PDCA
4LXL
[47]
KDM4D
H3K9me3, Ni(II), 2OG,
4HON
[48]
KDM6A
H3K27me3, Ni(II), 2OG,
3AVR
[49]
Kdm6B
H3K27me3, Ni(II), NOG
4EZH
[50]
KDM6B
H3A21M, Fe(II), 2OG
5OY3
[51]
KDM7B
H3K4me3K9me2, Ni(II), 2OG
3KV4
[8]
Note all are human JmjC-KDMs except Kdm2A and Kdm6B which are from Mus musculus
Inhibitors of JmjC-Containing Histone Demethylases
229
Despite the high conservation in the active site of JmjC-KDMs, the individual
subfamilies have distinct substrate specificities (Table 1). Structural information is
available for some JmjC-KDMs complexed with histone substrates, which provide
some insight into the unique features of these family of proteins (Table 3).
Recognition of Methylated Lysines Structures of KDM4A in complex with
H3K9me3/2/1 revealed that the size of the active site region can, to some degree,
confer methylation state selectivity in KDM4A [43] (Fig. 4a–c). The tri-Nε-methylated
lysine (Kme3) fits tightly in the active site pocket composed of Y177, E190, S288 and
N290 and one methyl group projects towards the catalytic metal (position b), whereas
the other two point towards Y177 (position c) and N290 (position a). In di-Nε-methylated lysine (Kme2) structures, the methyl group can either occupy a productive conformation pointing towards the metal or a nonproductive conformation towards
Y177 and N290. In the case of mono Nε-methylated lysine, the water molecules are
positioned to direct the methyl group away from the metal, stabilising the unproductive
Table 3 Structures of JmjC-KDMs in complex with histone peptides
KDM(JmjC)
Ligands
PDB
References
Kdm2A
H3K36me1, Ni(II), NOG
4QXH
[42]
H3K36me1, Ni(II), 2OG
4QWN
[42]
H3K36me2, Ni(II), NOG
4QXC
[42]
H3K36me2, Ni(II), 2OG
4QX7
[42]
H3K36me, Ni(II), NOG
4QXB
[42]
H3K36me3, Ni(II), 2OG
4QX8
[42]
KDM4A
H3K9me3, Ni(II), 2OG
2OQ6
[43]
2Q8C
[44]
H3K9me2, Ni(II), 2OG
2OX0
[43]
H3K9me1, Ni(II), 2OG
2OT7
[43]
H3K36me2, Ni(II), succinate
2Q8D
[44]
H3K36me3, Ni(II), 2OG
2OS2
[43]
H3K36me3, Ni(II), 2OG
2P5B
[44]
H3K36me3, Ni(II), 2OG
2Q8E
[45]
H3K36me1, Fe(II), 2OG
2PXJ
[45]
H4R3me2s, Ni(II), 2OG
5FWE
[7]
H3K27me3, Ni(II), 2OG
4V2W
[46]
KDM4B
H3K9me3, Ni(II), 24PDCA
4LXL
[47]
KDM4D
H3K9me3, Ni(II), 2OG,
4HON
[48]
KDM6A
H3K27me3, Ni(II), 2OG,
3AVR
[49]
Kdm6B
H3K27me3, Ni(II), NOG
4EZH
[50]
KDM6B
H3A21M, Fe(II), 2OG
5OY3
[51]
KDM7B
H3K4me3K9me2, Ni(II), 2OG
3KV4
[8]
Note all are human JmjC-KDMs except Kdm2A and Kdm6B which are from Mus musculus
Inhibitors of JmjC-Containing Histone Demethylases
229