Unlike all other KDMs, JMJD1C (KDM3C) contains a glutamine rather than a
lysine at this position in the sequence which overlaps well with the analogous lysine
interaction. Other key residues interacting with the carboxylate include tyrosine and
threonine. KDM2A, KDM3C and KDM7A/B/C have a threonine within hydrogenbonding distance to the carboxylate. KDM6A/B/C have a threonine and asparagine
residues in addition to the lysine that can hydrogen bond to the carboxylate
(Table 2).
Unlike the other KDMs, KDM4 (JMJD2) and KDM5 (JARID1) contain a
tyrosine which interacts with the carboxylate of 2OG. This key structural difference
in the binding site can be exploited in inhibitor design to give KDM4/5 inhibitors
that are selective over the other KDMs. However, selectivity between KDM4 and
KDM5 is difficult to achieve due to identical residues in the primary sphere of the
binding pocket. Differences in the second sphere of amino acids can confer different
conformations to the binding residues which can result in improved selectivity.
Structural information obtained from different co-crystal structures with inhibitors
has shown that this key tyrosine residue is more flexible in KDM5 than KDM4.
Some selectivity for KDM5 has therefore been observed with cyanopyrazoles, as the
tyrosine side chain can be displaced to allow binding in KDM5 [41].
Table 2 Comparison of residues interacting with carboxylate in KDM structures on different β
strands
Strands
Nterminal
anti-β
strands
DSBH
β1
βII
βIII
βIV
βV βVI βVII
βVIII
KDM2A
T209
K229
KDM3B
T1557
K1699
JMJD1C
T2333
Q2476
KDM4A Y132
K206
KDM4B Y133
K207
KDM4C Y134
K208
KDM4D Y136
K210
KDM5A Y409
K501
KDM5B Y425
K517
KDM5C Y440
K532
KDM6A
K1137 T1143 N1156
KDM6B
K1381 T1387 N1400
KDM6C
K1084 T1090 N1103
KDM7A
T279
Y292
K299
KDM7B
T244
K263
PHF2
Y258
K266
T323
All JmjC-KDMs have a lysine residue (green) that forms a salt bridge to a carboxylate in 2OG and
inhibitors, with the exception of KDM3C which has a glutamine (grey). Further hydrogen bonds to
the substrate/inhibitor carboxylate are made by threonine (salmon), tyrosine (yellow) and asparagine (blue)
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M. Wright et al.
lysine at this position in the sequence which overlaps well with the analogous lysine
interaction. Other key residues interacting with the carboxylate include tyrosine and
threonine. KDM2A, KDM3C and KDM7A/B/C have a threonine within hydrogenbonding distance to the carboxylate. KDM6A/B/C have a threonine and asparagine
residues in addition to the lysine that can hydrogen bond to the carboxylate
(Table 2).
Unlike the other KDMs, KDM4 (JMJD2) and KDM5 (JARID1) contain a
tyrosine which interacts with the carboxylate of 2OG. This key structural difference
in the binding site can be exploited in inhibitor design to give KDM4/5 inhibitors
that are selective over the other KDMs. However, selectivity between KDM4 and
KDM5 is difficult to achieve due to identical residues in the primary sphere of the
binding pocket. Differences in the second sphere of amino acids can confer different
conformations to the binding residues which can result in improved selectivity.
Structural information obtained from different co-crystal structures with inhibitors
has shown that this key tyrosine residue is more flexible in KDM5 than KDM4.
Some selectivity for KDM5 has therefore been observed with cyanopyrazoles, as the
tyrosine side chain can be displaced to allow binding in KDM5 [41].
Table 2 Comparison of residues interacting with carboxylate in KDM structures on different β
strands
Strands
Nterminal
anti-β
strands
DSBH
β1
βII
βIII
βIV
βV βVI βVII
βVIII
KDM2A
T209
K229
KDM3B
T1557
K1699
JMJD1C
T2333
Q2476
KDM4A Y132
K206
KDM4B Y133
K207
KDM4C Y134
K208
KDM4D Y136
K210
KDM5A Y409
K501
KDM5B Y425
K517
KDM5C Y440
K532
KDM6A
K1137 T1143 N1156
KDM6B
K1381 T1387 N1400
KDM6C
K1084 T1090 N1103
KDM7A
T279
Y292
K299
KDM7B
T244
K263
PHF2
Y258
K266
T323
All JmjC-KDMs have a lysine residue (green) that forms a salt bridge to a carboxylate in 2OG and
inhibitors, with the exception of KDM3C which has a glutamine (grey). Further hydrogen bonds to
the substrate/inhibitor carboxylate are made by threonine (salmon), tyrosine (yellow) and asparagine (blue)
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M. Wright et al.