Abbreviations
2,4-PDCA
2,4-Pyridine dicarboxylate
2OG
2-Oxoglutarate
8HQ
8-Hydroxyquinoline
Bpy
4
0 -Carboxy 2,2
0 -bipyridine
H3
Histone H3
HMT
Histone methyltransferase
JmjC
Jumonji-C
KDM
Lysine demethylase
Kme n
Methylated lysine (n ¼ 1, mono-; n ¼ 2, di-; n ¼ 3, tri-)
NOG
N-oxalylglycine
PHD-finger Plant homeodomain finger
1 Introduction
Histone demethylases (KDMs) catalyse the removal of N-methyl marks on histones
and play important roles in epigenetic regulation. Abnormal histone methylation and
dysregulation of KDMs have been linked to multiple diseases. The majority of
KDMs are JmjC-domain-containing KDMs (JmjC-KDMs) that belong to the superfamily of Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases. JmjC-KDMs are
emerging as promising therapeutic targets, in particular, in cancer. The availability
of crystal structures has provided understanding of the mechanism, function and
selectivity of JmjC-KDMs at the molecular level and has aided structure-based
inhibitor design. This chapter provides an overview of recent advances in JmjCKDM inhibitor development from a structural perspective.
1.1 JmjC-Domain-Containing Histone Demethylases
Post-translational modifications on histones, including lysine methylation, have key
roles in transcriptional control and cellular function. Lysines on histone tails can be
mono-(me1), di-(me2) or tri-(me3)methylated and dynamically regulated by histone
methyltransferases (HMTs) and lysine demethylases (KDMs) [1].
There are two distinct families of KDMs that catalyse the demethylation of Nmethyllysines on histones. KDM1/LSDs belong to the flavin adenine dinucleotide
(FAD)-dependent monoamine oxidase superfamily, and Jumonji-C (JmjC) domaincontaining KDMs (JmjC-KDMs), the larger of the two KDM families, belong to the
Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase superfamily. There are at
least six human subfamilies of JmjC-KDMs (KDM2–7), based on homologies of
their catalytic JmjC-domains, with each having distinct sequence and N-methylation
222
M. Wright et al.
2,4-PDCA
2,4-Pyridine dicarboxylate
2OG
2-Oxoglutarate
8HQ
8-Hydroxyquinoline
Bpy
4
0 -Carboxy 2,2
0 -bipyridine
H3
Histone H3
HMT
Histone methyltransferase
JmjC
Jumonji-C
KDM
Lysine demethylase
Kme n
Methylated lysine (n ¼ 1, mono-; n ¼ 2, di-; n ¼ 3, tri-)
NOG
N-oxalylglycine
PHD-finger Plant homeodomain finger
1 Introduction
Histone demethylases (KDMs) catalyse the removal of N-methyl marks on histones
and play important roles in epigenetic regulation. Abnormal histone methylation and
dysregulation of KDMs have been linked to multiple diseases. The majority of
KDMs are JmjC-domain-containing KDMs (JmjC-KDMs) that belong to the superfamily of Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases. JmjC-KDMs are
emerging as promising therapeutic targets, in particular, in cancer. The availability
of crystal structures has provided understanding of the mechanism, function and
selectivity of JmjC-KDMs at the molecular level and has aided structure-based
inhibitor design. This chapter provides an overview of recent advances in JmjCKDM inhibitor development from a structural perspective.
1.1 JmjC-Domain-Containing Histone Demethylases
Post-translational modifications on histones, including lysine methylation, have key
roles in transcriptional control and cellular function. Lysines on histone tails can be
mono-(me1), di-(me2) or tri-(me3)methylated and dynamically regulated by histone
methyltransferases (HMTs) and lysine demethylases (KDMs) [1].
There are two distinct families of KDMs that catalyse the demethylation of Nmethyllysines on histones. KDM1/LSDs belong to the flavin adenine dinucleotide
(FAD)-dependent monoamine oxidase superfamily, and Jumonji-C (JmjC) domaincontaining KDMs (JmjC-KDMs), the larger of the two KDM families, belong to the
Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase superfamily. There are at
least six human subfamilies of JmjC-KDMs (KDM2–7), based on homologies of
their catalytic JmjC-domains, with each having distinct sequence and N-methylation
222
M. Wright et al.