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PDBsum entry 5f2s
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Oxidoreductase
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PDB id
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5f2s
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Crystal structure of human kdm4a in complex with compound 15
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Structure:
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Lysine-specific demethylase 4a. Chain: a, b, c, d. Synonym: jmjc domain-containing histone demethylation protein 3a, jumonji domain-containing protein 2a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm4a, jhdm3a, jmjd2, jmjd2a, kiaa0677. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta2.
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Resolution:
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2.08Å
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R-factor:
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0.165
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R-free:
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0.191
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Authors:
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Y.-V.Le Bihan,S.Dempster,I.M.Westwood,R.L.M.Van Montfort
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Key ref:
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V.Bavetsias
et al.
(2016).
8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
J Med Chem,
59,
1388-1409.
PubMed id:
DOI:
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Date:
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02-Dec-15
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Release date:
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20-Jan-16
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PROCHECK
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Headers
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References
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O75164
(KDM4A_HUMAN) -
Lysine-specific demethylase 4A from Homo sapiens
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Seq:
Struc:
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1064 a.a.
342 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class 2:
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E.C.1.14.11.66
- [histone H3]-trimethyl-L-lysine(9) demethylase.
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Reaction:
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N6,N6,N6-trimethyl-L-lysyl9-[histone H3] + 2 2-oxoglutarate + 2 O2 = N6-methyl-L-lysyl9-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2
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N(6),N(6),N(6)-trimethyl-L-lysyl(9)-[histone H3]
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+
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2
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2-oxoglutarate
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+
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2
×
O2
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=
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N(6)-methyl-L-lysyl(9)-[histone H3]
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+
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2
×
formaldehyde
Bound ligand (Het Group name = )
matches with 50.00% similarity
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+
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2
×
succinate
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+
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2
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CO2
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Enzyme class 3:
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E.C.1.14.11.69
- [histone H3]-trimethyl-L-lysine(36) demethylase.
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Reaction:
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N6,N6,N6-trimethyl-L-lysyl36-[histone H3] + 2 2-oxoglutarate + 2 O2 = N6-methyl-L-lysyl36-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2
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N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3]
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+
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2
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2-oxoglutarate
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+
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2
×
O2
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=
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N(6)-methyl-L-lysyl(36)-[histone H3]
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+
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2
×
formaldehyde
Bound ligand (Het Group name = )
matches with 50.00% similarity
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+
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2
×
succinate
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+
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2
×
CO2
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
59:1388-1409
(2016)
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PubMed id:
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8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
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V.Bavetsias,
R.M.Lanigan,
G.F.Ruda,
B.Atrash,
M.G.McLaughlin,
A.Tumber,
N.Y.Mok,
Y.V.Le Bihan,
S.Dempster,
K.J.Boxall,
F.Jeganathan,
S.B.Hatch,
P.Savitsky,
S.Velupillai,
T.Krojer,
K.S.England,
J.Sejberg,
C.Thai,
A.Donovan,
A.Pal,
G.Scozzafava,
J.M.Bennett,
A.Kawamura,
C.Johansson,
A.Szykowska,
C.Gileadi,
N.A.Burgess-Brown,
F.von Delft,
U.Oppermann,
Z.Walters,
J.Shipley,
F.I.Raynaud,
S.M.Westaway,
R.K.Prinjha,
O.Fedorov,
R.Burke,
C.J.Schofield,
I.M.Westwood,
C.Bountra,
S.Müller,
R.L.van Montfort,
P.E.Brennan,
J.Blagg.
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ABSTRACT
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We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine
derivatives and their subsequent optimization, guided by structure-based design,
to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent
JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II)
in the active site. Substitution from C4 of the pyrazole moiety allows access to
the histone peptide substrate binding site; incorporation of a conformationally
constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k
which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1)
subfamily demethylases, selectivity over representative exemplars of the KDM2,
KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for
54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
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