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PDBsum entry 5k4l
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Oxidoreductase/inhibitor
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PDB id
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5k4l
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PDB id:
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| Name: |
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Oxidoreductase/inhibitor
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Title:
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Crystal structure of kdm5a in complex with a naphthyridone inhibitor
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Structure:
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Lysine-specific demethylase 5a. Chain: a, b. Fragment: unp residues 12-797. Synonym: histone demethylase jarid1a,jumonji/arid domain-containing protein 1a,retinoblastoma-binding protein 2,rbbp-2. Engineered: yes. Unknown peptide. Chain: f, g. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm5a, jarid1a, rbbp2, rbp2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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3.18Å
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R-factor:
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0.224
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R-free:
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0.257
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Authors:
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J.R.Kiefer,M.V.Vinogradova
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Key ref:
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S.S.Labadie
et al.
(2016).
Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.
Bioorg Med Chem Lett,
26,
4492-4496.
PubMed id:
DOI:
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Date:
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20-May-16
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Release date:
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10-Aug-16
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PROCHECK
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Headers
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References
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P29375
(KDM5A_HUMAN) -
Lysine-specific demethylase 5A from Homo sapiens
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Seq:
Struc:
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1690 a.a.
577 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:
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E.C.1.14.11.67
- [histone H3]-trimethyl-L-lysine(4) demethylase.
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Reaction:
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N6,N6,N6-trimethyl-L-lysyl4-[histone H3] + 3 2-oxoglutarate + 3 O2 = L-lysyl4-[histone H3] + 3 formaldehyde + 3 succinate + 3 CO2
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N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3]
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+
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3
×
2-oxoglutarate
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+
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3
×
O2
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=
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L-lysyl(4)-[histone H3]
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+
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3
×
formaldehyde
Bound ligand (Het Group name = )
matches with 44.44% similarity
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+
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3
×
succinate
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+
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3
×
CO2
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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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Bioorg Med Chem Lett
26:4492-4496
(2016)
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PubMed id:
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Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.
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S.S.Labadie,
P.S.Dragovich,
R.T.Cummings,
G.Deshmukh,
A.Gustafson,
N.Han,
J.C.Harmange,
J.R.Kiefer,
Y.Li,
J.Liang,
B.M.Liederer,
Y.Liu,
W.Manieri,
W.Mao,
L.Murray,
D.F.Ortwine,
P.Trojer,
E.VanderPorten,
M.Vinogradova,
L.Wen.
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ABSTRACT
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Features from a high throughput screening (HTS) hit and a previously reported
scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme
inhibitors with nanomolar potencies. These molecules exhibited high selectivity
over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a
representative molecule bound to KDM5A showed that these inhibitors are
competitive with the co-substrate (2-oxoglutarate or 2-OG).
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