 |
PDBsum entry 4xrx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase/oxidoreductase inhibitor
|
PDB id
|
|
|
|
4xrx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Oxidoreductase/oxidoreductase inhibitor
|
|
|
Title:
|
|
Crystal structure of a metabolic reductase with (e)-5-((1-methyl-5- oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1h)-one
|
|
Structure:
|
|
Isocitrate dehydrogenase [nadp] cytoplasmic. Chain: a, b. Synonym: idh,cytosolic NADP-isocitrate dehydrogenase,idp,NADP(+)- specific icdh,oxalosuccinate decarboxylase. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: idh1, picd. Expressed in: escherichia coli. Expression_system_taxid: 562.
|
|
Resolution:
|
|
|
3.20Å
|
R-factor:
|
0.195
|
R-free:
|
0.277
|
|
|
Authors:
|
|
B.Zheng,F.Wu,H.Jiang,M.Kogiso,Y.Yao,C.Zhou,X.Li,Y.Song
|
|
Key ref:
|
|
F.Wu
et al.
(2015).
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
J Med Chem,
58,
6899-6908.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
21-Jan-15
|
Release date:
|
09-Dec-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
O75874
(IDHC_HUMAN) -
Isocitrate dehydrogenase [NADP] cytoplasmic from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
414 a.a.
390 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.1.1.1.42
- isocitrate dehydrogenase (NADP(+)).
|
|
|
|
|
|
|
Pathway:
|
|
Citric acid cycle
|
|
|
|
|
|
Reaction:
|
|
D-threo-isocitrate + NADP+ = 2-oxoglutarate + CO2 + NADPH
|
|
|
|
|
|
D-threo-isocitrate
|
+
|
NADP(+)
Bound ligand (Het Group name = )
corresponds exactly
|
=
|
2-oxoglutarate
|
+
|
CO2
|
+
|
NADPH
|
|
|
|
|
|
|
|
|
|
Cofactor:
|
|
Mn(2+) or Mg(2+)
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
58:6899-6908
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
|
|
F.Wu,
H.Jiang,
B.Zheng,
M.Kogiso,
Y.Yao,
C.Zhou,
X.N.Li,
Y.Song.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently
found in certain cancers such as glioma. With losing the activity of wild-type
IDH1, the R132H and R132C mutant proteins can reduce α-ketoglutaric acid
(α-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of
D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases,
to cause broad histone hypermethylation. These aberrant epigenetic changes are
responsible for the initiation of these cancers. We report the synthesis,
structure-activity relationships, enzyme kinetics, and binding thermodynamics of
a novel series of 2-thiohydantoin and related compounds, among which several
compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray
crystal structures of IDH1(R132H) in complex with two inhibitors are reported,
showing their inhibitor-protein interactions. These compounds can decrease the
cellular concentration of D2HG, reduce the levels of histone methylation, and
suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1
R132H mutation.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
