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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of aurora b kinase in complex with reversine inhibitor
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Structure:
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Serine/threonine-protein kinase 12-a. Chain: a, b. Fragment: residues 78-361. Synonym: aurora b kinase, aurora-b-a, aurora/ipl1-related kinase 2-a, airk2-a. Engineered: yes. Inner centromere protein a. Chain: c, d. Fragment: residues 797-840.
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Source:
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Xenopus laevis. African clawed frog. Organism_taxid: 8355. Expressed in: escherichia coli. Expression_system_taxid: 511693.
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Resolution:
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1.70Å
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R-factor:
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0.199
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R-free:
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0.229
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Authors:
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A.M.D'Alise,G.Amabile,M.Iovino,F.P.Di Giorgio,M.Bartiromo,F.Sessa, F.Villa,A.Musacchio,R.Cortese
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Key ref:
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A.M.D'Alise
et al.
(2008).
Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells.
Mol Cancer Ther,
7,
1140-1149.
PubMed id:
DOI:
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Date:
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15-Nov-07
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Release date:
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28-Oct-08
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PROCHECK
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Headers
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References
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Q6DE08
(AUKBA_XENLA) -
Aurora kinase B-A from Xenopus laevis
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Seq:
Struc:
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361 a.a.
269 a.a.*
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Enzyme class:
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Chains A, B:
E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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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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Mol Cancer Ther
7:1140-1149
(2008)
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PubMed id:
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Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells.
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A.M.D'Alise,
G.Amabile,
M.Iovino,
F.P.Di Giorgio,
M.Bartiromo,
F.Sessa,
F.Villa,
A.Musacchio,
R.Cortese.
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ABSTRACT
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The demonstration that the small synthetic molecule reversine
[2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of
committed cells into multipotent progenitor-type cells has raised hopes on the
exploitation of this small chemical tool for the generation of stem cells. Here,
we show that reversine causes a failure in cytokinesis and induces
polyploidization. These effects of reversine are due to the inhibition of Aurora
A and B, two related kinases that are implicated in several aspects of mitosis
and that are frequently amplified and overexpressed in human tumors. Reversine
inhibits the phosphorylation of histone H3, a direct downstream target of Aurora
kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently
entered phase II clinical trials for cancer treatment, reversine inhibited
colony formation of leukemic cells from patients with acute myeloid leukemia but
was significantly less toxic than VX-680 on cells from healthy donors. The
crystal structure of the reversine-Aurora B kinase complex shows that reversine
is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our
studies raise serious doubts on the application of reversine in regenerative
medicine, they support the paradigm that reversine might be a useful agent in
cancer chemotherapy.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Ao,
J.Hao,
and
C.C.Hong
(2011).
Regenerative chemical biology: current challenges and future potential.
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Chem Biol,
18,
413-424.
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W.Qi,
L.S.Cooke,
X.Liu,
L.Rimsza,
D.J.Roe,
A.Manziolli,
D.O.Persky,
T.P.Miller,
and
D.Mahadevan
(2011).
Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma.
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Biochem Pharmacol,
81,
881-890.
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L.Anastasia,
G.Pelissero,
B.Venerando,
and
G.Tettamanti
(2010).
Cell reprogramming: expectations and challenges for chemistry in stem cell biology and regenerative medicine.
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Cell Death Differ,
17,
1230-1237.
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S.Santaguida,
A.Tighe,
A.M.D'Alise,
S.S.Taylor,
and
A.Musacchio
(2010).
Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine.
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J Cell Biol,
190,
73-87.
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W.Lan,
and
D.W.Cleveland
(2010).
A chemical tool box defines mitotic and interphase roles for Mps1 kinase.
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J Cell Biol,
190,
21-24.
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C.Fania,
L.Anastasia,
M.Vasso,
N.Papini,
D.Capitanio,
B.Venerando,
and
C.Gelfi
(2009).
Proteomic signature of reversine-treated murine fibroblasts by 2-D difference gel electrophoresis and MS: possible associations with cell signalling networks.
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Electrophoresis,
30,
2193-2206.
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G.Amabile,
A.M.D'Alise,
M.Iovino,
P.Jones,
S.Santaguida,
A.Musacchio,
S.Taylor,
and
R.Cortese
(2009).
The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts.
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Cell Death Differ,
16,
321-330.
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N.Jetton,
K.G.Rothberg,
J.G.Hubbard,
J.Wise,
Y.Li,
H.L.Ball,
and
L.Ruben
(2009).
The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms.
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Mol Microbiol,
72,
442-458.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
