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PDBsum entry 3f9n
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Contents |
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* Residue conservation analysis
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Enzyme class:
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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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Bioorg Med Chem Lett
19:1240-1244
(2009)
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PubMed id:
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Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.
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A.Converso,
T.Hartingh,
R.M.Garbaccio,
E.Tasber,
K.Rickert,
M.E.Fraley,
Y.Yan,
C.Kreatsoulas,
S.Stirdivant,
B.Drakas,
E.S.Walsh,
K.Hamilton,
C.A.Buser,
X.Mao,
M.T.Abrams,
S.C.Beck,
W.Tao,
R.Lobell,
L.Sepp-Lorenzino,
J.Zugay-Murphy,
V.Sardana,
S.K.Munshi,
S.M.Jezequel-Sur,
P.D.Zuck,
G.D.Hartman.
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ABSTRACT
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A high throughput screening campaign was designed to identify allosteric
inhibitors of Chk1 kinase by testing compounds at high concentration. Activity
was then observed at K(m) for ATP and at near-physiological concentrations of
ATP. This strategy led to the discovery of a non-ATP competitive
thioquinazolinone series which was optimized for potency and stability. An X-ray
crystal structure for the complex of our best inhibitor bound to Chk1 was
solved, indicating that it binds to an allosteric site approximately 13A from
the ATP binding site. Preliminary data is presented for several of these
compounds.
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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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C.X.Ma,
J.W.Janetka,
and
H.Piwnica-Worms
(2011).
Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics.
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Trends Mol Med,
17,
88-96.
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R.Eglen,
and
T.Reisine
(2011).
Drug discovery and the human kinome: recent trends.
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Pharmacol Ther,
130,
144-156.
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J.Zhang,
F.J.Adrián,
W.Jahnke,
S.W.Cowan-Jacob,
A.G.Li,
R.E.Iacob,
T.Sim,
J.Powers,
C.Dierks,
F.Sun,
G.R.Guo,
Q.Ding,
B.Okram,
Y.Choi,
A.Wojciechowski,
X.Deng,
G.Liu,
G.Fendrich,
A.Strauss,
N.Vajpai,
S.Grzesiek,
T.Tuntland,
Y.Liu,
B.Bursulaya,
M.Azam,
P.W.Manley,
J.R.Engen,
G.Q.Daley,
M.Warmuth,
and
N.S.Gray
(2010).
Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
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Nature,
463,
501-506.
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PDB code:
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W.I.Wu,
W.C.Voegtli,
H.L.Sturgis,
F.P.Dizon,
G.P.Vigers,
and
B.J.Brandhuber
(2010).
Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition.
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PLoS One,
5,
e12913.
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PDB code:
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L.A.Smyth,
and
I.Collins
(2009).
Measuring and interpreting the selectivity of protein kinase inhibitors.
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J Chem Biol,
2,
131-151.
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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.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
