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PDBsum entry 2c3j
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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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DOI no:
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Bioorg Med Chem Lett
14:1792-1804
(2006)
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PubMed id:
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Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification.
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N.Foloppe,
L.M.Fisher,
G.Francis,
R.Howes,
P.Kierstan,
A.Potter.
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ABSTRACT
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Inhibition of the Chk1 kinase by small molecules binding to its active site is a
strategy of great therapeutic interest for oncology. We report how computational
modelling predicted the binding mode of ligands of special interest to the Chk1
ATP site, for representatives of an indazole series and debromohymenialdisine.
These binding modes were subsequently confirmed by X-ray crystallography. The
binding mode of a potent indazole derivative involves non-conventional C-H...O
and N-H...pi-aromatic interactions with the protein. These interactions are
formed in a buried pocket at the periphery of the ATP-binding site, the
importance of which has previously been overlooked for ligand design against
Chk1. It is demonstrated that filling this pocket can confer ligands with
dramatically enhanced affinity for Chk1. Structural arguments in conjunction
with assay data explain why targeting this pocket is also advantageous for
selective binding to Chk1. Structural overlays of known inhibitors complexed
with Chk1 show that only the indazole series utilizes the pocket of interest.
Therefore, the analysis presented here should prove helpful in guiding future
structure-based ligand design efforts against Chk1.
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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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S.Y.Lu,
Y.J.Jiang,
J.W.Zou,
H.B.Luo,
and
T.X.Wu
(2011).
Insight into analysis of interactions of GW9508 to wild-type and H86F and H137F GPR40: a combined QM/MM study and pharmacophore modeling.
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J Mol Graph Model,
29,
818-825.
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X.M.Chen,
T.Lu,
S.Lu,
H.F.Li,
H.L.Yuan,
T.Ran,
H.C.Liu,
and
Y.D.Chen
(2010).
Structure-based and shape-complemented pharmacophore modeling for the discovery of novel checkpoint kinase 1 inhibitors.
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J Mol Model,
16,
1195-1204.
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G.T.Lountos,
J.E.Tropea,
D.Zhang,
A.G.Jobson,
Y.Pommier,
R.H.Shoemaker,
and
D.S.Waugh
(2009).
Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor.
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Protein Sci,
18,
92.
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PDB code:
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K.L.Arrington,
and
V.Y.Dudkin
(2007).
Novel Inhibitors of Checkpoint Kinase 1.
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ChemMedChem,
2,
1571-1585.
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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
