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PDBsum entry 2wms
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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 checkpoint kinase 1 (chk1) in complex with inhibitors
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Structure:
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Serine/threonine-protein kinase chk1. Chain: a. Fragment: kinase domain, residues 1-289. Synonym: checkpoint kinase 1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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2.70Å
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R-factor:
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0.225
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R-free:
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0.259
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Authors:
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T.P.Matthews,S.Klair,S.Burns,K.Boxall,M.Cherry,M.Fisher,I.M.Westwood, M.I.Walton,T.Mchardy,K.-M.J.Cheung,R.Van Montfort,D.Williams, G.W.Aherne,M.D.Garrett,J.Reader,I.Collins
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Key ref:
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T.P.Matthews
et al.
(2009).
Identification of inhibitors of checkpoint kinase 1 through template screening.
J Med Chem,
52,
4810-4819.
PubMed id:
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Date:
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03-Jul-09
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Release date:
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28-Jul-09
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PROCHECK
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Headers
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References
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O14757
(CHK1_HUMAN) -
Serine/threonine-protein kinase Chk1 from Homo sapiens
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Seq:
Struc:
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476 a.a.
243 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.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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J Med Chem
52:4810-4819
(2009)
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PubMed id:
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Identification of inhibitors of checkpoint kinase 1 through template screening.
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T.P.Matthews,
S.Klair,
S.Burns,
K.Boxall,
M.Cherry,
M.Fisher,
I.M.Westwood,
M.I.Walton,
T.McHardy,
K.M.Cheung,
R.Van Montfort,
D.Williams,
G.W.Aherne,
M.D.Garrett,
J.Reader,
I.Collins.
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ABSTRACT
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Checkpoint kinase 1 (CHK1) is an oncology target of significant current
interest. Inhibition of CHK1 abrogates DNA damage-induced cell cycle checkpoints
and sensitizes p53 deficient cancer cells to genotoxic therapies. Using template
screening, a fragment-based approach to small molecule hit generation, we have
identified multiple CHK1 inhibitor scaffolds suitable for further optimization.
The sequential combination of in silico low molecular weight template selection,
a high concentration biochemical assay and hit validation through protein-ligand
X-ray crystallography provided 13 template hits from an initial in silico
screening library of ca. 15000 compounds. The use of appropriate
counter-screening to rule out nonspecific aggregation by test compounds was
essential for optimum performance of the high concentration bioassay. One low
molecular weight, weakly active purine template hit was progressed by iterative
structure-based design to give submicromolar pyrazolopyridines with good ligand
efficiency and appropriate CHK1-mediated cellular activity in HT29 colon cancer
cells.
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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.W.Murray,
and
T.L.Blundell
(2010).
Structural biology in fragment-based drug design.
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Curr Opin Struct Biol,
20,
497-507.
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T.McHardy,
J.J.Caldwell,
K.M.Cheung,
L.J.Hunter,
K.Taylor,
M.Rowlands,
R.Ruddle,
A.Henley,
A.de Haven Brandon,
M.Valenti,
T.G.Davies,
L.Fazal,
L.Seavers,
F.I.Raynaud,
S.A.Eccles,
G.W.Aherne,
M.D.Garrett,
and
I.Collins
(2010).
Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).
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J Med Chem,
53,
2239-2249.
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PDB codes:
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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
codes are
shown on the right.
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Links
