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PDBsum entry 4bdi
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PDB id:
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Transferase
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Title:
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Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (chk2)
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Structure:
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Serine/threonine-protein kinase chk2. Chain: a. Fragment: kinase domain, residues 210-531. Synonym: chk2 checkpoint homolog, cds1 homolog, hucds1, hcds1, checkpoint kinase 2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta2 plyss.
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Resolution:
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2.32Å
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R-factor:
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0.190
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R-free:
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0.221
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Authors:
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M.C.Silva-Santisteban,I.M.Westwood,K.Boxall,N.Brown,S.Peacock, C.Mcandrew,E.Barrie,M.Richards,A.Mirza,A.W.Oliver,R.Burke,S.Hoelder, K.Jones,G.W.Aherne,J.Blagg,I.Collins,M.D.Garrett,R.L.M.Van Montfort
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Key ref:
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M.C.Silva-Santisteban
et al.
(2013).
Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2.
Plos One,
8,
e65689.
PubMed id:
DOI:
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Date:
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05-Oct-12
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Release date:
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26-Jun-13
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PROCHECK
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Headers
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References
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O96017
(CHK2_HUMAN) -
Serine/threonine-protein kinase Chk2 from Homo sapiens
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Seq:
Struc:
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543 a.a.
290 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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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Plos One
8:e65689
(2013)
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PubMed id:
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Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2.
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M.C.Silva-Santisteban,
I.M.Westwood,
K.Boxall,
N.Brown,
S.Peacock,
C.McAndrew,
E.Barrie,
M.Richards,
A.Mirza,
A.W.Oliver,
R.Burke,
S.Hoelder,
K.Jones,
G.W.Aherne,
J.Blagg,
I.Collins,
M.D.Garrett,
R.L.van Montfort.
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ABSTRACT
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Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the
cellular response to DNA damage. A fragment-based screening campaign using a
combination of a high-concentration AlphaScreen™ kinase assay and a
biophysical thermal shift assay, followed by X-ray crystallography, identified a
number of chemically different ligand-efficient CHK2 hinge-binding scaffolds
that have not been exploited in known CHK2 inhibitors. In addition, it showed
that the use of these orthogonal techniques allowed efficient discrimination
between genuine hit matter and false positives from each individual assay
technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based
fragment and its follow-up compound highlight a hydrophobic area above the hinge
region not previously explored in rational CHK2 inhibitor design, but which
might be exploited to enhance both potency and selectivity of CHK2 inhibitors.
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Links
