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PDBsum entry 4a9r
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PDB id:
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Transferase
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Title:
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Crystal structure of human chk2 in complex with benzimidazole carboxamide inhibitor
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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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2.85Å
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R-factor:
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0.187
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R-free:
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0.235
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Authors:
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C.Matijssen,M.C.Silva-Santisteban,I.M.Westwood,S.Siddique,V.Choi, P.Sheldrake,R.L.M.Van Montfort,J.Blagg
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Key ref:
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C.Matijssen
et al.
(2012).
Benzimidazole inhibitors of the protein kinase CHK2: clarification of the binding mode by flexible side chain docking and protein-ligand crystallography.
Bioorg Med Chem Lett,
20,
6630-6639.
PubMed id:
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Date:
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28-Nov-11
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Release date:
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10-Oct-12
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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.
286 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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Bioorg Med Chem Lett
20:6630-6639
(2012)
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PubMed id:
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Benzimidazole inhibitors of the protein kinase CHK2: clarification of the binding mode by flexible side chain docking and protein-ligand crystallography.
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C.Matijssen,
M.C.Silva-Santisteban,
I.M.Westwood,
S.Siddique,
V.Choi,
P.Sheldrake,
R.L.van Montfort,
J.Blagg.
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ABSTRACT
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Two closely related binding modes have previously been proposed for the
ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors;
however, neither binding mode is entirely consistent with the reported SAR.
Unconstrained rigid docking of benzimidazole ligands into representative CHK2
protein crystal structures reveals an alternative binding mode involving a
water-mediated interaction with the hinge region; docking which incorporates
protein side chain flexibility for selected residues in the ATP binding site
resulted in a refinement of the water-mediated hinge binding mode that is
consistent with observed SAR. The flexible docking results are in good agreement
with the crystal structures of four exemplar benzimidazole ligands bound to CHK2
which unambiguously confirmed the binding mode of these inhibitors, including
the water-mediated interaction with the hinge region, and which is significantly
different from binding modes previously postulated in the literature.
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