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PDBsum entry 2wtj
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Contents |
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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 chk2 in complex with an inhibitor
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Structure:
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Checkpoint kinase 2. Chain: a. Fragment: kinase domain, residues 1-310. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.10Å
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R-factor:
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0.189
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R-free:
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0.217
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Authors:
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S.Hilton,S.Naud,J.J.Caldwell,K.Boxall,S.Burns,V.E.Anderson,L.Antoni, C.E.Allen,L.H.Pearl,A.W.Oliver,G.W.Aherne,M.D.Garrett,I.Collins
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Key ref:
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S.Hilton
et al.
(2010).
Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.
Bioorg Med Chem Lett,
18,
707-718.
PubMed id:
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Date:
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16-Sep-09
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Release date:
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29-Dec-09
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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.
287 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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Bioorg Med Chem Lett
18:707-718
(2010)
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PubMed id:
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Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2.
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S.Hilton,
S.Naud,
J.J.Caldwell,
K.Boxall,
S.Burns,
V.E.Anderson,
L.Antoni,
C.E.Allen,
L.H.Pearl,
A.W.Oliver,
G.Wynne Aherne,
M.D.Garrett,
I.Collins.
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ABSTRACT
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5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were
identified from high throughput screening of a kinase-focussed compound library.
Rapid exploration of the hits through straightforward chemistry established
structure-activity relationships and a proposed ATP-competitive binding mode
which was verified by X-ray crystallography of several analogues bound to CHK2.
Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and
dioxane groups which improved the affinity and the selectivity of the compounds
for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be
successfully replaced by acyclic omega-aminoalkylamides, which made additional
polar interactions within the binding site and led to more potent inhibitors of
CHK2. Compounds from this series showed activity in cell-based mechanistic
assays for inhibition of CHK2.
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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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D.K.Whelligan,
S.Solanki,
D.Taylor,
D.W.Thomson,
K.M.Cheung,
K.Boxall,
C.Mas-Droux,
C.Barillari,
S.Burns,
C.G.Grummitt,
I.Collins,
R.L.van Montfort,
G.W.Aherne,
R.Bayliss,
and
S.Hoelder
(2010).
Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization.
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J Med Chem,
53,
7682-7698.
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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
