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PDBsum entry 3qa0
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References listed in PDB file
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Key reference
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Title
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Structural and functional analysis of the flexible regions of the catalytic α-Subunit of protein kinase ck2.
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Authors
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E.Papinutto,
A.Ranchio,
G.Lolli,
L.A.Pinna,
R.Battistutta.
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Ref.
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J Struct Biol, 2012,
177,
382-391.
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
95%.
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Abstract
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CK2 is a Ser/Thr protein kinase essential for cell viability. Its activity is
anomalously high in several solid (prostate, mammary gland, lung, kidney and
head and neck) and haematological tumours (AML, CML and PML), creating
conditions favouring the onset of cancer. Cancer cells become addicted to high
levels of CK2 activity and therefore this kinase is a remarkable example of
"non-oncogene addiction". CK2 is a validated target for cancer therapy with one
inhibitor in phase I clinical trials. Several crystal structures of CK2 are
available, many in complex with ATP-competitive inhibitors, showing the presence
of regions with remarkable flexibility. We present the structural
characterisation of these regions by means of seven new crystal structures, in
the apo form and in complex with inhibitors. We confirm previous findings about
the unique flexibility of the CK2α catalytic subunit in the hinge/αD region,
the p-loop and the β4β5 loop, and show here that there is no clear-cut
correlation between the conformations of these flexible zones. Our findings
challenge some of the current interpretations on the functional role of these
regions and dispute the hypothesis that small ligands stabilize an inactive
state. The mobility of the hinge/αD region in the human enzyme is unique among
protein kinases, and this can be exploited for the development of more selective
ATP-competitive inhibitors. The identification of different ligand binding modes
to a secondary site can provide hints for the design of non-ATP-competitive
inhibitors targeting the interaction between the α catalytic and the β
regulatory subunits.
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