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PDBsum entry 1m2r
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Inhibition of protein kinase ck2 by anthraquinone-Related compounds. A structural insight.
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Authors
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E.De moliner,
S.Moro,
S.Sarno,
G.Zagotto,
G.Zanotti,
L.A.Pinna,
R.Battistutta.
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Ref.
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J Biol Chem, 2003,
278,
1831-1836.
[DOI no: ]
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PubMed id
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Abstract
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Protein kinases play key roles in signal transduction and therefore are among
the most attractive targets for drug design. The pharmacological aptitude of
protein kinase inhibitors is highlighted by the observation that various
diseases with special reference to cancer are because of the abnormal
expression/activity of individual kinases. The resolution of the
three-dimensional structure of the target kinase in complex with inhibitors is
often the starting point for the rational design of this kind of drugs, some of
which are already in advanced clinical trial or even in clinical practice. Here
we present and discuss three new crystal structures of ATP site-directed
inhibitors in complex with "casein kinase-2" (CK2), a constitutively
active protein kinase implicated in a variety of cellular functions and
misfunctions. With the help of theoretical calculations, we disclose some key
features underlying the inhibitory efficiency of anthraquinone derivatives,
outlining three different binding modes into the active site. In particular, we
show that a nitro group in a hydroxyanthraquinone scaffold decreases the
inhibitory constants K(i) because of electron-withdrawing and resonance effects
that enhance the polarization of hydroxylic substituents in paraposition.
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Figure 2.
Fig. 2. Overview of CK2 three-dimensional folding. The
ribbon diagram of CK2 in complex with MNA (in ball-and-stick)
bound in the ATP binding site between the N- and the C-terminal
lobes is shown (gray). The location of the inhibitor DAA is also
shown (ball-and-stick in black). On the top right are shown the
two different positions of the loop 102-108 in the case of the
MNA complex (gray) and DAA (or MNX) complex (black) that
correspond to a long b-cell axis (around 59.5 Å) and a
short one (around 52.2 Å), respectively.
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Figure 4.
Fig. 4. Polar interactions (dotted lines) of MNA , MNX,
and DAA when bound to CK2. Distances are reported in angstroms.
In the DAA scheme, interactions between ATP and residues Glu-114
and Val-116 are reported for comparison (21).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
1831-1836)
copyright 2003.
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