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PDBsum entry 2jav
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References listed in PDB file
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Key reference
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Title
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Structure and regulation of the human nek2 centrosomal kinase.
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Authors
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P.Rellos,
F.J.Ivins,
J.E.Baxter,
A.Pike,
T.J.Nott,
D.M.Parkinson,
S.Das,
S.Howell,
O.Fedorov,
Q.Y.Shen,
A.M.Fry,
S.Knapp,
S.J.Smerdon.
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Ref.
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J Biol Chem, 2007,
282,
6833-6842.
[DOI no: ]
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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
perfect match.
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Abstract
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The dimeric Ser/Thr kinase Nek2 regulates centrosome cohesion and separation
through phosphorylation of structural components of the centrosome, and aberrant
regulation of Nek2 activity can lead to aneuploid defects characteristic of
cancer cells. Mutational analysis of autophosphorylation sites within the kinase
domain identified by mass spectrometry shows a complex pattern of positive and
negative regulatory effects on kinase activity that are correlated with effects
on centrosomal splitting efficiency in vivo. The 2.2-A resolution x-ray
structure of the Nek2 kinase domain in complex with a pyrrole-indolinone
inhibitor reveals an inhibitory helical motif within the activation loop. This
helix presents a steric barrier to formation of the active enzyme and generates
a surface that may be exploitable in the design of specific inhibitors that
selectively target the inactive state. Comparison of this
"auto-inhibitory" conformation with similar arrangements in
cyclin-dependent kinase 2 and epidermal growth factor receptor kinase suggests a
role for dimerization-dependent allosteric regulation that combines with
autophosphorylation and protein phosphatase 1c phosphatase activity to generate
the precise spatial and temporal control required for Nek2 function in
centrosomal maturation.
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Figure 1.
FIGURE 1. Structure and autophosphorylation of human Nek2.
A, schematic showing the major structural and functional
features Nek2A organization. Sites of autophosphorylation within
both the catalytic and C-terminal regions are shown. PP1c,
protein phosphatase 1c. B, a section of the 2F[o] - F[c]
electron density map around the SU11652 inhibitor, contoured at
1  .
C, structure of the Nek2 kinase domain-SU11652 complex. The N
and C lobes are colored blue and red, respectively, the hinge
region is highlighted in yellow, and the inhibitor is shown in
green. Regions of disorder in the structure are included as
dashed lines. D, phylogenetic tree showing the sequence
relationships between the eleven human Nek-family members.
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Figure 3.
FIGURE 3. Structural basis of inhibition. The SU11652
inhibitor interacts with the ATP binding cleft through a network
of hydrogen-bonding interactions with main-chain atoms from the
kinase hinge region and van der Waals interactions with residues
from the N and C lobe together with Leu-162 from the  T helix.
The structure of the inhibitor is shown in the inset. The
(diethylamino)ethyl moiety (highlighted) is disordered in the
crystal structure.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
6833-6842)
copyright 2007.
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