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PDBsum entry 1xr1
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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 basis of constitutive activity and a unique nucleotide binding mode of human pim-1 kinase.
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Authors
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K.C.Qian,
L.Wang,
E.R.Hickey,
J.Studts,
K.Barringer,
C.Peng,
A.Kronkaitis,
J.Li,
A.White,
S.Mische,
B.Farmer.
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Ref.
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J Biol Chem, 2005,
280,
6130-6137.
[DOI no: ]
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PubMed id
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Abstract
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Pim-1 kinase is a member of a distinct class of serine/threonine kinases
consisting of Pim-1, Pim-2, and Pim-3. Pim kinases are highly homologous to one
another and share a unique consensus hinge region sequence, ER-PXPX, with its
two proline residues separated by a non-conserved residue, but they (Pim
kinases) have <30% sequence identity with other kinases. Pim-1 has been
implicated in both cytokine-induced signal transduction and the development of
lymphoid malignancies. We have determined the crystal structures of apo Pim-1
kinase and its AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) complex to
2.1-angstroms resolutions. The structures reveal the following. 1) The kinase
adopts a constitutively active conformation, and extensive hydrophobic and
hydrogen bond interactions between the activation loop and the catalytic loop
might be the structural basis for maintaining such a conformation. 2) The hinge
region has a novel architecture and hydrogen-bonding pattern, which not only
expand the ATP pocket but also serve to establish unambiguously the alignment of
the Pim-1 hinge region with that of other kinases. 3) The binding mode of
AMP-PNP to Pim-1 kinase is unique and does not involve a critical hinge region
hydrogen bond interaction. Analysis of the reported Pim-1 kinase-domain
structures leads to a hypothesis as to how Pim kinase activity might be
regulated in vivo.
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Figure 1.
FIG. 1. Pim-1 adopts a typical kinase fold. a, ribbon
diagram of apo Pim-1 kinase crystal structure produced using
Ribbons (35). The secondary structure  -helix and  -strand
are labeled following the conventions of the literature. The
H1-
and H2-strands are unique to
Pim-1 kinase structure and are so named for their helical
structure in cAPK. The shaded area represents the ATP binding
pocket with the active site residues shown and labeled with
single letter amino acid abbreviations and position numbers. b,
an overlay of Pim-1 and PhK using catalytic loops (produced
using Quanta). The active site residues that bind or catalyze
ATP were shown and and labeled (with single letter amino acid
abbreviations and position numbers) on the C trace of selected
regions.
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Figure 4.
FIG. 4. The atoms are colored as gray, blue, red, and
yellow for carbon, nitrogen, oxygen, and phosphor, respectively
and panels a and b were produced using Quanta. a, stereo view of
electron density (2F[o] - F[c] coefficients, 1.0  level)
for AMP-PNP with two bound magnesium ions. b, the binding
interactions of AMP-PNP phosphates with Pim-1. Lys169 does not
bind AMP-PNP in Pim-1, contrasting with what is observed in
other kinases. Single letter amino acid abbreviations are used
with position numbers.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
6130-6137)
copyright 2005.
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