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PDBsum entry 2z7q
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References listed in PDB file
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Key reference
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Title
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Crystal structures of the n-Terminal kinase domain of human rsk1 bound to three different ligands: implications for the design of rsk1 specific inhibitors.
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Authors
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M.Ikuta,
M.Kornienko,
N.Byrne,
J.C.Reid,
S.Mizuarai,
H.Kotani,
S.K.Munshi.
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Ref.
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Protein Sci, 2007,
16,
2626-2635.
[DOI no: ]
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PubMed id
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Abstract
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The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine
protein kinases that are activated by ERK or PDK1 and act as downstream
effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK
family, contains two distinct kinase domains in a single polypeptide chain, the
regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase
domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD
that subsequently phosphorylates downstream substrates. Here we report the
crystal structures of the unactivated RSK1 NTKD bound to different ligands at
2.0 A resolution. The activation loop and helix alphaC, key regulatory elements
of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an
"active-like" conformation. The beta-PO(4) group in the AMP-PCP
complex adopts a unique conformation that may contribute to inactivity of the
enzyme. Structures of RSK1 ligand complexes offer insights into the design of
novel anticancer agents and into the regulation of the catalytic activity of
RSKs.
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Figure 1.
Domain organization of RSKs. RSK1 has two kinase domains that
can be activated by ERK and PDK1. The current model for
activation suggests that, following mitogen stimulation, ERK
phosphorylates Thr573, which is located in the activation loop
of the CTKD of RSK1, and Thr359 and Ser363, which are in the
linker region of RSK1 (Gavin and Nebreda 1999; Smith et al.
1999). Activation of the CTKD by ERK leads to
autophosphorylation of Ser380 which is also located in the
linker region. Ser380 is located in a hydrophobic motif
conserved among a large number of the AGC family kinases. The
result is a conformational alteration of RSK1, creating a
docking site for PDK1, which then fully activates RSK1 by
phosphorylation of Ser221 in the activation loop of the NTKD.
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Figure 3.
Close-up view of the ATP-binding site. (A) Stereoview of RSK1
with bound AMP --PCP. Magnesium ion is shown as a green sphere.
The P-loop is colored green. (B) 2Fo[minus sign]Fc map contoured
at 1.5[sigma] for AMP --PCP bound to RSK1. (C) Superimposed AMP
--PCP of RSK1 (green) and AMP --PNP in unphosphorylated EphA2
(cyan) (PDB code 1MQB). The Mg^2+ ion bound to RSK1 is shown as
a magenta-colored sphere. (D) Superimposed AMP --PCP of RSK1
(green) and ATP in active PKA (gray) (PDB code 1ATP). Two Mg^2+
ions bound to PKA are shown as a purple-colored sphere. (E)
Superimposed ATP of PKA (gray) and AMP --PNP in unphosphorylated
EphA2 (cyan). In the inactive RSK1 structure, the sugar ring is
in a different conformation compared to EphA2 and PKA. The
phosphate groups in PKA and EphA2 are similarly oriented.
However, [beta]-phosphate in RSK1 meanders in an opposite
direction.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2007,
16,
2626-2635)
copyright 2007.
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