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PDBsum entry 2c30
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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 p21-Activated kinases pak4, Pak5, And pak6 reveal catalytic domain plasticity of active group ii paks.
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Authors
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J.Eswaran,
W.H.Lee,
J.E.Debreczeni,
P.Filippakopoulos,
A.Turnbull,
O.Fedorov,
S.W.Deacon,
J.R.Peterson,
S.Knapp.
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Ref.
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Structure, 2007,
15,
201-213.
[DOI no: ]
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PubMed id
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Abstract
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p21-activated kinases have been classified into two groups based on their domain
architecture. Group II PAKs (PAK4-6) regulate a wide variety of cellular
functions, and PAK deregulation has been linked to tumor development. Structural
comparison of five high-resolution structures comprising all active,
monophosphorylated group II catalytic domains revealed a surprising degree of
domain plasticity, including a number of catalytically productive and
nonproductive conformers. Rearrangements of helix alphaC, a key regulatory
element of kinase function, resulted in an additional helical turn at the alphaC
N terminus and a distortion of its C terminus, a movement hitherto unseen in
protein kinases. The observed structural changes led to the formation of
interactions between conserved residues that structurally link the glycine-rich
loop, alphaC, and the activation segment and firmly anchor alphaC in an active
conformation. Inhibitor screening identified six potent PAK inhibitors from
which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.
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Figure 3.
Figure 3. Binding of the Purine Inhibitor
(A and B)
Superimposition of PAK4 and PAK5 showing the (A) binding modes
of the purine inhibitor and (B) interaction with active site
residues in PAK4. A superimposition of the C-terminal lobes was
used to generate the figure shown in (A). PAK4 is shown in
yellow, and PAK5 is shown in orange.
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Figure 5.
Figure 5. Rearrangement of Helix αC
(A) Superimposition
of central residues in the PAK5 αC helices showing the
remodeling of the αC termini. The central residues stay in
position, whereas conversion into an active state (PAK5 purine
complex) results in the addition of an N-terminal α helix and
disruption of the αC terminus.
(B) Structural changes at
the αC C terminus brings Asn493 (Asn365, PAK4) into position to
hydrogen bond with the DFG glycine (Gly588) and a conserved
activation segment cysteine (Cys590 and Cys462 in PAK5 and PAK4,
respectively), resulting in the formation of the αC anchor
point with the activation segment. In the PAK4 structures, this
movement is not completed, and only one hydrogen bond is formed
with Cys462.
(C) Swinging movement of the conserved αC
Arg487 (Arg359 in PAK4) between the glycine-rich loop and the
phosphoserine activation loop residue. Upon extension of the αC
helix by one turn at the N –terminus, Arg487 forms three
hydrogen bonds with the glycine-rich loop, stabilizing an
extremely closed conformation (PAK5 purine complex, orange). In
the short αC conformation, the corresponding arginine in PAK4
interacts with the phosphoserine residue in the activation
segment. This conformation also results in a partially open
conformation of the glycine-rich loop stabilized by a hydrogen
bond formed by the conserved Gln357. When αC swings away (as
observed in apo-PAK5, cyan, or PAK6 [not shown]), the N- and
C-terminal anchor points break, resulting in an open
glycine-rich loop conformation. During the swinging movement,
Arg487 in the PAK5 apo structure was observed in a disordered
state beyond the γ carbon (indicated by white balls and
sticks).
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The above figures are
reprinted
from an Open Access publication published by Cell Press:
Structure
(2007,
15,
201-213)
copyright 2007.
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