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PDBsum entry 1gng
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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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The structure of phosphorylated gsk-3beta complexed with a peptide, Frattide, That inhibits beta-Catenin phosphorylation.
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Authors
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B.Bax,
P.S.Carter,
C.Lewis,
A.R.Guy,
A.Bridges,
R.Tanner,
G.Pettman,
C.Mannix,
A.A.Culbert,
M.J.Brown,
D.G.Smith,
A.D.Reith.
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Ref.
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Structure, 2001,
9,
1143-1152.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: Glycogen synthase kinase-3 (GSK-3) sequentially phosphorylates four
serine residues on glycogen synthase (GS), in the sequence
SxxxSxxxSxxx-SxxxS(p), by recognizing and phosphorylating the first serine in
the sequence motif SxxxS(P) (where S(p) represents a phosphoserine). FRATtide (a
peptide derived from a GSK-3 binding protein) binds to GSK-3 and blocks GSK-3
from interacting with Axin. This inhibits the Axin-dependent phosphorylation of
beta-catenin by GSK-3. RESULTS: Structures of uncomplexed Tyr216 phosphorylated
GSK-3beta and of its complex with a peptide and a sulfate ion both show the
activation loop adopting a conformation similar to that in the phosphorylated
and active forms of the related kinases CDK2 and ERK2. The sulfate ion, adjacent
to Val214 on the activation loop, represents the binding site for the
phosphoserine residue on 'primed' substrates. The peptide FRATtide forms a
helix-turn-helix motif in binding to the C-terminal lobe of the kinase domain;
the FRATtide binding site is close to, but does not obstruct, the substrate
binding channel of GSK-3. FRATtide (and FRAT1) does not inhibit the activity of
GSK-3 toward GS. CONCLUSIONS: The Axin binding site on GSK-3 presumably overlaps
with that for FRATtide; its proximity to the active site explains how Axin may
act as a scaffold protein promoting beta-catenin phosphorylation. Tyrosine 216
phosphorylation can induce an active conformation in the activation loop.
Pre-phosphorylated substrate peptides can be modeled into the active site of the
enzyme, with the P1 residue occupying a pocket partially formed by
phosphotyrosine 216 and the P4 phosphoserine occupying the 'primed' binding site.
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Figure 2.
Figure 2. The Activation Loop and Substrate Binding(a) The
structure of CDK2 (red) with a substrate peptide (purple) and a
nonhydrolizable analog of ATP (labeled ATP; only the terminal
phosphate group is visible; PDB code 1QMZ; [28]). Ser 5 is the
phosphorylatable serine in the substrate. Lysine 8 from the
substrate peptide interacts with phosphothreonine 160.(b)
Superposed structures of CDK2 (red), ERK2 (yellow; PDB code
2ERK; [27]) and GSK-3 (green; FS crystal form). The sulfate in
GSK-3 is labeled and superposes on phosphothreonine residues in
CDK2 and ERK2.(c) Coordinates of GSK-3 (green) are shown with a
substrate peptide (blue) modeled in the active site. The peptide
has been modeled on the peptide in the CDK2 crystal structure
(a) with the phosphothreonine residue at position 9 modeled with
its phosphate group occupying the position occupied by the
sulfate in the crystal structure of the FS crystal form of
GSK-3. The figure was drawn with GRASP [47].
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2001,
9,
1143-1152)
copyright 2001.
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