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PDBsum entry 1p5t
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Signaling protein
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PDB id
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1p5t
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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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Structural basis for the specific recognition of ret by the dok1 phosphotyrosine binding domain.
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Authors
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N.Shi,
S.Ye,
M.Bartlam,
M.Yang,
J.Wu,
Y.Liu,
F.Sun,
X.Han,
X.Peng,
B.Qiang,
J.Yuan,
Z.Rao.
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Ref.
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J Biol Chem, 2004,
279,
4962-4969.
[DOI no: ]
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PubMed id
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Abstract
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Dok1 is a common substrate of activated protein-tyrosine kinases. It is rapidly
tyrosine-phosphorylated in response to receptor tyrosine activation and
interacts with ras GTPase-activating protein and Nck, leading to inhibition of
ras signaling pathway activation and the c-Jun N-terminal kinase (JNK) and c-Jun
activation, respectively. In chronic myelogenous leukemia cells, it has shown
constitutive phosphorylation. The N-terminal phosphotyrosine binding (PTB)
domain of Dok1 can recognize and bind specifically to phosphotyrosine-containing
motifs of receptors. Here we report the crystal structure of the Dok1 PTB domain
alone and in complex with a phosphopeptide derived from RET receptor tyrosine
kinase. The structure consists of a beta-sandwich composed of two nearly
orthogonal, 7-stranded, antiparallel beta-sheets, and it is capped at one side
by a C-terminal alpha-helix. The RET phosphopeptide binds to Dok1 via a surface
groove formed between strand beta5 and the C-terminal alpha-helix of the PTB
domain. The structures reveal the molecular basis for the specific recognition
of RET by the Dok1 PTB domain. We also show that Dok1 does not recognize peptide
sequences from TrkA and IL-4, which are recognized by Shc and IRS1, respectively.
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Figure 2.
FIG. 2. Overall structure of dok1 PTB domain. a, ribbon
stereo diagram showing the fold of the Dok1 PTB domain (green)
and the orientation of the bound RET phosphopeptide (white). The
ribbon diagram was generated with the program BOBSCRIPT (11). b,
structure-based sequence alignments of the nine Doks and hIRS1
PTB domains. Sequences of mouse Dok1-(147-264), human
dok1-(147-264), mouse Dok2-(144-259), human Dok2-(141-257),
mouse Dok3-(156-266), mouse Dok4-(133-242), human
Dok4-(133-242), mouse Dok5-(134-242), human Dok5-(129-232), and
human IRS1-(160-262) were aligned. Numbers refer to mouse Dok1.
The conserving residues were boxed in red and blue. Critical
arginines for phosphotyrosine recognition are indicated by green
dots. Alignment was generated using CLUSTAL X (1.8).
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Figure 5.
FIG. 5. Stereo view of the interactions between residues at
pY-1 of the phosphopeptide, shown in brown, and Dok1 (a) or IRS1
(b) PTB domain. Residues involved in important interactions are
shown in ball-and-stick representation. The residues interacting
with pY-1 are represented as green; the sulfur atom is
represented in yellow.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
4962-4969)
copyright 2004.
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