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PDBsum entry 2abl
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References listed in PDB file
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Key reference
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Title
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Intramolecular interactions of the regulatory domains of the bcr-Abl kinase reveal a novel control mechanism.
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Authors
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H.J.Nam,
W.G.Haser,
T.M.Roberts,
C.A.Frederick.
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Ref.
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Structure, 1996,
4,
1105-1114.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND. The Abl nonreceptor tyrosine kinase is implicated in a range of
cellular processes and its transforming variants are involved in human
leukemias. The N-terminal regulatory region of the Abl protein contains Src
homology domains SH2 and SH3 which have been shown to be important for the
regulation of its activity in vivo. These domains are often found together in
the same protein and biochemical data suggest that the functions of one domain
can be influenced by the other. RESULTS. We have determined the crystal
structure of the Abl regulatory region containing the SH3 and SH2 domains. In
general, the individual domains are very similar to those of previously solved
structures, although the Abl SH2 domain contains a loop which is extended so
that one side of the resulting phosphotyrosine-binding pocket is open. In our
structure the protein exists as a monomer with no intermolecular contacts to
which a biological function may be attributed. However, there is a significant
intramolecular contact between a loop of the SH3 domain and the extended loop of
the SH2 domain. This contact surface includes the SH2 loop segment that is
responsible for binding the phosphate moiety of phosphotyrosine-containing
proteins and is therefore critical for orienting peptide interactions.
CONCLUSIONS. The crystal structure of the composite Abl SH3-SH2 domain provides
the first indication of how SH2 and SH3 domains communicate with each other
within the same molecule and why the presence of one directly influences the
activity of the other. This is the first clear evidence that these two domains
are in contact with each other. The results suggest that this direct interaction
between the two domains may affect the ligand binding properties of the SH2
domain, thus providing an explanation for biochemical and functional data
concerning the Bcr-Abl kinase.
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Figure 2.
Figure 2. Schematic diagram and surface structure of the Abl
SH3–SH2 regulatory region. (a) Richardson diagram of the Abl
SH3–SH2 protein showing the relative positions of the SH3 and
SH2 domains in one molecule. The SH2 domain is at the top of the
figure and the SH3 domain at the bottom. In the SH2 domain the
β strands are shown in red and the α helices in green; in the
SH3 domain the β strands are in yellow. The secondary structure
elements are numbered according to the convention of Eck, et
al. [31] with individual residues identified by their position
within each element or connecting loop; this numbering is used
throughout. (The figure was made with the program MOLSCRIPT
[51].) (b) The molecular surface of the Abl SH3–SH2 structure.
The surface is colored according to the local electrostatic
potential, ranging from blue (the most positive region) to red
(the most negative). The putative phosphotyrosine-binding pocket
and a hydrophobic (pTyr + 3 pocket are indicated. Important
residues for the ligand binding of the SH3 domain are also
indicated. Figure 2. Schematic diagram and surface structure
of the Abl SH3–SH2 regulatory region. (a) Richardson diagram
of the Abl SH3–SH2 protein showing the relative positions of
the SH3 and SH2 domains in one molecule. The SH2 domain is at
the top of the figure and the SH3 domain at the bottom. In the
SH2 domain the β strands are shown in red and the α helices in
green; in the SH3 domain the β strands are in yellow. The
secondary structure elements are numbered according to the
convention of Eck, et al. [[3]31] with individual residues
identified by their position within each element or connecting
loop; this numbering is used throughout. (The figure was made
with the program MOLSCRIPT [[4]51].) (b) The molecular surface
of the Abl SH3–SH2 structure. The surface is colored according
to the local electrostatic potential, ranging from blue (the
most positive region) to red (the most negative). The putative
phosphotyrosine-binding pocket and a hydrophobic (pTyr + 3
pocket are indicated. Important residues for the ligand binding
of the SH3 domain are also indicated. (The figure was made using
the program GRASP [[5]52].)
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Figure 6.
Figure 6. Ramachandram plot of the refined structure. Glycine
and non-glycine ψ, φ pairs are designated by triangles and
squares, respectively. Disallowed, generously allowed, favorable
and most favorable regions are indicated by progressively
darker shading. Of all the residues, 89% are in the most
favorable regions and none of the residues are in disallowed
regions. Figure 6. Ramachandram plot of the refined
structure. Glycine and non-glycine ψ, φ pairs are designated
by triangles and squares, respectively. Disallowed, generously
allowed, favorable and most favorable regions are indicated by
progressively darker shading. Of all the residues, 89% are in
the most favorable regions and none of the residues are in
disallowed regions.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(1996,
4,
1105-1114)
copyright 1996.
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