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PDBsum entry 2fo0
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References listed in PDB file
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Key reference
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Title
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Organization of the sh3-Sh2 unit in active and inactive forms of the c-Abl tyrosine kinase.
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Authors
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B.Nagar,
O.Hantschel,
M.Seeliger,
J.M.Davies,
W.I.Weis,
G.Superti-Furga,
J.Kuriyan.
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Ref.
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Mol Cell, 2006,
21,
787-798.
[DOI no: ]
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PubMed id
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Abstract
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The tyrosine kinase c-Abl is inactivated by interactions made by its SH3 and SH2
domains with the distal surface of the kinase domain. We present a crystal
structure of a fragment of c-Abl which reveals that a critical N-terminal cap
segment, not visualized in previous structures, buttresses the SH3-SH2
substructure in the autoinhibited state and locks it onto the distal surface of
the kinase domain. Surprisingly, the N-terminal cap is phosphorylated on a
serine residue that interacts with the connector between the SH3 and SH2
domains. Small-angle X-ray scattering (SAXS) analysis shows that a mutated form
of c-Abl, in which the N-terminal cap and two other key contacts in the
autoinhibited state are deleted, exists in an extended array of the SH3, SH2,
and kinase domains. This alternative conformation of Abl is likely to prolong
the active state of the kinase by preventing it from returning to the
autoinhibited state.
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Figure 1.
Figure 1. Schematic Diagram of the c-Abl Constructs Used and
the Structure of the Cap Region
(A) Abl^N-cap was used for
both the crystal structure and SAXS analyses. Residues from the
N-terminal cap in Abl^N-cap that were deleted are indicated with
gray shading, and residues that were included are highlighted in
pink.
(B) Surface representation of Abl^N-cap with the cap
region shown as a backbone model in pink. Residues that connect
the cap to the myristoyl but could not be modeled are shown as
pink spheres. Helix αI of the kinase domain is colored purple.
A black box indicates the region magnified in (C).
(C)
Hydrophobic surface rendition of Abl^N-cap showing cap
interactions with the SH2 domain and SH3-SH2 connector.
Increasing hydrophobicity of the surface is indicated with
darker shades of green. The cap is shown as sticks, where
carbon, nitrogen, and oxygen atoms are colored orange, blue, and
red, respectively. Labeled are residues that are well ordered
and make direct interactions with the protein. The water
molecule hydrogen bonded to Lys70 is shown as a blue sphere.
Molecular figures were generated with PyMOL (DeLano, 2002).
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Figure 4.
Figure 4. Shape Reconstructions
(A) Kinase domain. The
backbone of the crystal structure of the c-Abl kinase domain
(blue; PDB code 1OPJ) is superimposed onto the shape
reconstruction (shown as green mesh).
(B) Abl^N-cap.
Superimposed is the crystal structure of Abl^N-cap shown as a
green backbone onto the shape reconstruction (gray mesh).
(C) Abl^activated. The kinase domain and SH2 and SH3 domains are
colored red, green, and blue, respectively. Indicated on the
right view is the part of the model that may correspond to the
crystal structure of disassembled c-Abl from the original
crystallographic analysis of c-Abl 1b. The SH3 domain was placed
by visual inspection, ensuring that its C terminus was in close
proximity to the N terminus of the SH2 domain.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2006,
21,
787-798)
copyright 2006.
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