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PDBsum entry 1y57
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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 crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation.
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Authors
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S.W.Cowan-Jacob,
G.Fendrich,
P.W.Manley,
W.Jahnke,
D.Fabbro,
J.Liebetanz,
T.Meyer.
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Ref.
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Structure, 2005,
13,
861-871.
[DOI no: ]
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PubMed id
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Abstract
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The regulation of the activity of Abl and Src family tyrosine kinases is
mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1)
domains. We have determined the crystal structure of an unphosphorylated form of
c-Src in which the SH2 domain is not bound to the C-terminal tail. This results
in an open structure where the kinase domain adopts an active conformation and
the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR
binding studies support the hypothesis that an N-terminal myristate could bind
in this pocket, as observed for Abl, suggesting that c-Src may also be regulated
by myristate binding. In addition, the structure contains a des-methyl analog of
the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the
drug shows a low affinity for active kinase conformations, contributing to its
excellent kinase selectivity profile.
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Figure 2.
Figure 2. Conformational States of c-Src
Comparison of
the structures of human c-Src phosphorylated on Tyr527 (left)
and in the unphosphorylated state (right). Both structures have
the same orientation with respect to their C-terminal lobes,
which were superimposed. The ribbon diagrams are colored from
dark blue at the N terminus to red at the C terminus; thus, the
SH3 domain is blue, the SH2 domain is light blue and green, the
linker is aqua, the N-terminal lobe is green, the C-terminal
lobe is light green and orange, the activation loop is yellow,
and the C-terminal tail is red. The ligands (magenta), sulfate
groups (yellow and red), and certain side chains (yellow)
discussed in the text are also represented.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2005,
13,
861-871)
copyright 2005.
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