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PDBsum entry 2src
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Tyrosine-protein kinase
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PDB id
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2src
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References listed in PDB file
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Key reference
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Title
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Crystal structures of c-Src reveal features of its autoinhibitory mechanism.
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Authors
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W.Xu,
A.Doshi,
M.Lei,
M.J.Eck,
S.C.Harrison.
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Ref.
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Mol Cell, 1999,
3,
629-638.
[DOI no: ]
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PubMed id
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Abstract
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Src family kinases are maintained in an assembled, inactive conformation by
intramolecular interactions of their SH2 and SH3 domains. Full catalytic
activity requires release of these restraints as well as phosphorylation of
Tyr-416 in the activation loop. In previous structures of inactive Src kinases,
Tyr-416 and flanking residues are disordered. We report here four additional
c-Src structures in which this segment adopts an ordered but inhibitory
conformation. The ordered activation loop forms an alpha helix that stabilizes
the inactive conformation of the kinase domain, blocks the peptide
substrate-binding site, and prevents Tyr-416 phosphorylation. Disassembly of the
regulatory domains, induced by SH2 or SH3 ligands, or by dephosphorylation of
Tyr-527, could lead to exposure and phosphorylation of Tyr-416.
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Figure 3.
Figure 3. Ribbon Diagram Showing the Overall Organization of
Src-2The SH3 (yellow) and SH2 (green) domains coordinate the
linker and phosphorylated tail segments, respectively. The
tyrosine kinase domain is colored blue; AMP–PNP (red) is bound
in the active site. The A loop helix packs between the N and C
lobes of the kinase and sequesters Tyr-416.
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Figure 7.
Figure 7. A Model for Src Activation(a) The restrained
conformation of c-Src is stabilized by intramolecular
interactions among the kinase domain, the SH2/SH3 domains, and
the phosphorylated C-terminal tail. In this state, an inhibitory
conformation of the activation loop helps disrupt the kinase
active site by stabilizing a displacement of the C helix. The
formation of the A loop helix, which interferes with substrate
binding and protects Tyr-416 from phosphorylation, relies on a
particular register of the two kinase lobes.(b) Displacement of
SH2 and/or SH3 domains, either by C-terminal tail
dephosphorylation or by competitive binding of optimal SH2/SH3
domain ligands, allows the kinase domain to open, disrupting the
A loop helix and exposing Tyr-416 to phosphorylation.(c)
Phosphorylation of Tyr-416 initiates a conformational
reorganization of the whole activation loop, relieving the
steric barrier for substrate binding, allowing the C-terminal
helix to move back into the active site, and reconstituting a
fully active tyrosine kinase.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(1999,
3,
629-638)
copyright 1999.
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