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PDBsum entry 3d7t
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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 recognition of c-Src by its inactivator csk.
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Authors
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N.M.Levinson,
M.A.Seeliger,
P.A.Cole,
J.Kuriyan.
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Ref.
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Cell, 2008,
134,
124-134.
[DOI no: ]
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PubMed id
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Abstract
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The catalytic activity of the Src family of tyrosine kinases is suppressed by
phosphorylation on a tyrosine residue located near the C terminus (Tyr 527 in
c-Src), which is catalyzed by C-terminal Src Kinase (Csk). Given the promiscuity
of most tyrosine kinases, it is remarkable that the C-terminal tails of the Src
family kinases are the only known targets of Csk. We have determined the crystal
structure of a complex between the kinase domains of Csk and c-Src at 2.9 A
resolution, revealing that interactions between these kinases position the
C-terminal tail of c-Src at the edge of the active site of Csk. Csk cannot
phosphorylate substrates that lack this docking mechanism because the
conventional substrate binding site used by most tyrosine kinases to recognize
substrates is destabilized in Csk by a deletion in the activation loop.
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Figure 5.
Figure 5. Activation Loop Anchoring in Tyrosine Kinases
(A) The structure of the insulin receptor kinase domain (IRK)
bound to a substrate peptide is shown. The panel on the right
shows an enlarged view depicting the two anchor points and the
loops to which they form hydrogen bonds (shown as dashed lines).
(B) The activation loops from 12 structures of active
tyrosine kinases (see Experimental Procedures). The structures
were aligned on the catalytic loops, but only the activation
loops are shown.
(C) Hydrophobic interactions couple anchor
point 2 to the peptide-binding site. The structure of IRK is
shown. Residues of the substrate peptide that interact with the
hydrophobic residues are indicated.
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Figure 7.
Figure 7. The Inactive Assembled State of c-Src Is
Incompatible with the Csk:c-Src Complex
(A) The crystal
structure of inactive assembled c-Src (PDB code 2SRC) is aligned
on the C-terminal lobe of c-Src from our Csk[KD]:c-Src[KD]
structure. Clashes between the tail of inactive c-Src and the C
lobe of Csk are highlighted in black.
(B) Csk cannot bind
tail-phosphorylated c-Src as measured by surface plasmon
resonance. A construct of c-Src that contains the SH2, SH3, and
kinase domains (Src[3D]) was phosphorylated by Csk on Tyr 527
(Src[3D] pY527) prior to immobilization on the sensor surface.
The binding of Csk[FL] (10 μM) to the surface was then
measured. The graphs show the mean and standard deviation of two
experiments.
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The above figures are
reprinted
from an Open Access publication published by Cell Press:
Cell
(2008,
134,
124-134)
copyright 2008.
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