 |
PDBsum entry 3cd3
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Structural coupling of sh2-Kinase domains links fes and abl substrate recognition and kinase activation.
|
|
|
Authors
|
|
P.Filippakopoulos,
M.Kofler,
O.Hantschel,
G.D.Gish,
F.Grebien,
E.Salah,
P.Neudecker,
L.E.Kay,
B.E.Turk,
G.Superti-Furga,
T.Pawson,
S.Knapp.
|
|
|
Ref.
|
|
Cell, 2008,
134,
793-803.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
The SH2 domain of cytoplasmic tyrosine kinases can enhance catalytic activity
and substrate recognition, but the molecular mechanisms by which this is
achieved are poorly understood. We have solved the structure of the prototypic
SH2-kinase unit of the human Fes tyrosine kinase, which appears specialized for
positive signaling. In its active conformation, the SH2 domain tightly interacts
with the kinase N-terminal lobe and positions the kinase alphaC helix in an
active configuration through essential packing and electrostatic interactions.
This interaction is stabilized by ligand binding to the SH2 domain. Our data
indicate that Fes kinase activation is closely coupled to substrate recognition
through cooperative SH2-kinase-substrate interactions. Similarly, we find that
the SH2 domain of the active Abl kinase stimulates catalytic activity and
substrate phosphorylation through a distinct SH2-kinase interface. Thus, the SH2
and catalytic domains of active Fes and Abl pro-oncogenic kinases form
integrated structures essential for effective tyrosine kinase signaling.
|
|
|
|
|
|
|
|
Figure 4.
Substrate Interaction with the Fes Kinase Domain (A) Details
of the substrate peptide (IYESL) interaction with the kinase
domain. (B) Structure of the Fes-substrate complex showing a
detail of the location of the peptide (shown in sticks). The
surface has been colored by electrostatic potential between
[minus sign]10 and +10 kcal/mol. (C) 2F[o] -- F[c] electron
density map contoured at 2[sigma] around the substrate peptide
residues. Cell. 2008 September 5; 134(5): 793–803. doi:
10.1016/j.cell.2008.07.047. Copyright [copyright] 2008 ELL &
Excerpta Medica
|
|
Figure 7.
Cartoon Representation of Fes Activation In its unligated and
unphosphorylated state, the Fes SH2 domain (blue), [alpha]C
(red), and activation segment (purple) are significantly
disordered (left). Binding of a primed peptide (yellow)
stabilizes the SH2 domain, leading to a productive orientation
of the SH2 domain, with respect to the kinase domain, and stable
positioning of [alpha]C (middle). Phosphorylation of the
activation segment at Y713 and binding of the substrate molecule
to the kinase domain stabilizes the activation segment in a
conformation suitable for catalysis (right). Cell. 2008
September 5; 134(5): 793–803. doi: 10.1016/j.cell.2008.07.047.
Copyright [copyright] 2008 ELL & Excerpta Medica
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Cell Press:
Cell
(2008,
134,
793-803)
copyright 2008.
|
|
|
|
|
|
|
