 |
PDBsum entry 1opj
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for the autoinhibition of c-Abl tyrosine kinase.
|
|
|
Authors
|
|
B.Nagar,
O.Hantschel,
M.A.Young,
K.Scheffzek,
D.Veach,
W.Bornmann,
B.Clarkson,
G.Superti-Furga,
J.Kuriyan.
|
|
|
Ref.
|
|
Cell, 2003,
112,
859-871.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of
which leads to chronic myelogenous leukemia. The details of this mechanism have
been elusive because c-Abl lacks a phosphotyrosine residue that triggers the
assembly of the autoinhibited form of the closely related Src kinases by
internally engaging the SH2 domain. Crystal structures of c-Abl show that the
N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and
induces conformational changes that allow the SH2 and SH3 domains to dock onto
it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of
inactive Src kinases but with specific differences that explain the differential
ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic
activity of Abl, but not that of c-Src.
|
|
|
|
|
|
|
|
Figure 2.
Figure 2. Structure of Assembled c-Abl(A) Ribbon and
surface representations of c-Abl (Structure C).(B) Superposition
of the structure of c-Src (red; PDB code 2SRC) onto the SH3 and
SH2 domains (residues 83–233) of Abl^46–534 (Structure C;
green).
|
|
Figure 4.
Figure 4. SH2 Gating MechanismRibbon and surface
representation of Abl^46–534 (Structure C) depicting the clash
that occurs between helix αI in the myristoyl unbound form and
the SH2 domain. Helix αI from the structure of the isolated
kinase domain in the absence of myristoyl (PDB code 1M52) is
colored red and the new helices (αI and αI′) formed upon
binding of myristate are colored blue. Shown in shaded gray
ellipses are regions that contain isolated patches of unmodeled
electron density, potentially due to residues from the
N-terminal cap region.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Cell Press:
Cell
(2003,
112,
859-871)
copyright 2003.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
A myristoyl/phosphotyrosine switch regulates c-Abl.
|
|
|
Authors
|
|
O.Hantschel,
B.Nagar,
S.Guettler,
J.Kretzschmar,
K.Dorey,
J.Kuriyan,
G.Superti-Furga.
|
|
|
Ref.
|
|
Cell, 2003,
112,
845-857.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. Subcellular Localization of Abl(A) VERO cells
were transiently transfected with the indicated Abl expression
constructs, fixed 40 hr later, and immunostained with an
anti-Abl antibody (first panel). DNA was stained with DAPI
(second panel), and colocalization of Abl with actin was
revealed using phalloidin-rhodamine (third panel, actin; fourth
panel, merge Abl and actin). Images show 1 μm confocal sections
in the midnuclear planes.(B) HEK 293 cells transiently
transfected with the indicated Abl constructs were
fractionated by differential velocity centrifugation. Equal
protein amounts were analyzed by immunoblotting using an
anti-Abl antibody (top) and antibodies against marker proteins
for the different subcellular compartments (bottom; nuclear
marker, RCC1; cytosolic marker, β-actin; membrane marker,
presenilin-1). P100 indicates the crude membrane fraction.
|
|
Figure 7.
Figure 7. Schematic Representation of c-Abl Activation
Modes(A) Schematic representation of regulated c-Abl 1b
(center). The domains and linkers are colored as in all other
figures. Surrounding the central figure, four potential
activation mechanisms for c-Abl 1b and their concomitant
potential domain rearrangements are shown: SH3 domain-dependent
activation (upper left), SH2 domain-dependent activation (lower
left), activation by phosphorylation on Tyr-412 (activation
loop) or Tyr-245 (SH2-kinase linker) (upper right), and
activation by myristoyl displacement (lower right).(B) Schematic
representation of fully active c-Abl 1b.
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
with permission from Cell Press
|
|
|
|
|
|
|
