 |
PDBsum entry 1t45
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase activator
|
PDB id
|
|
|
|
1t45
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural basis for the autoinhibition and sti-571 inhibition of c-Kit tyrosine kinase.
|
|
|
Authors
|
|
C.D.Mol,
D.R.Dougan,
T.R.Schneider,
R.J.Skene,
M.L.Kraus,
D.N.Scheibe,
G.P.Snell,
H.Zou,
B.C.Sang,
K.P.Wilson.
|
|
|
Ref.
|
|
J Biol Chem, 2004,
279,
31655-31663.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated
in normal cells, whereas deregulated c-Kit kinase activity is implicated in the
pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have
an autoinhibitory function; however the precise mechanism by which c-Kit is
maintained in an autoinhibited state is not known. We report the 1.9-A
resolution crystal structure of native c-Kit kinase in an autoinhibited
conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is
stabilized by the juxtamembrane domain, which inserts into the kinase-active
site and disrupts formation of the activated structure. A 1.6-A crystal
structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates
that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in
an autoinhibited state. Together, these results provide a structural basis for
understanding c-Kit kinase autoinhibition and will facilitate the
structure-guided design of specific inhibitors that target the activated and
autoinhibited conformations of c-Kit kinase.
|
|
|
|
|
|
|
|
Figure 4.
FIG. 4. The structure and environment surrounding the
frequently mutated residue Asp816 in the autoinhibited and
activated c-Kit kinase structures. A, view of the structural
environment surrounding Asp816 in the autoinhibited kinase
structure. Asp816 is situated between the P-loop and a short
region of 3[10] helix where the negatively charged Asp side
chain can stabilize the positively charged helical dipole. B,
view of the structural environment surrounding Asp816 in the
activated kinase structure. Arg815 and Ile^817 form  -sheet
hydrogen bonding interactions with Ile^79 and Asn787 of the
C-lobe to stabilize the activation loop in an extended
conformation.
|
|
Figure 7.
FIG. 7. STI-571 binding and interactions with c-Kit kinase.
A, chemical structure of STI-571 and F[obs] - F[calc] omit
difference electron density calculated prior to building the
inhibitor into the co-crystal structure, contoured at 3  (blue)
and 6 (red). Key hydrogen
bonds are depicted. B, stereo view of STI-571 (purple) binding
to c-Kit showing key hydrogen bonds formed with the hinge
residue Cys673, gatekeeper residue Thr670, and conserved residue
Glu640. The polypeptide surrounding Trp557 from the virgin
autoinhibited c-Kit structure is shown superimposed on the
STI-571 complex structure.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
31655-31663)
copyright 2004.
|
|
|
|
|
|
|
