 |
PDBsum entry 2pvy
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.
|
|
|
Authors
|
|
H.Chen,
J.Ma,
W.Li,
A.V.Eliseenkova,
C.Xu,
T.A.Neubert,
W.T.Miller,
M.Mohammadi.
|
|
|
Ref.
|
|
Mol Cell, 2007,
27,
717-730.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases
(RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures
of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those
of seven unphosphorylated pathogenic mutants reveals an autoinhibitory
"molecular brake" mediated by a triad of residues in the kinase hinge
region of all FGFRs. Structural analysis shows that many other RTKs, including
PDGFRs, VEGFRs, KIT, CSF1R, FLT3, TEK, and TIE, are also subject to regulation
by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging
the brake either directly or indirectly.
|
|
|
|
|
|
|
|
Figure 3.
Figure 3. The Molecular Brake at the Kinase Hinge Region of
FGFR2K Regulates the Kinase Activation and Is Disengaged Either
by A Loop Tyrosine Phosphorylation or Directly by the Pathogenic
Mutations
(A) In the unphosphorylated wild-type structure,
residues N549, E565, and K641 form a network of hydrogen bonds
in the kinase hinge region, which serves as a molecular brake to
keep the enzyme in an inactive state.
(B) The molecular
brake is disengaged in the A loop tyrosine phosphorylated
wild-type FGFR2K structure. This molecular brake is also
disengaged in the unphosphorylated mutant FGFR2K structures
(C–G). To assist the readers, the whole unphosphorylated
wild-type FGFR2K structure is also shown in cartoon and solid
semitransparent surface, and the kinase hinge region is boxed.
Atom colorings are as follows: oxygens in red, nitrogens in
blue, and carbons are colored according to the kinase region to
which they belong. The kinase hinge, the αC-β4 loop (shown in
sticks in [A]–[G]), and β8 strand are colored green, wheat,
and cyan, respectively. The rest of the N lobe and C lobe is
colored light purple and light blue, respectively. The three
critical hydrogen bonds between N549 and the backbone atoms of
αC-β4 loop are highlighted by red dashed lines. The remaining
hydrogen bonds are shown as black dashed lines.
|
|
Figure 6.
Figure 6. The Autoinhibition by the Molecular Brake Is a
Common Regulatory Mechanism for Many RTKs
(A)–(E) show
the presence of the engaged molecular brake at the kinase hinge
region of unphosphorylated wild-type FGFR1 (PDB ID: 1FGK), CSF1R
(PDB ID: 2I1M), VEGFR2 (PDB ID: 1VR2), TEK (PDB ID: 1FVR), and
c-KIT (PDB ID: 1T45) kinases, respectively. (F) shows the
disengagement of the molecular brake at the kinase hinge region
of an “active” c-KIT kinase (PDB ID: 1PKG). Coloring scheme
is as in Figure 3.
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by Cell Press:
Mol Cell
(2007,
27,
717-730)
copyright 2007.
|
|
|
|
|
|
|
