 |
PDBsum entry 3d94
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.1
- receptor protein-tyrosine kinase.
|
|
|
|
|
|
|
Reaction:
|
|
L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
|
|
|
|
|
|
L-tyrosyl-[protein]
|
+
|
ATP
|
=
|
O-phospho-L-tyrosyl-[protein]
|
+
|
ADP
|
+
|
H(+)
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
Embo J
27:1985-1994
(2008)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.
|
|
J.Wu,
W.Li,
B.P.Craddock,
K.W.Foreman,
M.J.Mulvihill,
Q.S.Ji,
W.T.Miller,
S.R.Hubbard.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase
(RTK) that has a critical role in mitogenic signalling during embryogenesis and
an antiapoptotic role in the survival and progression of many human tumours.
Here, we present the crystal structure of the tyrosine kinase domain of IGF1R
(IGF1RK), in its unphosphorylated state, in complex with a novel compound,
cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine
(PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal)
and phosphorylated (activated) states of the kinase. PQIP interacts with
residues in the ATP-binding pocket and in the activation loop, which confers
specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In
this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the
activation loop of an symmetry (two-fold)-related molecule. This dimeric
arrangement affords, for the first time, a visualization of the initial
trans-phosphorylation event in the activation loop of an RTK, and provides a
molecular rationale for a naturally occurring mutation in the activation loop of
the IR that causes type II diabetes mellitus.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
E.Bergamin,
P.T.Hallock,
S.J.Burden,
and
S.R.Hubbard
(2010).
The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.
|
| |
Mol Cell,
39,
100-109.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
X.Y.Chu,
J.Tian,
N.F.Wu,
and
Y.L.Fan
(2010).
An intramolecular disulfide bond is required for the thermostability of methyl parathion hydrolase, OPHC2.
|
| |
Appl Microbiol Biotechnol,
88,
125-131.
|
|
|
|
|
|
|
M.Yin,
X.Guan,
Z.Liao,
and
Q.Wei
(2009).
Insulin-like growth factor-1 receptor-targeted therapy for non-small cell lung cancer: a mini review.
|
| |
Am J Transl Res,
1,
101-114.
|
|
|
|
|
|
|
R.Li,
A.Pourpak,
and
S.W.Morris
(2009).
Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach.
|
| |
J Med Chem,
52,
4981-5004.
|
|
|
|
|
|
|
D.Komander,
R.Garg,
P.T.Wan,
A.J.Ridley,
and
D.Barford
(2008).
Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure.
|
| |
EMBO J,
27,
3175-3185.
|
|
|
PDB code:
|
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
|
|
Links
