 |
PDBsum entry 3el7
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.2.7.10.2
- non-specific 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
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
|
Chem Biol
15:1015-1022
(2008)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Small molecule recognition of c-Src via the Imatinib-binding conformation.
|
|
A.C.Dar,
M.S.Lopez,
K.M.Shokat.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not
inhibit the closely related kinase c-Src. This one drug and its ability to
selectively inhibit Abl over c-Src has been a guiding principle in virtually all
kinase drug discovery efforts in the last 15 years. A prominent hypothesis
explaining the selectivity of Imatinib is that Abl has an intrinsic ability to
adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a
high intrinsic energetic penalty for adopting this conformation, effectively
excluding Imatinib from its ATP pocket. This explanation of the difference in
binding affinity of Imatinib for Abl versus c-Src makes the striking prediction
that it would not be possible to design an inhibitor that binds to the DFG-out
conformation of c-Src with high affinity. We report the discovery of a series of
such inhibitors. We use structure-activity relationships and X-ray
crystallography to confirm our findings. These studies suggest that small
molecules are capable of inducing the generally unfavorable DFG-out conformation
in c-Src. Structural comparison between c-Src in complex with these inhibitors
allows us to speculate on the differential selectivity of Imatinib for c-Src and
Abl.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
A.C.Dar,
T.K.Das,
K.M.Shokat,
and
R.L.Cagan
(2012).
Chemical genetic discovery of targets and anti-targets for cancer polypharmacology.
|
| |
Nature,
486,
80-84.
|
|
|
|
|
|
|
C.A.Dodson,
M.Kosmopoulou,
M.W.Richards,
B.Atrash,
V.Bavetsias,
J.Blagg,
and
R.Bayliss
(2010).
Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design.
|
| |
Biochem J,
427,
19-28.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
P.Ranjitkar,
A.M.Brock,
and
D.J.Maly
(2010).
Affinity reagents that target a specific inactive form of protein kinases.
|
| |
Chem Biol,
17,
195-206.
|
|
|
|
|
|
|
T.Zhou,
L.Commodore,
W.S.Huang,
Y.Wang,
T.K.Sawyer,
W.C.Shakespeare,
T.Clackson,
X.Zhu,
and
D.C.Dalgarno
(2010).
Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
|
| |
Chem Biol Drug Des,
75,
18-28.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
J.R.Simard,
S.Klüter,
C.Grütter,
M.Getlik,
M.Rabiller,
H.B.Rode,
and
D.Rauh
(2009).
A new screening assay for allosteric inhibitors of cSrc.
|
| |
Nat Chem Biol,
5,
394-396.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
M.Klein,
P.Dinér,
D.Dorin-Semblat,
C.Doerig,
and
M.Grøtli
(2009).
Synthesis of 3-(1,2,3-triazol-1-yl)- and 3-(1,2,3-triazol-4-yl)-substituted pyrazolo[3,4-d]pyrimidin-4-amines via click chemistry: potential inhibitors of the Plasmodium falciparum PfPK7 protein kinase.
|
| |
Org Biomol Chem,
7,
3421-3429.
|
|
|
|
|
|
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
codes are
shown on the right.
|
|
Links
