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* Residue conservation analysis
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Enzyme class:
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Chains A, B:
E.C.2.7.10.2
- non-specific protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Acta Crystallogr D Biol Crystallogr
63:80-93
(2007)
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PubMed id:
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Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
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S.W.Cowan-Jacob,
G.Fendrich,
A.Floersheimer,
P.Furet,
J.Liebetanz,
G.Rummel,
P.Rheinberger,
M.Centeleghe,
D.Fabbro,
P.W.Manley.
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ABSTRACT
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Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which
has a constitutively activated Abl tyrosine kinase domain. Although most chronic
phase CML patients treated with imatinib as first-line therapy maintain
excellent durable responses, patients who have progressed to advanced-stage CML
frequently fail to respond or lose their response to therapy owing to the
emergence of drug-resistant mutants of the protein. More than 40 such point
mutations have been observed in imatinib-resistant patients. The crystal
structures of wild-type and mutant Abl kinase in complex with imatinib and other
small-molecule Abl inhibitors were determined, with the aim of understanding the
molecular basis of resistance and to aid in the design and optimization of
inhibitors active against the resistance mutants. These results are presented in
a way which illustrates the approaches used to generate multiple structures, the
type of information that can be gained and the way that this information is used
to support drug discovery.
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Selected figure(s)
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Figure 4.
Figure 4 (a) Superposition of the four main DFG conformations
observed in Abl kinase structures, with the active conformation
in cyan, the DFG-out conformation in yellow, the DFG-flip
conformation in grey and the Src-like inactive conformation in
green. (b) Superposition of all structures reported here plus
PDB entry 2g1t . The P-loop is shown in red, the C-helix is
cyan, the A-loop is blue and all the ligands are shown in green.
The superposition is based on an alignment of the C-terminal
lobes to emphasize the relative differences in angles between
the N- and C-terminal lobes of the kinase. (c) A stereoview of
all the ligands superimposed (imatinib, magenta C atoms;
NVP-AFN941, cyan C atoms; NVP-AFG210, yellow C atoms;
NVP-AEG082, green C atoms; PD180970, grey C atoms).
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Figure 6.
Figure 6 Comparison of the surfaces for all five structures
reported here. The inhibitor is shown with solid sticks (C,
yellow; N, blue; O, red; Cl, green; F, cyan) and the
solvent-accessible surface is coloured according to the atom
type that forms it (C, white; N, blue; O, red; S, orange). The
surface is transparent to show the buried parts of the binding
site, which are darker for the same reason. The C^  trace
of the protein is shown with white lines. (a) Imatinib, (b)
NVP-AFN941, (c) PD180970, (d) NVP-AEG082, (e) NVP-AFG210.
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The above figures are
reprinted
from an Open Access publication published by the IUCr:
Acta Crystallogr D Biol Crystallogr
(2007,
63,
80-93)
copyright 2007.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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S.Schenone,
O.Bruno,
M.Radi,
and
M.Botta
(2011).
New insights into small-molecule inhibitors of Bcr-Abl.
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Med Res Rev,
31,
1.
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C.Tanaka,
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V.Sethuraman,
T.Smith,
X.Wang,
K.Grouss,
H.Kantarjian,
F.Giles,
O.G.Ottmann,
L.Galitz,
and
H.Schran
(2010).
Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib.
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Clin Pharmacol Ther,
87,
197-203.
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D.D.Robinson,
W.Sherman,
and
R.Farid
(2010).
Understanding kinase selectivity through energetic analysis of binding site waters.
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ChemMedChem,
5,
618-627.
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O.A.Gani,
and
R.A.Engh
(2010).
Protein kinase inhibition of clinically important staurosporine analogues.
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Nat Prod Rep,
27,
489-498.
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P.Roversi,
S.Johnson,
and
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(2010).
With phases: how two wrongs can sometimes make a right.
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Acta Crystallogr D Biol Crystallogr,
66,
420-425.
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R.Krishnamurty,
and
D.J.Maly
(2010).
Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors.
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ACS Chem Biol,
5,
121-138.
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S.Lü,
Q.Luo,
X.Li,
J.Wu,
J.Liu,
S.Xiong,
Y.Q.Feng,
and
F.Wang
(2010).
Inhibitor screening of protein kinases using MALDI-TOF MS combined with separation and enrichment of phosphopeptides by TiO2 nanoparticle deposited capillary column.
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Analyst,
135,
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P.Browne,
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E.Dimmer,
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A.Fedotov,
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J.Jacobsen,
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D.Legge,
Q.Lin,
W.Liu,
J.Luo,
S.Orchard,
S.Patient,
D.Poggioli,
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P.van Rensburg,
A.Bairoch,
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I.Xenarios,
S.Altairac,
A.Auchincloss,
G.Argoud-Puy,
K.Axelsen,
D.Baratin,
M.C.Blatter,
B.Boeckmann,
J.Bolleman,
L.Bollondi,
E.Boutet,
S.B.Quintaje,
L.Breuza,
A.Bridge,
E.de Castro,
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D.Coral,
E.Coudert,
I.Cusin,
F.David,
G.Delbard,
M.Doche,
D.Dornevil,
P.D.Roggli,
S.Duvaud,
A.Estreicher,
L.Famiglietti,
M.Feuermann,
S.Gehant,
N.Farriol-Mathis,
S.Ferro,
E.Gasteiger,
A.Gateau,
V.Gerritsen,
A.Gos,
N.Gruaz-Gumowski,
U.Hinz,
C.Hulo,
N.Hulo,
J.James,
S.Jimenez,
F.Jungo,
T.Kappler,
G.Keller,
C.Lachaize,
L.Lane-Guermonprez,
P.Langendijk-Genevaux,
V.Lara,
P.Lemercier,
D.Lieberherr,
T.d.e. .O.Lima,
V.Mangold,
X.Martin,
P.Masson,
M.Moinat,
A.Morgat,
A.Mottaz,
S.Paesano,
I.Pedruzzi,
S.Pilbout,
V.Pillet,
and
S.Poux
(2010).
From protein sequences to 3D-structures and beyond: the example of the UniProt knowledgebase.
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Cell Mol Life Sci,
67,
1049-1064.
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W.Pao,
and
J.Chmielecki
(2010).
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer.
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Nat Rev Cancer,
10,
760-774.
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J.A.Winger,
O.Hantschel,
G.Superti-Furga,
and
J.Kuriyan
(2009).
The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2).
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BMC Struct Biol,
9,
7.
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PDB code:
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L.J.Yang,
J.Zou,
H.Z.Xie,
L.L.Li,
Y.Q.Wei,
and
S.Y.Yang
(2009).
Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl.
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PLoS One,
4,
e8470.
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R.Barouch-Bentov,
J.Che,
C.C.Lee,
Y.Yang,
A.Herman,
Y.Jia,
A.Velentza,
J.Watson,
L.Sternberg,
S.Kim,
N.Ziaee,
A.Miller,
C.Jackson,
M.Fujimoto,
M.Young,
S.Batalov,
Y.Liu,
M.Warmuth,
T.Wiltshire,
M.P.Cooke,
and
K.Sauer
(2009).
A conserved salt bridge in the G loop of multiple protein kinases is important for catalysis and for in vivo Lyn function.
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Mol Cell,
33,
43-52.
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Y.Asses,
V.Leroux,
S.Tairi-Kellou,
R.Dono,
F.Maina,
and
B.Maigret
(2009).
Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands.
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Chem Biol Drug Des,
74,
560-570.
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C.Kunick,
and
A.M.Egert-Schmidt
(2008).
[The short history of protein kinase inhibitors. New, competitive, successful]
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Pharm Unserer Zeit,
37,
360-368.
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E.Weisberg,
J.Roesel,
G.Bold,
P.Furet,
J.Jiang,
J.Cools,
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E.Nelson,
R.Barrett,
A.Ray,
D.Moreno,
E.Hall-Meyers,
R.Stone,
I.Galinsky,
E.Fox,
G.Gilliland,
J.F.Daley,
S.Lazo-Kallanian,
A.L.Kung,
and
J.D.Griffin
(2008).
Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells.
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Blood,
112,
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L.M.O'Connor,
S.Langabeer,
S.R.McCann,
and
E.Conneally
(2008).
Restoration of donor chimerism by nilotinib in a chronic myeloid leukaemia patient post mutation-associated imatinib mesylate resistance and allogeneic stem cell transplant failure.
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Bone Marrow Transplant,
42,
833-835.
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M.Totrov,
and
R.Abagyan
(2008).
Flexible ligand docking to multiple receptor conformations: a practical alternative.
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Curr Opin Struct Biol,
18,
178-184.
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N.Vajpai,
A.Strauss,
G.Fendrich,
S.W.Cowan-Jacob,
P.W.Manley,
S.Grzesiek,
and
W.Jahnke
(2008).
Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib.
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J Biol Chem,
283,
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S.Baumli,
G.Lolli,
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A.N.Bullock,
J.E.Debreczeni,
S.Knapp,
and
L.N.Johnson
(2008).
The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation.
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EMBO J,
27,
1907-1918.
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PDB codes:
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T.S.Lee,
S.J.Potts,
H.Kantarjian,
J.Cortes,
F.Giles,
and
M.Albitar
(2008).
Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulations.
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Cancer,
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1744-1753.
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Y.Tanrikulu,
and
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(2008).
Pseudoreceptor models in drug design: bridging ligand- and receptor-based virtual screening.
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Nat Rev Drug Discov,
7,
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A.Weitzman,
A.Hochhaus,
and
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(2007).
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance.
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Blood,
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L.Kujawski,
and
M.Talpaz
(2007).
Strategies for overcoming imatinib resistance in chronic myeloid leukemia.
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Leuk Lymphoma,
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T.Hunter
(2007).
Treatment for chronic myelogenous leukemia: the long road to imatinib.
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J Clin Invest,
117,
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T.Zhou,
L.Parillon,
F.Li,
Y.Wang,
J.Keats,
S.Lamore,
Q.Xu,
W.Shakespeare,
D.Dalgarno,
and
X.Zhu
(2007).
Crystal structure of the T315I mutant of AbI kinase.
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Chem Biol Drug Des,
70,
171-181.
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PDB codes:
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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.
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Links
