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PDBsum entry 1rjb
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of flt3
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Structure:
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Fl cytokine receptor. Chain: a. Fragment: catalytic domain. Synonym: tyrosine-protein kinase receptor flt3, stem cell tyrosine kinase 1, stk-1, cd135 antigen. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
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Resolution:
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2.10Å
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R-factor:
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0.220
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R-free:
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0.248
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Authors:
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J.Griffith,J.Black,C.Faerman,L.Swenson,M.Wynn,F.Lu,J.Lippke,K.Saxena
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Key ref:
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J.Griffith
et al.
(2004).
The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.
Mol Cell,
13,
169-178.
PubMed id:
DOI:
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Date:
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19-Nov-03
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Release date:
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03-Feb-04
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PROCHECK
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Headers
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References
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P36888
(FLT3_HUMAN) -
Receptor-type tyrosine-protein kinase FLT3 from Homo sapiens
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Seq:
Struc:
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993 a.a.
298 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.10.1
- receptor 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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Mol Cell
13:169-178
(2004)
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PubMed id:
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The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.
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J.Griffith,
J.Black,
C.Faerman,
L.Swenson,
M.Wynn,
F.Lu,
J.Lippke,
K.Saxena.
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ABSTRACT
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FLT3 is a type III receptor tyrosine kinase that is thought to play a key role
in hematopoiesis. Certain classes of FLT3 mutations cause constitutively
activated forms of the receptor that are found in significant numbers of
patients with acute myelogenous leukemia (AML). The mutations occur either in
the activation loop, for example, as point mutations of Asp835 or as internal
tandem duplication (ITD) sequences in the juxtamembrane (JM) domain. To further
understand the nature of FLT3 autoinhibition and regulation, we have determined
the crystal structure of the autoinhibited form of FLT3. This structure shows
the autoinhibitory conformation of a complete JM domain in this class of
receptor tyrosine kinases. The detailed inhibitory mechanism of the JM domain is
revealed, which is likely utilized by other members of type III receptor
tyrosine kinases.
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Selected figure(s)
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Figure 4.
Figure 4. Active Site of FLT3Closeup view of the active
site region of FLT3 showing the relationship of Tyr572 and
Tyr842 hydrogen bonded to Glu661 and Asp811, respectively, which
in turn are involved in salt bridges.
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Figure 5.
Figure 5. Activation Loops Can Adopt a Wide Range of
ConformationsThe superposition of the closed activation loop
from FLT3 onto (A) the closed IRK-I activation loop (blue), (B)
the partially open FGFR activation loop (red), and (C) the fully
open IRK-A activation loop (blue).
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2004,
13,
169-178)
copyright 2004.
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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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C.C.Smith,
Q.Wang,
C.S.Chin,
S.Salerno,
L.E.Damon,
M.J.Levis,
A.E.Perl,
K.J.Travers,
S.Wang,
J.P.Hunt,
P.P.Zarrinkar,
E.E.Schadt,
A.Kasarskis,
J.Kuriyan,
and
N.P.Shah
(2012).
Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia.
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Nature,
485,
260-263.
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K.Verstraete,
and
S.N.Savvides
(2012).
Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases.
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Nat Rev Cancer,
12,
753-766.
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I.E.Michailidis,
R.Rusinova,
A.Georgakopoulos,
Y.Chen,
R.Iyengar,
N.K.Robakis,
D.E.Logothetis,
and
L.Baki
(2011).
Phosphatidylinositol-4,5-bisphosphate regulates epidermal growth factor receptor activation.
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Pflugers Arch,
461,
387-397.
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N.Singla,
H.Erdjument-Bromage,
J.P.Himanen,
T.W.Muir,
and
D.B.Nikolov
(2011).
A semisynthetic Eph receptor tyrosine kinase provides insight into ligand-induced kinase activation.
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Chem Biol,
18,
361-371.
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P.M.Chan
(2011).
Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model.
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Protein Cell,
2,
108-115.
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A.Gangjee,
N.Zaware,
S.Raghavan,
M.Ihnat,
S.Shenoy,
and
R.L.Kisliuk
(2010).
Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
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J Med Chem,
53,
1563-1578.
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E.Scott,
E.Hexner,
A.Perl,
and
M.Carroll
(2010).
Targeted signal transduction therapies in myeloid malignancies.
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Curr Oncol Rep,
12,
358-365.
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F.Toffalini,
and
J.B.Demoulin
(2010).
New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases.
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Blood,
116,
2429-2437.
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K.W.Pratz,
and
M.J.Levis
(2010).
Bench to bedside targeting of FLT3 in acute leukemia.
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Curr Drug Targets,
11,
781-789.
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L.M.Wodicka,
P.Ciceri,
M.I.Davis,
J.P.Hunt,
M.Floyd,
S.Salerno,
X.H.Hua,
J.M.Ford,
R.C.Armstrong,
P.P.Zarrinkar,
and
D.K.Treiber
(2010).
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
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Chem Biol,
17,
1241-1249.
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M.Rabiller,
M.Getlik,
S.Klüter,
A.Richters,
S.Tückmantel,
J.R.Simard,
and
D.Rauh
(2010).
Proteus in the world of proteins: conformational changes in protein kinases.
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Arch Pharm (Weinheim),
343,
193-206.
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A.Dixit,
L.Yi,
R.Gowthaman,
A.Torkamani,
N.J.Schork,
and
G.M.Verkhivker
(2009).
Sequence and structure signatures of cancer mutation hotspots in protein kinases.
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PLoS One,
4,
e7485.
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A.Torkamani,
G.Verkhivker,
and
N.J.Schork
(2009).
Cancer driver mutations in protein kinase genes.
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Cancer Lett,
281,
117-127.
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D.Schmidt-Arras,
S.A.Böhmer,
S.Koch,
J.P.Müller,
L.Blei,
H.Cornils,
R.Bauer,
S.Korasikha,
C.Thiede,
and
F.D.Böhmer
(2009).
Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality.
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Blood,
113,
3568-3576.
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F.Breitenbuecher,
S.Schnittger,
R.Grundler,
B.Markova,
B.Carius,
A.Brecht,
J.Duyster,
T.Haferlach,
C.Huber,
and
T.Fischer
(2009).
Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor.
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Blood,
113,
4074-4077.
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F.Heidel,
D.B.Lipka,
F.K.Mirea,
S.Mahboobi,
R.Grundler,
R.K.Kancha,
J.Duyster,
M.Naumann,
C.Huber,
F.D.Böhmer,
and
T.Fischer
(2009).
Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.
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Br J Haematol,
144,
865-874.
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K.Fukushima,
I.Matsumura,
S.Ezoe,
M.Tokunaga,
M.Yasumi,
Y.Satoh,
H.Shibayama,
H.Tanaka,
A.Iwama,
and
Y.Kanakura
(2009).
FIP1L1-PDGFR{alpha} Imposes Eosinophil Lineage Commitment on Hematopoietic Stem/Progenitor Cells.
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J Biol Chem,
284,
7719-7732.
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K.Masson,
T.Liu,
R.Khan,
J.Sun,
and
L.Rönnstrand
(2009).
A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival.
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Br J Haematol,
146,
193-202.
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M.Red Brewer,
S.H.Choi,
D.Alvarado,
K.Moravcevic,
A.Pozzi,
M.A.Lemmon,
and
G.Carpenter
(2009).
The juxtamembrane region of the EGF receptor functions as an activation domain.
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Mol Cell,
34,
641-651.
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PDB code:
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M.Sanz,
A.Burnett,
F.Lo-Coco,
and
B.Löwenberg
(2009).
FLT3 inhibition as a targeted therapy for acute myeloid leukemia.
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Curr Opin Oncol,
21,
594-600.
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S.Kayser,
R.F.Schlenk,
M.C.Londono,
F.Breitenbuecher,
K.Wittke,
J.Du,
S.Groner,
D.Späth,
J.Krauter,
A.Ganser,
H.Döhner,
T.Fischer,
and
K.Döhner
(2009).
Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome.
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Blood,
114,
2386-2392.
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S.Meshinchi,
and
F.R.Appelbaum
(2009).
Structural and functional alterations of FLT3 in acute myeloid leukemia.
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Clin Cancer Res,
15,
4263-4269.
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S.Salemi,
S.Yousefi,
D.Simon,
I.Schmid,
L.Moretti,
L.Scapozza,
and
H.U.Simon
(2009).
A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome.
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Allergy,
64,
913-918.
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A.C.Dar,
M.S.Lopez,
and
K.M.Shokat
(2008).
Small molecule recognition of c-Src via the Imatinib-binding conformation.
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Chem Biol,
15,
1015-1022.
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PDB codes:
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A.J.Mead,
R.E.Gale,
P.D.Kottaridis,
S.Matsuda,
A.Khwaja,
and
D.C.Linch
(2008).
Acute myeloid leukaemia blast cells with a tyrosine kinase domain mutation of FLT3 are less sensitive to lestaurtinib than those with a FLT3 internal tandem duplication.
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Br J Haematol,
141,
454-460.
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C.J.Park,
Y.Peng,
X.Chen,
C.Dardick,
D.Ruan,
R.Bart,
P.E.Canlas,
and
P.C.Ronald
(2008).
Rice XB15, a protein phosphatase 2C, negatively regulates cell death and XA21-mediated innate immunity.
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PLoS Biol,
6,
e231.
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C.V.Cotta,
and
R.R.Tubbs
(2008).
Mutations in myeloid neoplasms.
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Diagn Mol Pathol,
17,
191-199.
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D.Lietha,
and
M.J.Eck
(2008).
Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation.
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PLoS ONE,
3,
e3800.
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PDB codes:
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H.L.Peng,
G.S.Zhang,
F.J.Gong,
J.K.Shen,
Y.Zhang,
Y.X.Xu,
W.L.Zheng,
C.W.Dai,
M.F.Pei,
and
J.J.Yang
(2008).
Fms-like tyrosine kinase (FLT) 3 and FLT3 internal tandem duplication in different types of adult leukemia: analysis of 147 patients.
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Croat Med J,
49,
650-669.
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J.Gotlib,
and
J.Cools
(2008).
Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias.
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Leukemia,
22,
1999-2010.
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J.Zou,
Y.D.Wang,
F.X.Ma,
M.L.Xiang,
B.Shi,
Y.Q.Wei,
and
S.Y.Yang
(2008).
Detailed conformational dynamics of juxtamembrane region and activation loop in c-Kit kinase activation process.
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Proteins,
72,
323-332.
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K.Pratz,
and
M.Levis
(2008).
Incorporating FLT3 inhibitors into acute myeloid leukemia treatment regimens.
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Leuk Lymphoma,
49,
852-863.
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L.Bullinger,
K.Döhner,
R.Kranz,
C.Stirner,
S.Fröhling,
C.Scholl,
Y.H.Kim,
R.F.Schlenk,
R.Tibshirani,
H.Döhner,
and
J.R.Pollack
(2008).
An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML.
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Blood,
111,
4490-4495.
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M.D.Jacobs,
P.R.Caron,
and
B.J.Hare
(2008).
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex.
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Proteins,
70,
1451-1460.
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PDB code:
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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,
18292-18302.
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R.E.Gale,
C.Green,
C.Allen,
A.J.Mead,
A.K.Burnett,
R.K.Hills,
and
D.C.Linch
(2008).
The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.
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Blood,
111,
2776-2784.
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R.L.Levine,
and
D.G.Gilliland
(2008).
Myeloproliferative disorders.
|
| |
Blood,
112,
2190-2198.
|
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S.Meshinchi,
D.L.Stirewalt,
T.A.Alonzo,
T.J.Boggon,
R.B.Gerbing,
J.L.Rocnik,
B.J.Lange,
D.G.Gilliland,
and
J.P.Radich
(2008).
Structural and numerical variation of FLT3/ITD in pediatric AML.
|
| |
Blood,
111,
4930-4933.
|
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S.Mori,
J.Cortes,
H.Kantarjian,
W.Zhang,
M.Andreef,
and
F.Ravandi
(2008).
Potential role of sorafenib in the treatment of acute myeloid leukemia.
|
| |
Leuk Lymphoma,
49,
2246-2255.
|
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T.Grafone,
M.Palmisano,
C.Nicci,
A.M.Martelli,
O.Emanuela,
S.Storti,
M.Baccarani,
and
G.Martinelli
(2008).
Monitoring of FLT3 phosphorylation status and its response to drugs by flow cytometry in AML blast cells.
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| |
Hematol Oncol,
26,
159-166.
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Y.Mori,
T.Hirokawa,
K.Aoki,
H.Satomi,
S.Takeda,
M.Aburada,
and
K.Miyamoto
(2008).
Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling.
|
| |
Chem Pharm Bull (Tokyo),
56,
682-687.
|
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A.J.Mead,
D.C.Linch,
R.K.Hills,
K.Wheatley,
A.K.Burnett,
and
R.E.Gale
(2007).
FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia.
|
| |
Blood,
110,
1262-1270.
|
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B.P.Craddock,
C.Cotter,
and
W.T.Miller
(2007).
Autoinhibition of the insulin-like growth factor I receptor by the juxtamembrane region.
|
| |
FEBS Lett,
581,
3235-3240.
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C.Schalk-Hihi,
H.C.Ma,
G.T.Struble,
S.Bayoumy,
R.Williams,
E.Devine,
I.P.Petrounia,
T.Mezzasalma,
L.Zeng,
C.Schubert,
B.Grasberger,
B.A.Springer,
and
I.C.Deckman
(2007).
Protein engineering of the colony-stimulating factor-1 receptor kinase domain for structural studies.
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| |
J Biol Chem,
282,
4085-4093.
|
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C.Schubert,
C.Schalk-Hihi,
G.T.Struble,
H.C.Ma,
I.P.Petrounia,
B.Brandt,
I.C.Deckman,
R.J.Patch,
M.R.Player,
J.C.Spurlino,
and
B.A.Springer
(2007).
Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.
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| |
J Biol Chem,
282,
4094-4101.
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PDB codes:
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R.A.Van Etten
(2007).
Aberrant cytokine signaling in leukemia.
|
| |
Oncogene,
26,
6738-6749.
|
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S.Fröhling,
C.Scholl,
R.L.Levine,
M.Loriaux,
T.J.Boggon,
O.A.Bernard,
R.Berger,
H.Döhner,
K.Döhner,
B.L.Ebert,
S.Teckie,
T.R.Golub,
J.Jiang,
M.M.Schittenhelm,
B.H.Lee,
J.D.Griffin,
R.M.Stone,
M.C.Heinrich,
M.W.Deininger,
B.J.Druker,
and
D.G.Gilliland
(2007).
Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles.
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| |
Cancer Cell,
12,
501-513.
|
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B.W.Parcells,
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Stem Cells,
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Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia.
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Blood,
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Leukemia,
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Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD.
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A Src-like inactive conformation in the abl tyrosine kinase domain.
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PLoS Biol,
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PDB codes:
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R.Jauch,
M.K.Cho,
S.Jäkel,
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EMBO J,
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PDB codes:
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B.Steffen,
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J.Schwäble,
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Crit Rev Oncol Hematol,
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S.Schnittger,
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The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice.
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J Clin Invest,
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Structure,
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PDB codes:
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M.Levis,
K.M.Murphy,
R.Pham,
K.T.Kim,
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PDB codes:
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C.M.Rohde,
J.Schrum,
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A juxtamembrane tyrosine in the colony stimulating factor-1 receptor regulates ligand-induced Src association, receptor kinase function, and down-regulation.
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J Biol Chem,
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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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|
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