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PDBsum entry 2oiq
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Contents |
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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 chicken c-src kinase domain in complex with the cancer drug imatinib.
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Structure:
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Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Fragment: kinase domain. Synonym: p60-src, c- src, pp60c-src. Engineered: yes
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Source:
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Gallus gallus. Chicken. Organism_taxid: 9031. Gene: src. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.07Å
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R-factor:
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0.227
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R-free:
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0.263
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Authors:
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M.A.Seeliger,B.Nagar,F.Frank,X.Cao,M.N.Henderson,J.Kuriyan
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Key ref:
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M.A.Seeliger
et al.
(2007).
c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty.
Structure,
15,
299-311.
PubMed id:
DOI:
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Date:
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11-Jan-07
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Release date:
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20-Mar-07
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PROCHECK
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Headers
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References
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P00523
(SRC_CHICK) -
Proto-oncogene tyrosine-protein kinase Src from Gallus gallus
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Seq:
Struc:
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533 a.a.
265 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.2.7.10.2
- 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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Structure
15:299-311
(2007)
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PubMed id:
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c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty.
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M.A.Seeliger,
B.Nagar,
F.Frank,
X.Cao,
M.N.Henderson,
J.Kuriyan.
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ABSTRACT
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The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the
PDGF receptor. Imatinib is less effective against c-Src, which is difficult to
understand because residues interacting with imatinib in crystal structures of
Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase
domain in complex with imatinib closely resembles that of Abl*imatinib and
c-Kit*imatinib, and differs significantly from the inactive "Src/CDK"
conformation of the Src family kinases. Attempts to increase the affinity of
c-Src for imatinib by swapping residues with the corresponding residues in Abl
have not been successful, suggesting that the thermodynamic penalty for adoption
of the imatinib-binding conformation by c-Src is distributed over a broad region
of the structure. Two mutations that are expected to destabilize the inactive
Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the
free-energy balance between different inactive states is a key to imatinib
binding.
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Selected figure(s)
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Figure 1.
Figure 1. The Imatinib-Binding Pocket
(A) Chemical
structure of imatinib.
(B) The imatinib-binding pocket in
Abl (PDB code 1OPJ) (Nagar et al., 2003). The Cα atoms of
residues that interact with imatinib are depicted as spheres.
Blue, residues that are invariant among Abl, c-Src, Lck, Hck,
PDGFR, and c-Kit; yellow, residues that are identical between
Abl and c-Src, but not between Abl and c-Kit or PDGFR; red,
residues unique to Abl.
(C) Sequence alignment of Abl,
c-Src, Hck, Lck, PDGFR, and c-Kit kinase domains. Residues that
are the same as in Abl are yellow. Residues that interact with
imatinib in the structure of Abl are in orange. Stars are color
coded according to the spheres in (B).
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Figure 7.
Figure 7. Comparison of Imatinib-Bound Structures
(A)
Structure of c-Src•imatinib (this work, PDB code 2OIQ). The
activation loop is disordered from residue 408 to residue 420,
and the phosphate-binding P loop is extended, leaving the
phenylalanine side chain solvent exposed.
(B) Structure of
Abl•imatinib (PDB code 1OPJ [Nagar et al., 2002]). The
phosphate-binding loop is kinked toward the C lobe of the
kinase, allowing for hydrogen bonds between Tyr253 and Asn322
(not shown).
(C) Structure of c-Kit•imatinib (PDB code
1T46 [Mol et al., 2004]). The phosphate-binding loop is
extended, as seen in the structure of c-Src, and Phe600 is
solvent exposed.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2007,
15,
299-311)
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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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.
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Biochem J,
427,
19-28.
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PDB codes:
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J.B.Bruning,
A.A.Parent,
G.Gil,
M.Zhao,
J.Nowak,
M.C.Pace,
C.L.Smith,
P.V.Afonine,
P.D.Adams,
J.A.Katzenellenbogen,
and
K.W.Nettles
(2010).
Coupling of receptor conformation and ligand orientation determine graded activity.
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Nat Chem Biol,
6,
837-843.
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PDB codes:
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J.E.Sylvester,
and
S.J.Kron
(2010).
A bead-based activity screen for small-molecule inhibitors of signal transduction in chronic myelogenous leukemia cells.
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Mol Cancer Ther,
9,
1469-1481.
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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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P.Ranjitkar,
A.M.Brock,
and
D.J.Maly
(2010).
Affinity reagents that target a specific inactive form of protein kinases.
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Chem Biol,
17,
195-206.
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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.
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Chem Biol Drug Des,
75,
18-28.
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PDB codes:
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A.Dixit,
and
G.M.Verkhivker
(2009).
Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.
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PLoS Comput Biol,
5,
e1000487.
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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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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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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.
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Nat Chem Biol,
5,
394-396.
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PDB codes:
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K.H.Biswas,
A.R.Shenoy,
A.Dutta,
and
S.S.Visweswariah
(2009).
The evolution of guanylyl cyclases as multidomain proteins: conserved features of kinase-cyclase domain fusions.
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J Mol Evol,
68,
587-602.
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M.A.Seeliger,
P.Ranjitkar,
C.Kasap,
Y.Shan,
D.E.Shaw,
N.P.Shah,
J.Kuriyan,
and
D.J.Maly
(2009).
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations.
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Cancer Res,
69,
2384-2392.
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PDB codes:
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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.V.Statsuk,
D.J.Maly,
M.A.Seeliger,
M.A.Fabian,
W.H.Biggs,
D.J.Lockhart,
P.P.Zarrinkar,
J.Kuriyan,
and
K.M.Shokat
(2008).
Tuning a three-component reaction for trapping kinase substrate complexes.
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J Am Chem Soc,
130,
17568-17574.
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PDB code:
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B.D.Marsden,
and
S.Knapp
(2008).
Doing more than just the structure-structural genomics in kinase drug discovery.
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Curr Opin Chem Biol,
12,
40-45.
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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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I.Kufareva,
and
R.Abagyan
(2008).
Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.
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J Med Chem,
51,
7921-7932.
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M.Azam,
M.A.Seeliger,
N.S.Gray,
J.Kuriyan,
and
G.Q.Daley
(2008).
Activation of tyrosine kinases by mutation of the gatekeeper threonine.
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Nat Struct Mol Biol,
15,
1109-1118.
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PDB codes:
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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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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.
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Links
