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PDBsum entry 1byg
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Contents |
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* Residue conservation analysis
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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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J Mol Biol
285:713-725
(1999)
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PubMed id:
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Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine.
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M.B.Lamers,
A.A.Antson,
R.E.Hubbard,
R.K.Scott,
D.H.Williams.
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ABSTRACT
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The crystal structure of the kinase domain of C-terminal Src kinase (CSK) has
been determined by molecular replacement, co-complexed with the protein kinase
inhibitor staurosporine (crystals belong to the space group P21212 with a=44.5
A, b=120.6 A, c=48.3 A). The final model of CSK has been refined to an R-factor
of 19.9 % (Rfree=28.7 %) at 2.4 A resolution. The structure consists of a small,
N-terminal lobe made up mostly of a beta-sheet, and a larger C-terminal lobe
made up mostly of alpha-helices. The structure reveals atomic details of
interactions with staurosporine, which binds in a deep cleft between the lobes.
The polypeptide chain fold of CSK is most similar to c-Src, Hck and fibroblast
growth factor receptor 1 kinase (FGFR1K) and most dissimilar to insulin receptor
kinase (IRK).Interactions between the N and C-terminal lobe are mediated by the
bound staurosporine molecule and by hydrogen bonds. In addition, there are
several water molecules forming lobe-bridging hydrogen bonds, which may be
important for maintaining the catalytic integrity of the kinase. Furthermore,
the conserved Lys328 and Glu267 residues utilise water in the formation of a
molecular pivot which is essential in allowing relative movement of the N and
C-terminal lobes. An analysis of the residues around the ATP-binding site
reveals structural differences with other protein tyrosine kinases. Most notable
of these are different orientations of the conserved residues Asp332 and Phe333,
suggesting that inhibitor binding proceeds via an induced fit.These structural
observations have implications for understanding protein tyrosine kinase
catalytic mechanisms and for the design of ATP-mimicking inhibitors of protein
kinases.
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Selected figure(s)
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Figure 4.
Figure 4. Overlay of the C-terminal domains of IRK and CSK.
The IRK is shown in blue and the CSK in green; the helices are
displayed as cylinders. The regulatory loop is displayed in
purple and the catalytic loop in red. Residue numbers in blue
indicate the IRK insertion loop and the residue numbers in green
indicate the divergence in the CSK hot loop.
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Figure 6.
Figure 6. C^a trace of CSK with the key water molecules and
residues at the lobe junction. Side-by-side stereo image
generated using the smm external display utility in Quanta97.
The side-chain atom colours are: green, carbon; blue, nitrogen;
red, oxygen; the solvent atoms are displayed as red spheres.
Potential hydrogen bonds are displayed as broken white lines.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1999,
285,
713-725)
copyright 1999.
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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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M.Mustafa,
A.Mirza,
and
N.Kannan
(2011).
Conformational regulation of the EGFR kinase core by the juxtamembrane and C-terminal tail: a molecular dynamics study.
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Proteins,
79,
99.
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C.E.Cassidy,
and
W.N.Setzer
(2010).
Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis.
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J Mol Model,
16,
311-326.
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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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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.T.Fathi,
and
M.Levis
(2009).
Lestaurtinib: a multi-targeted FLT3 inhibitor.
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Expert Rev Hematol,
2,
17-26.
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C.D.Shomin,
S.C.Meyer,
and
I.Ghosh
(2009).
Staurosporine tethered peptide ligands that target cAMP-dependent protein kinase (PKA): optimization and selectivity profiling.
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Bioorg Med Chem,
17,
6196-6202.
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K.Huang,
Y.H.Wang,
A.Brown,
and
G.Sun
(2009).
Identification of N-terminal lobe motifs that determine the kinase activity of the catalytic domains and regulatory strategies of Src and Csk protein tyrosine kinases.
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J Mol Biol,
386,
1066-1077.
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R.E.Joseph,
and
A.H.Andreotti
(2009).
Conformational snapshots of Tec kinases during signaling.
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Immunol Rev,
228,
74-92.
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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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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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N.Kannan,
A.F.Neuwald,
and
S.S.Taylor
(2008).
Analogous regulatory sites within the alphaC-beta4 loop regions of ZAP-70 tyrosine kinase and AGC kinases.
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Biochim Biophys Acta,
1784,
27-32.
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G.Bunkoczi,
E.Salah,
P.Filippakopoulos,
O.Fedorov,
S.Müller,
F.Sobott,
S.A.Parker,
H.Zhang,
W.Min,
B.E.Turk,
and
S.Knapp
(2007).
Structural and functional characterization of the human protein kinase ASK1.
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Structure,
15,
1215-1226.
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PDB code:
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J.H.Carra,
C.A.McHugh,
S.Mulligan,
L.M.Machiesky,
A.S.Soares,
and
C.B.Millard
(2007).
Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site.
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BMC Struct Biol,
7,
72.
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PDB codes:
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N.Kannan,
N.Haste,
S.S.Taylor,
and
A.F.Neuwald
(2007).
The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module.
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Proc Natl Acad Sci U S A,
104,
1272-1277.
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C.Sánchez,
C.Méndez,
and
J.A.Salas
(2006).
Indolocarbazole natural products: occurrence, biosynthesis, and biological activity.
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Nat Prod Rep,
23,
1007-1045.
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N.M.Levinson,
O.Kuchment,
K.Shen,
M.A.Young,
M.Koldobskiy,
M.Karplus,
P.A.Cole,
and
J.Kuriyan
(2006).
A Src-like inactive conformation in the abl tyrosine kinase domain.
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PLoS Biol,
4,
e144.
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PDB codes:
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P.Rudrabhatla,
M.M.Reddy,
and
R.Rajasekharan
(2006).
Genome-wide analysis and experimentation of plant serine/ threonine/tyrosine-specific protein kinases.
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Plant Mol Biol,
60,
293-319.
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R.L.Levine,
M.Wadleigh,
J.Cools,
B.L.Ebert,
G.Wernig,
B.J.Huntly,
T.J.Boggon,
I.Wlodarska,
J.J.Clark,
S.Moore,
J.Adelsperger,
S.Koo,
J.C.Lee,
S.Gabriel,
T.Mercher,
A.D'Andrea,
S.Fröhling,
K.Döhner,
P.Marynen,
P.Vandenberghe,
R.A.Mesa,
A.Tefferi,
J.D.Griffin,
M.J.Eck,
W.R.Sellers,
M.Meyerson,
T.R.Golub,
S.J.Lee,
and
D.G.Gilliland
(2005).
Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.
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Cancer Cell,
7,
387-397.
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S.Yoshida,
and
M.Parniske
(2005).
Regulation of plant symbiosis receptor kinase through serine and threonine phosphorylation.
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J Biol Chem,
280,
9203-9209.
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Y.P.Chong,
T.D.Mulhern,
and
H.C.Cheng
(2005).
C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)--endogenous negative regulators of Src-family protein kinases.
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Growth Factors,
23,
233-244.
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J.Chen,
N.R.Wall,
K.Kocher,
N.Duclos,
D.Fabbro,
D.Neuberg,
J.D.Griffin,
Y.Shi,
and
D.G.Gilliland
(2004).
Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin.
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J Clin Invest,
113,
1784-1791.
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L.Jin,
S.Pluskey,
E.C.Petrella,
S.M.Cantin,
J.C.Gorga,
M.J.Rynkiewicz,
P.Pandey,
J.E.Strickler,
R.E.Babine,
D.T.Weaver,
and
K.J.Seidl
(2004).
The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.
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J Biol Chem,
279,
42818-42825.
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PDB code:
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M.Gassel,
C.B.Breitenlechner,
N.König,
R.Huber,
R.A.Engh,
and
D.Bossemeyer
(2004).
The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A.
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J Biol Chem,
279,
23679-23690.
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PDB code:
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D.D.Clark,
and
B.R.Peterson
(2003).
Analysis of protein tyrosine kinase inhibitors in recombinant yeast lacking the ERG6 gene.
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Chembiochem,
4,
101-107.
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E.De Moliner,
N.R.Brown,
and
L.N.Johnson
(2003).
Alternative binding modes of an inhibitor to two different kinases.
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Eur J Biochem,
270,
3174-3181.
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PDB code:
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J.L.Hays,
and
S.J.Watowich
(2003).
Oligomerization-induced modulation of TPR-MET tyrosine kinase activity.
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J Biol Chem,
278,
27456-27463.
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M.Levis,
and
D.Small
(2003).
Novel FLT3 tyrosine kinase inhibitors.
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Expert Opin Investig Drugs,
12,
1951-1962.
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M.Ortiz-Lombardía,
F.Pompeo,
B.Boitel,
and
P.M.Alzari
(2003).
Crystal structure of the catalytic domain of the PknB serine/threonine kinase from Mycobacterium tuberculosis.
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J Biol Chem,
278,
13094-13100.
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PDB code:
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N.Schiering,
S.Knapp,
M.Marconi,
M.M.Flocco,
J.Cui,
R.Perego,
L.Rusconi,
and
C.Cristiani
(2003).
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a.
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Proc Natl Acad Sci U S A,
100,
12654-12659.
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PDB codes:
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S.Lee,
X.Lin,
N.H.Nam,
K.Parang,
and
G.Sun
(2003).
Determination of the substrate-docking site of protein tyrosine kinase C-terminal Src kinase.
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Proc Natl Acad Sci U S A,
100,
14707-14712.
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X.Lin,
S.Lee,
and
G.Sun
(2003).
Functions of the activation loop in Csk protein-tyrosine kinase.
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J Biol Chem,
278,
24072-24077.
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A.Ogawa,
Y.Takayama,
H.Sakai,
K.T.Chong,
S.Takeuchi,
A.Nakagawa,
S.Nada,
M.Okada,
and
T.Tsukihara
(2002).
Structure of the carboxyl-terminal Src kinase, Csk.
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J Biol Chem,
277,
14351-14354.
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PDB code:
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G.M.Cheetham,
R.M.Knegtel,
J.T.Coll,
S.B.Renwick,
L.Swenson,
P.Weber,
J.A.Lippke,
and
D.A.Austen
(2002).
Crystal structure of aurora-2, an oncogenic serine/threonine kinase.
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J Biol Chem,
277,
42419-42422.
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PDB code:
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P.P.Roux,
G.Dorval,
M.Boudreau,
A.Angers-Loustau,
S.J.Morris,
J.Makkerh,
and
P.A.Barker
(2002).
K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK.
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J Biol Chem,
277,
49473-49480.
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R.A.Engh,
and
D.Bossemeyer
(2002).
Structural aspects of protein kinase control-role of conformational flexibility.
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Pharmacol Ther,
93,
99.
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S.Sarno,
S.Moro,
F.Meggio,
G.Zagotto,
D.Dal Ben,
P.Ghisellini,
R.Battistutta,
G.Zanotti,
and
L.A.Pinna
(2002).
Toward the rational design of protein kinase casein kinase-2 inhibitors.
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Pharmacol Ther,
93,
159-168.
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J.Shaffer,
G.Sun,
and
J.A.Adams
(2001).
Nucleotide release and associated conformational changes regulate function in the COOH-terminal Src kinase, Csk.
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Biochemistry,
40,
11149-11155.
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P.R.Caron,
M.D.Mullican,
R.D.Mashal,
K.P.Wilson,
M.S.Su,
and
M.A.Murcko
(2001).
Chemogenomic approaches to drug discovery.
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Curr Opin Chem Biol,
5,
464-470.
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R.Battistutta,
E.De Moliner,
S.Sarno,
G.Zanotti,
and
L.A.Pinna
(2001).
Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole.
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Protein Sci,
10,
2200-2206.
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PDB codes:
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E.H.Walker,
M.E.Pacold,
O.Perisic,
L.Stephens,
P.T.Hawkins,
M.P.Wymann,
and
R.L.Williams
(2000).
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.
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Mol Cell,
6,
909-919.
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PDB codes:
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S.R.Hubbard,
and
J.H.Till
(2000).
Protein tyrosine kinase structure and function.
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Annu Rev Biochem,
69,
373-398.
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J.R.Burke,
M.K.Wood,
R.P.Ryseck,
S.Walther,
and
C.A.Meyers
(1999).
Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2.
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J Biol Chem,
274,
36146-36152.
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X.Zhu,
J.L.Kim,
J.R.Newcomb,
P.E.Rose,
D.R.Stover,
L.M.Toledo,
H.Zhao,
and
K.A.Morgenstern
(1999).
Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.
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Structure,
7,
651-661.
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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
codes are
shown on the right.
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Links
