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PDBsum entry 1kv2
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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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Human p38 map kinase in complex with birb 796
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Structure:
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P38 map kinase. Chain: a. Synonym: mitogen-activated protein kinase p38, mitogen-activated protein kinase 14. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.80Å
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R-factor:
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0.228
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R-free:
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0.318
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Authors:
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C.Pargellis,L.Tong,L.Churchill,P.F.Cirillo,T.Gilmore,A.G.Graham, P.M.Grob,E.R.Hickey,N.Moss,S.Pav,J.Regan
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Key ref:
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C.Pargellis
et al.
(2002).
Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site.
Nat Struct Biol,
9,
268-272.
PubMed id:
DOI:
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Date:
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23-Jan-02
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Release date:
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27-Mar-02
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PROCHECK
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Headers
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References
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Q16539
(MK14_HUMAN) -
Mitogen-activated protein kinase 14 from Homo sapiens
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Seq:
Struc:
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360 a.a.
325 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.2.7.11.24
- mitogen-activated protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[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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Nat Struct Biol
9:268-272
(2002)
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PubMed id:
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Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site.
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C.Pargellis,
L.Tong,
L.Churchill,
P.F.Cirillo,
T.Gilmore,
A.G.Graham,
P.M.Grob,
E.R.Hickey,
N.Moss,
S.Pav,
J.Regan.
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ABSTRACT
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The p38 MAP kinase plays a crucial role in regulating the production of
proinflammatory cytokines, such as tumor necrosis factor and interleukin-1.
Blocking this kinase may offer an effective therapy for treating many
inflammatory diseases. Here we report a new allosteric binding site for a diaryl
urea class of highly potent and selective inhibitors against human p38 MAP
kinase. The formation of this binding site requires a large conformational
change not observed previously for any of the protein Ser/Thr kinases. This
change is in the highly conserved Asp-Phe-Gly motif within the active site of
the kinase. Solution studies demonstrate that this class of compounds has slow
binding kinetics, consistent with the requirement for conformational change.
Improving interactions in this allosteric pocket, as well as establishing
binding interactions in the ATP pocket, enhanced the affinity of the inhibitors
by 12,000-fold. One of the most potent compounds in this series, BIRB 796, has
picomolar affinity for the kinase and low nanomolar inhibitory activity in cell
culture.
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Selected figure(s)
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Figure 2.
Figure 2. A new allosteric binding pocket for compound 1 in
human p38 MAP kinase. a, Schematic drawing of the structure
of p38 MAP kinase in complex with compound 1. The inhibitor is
shown as a stick model, with carbon atoms in green. The expected
location of the ATP molecule^8 (purple for carbon atoms) is
shown for reference. b, Final 2F[o] - F[c] electron density map
for compound 1, contoured at 1  level.
Panel (a) is produced with RIBBONS27 and panel (b) with SETOR28.
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Figure 3.
Figure 3. A conformational change in the kinase is required for
the binding of diaryl urea inhibitors. a, Stereo view showing
the conformational change for the DFG motif. The DFG-in
conformation is shown with the carbon atoms in light blue, and
the DFG-out conformation is in gray. Also shown is the overlay
of the binding modes of compound 1 (green), the 3'-iodo analog
of SB 203580 (cyan)8 and ATP (purple). b, Molecular surface of
the p38 MAP kinase in the active site region in complex with
compound 1. For clarity, residues in the DFG motif are shown as
a stick model. The ATP molecule is shown for reference. c,
Stereo view showing the binding pocket (gray for carbon atoms)
for BIRB 796 (green). Also shown is compound 1 and the
conformation of Glu 71 (cyan) in that complex. Produced with
GRASP29.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
268-272)
copyright 2002.
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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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A.Sukhwal,
M.Bhattacharyya,
and
S.Vishveshwara
(2011).
Network approach for capturing ligand-induced subtle global changes in protein structures.
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Acta Crystallogr D Biol Crystallogr,
67,
429-439.
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N.Handa,
T.Takagi,
S.Saijo,
S.Kishishita,
D.Takaya,
M.Toyama,
T.Terada,
M.Shirouzu,
A.Suzuki,
S.Lee,
T.Yamauchi,
M.Okada-Iwabu,
M.Iwabu,
T.Kadowaki,
Y.Minokoshi,
and
S.Yokoyama
(2011).
Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain.
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Acta Crystallogr D Biol Crystallogr,
67,
480-487.
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PDB codes:
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A.Bai,
and
Z.Peng
(2010).
Biological therapies of inflammatory bowel disease.
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Immunotherapy,
2,
727-742.
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A.Cuadrado,
and
A.R.Nebreda
(2010).
Mechanisms and functions of p38 MAPK signalling.
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Biochem J,
429,
403-417.
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A.Fujino,
K.Fukushima,
N.Namiki,
T.Kosugi,
and
M.Takimoto-Kamimura
(2010).
Structural analysis of an MK2-inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800.
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Acta Crystallogr D Biol Crystallogr,
66,
80-87.
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PDB code:
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B.S.Hendriks,
K.M.Seidl,
and
J.R.Chabot
(2010).
Two additive mechanisms impair the differentiation of 'substrate-selective' p38 inhibitors from classical p38 inhibitors in vitro.
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BMC Syst Biol,
4,
23.
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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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D.Falck,
J.S.de Vlieger,
W.M.Niessen,
J.Kool,
M.Honing,
M.Giera,
and
H.Irth
(2010).
Development of an online p38α mitogen-activated protein kinase binding assay and integration of LC-HR-MS.
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Anal Bioanal Chem,
398,
1771-1780.
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D.Huang,
T.Zhou,
K.Lafleur,
C.Nevado,
and
A.Caflisch
(2010).
Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis.
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Bioinformatics,
26,
198-204.
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E.A.Murphy,
D.J.Shields,
K.Stoletov,
E.Dneprovskaia,
M.McElroy,
J.I.Greenberg,
J.Lindquist,
L.M.Acevedo,
S.Anand,
B.K.Majeti,
I.Tsigelny,
A.Saldanha,
B.Walsh,
R.M.Hoffman,
M.Bouvet,
R.L.Klemke,
P.K.Vogt,
L.Arnold,
W.Wrasidlo,
and
D.A.Cheresh
(2010).
Disruption of angiogenesis and tumor growth with an orally active drug that stabilizes the inactive state of PDGFRbeta/B-RAF.
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Proc Natl Acad Sci U S A,
107,
4299-4304.
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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.J.Rudolph,
G.A.Amodeo,
and
L.Tong
(2010).
An inhibited conformation for the protein kinase domain of the Saccharomyces cerevisiae AMPK homolog Snf1.
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Acta Crystallogr Sect F Struct Biol Cryst Commun,
66,
999.
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PDB code:
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N.Dzamko,
M.Deak,
F.Hentati,
A.D.Reith,
A.R.Prescott,
D.R.Alessi,
and
R.J.Nichols
(2010).
Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization.
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Biochem J,
430,
405-413.
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N.Huang,
and
M.P.Jacobson
(2010).
Binding-site assessment by virtual fragment screening.
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PLoS One,
5,
e10109.
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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.H.Page,
A.Brown,
E.M.Timms,
B.M.Foxwell,
and
K.P.Ray
(2010).
Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: does variable inhibition of interleukin-6 production limit effectiveness in vivo?
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Arthritis Rheum,
62,
3221-3231.
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W.I.Wu,
W.C.Voegtli,
H.L.Sturgis,
F.P.Dizon,
G.P.Vigers,
and
B.J.Brandhuber
(2010).
Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition.
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PLoS One,
5,
e12913.
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PDB code:
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C.D.Wood,
T.M.Thornton,
G.Sabio,
R.A.Davis,
and
M.Rincon
(2009).
Nuclear localization of p38 MAPK in response to DNA damage.
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Int J Biol Sci,
5,
428-437.
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C.García-Echeverría
(2009).
Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.
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Purinergic Signal,
5,
117-125.
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G.T.Lountos,
J.E.Tropea,
D.Zhang,
A.G.Jobson,
Y.Pommier,
R.H.Shoemaker,
and
D.S.Waugh
(2009).
Crystal structure of checkpoint kinase 2 in complex with NSC 109555, a potent and selective inhibitor.
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Protein Sci,
18,
92.
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PDB code:
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J.Fastrez
(2009).
Engineering allosteric regulation into biological catalysts.
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Chembiochem,
10,
2824-2835.
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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.Abbas,
J.Breton,
C.R.Picot,
V.Quesniaux,
C.Bouton,
and
J.C.Drapier
(2009).
Signaling events leading to peroxiredoxin 5 up-regulation in immunostimulated macrophages.
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Free Radic Biol Med,
47,
794-802.
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K.Burkhard,
S.Smith,
R.Deshmukh,
A.D.MacKerell,
and
P.Shapiro
(2009).
Development of extracellular signal-regulated kinase inhibitors.
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Curr Top Med Chem,
9,
678-689.
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K.O.Wrzeszczynski,
and
B.Rost
(2009).
Cell cycle kinases predicted from conserved biophysical properties.
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Proteins,
74,
655-668.
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L.N.Johnson
(2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
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Q Rev Biophys,
42,
1.
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M.K.Tarrant,
and
P.A.Cole
(2009).
The chemical biology of protein phosphorylation.
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Annu Rev Biochem,
78,
797-825.
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R.Li,
A.Pourpak,
and
S.W.Morris
(2009).
Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach.
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J Med Chem,
52,
4981-5004.
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R.S.Armen,
J.Chen,
and
C.L.Brooks
(2009).
An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.
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J Chem Theory Comput,
5,
2909-2923.
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S.Han,
A.Mistry,
J.S.Chang,
D.Cunningham,
M.Griffor,
P.C.Bonnette,
H.Wang,
B.A.Chrunyk,
G.E.Aspnes,
D.P.Walker,
A.D.Brosius,
and
L.Buckbinder
(2009).
Structural Characterization of Proline-rich Tyrosine Kinase 2 (PYK2) Reveals a Unique (DFG-out) Conformation and Enables Inhibitor Design.
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J Biol Chem,
284,
13193-13201.
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PDB codes:
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S.Sen,
and
A.B.West
(2009).
The therapeutic potential of LRRK2 and alpha-synuclein in Parkinson's disease.
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Antioxid Redox Signal,
11,
2167-2187.
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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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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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B.Gorelik,
and
A.Goldblum
(2008).
High quality binding modes in docking ligands to proteins.
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Proteins,
71,
1373-1386.
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D.Leroy,
and
C.Doerig
(2008).
Drugging the Plasmodium kinome: the benefits of academia-industry synergy.
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Trends Pharmacol Sci,
29,
241-249.
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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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D.M.Goldstein,
N.S.Gray,
and
P.P.Zarrinkar
(2008).
High-throughput kinase profiling as a platform for drug discovery.
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Nat Rev Drug Discov,
7,
391-397.
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I.Reulecke,
G.Lange,
J.Albrecht,
R.Klein,
and
M.Rarey
(2008).
Towards an integrated description of hydrogen bonding and dehydration: decreasing false positives in virtual screening with the HYDE scoring function.
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ChemMedChem,
3,
885-897.
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J.S.Sack,
K.F.Kish,
M.Pokross,
D.Xie,
G.J.Duke,
J.A.Tredup,
S.E.Kiefer,
and
J.A.Newitt
(2008).
Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase.
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| |
Acta Crystallogr D Biol Crystallogr,
64,
705-710.
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J.Subramanian,
S.Sharma,
and
C.B-Rao
(2008).
Modeling and selection of flexible proteins for structure-based drug design: backbone and side chain movements in p38 MAPK.
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| |
ChemMedChem,
3,
336-344.
|
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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.
|
| |
Proteins,
72,
323-332.
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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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S.J.Cho,
and
Y.Sun
(2008).
Visual exploration of structure-activity relationship using maximum common framework.
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J Comput Aided Mol Des,
22,
571-578.
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S.Rao,
P.C.Sanschagrin,
J.R.Greenwood,
M.P.Repasky,
W.Sherman,
and
R.Farid
(2008).
Improving database enrichment through ensemble docking.
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J Comput Aided Mol Des,
22,
621-627.
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T.A.Binkowski,
and
A.Joachimiak
(2008).
Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.
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BMC Struct Biol,
8,
45.
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A.White,
C.A.Pargellis,
J.M.Studts,
B.G.Werneburg,
and
B.T.Farmer
(2007).
Molecular basis of MAPK-activated protein kinase 2:p38 assembly.
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Proc Natl Acad Sci U S A,
104,
6353-6358.
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PDB code:
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D.J.Diller,
and
D.W.Hobbs
(2007).
Understanding hERG inhibition with QSAR models based on a one-dimensional molecular representation.
|
| |
J Comput Aided Mol Des,
21,
379-393.
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D.Kuhn,
N.Weskamp,
E.Hüllermeier,
and
G.Klebe
(2007).
Functional Classification of Protein Kinase Binding Sites Using Cavbase.
|
| |
ChemMedChem,
2,
1432-1447.
|
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G.M.Verkhivker
(2007).
In silico profiling of tyrosine kinases binding specificity and drug resistance using Monte Carlo simulations with the ensembles of protein kinase crystal structures.
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| |
Biopolymers,
85,
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PDB codes:
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PDB code:
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J.F.Ohren,
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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.
|
|
Links
