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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 an activated akt/protein kinase b (pkb-pif chimera) ternary complex with amp-pnp and gsk3 peptide
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Structure:
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Rac-beta serine/threonine protein kinase. Chain: a. Fragment: kinase domain, residues 146 - 467. Synonym: protein kinase akt-2, protein kinase b beta rac-pk-beta, pkb beta. Engineered: yes. Mutation: yes. Other_details: pkbbeta residues 146-467 fused to eeqemfedfdyiadw.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Biol. unit:
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Dimer (from PDB file)
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Resolution:
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1.6Å
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R-factor:
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0.198
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R-free:
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0.227
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Authors:
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J.Yang,P.Cron,V.M.Good,V.Thompson,B.A.Hemmings,D.Barford
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Key ref:
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J.Yang
et al.
(2002).
Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP.
Nat Struct Biol,
9,
940-944.
PubMed id:
DOI:
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Date:
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08-Oct-02
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Release date:
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19-Nov-02
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PROCHECK
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Headers
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References
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P31751
(AKT2_HUMAN) -
RAC-beta serine/threonine-protein kinase
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Seq:
Struc:
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481 a.a.
317 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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*
PDB and UniProt seqs differ
at 13 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.11.1
- Non-specific serine/threonine protein kinase.
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Reaction:
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ATP + a protein = ADP + a phosphoprotein
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ATP
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+
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protein
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=
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ADP
Bound ligand (Het Group name = )
matches with 81.00% similarity
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+
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phosphoprotein
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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Gene Ontology (GO) functional annotation
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Biological process
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protein amino acid phosphorylation
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1 term
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Biochemical function
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protein kinase activity
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3 terms
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DOI no:
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Nat Struct Biol
9:940-944
(2002)
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PubMed id:
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Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP.
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J.Yang,
P.Cron,
V.M.Good,
V.Thompson,
B.A.Hemmings,
D.Barford.
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ABSTRACT
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The protein kinase Akt/PKB is stimulated by the phosphorylation of two
regulatory residues, Thr 309 of the activation segment and Ser 474 of the
hydrophobic motif (HM), that are structurally and functionally conserved within
the AGC kinase family. To understand the mechanism of PKB regulation, we
determined the crystal structures of activated kinase domains of PKB in complex
with a GSK3beta-peptide substrate and an ATP analog. The activated state of the
kinase was generated by phosphorylating Thr 309 using PDK1 and mimicking Ser 474
phosphorylation either with the S474D substitution or by replacing the HM of PKB
with that of PIFtide, a potent mimic of a phosphorylated HM. Comparison with the
inactive PKB structure indicates that the role of Ser 474 phosphorylation is to
promote the engagement of the HM with the N-lobe of the kinase domain, promoting
a disorder-to-order transition of the alphaC helix. The alphaC helix, by
interacting with pThr 309, restructures and orders the activation segment,
generating an active kinase conformation. Analysis of the interactions between
PKB and the GSK3beta-peptide explains how PKB selects for protein substrates
distinct from those of PKA.
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Selected figure(s)
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Figure 3.
Figure 3. Comparison of the hydrophobic motif engaged at the
N-lobe of a, PKB-PIF and b, PKB-S474D. The larger number of
interactions between the HM of PIF compared with those of the
authentic HM of PKB with the N-lobe explains the potent ability
of PIF to activate PKB^9.
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Figure 4.
Figure 4. Structural conservation of the substrate
peptide-binding site of PKB, SGK and p70 and p90 S6 kinases.
a, Surface representation of PKB with GSK3  -peptide
shown as sticks. The surface is colored according to sequence
conservation, ramped from red (invariant) to blue (not
conserved). b, Sequence conservation of key residues that
interact with the GSK3-peptide bound to PKB among various AGC
kinases.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
940-944)
copyright 2002.
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Figures were
selected
by the author.
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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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J.D.Sadowsky,
M.A.Burlingame,
D.W.Wolan,
C.L.McClendon,
M.P.Jacobson,
and
J.A.Wells
(2011).
Turning a protein kinase on or off from a single allosteric site via disulfide trapping.
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Proc Natl Acad Sci U S A, 108,
6056-6061.
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PDB codes:
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T.R.Fenton,
and
I.T.Gout
(2011).
Functions and regulation of the 70kDa ribosomal S6 kinases.
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Int J Biochem Cell Biol, 43,
47-59.
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X.N.Tang,
C.W.Lo,
Y.C.Chuang,
C.T.Chen,
Y.C.Sun,
Y.R.Hong,
and
C.N.Yang
(2011).
Prediction of the binding mode between GSK3β and a peptide derived from GSKIP using molecular dynamics simulation.
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Biopolymers, 95,
461-471.
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A.Najafov,
E.M.Sommer,
J.M.Axten,
M.P.Deyoung,
and
D.R.Alessi
(2010).
Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1.
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Biochem J, 433,
357-369.
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A.Peairs,
R.Dai,
L.Gan,
S.Shimp,
M.N.Rylander,
L.Li,
and
C.M.Reilly
(2010).
Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells.
|
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Cell Mol Immunol, 7,
123-132.
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C.A.Boguth,
P.Singh,
C.C.Huang,
and
J.J.Tesmer
(2010).
Molecular basis for activation of G protein-coupled receptor kinases.
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EMBO J, 29,
3249-3259.
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PDB codes:
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C.A.Sparks,
and
D.A.Guertin
(2010).
Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy.
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Oncogene, 29,
3733-3744.
|
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|
|
|
|
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I.Buch,
D.Fishelovitch,
N.London,
B.Raveh,
H.J.Wolfson,
and
R.Nussinov
(2010).
Allosteric regulation of glycogen synthase kinase 3β: a theoretical study.
|
| |
Biochemistry, 49,
10890-10901.
|
|
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|
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|
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J.H.Law,
Y.Li,
K.To,
M.Wang,
A.Astanehe,
K.Lambie,
J.Dhillon,
S.J.Jones,
M.E.Gleave,
C.J.Eaves,
and
S.E.Dunn
(2010).
Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability.
|
| |
PLoS One, 5,
0.
|
|
|
|
|
|
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J.J.Tesmer,
V.M.Tesmer,
D.T.Lodowski,
H.Steinhagen,
and
J.Huber
(2010).
Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol.
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J Med Chem, 53,
1867-1870.
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PDB codes:
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J.Mok,
P.M.Kim,
H.Y.Lam,
S.Piccirillo,
X.Zhou,
G.R.Jeschke,
D.L.Sheridan,
S.A.Parker,
V.Desai,
M.Jwa,
E.Cameroni,
H.Niu,
M.Good,
A.Remenyi,
J.L.Ma,
Y.J.Sheu,
H.E.Sassi,
R.Sopko,
C.S.Chan,
C.De Virgilio,
N.M.Hollingsworth,
W.A.Lim,
D.F.Stern,
B.Stillman,
B.J.Andrews,
M.B.Gerstein,
M.Snyder,
and
B.E.Turk
(2010).
Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs.
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Sci Signal, 3,
ra12.
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L.R.Pearce,
D.Komander,
and
D.R.Alessi
(2010).
The nuts and bolts of AGC protein kinases.
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| |
Nat Rev Mol Cell Biol, 11,
9.
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M.Pozuelo-Rubio,
N.R.Leslie,
J.Murphy,
and
C.Mackintosh
(2010).
Mechanism of activation of PKB/Akt by the protein phosphatase inhibitor Calyculin A.
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Cell Biochem Biophys, 58,
147-156.
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N.Kumar,
and
D.Mohanty
(2010).
Identification of substrates for Ser/Thr kinases using residue-based statistical pair potentials.
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Bioinformatics, 26,
189-197.
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|
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R.Mishra
(2010).
Glycogen synthase kinase 3 beta: can it be a target for oral cancer.
|
| |
Mol Cancer, 9,
144.
|
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|
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T.Takimura,
K.Kamata,
K.Fukasawa,
H.Ohsawa,
H.Komatani,
T.Yoshizumi,
I.Takahashi,
H.Kotani,
and
Y.Iwasawa
(2010).
Structures of the PKC-iota kinase domain in its ATP-bound and apo forms reveal defined structures of residues 533-551 in the C-terminal tail and their roles in ATP binding.
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Acta Crystallogr D Biol Crystallogr, 66,
577-583.
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PDB codes:
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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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Y.W.Ng,
D.Raghunathan,
P.M.Chan,
Y.Baskaran,
D.J.Smith,
C.H.Lee,
C.Verma,
and
E.Manser
(2010).
Why an A-loop phospho-mimetic fails to activate PAK1: understanding an inaccessible kinase state by molecular dynamics simulations.
|
| |
Structure, 18,
879-890.
|
|
|
|
|
|
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A.Filatova,
M.Leyerer,
V.Gorboulev,
C.Chintalapati,
Y.Reinders,
T.D.Müller,
A.Srinivasan,
S.Hübner,
and
H.Koepsell
(2009).
Novel shuttling domain in a regulator (RSC1A1) of transporter SGLT1 steers cell cycle-dependent nuclear location.
|
| |
Traffic, 10,
1599-1618.
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B.X.Huang,
and
H.Y.Kim
(2009).
Probing Akt-inhibitor interaction by chemical cross-linking and mass spectrometry.
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| |
J Am Soc Mass Spectrom, 20,
1504-1513.
|
|
|
|
|
|
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C.C.Dibble,
J.M.Asara,
and
B.D.Manning
(2009).
Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1.
|
| |
Mol Cell Biol, 29,
5657-5670.
|
|
|
|
|
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C.C.Huang,
K.Yoshino-Koh,
and
J.J.Tesmer
(2009).
A Surface of the Kinase Domain Critical for the Allosteric Activation of G Protein-coupled Receptor Kinases.
|
| |
J Biol Chem, 284,
17206-17215.
|
|
|
|
|
|
|
C.Zhang,
N.Yang,
C.H.Yang,
H.S.Ding,
C.Luo,
Y.Zhang,
M.J.Wu,
X.W.Zhang,
X.Shen,
H.L.Jiang,
L.H.Meng,
and
J.Ding
(2009).
S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton.
|
| |
PLoS ONE, 4,
e4881.
|
|
|
|
|
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H.Handoyo,
M.J.Stafford,
E.McManus,
D.Baltzis,
M.Peggie,
and
P.Cohen
(2009).
IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2.
|
| |
Biochem J, 424,
109-118.
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I.Rodríguez-Escudero,
A.Andrés-Pons,
R.Pulido,
M.Molina,
and
V.J.Cid
(2009).
Phosphatidylinositol 3-Kinase-dependent Activation of Mammalian Protein Kinase B/Akt in Saccharomyces cerevisiae, an in Vivo Model for the Functional Study of Akt Mutations.
|
| |
J Biol Chem, 284,
13373-13383.
|
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J.Park,
J.Feng,
Y.Li,
O.Hammarsten,
D.P.Brazil,
and
B.A.Hemmings
(2009).
DNA-dependent Protein Kinase-mediated Phosphorylation of Protein Kinase B Requires a Specific Recognition Sequence in the C-terminal Hydrophobic Motif.
|
| |
J Biol Chem, 284,
6169-6174.
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|
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K.Kaur,
and
T.T.Talele
(2009).
Structure-based CoMFA and CoMSIA study of indolinone inhibitors of PDK1.
|
| |
J Comput Aided Mol Des, 23,
25-36.
|
|
|
|
|
|
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L.Piao,
Y.Li,
K.J.Yang,
K.A.Park,
H.S.Byun,
M.Won,
J.Hong,
J.L.Kim,
G.R.Kweon,
G.M.Hur,
J.H.Seok,
J.Y.Cho,
T.Chun,
D.Hess,
R.Sack,
S.M.Maira,
D.P.Brazil,
B.A.Hemmings,
and
J.Park
(2009).
Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein.
|
| |
BMC Cell Biol, 10,
53.
|
|
|
|
|
|
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M.Guo,
B.X.Huang,
and
H.Y.Kim
(2009).
Conformational changes in Akt1 activation probed by amide hydrogen/deuterium exchange and nano-electrospray ionization mass spectrometry.
|
| |
Rapid Commun Mass Spectrom, 23,
1885-1891.
|
|
|
|
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|
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M.Malakhova,
I.Kurinov,
K.Liu,
D.Zheng,
I.D'Angelo,
J.H.Shim,
V.Steinman,
A.M.Bode,
and
Z.Dong
(2009).
Structural diversity of the active N-terminal kinase domain of p90 ribosomal S6 kinase 2.
|
| |
PLoS One, 4,
e8044.
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PDB code:
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R.Scholz,
M.Suter,
T.Weimann,
C.Polge,
P.V.Konarev,
R.F.Thali,
R.D.Tuerk,
B.Viollet,
T.Wallimann,
U.Schlattner,
and
D.Neumann
(2009).
Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix.
|
| |
J Biol Chem, 284,
27425-27437.
|
|
|
|
|
|
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S.B.Widenmaier,
A.V.Sampaio,
T.M.Underhill,
and
C.H.McIntosh
(2009).
Noncanonical Activation of Akt/Protein Kinase B in {beta}-Cells by the Incretin Hormone Glucose-dependent Insulinotropic Polypeptide.
|
| |
J Biol Chem, 284,
10764-10773.
|
|
|
|
|
|
|
S.Gaitonde,
S.K.De,
M.Tcherpakov,
A.Dewing,
H.Yuan,
M.Riel-Mehan,
S.Krajewski,
G.Robertson,
M.Pellecchia,
and
Z.Ronai
(2009).
BI-69A11-mediated inhibition of AKT leads to effective regression of xenograft melanoma.
|
| |
Pigment Cell Melanoma Res, 22,
187-195.
|
|
|
|
|
|
|
V.Calleja,
M.Laguerre,
and
B.Larijani
(2009).
3-D structure and dynamics of protein kinase B-new mechanism for the allosteric regulation of an AGC kinase.
|
| |
J Chem Biol, 2,
11-25.
|
|
|
|
|
|
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V.Calleja,
M.Laguerre,
P.J.Parker,
and
B.Larijani
(2009).
Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition.
|
| |
PLoS Biol, 7,
e17.
|
|
|
|
|
|
|
V.Hindie,
A.Stroba,
H.Zhang,
L.A.Lopez-Garcia,
L.Idrissova,
S.Zeuzem,
D.Hirschberg,
F.Schaeffer,
T.J.Jørgensen,
M.Engel,
P.M.Alzari,
and
R.M.Biondi
(2009).
Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1.
|
| |
Nat Chem Biol, 5,
758-764.
|
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PDB codes:
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B.E.Turk
(2008).
Understanding and exploiting substrate recognition by protein kinases.
|
| |
Curr Opin Chem Biol, 12,
4.
|
|
|
|
|
|
|
C.Garcia-Echeverria,
and
W.R.Sellers
(2008).
Drug discovery approaches targeting the PI3K/Akt pathway in cancer.
|
| |
Oncogene, 27,
5511-5526.
|
|
|
|
|
|
|
C.Volonté,
N.D'Ambrosi,
and
S.Amadio
(2008).
Protein cooperation: from neurons to networks.
|
| |
Prog Neurobiol, 86,
61-71.
|
|
|
|
|
|
|
D.Komander,
R.Garg,
P.T.Wan,
A.J.Ridley,
and
D.Barford
(2008).
Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure.
|
| |
EMBO J, 27,
3175-3185.
|
|
|
PDB code:
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|
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|
|
|
J.Eswaran,
A.Bernad,
J.M.Ligos,
B.Guinea,
J.E.Debreczeni,
F.Sobott,
S.A.Parker,
R.Najmanovich,
B.E.Turk,
and
S.Knapp
(2008).
Structure of the human protein kinase MPSK1 reveals an atypical activation loop architecture.
|
| |
Structure, 16,
115-124.
|
|
|
|
|
|
|
J.H.Lee,
S.Kumar,
and
D.S.Lawrence
(2008).
Stepwise combinatorial evolution of Akt bisubstrate inhibitors.
|
| |
Chembiochem, 9,
507-509.
|
|
|
|
|
|
|
K.J.Yang,
S.Shin,
L.Piao,
E.Shin,
Y.Li,
K.A.Park,
H.S.Byun,
M.Won,
J.Hong,
G.R.Kweon,
G.M.Hur,
J.H.Seok,
T.Chun,
D.P.Brazil,
B.A.Hemmings,
and
J.Park
(2008).
Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding.
|
| |
J Biol Chem, 283,
1480-1491.
|
|
|
|
|
|
|
S.Gentile,
N.Martin,
E.Scappini,
J.Williams,
C.Erxleben,
and
D.L.Armstrong
(2008).
The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity.
|
| |
Proc Natl Acad Sci U S A, 105,
14704-14708.
|
|
|
|
|
|
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V.Facchinetti,
W.Ouyang,
H.Wei,
N.Soto,
A.Lazorchak,
C.Gould,
C.Lowry,
A.C.Newton,
Y.Mao,
R.Q.Miao,
W.C.Sessa,
J.Qin,
P.Zhang,
B.Su,
and
E.Jacinto
(2008).
The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C.
|
| |
EMBO J, 27,
1932-1943.
|
|
|
|
|
|
|
Y.C.Kuo,
K.Y.Huang,
C.H.Yang,
Y.S.Yang,
W.Y.Lee,
and
C.W.Chiang
(2008).
Regulation of Phosphorylation of Thr-308 of Akt, Cell Proliferation, and Survival by the B55{alpha} Regulatory Subunit Targeting of the Protein Phosphatase 2A Holoenzyme to Akt.
|
| |
J Biol Chem, 283,
1882-1892.
|
|
|
|
|
|
|
A.J.Caplan,
A.K.Mandal,
and
M.A.Theodoraki
(2007).
Molecular chaperones and protein kinase quality control.
|
| |
Trends Cell Biol, 17,
87-92.
|
|
|
|
|
|
|
B.Ananthanarayanan,
M.Fosbrink,
M.Rahdar,
and
J.Zhang
(2007).
Live-cell molecular analysis of Akt activation reveals roles for activation loop phosphorylation.
|
| |
J Biol Chem, 282,
36634-36641.
|
|
|
|
|
|
|
B.D.Manning,
and
L.C.Cantley
(2007).
AKT/PKB signaling: navigating downstream.
|
| |
Cell, 129,
1261-1274.
|
|
|
|
|
|
|
B.Dong,
C.A.Valencia,
and
R.Liu
(2007).
Ca(2+)/calmodulin directly interacts with the pleckstrin homology domain of AKT1.
|
| |
J Biol Chem, 282,
25131-25140.
|
|
|
|
|
|
|
B.Zhao,
R.Lehr,
A.M.Smallwood,
T.F.Ho,
K.Maley,
T.Randall,
M.S.Head,
K.K.Koretke,
and
C.G.Schnackenberg
(2007).
Crystal structure of the kinase domain of serum and glucocorticoid-regulated kinase 1 in complex with AMP PNP.
|
| |
Protein Sci, 16,
2761-2769.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
C.Hauge,
T.L.Antal,
D.Hirschberg,
U.Doehn,
K.Thorup,
L.Idrissova,
K.Hansen,
O.N.Jensen,
T.J.Jørgensen,
R.M.Biondi,
and
M.Frödin
(2007).
Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation.
|
| |
EMBO J, 26,
2251-2261.
|
|
|
|
|
|
|
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.
|
| |
Structure, 15,
1215-1226.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
G.Rocher,
C.Letourneux,
P.Lenormand,
and
F.Porteu
(2007).
Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity.
|
| |
J Biol Chem, 282,
5468-5477.
|
|
|
|
|
|
|
H.Al-Ali,
T.J.Ragan,
X.Gao,
and
T.K.Harris
(2007).
Reconstitution of modular PDK1 functions on trans-splicing of the regulatory PH and catalytic kinase domains.
|
| |
Bioconjug Chem, 18,
1294-1302.
|
|
|
|
|
|
|
J.D.Knight,
B.Qian,
D.Baker,
and
R.Kothary
(2007).
Conservation, variability and the modeling of active protein kinases.
|
| |
PLoS ONE, 2,
e982.
|
|
|
|
|
|
|
M.Ikuta,
M.Kornienko,
N.Byrne,
J.C.Reid,
S.Mizuarai,
H.Kotani,
and
S.K.Munshi
(2007).
Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.
|
| |
Protein Sci, 16,
2626-2635.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.Ranganathan,
Y.Wang,
F.G.Kern,
Z.Qu,
and
R.Li
(2007).
Activation loop phosphorylation-independent kinase activity of human protein kinase C zeta.
|
| |
Proteins, 67,
709-719.
|
|
|
|
|
|
|
T.Sugahara,
Y.Yamashita,
M.Shinomi,
Y.Isobe,
B.Yamanoha,
H.Iseki,
A.Takeda,
Y.Okazaki,
K.Kawai,
H.Suemizu,
and
T.Andoh
(2007).
von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWD(m), induces apoptosis in HeLa cells.
|
| |
Cancer Sci, 98,
909-915.
|
|
|
|
|
|
|
V.Calleja,
D.Alcor,
M.Laguerre,
J.Park,
B.Vojnovic,
B.A.Hemmings,
J.Downward,
P.J.Parker,
and
B.Larijani
(2007).
Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo.
|
| |
PLoS Biol, 5,
e95.
|
|
|
|
|
|
|
V.S.Gowri,
K.Anamika,
S.Gore,
and
N.Srinivasan
(2007).
Analysis on sliding helices and strands in protein structural comparisons: a case study with protein kinases.
|
| |
J Biosci, 32,
921-928.
|
|
|
|
|
|
|
A.Breitkreutz,
and
M.Tyers
(2006).
Cell signaling. A sophisticated scaffold wields a new trick.
|
| |
Science, 311,
789-790.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
D.T.Lodowski,
V.M.Tesmer,
J.L.Benovic,
and
J.J.Tesmer
(2006).
The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs.
|
| |
J Biol Chem, 281,
16785-16793.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
H.Remaut,
and
G.Waksman
(2006).
Protein-protein interaction through beta-strand addition.
|
| |
Trends Biochem Sci, 31,
436-444.
|
|
|
|
|
|
|
I.Collins,
J.Caldwell,
T.Fonseca,
A.Donald,
V.Bavetsias,
L.J.Hunter,
M.D.Garrett,
M.G.Rowlands,
G.W.Aherne,
T.G.Davies,
V.Berdini,
S.J.Woodhead,
D.Davis,
L.C.Seavers,
P.G.Wyatt,
P.Workman,
and
E.McDonald
(2006).
Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
|
| |
Bioorg Med Chem, 14,
1255-1273.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
J.M.Jansen,
M.F.Barry,
C.K.Yoo,
and
E.L.Weiss
(2006).
Phosphoregulation of Cbk1 is critical for RAM network control of transcription and morphogenesis.
|
| |
J Cell Biol, 175,
755-766.
|
|
|
|
|
|
|
K.Strebhardt,
and
A.Ullrich
(2006).
Targeting polo-like kinase 1 for cancer therapy.
|
| |
Nat Rev Cancer, 6,
321-330.
|
|
|
|
|
|
|
L.Héron-Milhavet,
C.Franckhauser,
V.Rana,
C.Berthenet,
D.Fisher,
B.A.Hemmings,
A.Fernandez,
and
N.J.Lamb
(2006).
Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding.
|
| |
Mol Cell Biol, 26,
8267-8280.
|
|
|
|
|
|
|
M.A.Bogoyevitch,
and
B.Kobe
(2006).
Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases.
|
| |
Microbiol Mol Biol Rev, 70,
1061-1095.
|
|
|
|
|
|
|
M.G.Gold,
D.Barford,
and
D.Komander
(2006).
Lining the pockets of kinases and phosphatases.
|
| |
Curr Opin Struct Biol, 16,
693-701.
|
|
|
|
|
|
|
M.S.Gami,
W.B.Iser,
K.B.Hanselman,
and
C.A.Wolkow
(2006).
Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling.
|
| |
BMC Dev Biol, 6,
45.
|
|
|
|
|
|
|
M.Tessier,
and
J.R.Woodgett
(2006).
Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3.
|
| |
J Biol Chem, 281,
23978-23989.
|
|
|
|
|
|
|
R.Ilouz,
N.Kowalsman,
M.Eisenstein,
and
H.Eldar-Finkelman
(2006).
Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition.
|
| |
J Biol Chem, 281,
30621-30630.
|
|
|
|
|
|
|
R.L.Hurley,
L.K.Barré,
S.D.Wood,
K.A.Anderson,
B.E.Kemp,
A.R.Means,
and
L.A.Witters
(2006).
Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP.
|
| |
J Biol Chem, 281,
36662-36672.
|
|
|
|
|
|
|
S.Sánchez-Bautista,
A.Kazaks,
M.Beaulande,
A.Torrecillas,
S.Corbalán-García,
and
J.C.Gómez-Fernández
(2006).
Structural study of the catalytic domain of PKCzeta using infrared spectroscopy and two-dimensional infrared correlation spectroscopy.
|
| |
FEBS J, 273,
3273-3286.
|
|
|
|
|
|
|
S.S.Yeong,
Y.Zhu,
D.Smith,
C.Verma,
W.G.Lim,
B.J.Tan,
Q.T.Li,
N.S.Cheung,
M.Cai,
Y.Z.Zhu,
S.F.Zhou,
S.L.Tan,
and
W.Duan
(2006).
The last 10 amino acid residues beyond the hydrophobic motif are critical for the catalytic competence and function of protein kinase Calpha.
|
| |
J Biol Chem, 281,
30768-30781.
|
|
|
|
|
|
|
X.Zhang,
S.Zhang,
H.Yamane,
R.Wahl,
A.Ali,
J.A.Lofgren,
and
R.L.Kendall
(2006).
Kinetic mechanism of AKT/PKB enzyme family.
|
| |
J Biol Chem, 281,
13949-13956.
|
|
|
|
|
|
|
A.N.Bullock,
J.Debreczeni,
A.L.Amos,
S.Knapp,
and
B.E.Turk
(2005).
Structure and substrate specificity of the Pim-1 kinase.
|
| |
J Biol Chem, 280,
41675-41682.
|
|
|
|
|
|
|
C.C.Kumar,
and
V.Madison
(2005).
AKT crystal structure and AKT-specific inhibitors.
|
| |
Oncogene, 24,
7493-7501.
|
|
|
|
|
|
|
D.Komander,
G.Kular,
M.Deak,
D.R.Alessi,
and
D.M.van Aalten
(2005).
Role of T-loop phosphorylation in PDK1 activation, stability, and substrate binding.
|
| |
J Biol Chem, 280,
18797-18802.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
E.D.Scheeff,
and
P.E.Bourne
(2005).
Structural evolution of the protein kinase-like superfamily.
|
| |
PLoS Comput Biol, 1,
e49.
|
|
|
|
|
|
|
G.Zhu,
K.Fujii,
Y.Liu,
V.Codrea,
J.Herrero,
and
S.Shaw
(2005).
A single pair of acidic residues in the kinase major groove mediates strong substrate preference for P-2 or P-5 arginine in the AGC, CAMK, and STE kinase families.
|
| |
J Biol Chem, 280,
36372-36379.
|
|
|
|
|
|
|
I.A.Manke,
A.Nguyen,
D.Lim,
M.Q.Stewart,
A.E.Elia,
and
M.B.Yaffe
(2005).
MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.
|
| |
Mol Cell, 17,
37-48.
|
|
|
|
|
|
|
J.R.Woodgett
(2005).
Recent advances in the protein kinase B signaling pathway.
|
| |
Curr Opin Cell Biol, 17,
150-157.
|
|
|
|
|
|
|
M.R.Stegert,
A.Hergovich,
R.Tamaskovic,
S.J.Bichsel,
and
B.A.Hemmings
(2005).
Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3.
|
| |
Mol Cell Biol, 25,
11019-11029.
|
|
|
|
|
|
|
R.C.Hresko,
and
M.Mueckler
(2005).
mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes.
|
| |
J Biol Chem, 280,
40406-40416.
|
|
|
|
|
|
|
R.Forough,
B.Weylie,
C.Patel,
S.Ambrus,
U.S.Singh,
and
J.Zhu
(2005).
Role of AKT/PKB signaling in fibroblast growth factor-1 (FGF-1)-induced angiogenesis in the chicken chorioallantoic membrane (CAM).
|
| |
J Cell Biochem, 94,
109-116.
|
|
|
|
|
|
|
S.Schinner,
A.Barthel,
C.Dellas,
R.Grzeskowiak,
S.K.Sharma,
E.Oetjen,
R.Blume,
and
W.Knepel
(2005).
Protein kinase B activity is sufficient to mimic the effect of insulin on glucagon gene transcription.
|
| |
J Biol Chem, 280,
7369-7376.
|
|
|
|
|
|
|
A.Kumar,
A.Vaid,
C.Syin,
and
P.Sharma
(2004).
PfPKB, a novel protein kinase B-like enzyme from Plasmodium falciparum: I. Identification, characterization, and possible role in parasite development.
|
| |
J Biol Chem, 279,
24255-24264.
|
|
|
|
|
|
|
A.Mora,
D.Komander,
D.M.van Aalten,
and
D.R.Alessi
(2004).
PDK1, the master regulator of AGC kinase signal transduction.
|
| |
Semin Cell Dev Biol, 15,
161-170.
|
|
|
|
|
|
|
C.Rüegg,
O.Dormond,
and
A.Mariotti
(2004).
Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis.
|
| |
Biochim Biophys Acta, 1654,
51-67.
|
|
|
|
|
|
|
I.Remy,
A.Montmarquette,
and
S.W.Michnick
(2004).
PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3.
|
| |
Nat Cell Biol, 6,
358-365.
|
|
|
|
|
|
|
I.Remy,
and
S.W.Michnick
(2004).
Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt.
|
| |
Mol Cell Biol, 24,
1493-1504.
|
|
|
|
|
|
|
K.J.Smith,
P.S.Carter,
A.Bridges,
P.Horrocks,
C.Lewis,
G.Pettman,
A.Clarke,
M.Brown,
J.Hughes,
M.Wilkinson,
B.Bax,
and
A.Reith
(2004).
The structure of MSK1 reveals a novel autoinhibitory conformation for a dual kinase protein.
|
| |
Structure, 12,
1067-1077.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
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.
|
| |
J Biol Chem, 279,
23679-23690.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
M.Hiromura,
F.Okada,
T.Obata,
D.Auguin,
T.Shibata,
C.Roumestand,
and
M.Noguchi
(2004).
Inhibition of Akt kinase activity by a peptide spanning the betaA strand of the proto-oncogene TCL1.
|
| |
J Biol Chem, 279,
53407-53418.
|
|
|
|
|
|
|
M.R.Stegert,
R.Tamaskovic,
S.J.Bichsel,
A.Hergovich,
and
B.A.Hemmings
(2004).
Regulation of NDR2 protein kinase by multi-site phosphorylation and the S100B calcium-binding protein.
|
| |
J Biol Chem, 279,
23806-23812.
|
|
|
|
|
|
|
M.Y.Niv,
H.Rubin,
J.Cohen,
L.Tsirulnikov,
T.Licht,
A.Peretzman-Shemer,
E.Cna'an,
A.Tartakovsky,
I.Stein,
S.Albeck,
I.Weinstein,
M.Goldenberg-Furmanov,
D.Tobi,
E.Cohen,
M.Laster,
S.A.Ben-Sasson,
and
H.Reuveni
(2004).
Sequence-based design of kinase inhibitors applicable for therapeutics and target identification.
|
| |
J Biol Chem, 279,
1242-1255.
|
|
|
|
|
|
|
N.J.Dibb,
S.M.Dilworth,
and
C.D.Mol
(2004).
Switching on kinases: oncogenic activation of BRAF and the PDGFR family.
|
| |
Nat Rev Cancer, 4,
718-727.
|
|
|
|
|
|
|
O.J.Shah,
and
T.Hunter
(2004).
Critical role of T-loop and H-motif phosphorylation in the regulation of S6 kinase 1 by the tuberous sclerosis complex.
|
| |
J Biol Chem, 279,
20816-20823.
|
|
|
|
|
|
|
P.T.Wan,
M.J.Garnett,
S.M.Roe,
S.Lee,
D.Niculescu-Duvaz,
V.M.Good,
C.M.Jones,
C.J.Marshall,
C.J.Springer,
D.Barford,
and
R.Marais
(2004).
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
|
| |
Cell, 116,
855-867.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
S.George,
J.J.Rochford,
C.Wolfrum,
S.L.Gray,
S.Schinner,
J.C.Wilson,
M.A.Soos,
P.R.Murgatroyd,
R.M.Williams,
C.L.Acerini,
D.B.Dunger,
D.Barford,
A.M.Umpleby,
N.J.Wareham,
H.A.Davies,
A.J.Schafer,
M.Stoffel,
S.O'Rahilly,
and
I.Barroso
(2004).
A family with severe insulin resistance and diabetes due to a mutation in AKT2.
|
| |
Science, 304,
1325-1328.
|
|
|
|
|
|
|
S.Hövelmann,
T.L.Beckers,
and
M.Schmidt
(2004).
Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells.
|
| |
Br J Cancer, 90,
2370-2377.
|
|
|
|
|
|
|
Z.B.Xu,
D.Chaudhary,
S.Olland,
S.Wolfrom,
R.Czerwinski,
K.Malakian,
L.Lin,
M.L.Stahl,
D.Joseph-McCarthy,
C.Benander,
L.Fitz,
R.Greco,
W.S.Somers,
and
L.Mosyak
(2004).
Catalytic domain crystal structure of protein kinase C-theta (PKCtheta).
|
| |
J Biol Chem, 279,
50401-50409.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
A.Mora,
A.M.Davies,
L.Bertrand,
I.Sharif,
G.R.Budas,
S.Jovanović,
V.Mouton,
C.R.Kahn,
J.M.Lucocq,
G.A.Gray,
A.Jovanović,
and
D.R.Alessi
(2003).
Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia.
|
| |
EMBO J, 22,
4666-4676.
|
|
|
|
|
|
|
B.J.Collins,
M.Deak,
J.S.Arthur,
L.J.Armit,
and
D.R.Alessi
(2003).
In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation.
|
| |
EMBO J, 22,
4202-4211.
|
|
|
|
|
|
|
C.Breitenlechner,
M.Gassel,
H.Hidaka,
V.Kinzel,
R.Huber,
R.A.Engh,
and
D.Bossemeyer
(2003).
Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.
|
| |
Structure, 11,
1595-1607.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
D.T.Lodowski,
J.A.Pitcher,
W.D.Capel,
R.J.Lefkowitz,
and
J.J.Tesmer
(2003).
Keeping G proteins at bay: a complex between G protein-coupled receptor kinase 2 and Gbetagamma.
|
| |
Science, 300,
1256-1262.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
J.Luo,
B.D.Manning,
and
L.C.Cantley
(2003).
Targeting the PI3K-Akt pathway in human cancer: rationale and promise.
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Cancer Cell, 4,
257-262.
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S.Bhattacharya,
E.Large,
C.W.Heizmann,
B.Hemmings,
and
W.J.Chazin
(2003).
Structure of the Ca2+/S100B/NDR kinase peptide complex: insights into S100 target specificity and activation of the kinase.
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| |
Biochemistry, 42,
14416-14426.
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PDB code:
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S.L.Christian,
R.L.Lee,
S.J.McLeod,
A.E.Burgess,
A.H.Li,
M.Dang-Lawson,
K.B.Lin,
and
M.R.Gold
(2003).
Activation of the Rap GTPases in B lymphocytes modulates B cell antigen receptor-induced activation of Akt but has no effect on MAPK activation.
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J Biol Chem, 278,
41756-41767.
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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
