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PDBsum entry 1unp
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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 the pleckstrin homology domain of pkb alpha
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Structure:
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Rac-alpha serine/threonine kinase. Chain: a. Fragment: pleckstrin homology domain, residues 1-121. Synonym: rac-pk-alpha, protein kinase b, pkb, c-akt. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
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Resolution:
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1.65Å
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R-factor:
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0.201
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R-free:
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0.236
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Authors:
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C.C.Milburn,M.Deak,S.M.Kelly,N.C.Price,D.R.Alessi,D.M.F.Van Aalten
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Key ref:
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C.C.Milburn
et al.
(2003).
Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change.
Biochem J,
375,
531-538.
PubMed id:
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Date:
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12-Sep-03
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Release date:
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16-Sep-04
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PROCHECK
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Headers
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References
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P31749
(AKT1_HUMAN) -
RAC-alpha serine/threonine-protein kinase from Homo sapiens
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Seq:
Struc:
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480 a.a.
119 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.2.7.11.1
- non-specific serine/threonine 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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Biochem J
375:531-538
(2003)
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PubMed id:
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Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change.
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C.C.Milburn,
M.Deak,
S.M.Kelly,
N.C.Price,
D.R.Alessi,
D.M.Van Aalten.
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ABSTRACT
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Protein kinase B (PKB/Akt) is a key regulator of cell growth, proliferation and
metabolism. It possesses an N-terminal pleckstrin homology (PH) domain that
interacts with equal affinity with the second messengers PtdIns(3,4,5)P3 and
PtdIns(3,4)P2, generated through insulin and growth factor-mediated activation
of phosphoinositide 3-kinase (PI3K). The binding of PKB to
PtdIns(3,4,5)P3/PtdIns(3,4)P2 recruits PKB from the cytosol to the plasma
membrane and is also thought to induce a conformational change that converts PKB
into a substrate that can be activated by the phosphoinositide-dependent kinase
1 (PDK1). In this study we describe two high-resolution crystal structures of
the PH domain of PKBalpha in a noncomplexed form and compare this to a new
atomic resolution (0.98 A, where 1 A=0.1 nm) structure of the PH domain of
PKBalpha complexed to Ins(1,3,4,5)P4, the head group of PtdIns(3,4,5)P3.
Remarkably, in contrast to all other PH domains crystallized so far, our data
suggest that binding of Ins(1,3,4,5)P4 to the PH domain of PKB, induces a large
conformational change. This is characterized by marked changes in certain
residues making up the phosphoinositide-binding site, formation of a short
a-helix in variable loop 2, and a movement of variable loop 3 away from the
lipid-binding site. Solution studies with CD also provided evidence of
conformational changes taking place upon binding of Ins(1,3,4,5)P4 to the PH
domain of PKB. Our data provides the first structural insight into the mechanism
by which the interaction of PKB with PtdIns(3,4,5)P3/PtdIns(3,4)P2 induces
conformational changes that could enable PKB to be activated by PDK1.
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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.F.Rowland,
D.J.Fazakerley,
and
D.E.James
(2011).
Mapping Insulin/GLUT4 Circuitry.
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Traffic,
12,
672-681.
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B.X.Huang,
M.Akbar,
K.Kevala,
and
H.Y.Kim
(2011).
Phosphatidylserine is a critical modulator for Akt activation.
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J Cell Biol,
192,
979-992.
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S.A.Rosen,
P.R.Gaffney,
and
I.R.Gould
(2011).
A theoretical investigation of inositol 1,3,4,5-tetrakisphosphate.
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Phys Chem Chem Phys,
13,
1070-1081.
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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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D.Finlay,
and
D.Cantrell
(2010).
Phosphoinositide 3-kinase and the mammalian target of rapamycin pathways control T cell migration.
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Ann N Y Acad Sci,
1183,
149-157.
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E.Bjørgo,
S.A.Solheim,
H.Abrahamsen,
G.S.Baillie,
K.M.Brown,
T.Berge,
K.Okkenhaug,
M.D.Houslay,
and
K.Taskén
(2010).
Cross talk between phosphatidylinositol 3-kinase and cyclic AMP (cAMP)-protein kinase a signaling pathways at the level of a protein kinase B/beta-arrestin/cAMP phosphodiesterase 4 complex.
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Mol Cell Biol,
30,
1660-1672.
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I.Eke,
U.Koch,
S.Hehlgans,
V.Sandfort,
F.Stanchi,
D.Zips,
M.Baumann,
A.Shevchenko,
C.Pilarsky,
M.Haase,
G.B.Baretton,
V.Calleja,
B.Larijani,
R.Fässler,
and
N.Cordes
(2010).
PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1alpha.
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J Clin Invest,
120,
2516-2527.
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J.M.Askham,
F.Platt,
P.A.Chambers,
H.Snowden,
C.F.Taylor,
and
M.A.Knowles
(2010).
AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K.
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Oncogene,
29,
150-155.
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Q.L.Zhou,
Z.Y.Jiang,
A.S.Mabardy,
C.M.Del Campo,
D.G.Lambright,
J.Holik,
K.E.Fogarty,
J.Straubhaar,
S.Nicoloro,
A.Chawla,
and
M.P.Czech
(2010).
A novel pleckstrin homology domain-containing protein enhances insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes.
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J Biol Chem,
285,
27581-27589.
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T.G.Kutateladze
(2010).
Translation of the phosphoinositide code by PI effectors.
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Nat Chem Biol,
6,
507-513.
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T.McHardy,
J.J.Caldwell,
K.M.Cheung,
L.J.Hunter,
K.Taylor,
M.Rowlands,
R.Ruddle,
A.Henley,
A.de Haven Brandon,
M.Valenti,
T.G.Davies,
L.Fazal,
L.Seavers,
F.I.Raynaud,
S.A.Eccles,
G.W.Aherne,
M.D.Garrett,
and
I.Collins
(2010).
Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).
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J Med Chem,
53,
2239-2249.
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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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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.Waugh,
L.Sinclair,
D.Finlay,
J.R.Bayascas,
and
D.Cantrell
(2009).
Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation.
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Mol Cell Biol,
29,
5952-5962.
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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.
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J Biol Chem,
284,
13373-13383.
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L.Du-Cuny,
Z.Song,
S.Moses,
G.Powis,
E.A.Mash,
E.J.Meuillet,
and
S.Zhang
(2009).
Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain.
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Bioorg Med Chem,
17,
6983-6992.
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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.
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Rapid Commun Mass Spectrom,
23,
1885-1891.
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M.Rubio,
D.Avitabile,
K.Fischer,
G.Emmanuel,
N.Gude,
S.Miyamoto,
S.Mishra,
E.M.Schaefer,
J.H.Brown,
and
M.A.Sussman
(2009).
Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes.
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J Mol Cell Cardiol,
47,
96.
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S.A.Moses,
M.A.Ali,
S.Zuohe,
L.Du-Cuny,
L.L.Zhou,
R.Lemos,
N.Ihle,
A.G.Skillman,
S.Zhang,
E.A.Mash,
G.Powis,
and
E.J.Meuillet
(2009).
In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT.
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Cancer Res,
69,
5073-5081.
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S.Miyamoto,
M.Rubio,
and
M.A.Sussman
(2009).
Nuclear and mitochondrial signalling Akts in cardiomyocytes.
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Cardiovasc Res,
82,
272-285.
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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.
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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.
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PLoS Biol,
7,
e17.
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C.J.Green,
O.Göransson,
G.S.Kular,
N.R.Leslie,
A.Gray,
D.R.Alessi,
K.Sakamoto,
and
H.S.Hundal
(2008).
Use of Akt Inhibitor and a Drug-resistant Mutant Validates a Critical Role for Protein Kinase B/Akt in the Insulin-dependent Regulation of Glucose and System A Amino Acid Uptake.
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J Biol Chem,
283,
27653-27667.
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C.Volonté,
N.D'Ambrosi,
and
S.Amadio
(2008).
Protein cooperation: from neurons to networks.
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Prog Neurobiol,
86,
61-71.
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G.Li,
A.Rajala,
A.F.Wiechmann,
R.E.Anderson,
and
R.V.Rajala
(2008).
Activation and membrane binding of retinal protein kinase Balpha/Akt1 is regulated through light-dependent generation of phosphoinositides.
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J Neurochem,
107,
1382-1397.
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J.R.Bayascas,
S.Wullschleger,
K.Sakamoto,
J.M.García-Martínez,
C.Clacher,
D.Komander,
D.M.van Aalten,
K.M.Boini,
F.Lang,
C.Lipina,
L.Logie,
C.Sutherland,
J.A.Chudek,
J.A.van Diepen,
P.J.Voshol,
J.M.Lucocq,
and
D.R.Alessi
(2008).
Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance.
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Mol Cell Biol,
28,
3258-3272.
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PDB code:
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M.Leone,
E.C.Yu,
R.C.Liddington,
E.B.Pasquale,
and
M.Pellecchia
(2008).
The PTB domain of tensin: NMR solution structure and phosphoinositides binding studies.
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Biopolymers,
89,
86-92.
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PDB code:
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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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S.Wang,
and
M.D.Basson
(2008).
Identification of functional domains in AKT responsible for distinct roles of AKT isoforms in pressure-stimulated cancer cell adhesion.
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Exp Cell Res,
314,
286-296.
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T.J.Wiles,
B.K.Dhakal,
D.S.Eto,
and
M.A.Mulvey
(2008).
Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins.
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Mol Biol Cell,
19,
1427-1438.
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W.Nickel,
and
M.Seedorf
(2008).
Unconventional mechanisms of protein transport to the cell surface of eukaryotic cells.
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Annu Rev Cell Dev Biol,
24,
287-308.
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A.Rosenhouse-Dantsker,
and
D.E.Logothetis
(2007).
Molecular characteristics of phosphoinositide binding.
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Pflugers Arch,
455,
45-53.
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B.Dong,
C.A.Valencia,
and
R.Liu
(2007).
Ca(2+)/calmodulin directly interacts with the pleckstrin homology domain of AKT1.
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J Biol Chem,
282,
25131-25140.
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J.D.Carpten,
A.L.Faber,
C.Horn,
G.P.Donoho,
S.L.Briggs,
C.M.Robbins,
G.Hostetter,
S.Boguslawski,
T.Y.Moses,
S.Savage,
M.Uhlik,
A.Lin,
J.Du,
Y.W.Qian,
D.J.Zeckner,
G.Tucker-Kellogg,
J.Touchman,
K.Patel,
S.Mousses,
M.Bittner,
R.Schevitz,
M.H.Lai,
K.L.Blanchard,
and
J.E.Thomas
(2007).
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
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Nature,
448,
439-444.
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PDB codes:
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J.P.DiNitto,
A.Delprato,
M.T.Gabe Lee,
T.C.Cronin,
S.Huang,
A.Guilherme,
M.P.Czech,
and
D.G.Lambright
(2007).
Structural basis and mechanism of autoregulation in 3-phosphoinositide-dependent Grp1 family Arf GTPase exchange factors.
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Mol Cell,
28,
569-583.
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PDB codes:
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K.Okkenhaug,
K.Ali,
and
B.Vanhaesebroeck
(2007).
Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K.
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Trends Immunol,
28,
80-87.
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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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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.
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| |
PLoS Biol,
5,
e95.
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Y.Jia,
K.K.Subramanian,
C.Erneux,
V.Pouillon,
H.Hattori,
H.Jo,
J.You,
D.Zhu,
S.Schurmans,
and
H.R.Luo
(2007).
Inositol 1,3,4,5-tetrakisphosphate negatively regulates phosphatidylinositol-3,4,5- trisphosphate signaling in neutrophils.
|
| |
Immunity,
27,
453-467.
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X.Su,
I.J.Lodhi,
A.R.Saltiel,
and
P.D.Stahl
(2006).
Insulin-stimulated Interaction between insulin receptor substrate 1 and p85alpha and activation of protein kinase B/Akt require Rab5.
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| |
J Biol Chem,
281,
27982-27990.
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C.C.Kumar,
and
V.Madison
(2005).
AKT crystal structure and AKT-specific inhibitors.
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| |
Oncogene,
24,
7493-7501.
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D.Pim,
P.Massimi,
S.M.Dilworth,
and
L.Banks
(2005).
Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A.
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| |
Oncogene,
24,
7830-7838.
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J.A.Kim,
D.C.Yeh,
M.Ver,
Y.Li,
A.Carranza,
T.P.Conrads,
T.D.Veenstra,
M.A.Harrington,
and
M.J.Quon
(2005).
Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance.
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| |
J Biol Chem,
280,
23173-23183.
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M.A.Teitell
(2005).
The TCL1 family of oncoproteins: co-activators of transformation.
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| |
Nat Rev Cancer,
5,
640-648.
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M.P.Scheid,
M.Parsons,
and
J.R.Woodgett
(2005).
Phosphoinositide-dependent phosphorylation of PDK1 regulates nuclear translocation.
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| |
Mol Cell Biol,
25,
2347-2363.
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R.I.Feldman,
J.M.Wu,
M.A.Polokoff,
M.J.Kochanny,
H.Dinter,
D.Zhu,
S.L.Biroc,
B.Alicke,
J.Bryant,
S.Yuan,
B.O.Buckman,
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(2005).
Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.
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J Biol Chem,
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PDB code:
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V.Niggli
(2005).
Regulation of protein activities by phosphoinositide phosphates.
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Annu Rev Cell Dev Biol,
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A.Mora,
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D.M.van Aalten,
and
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(2004).
PDK1, the master regulator of AGC kinase signal transduction.
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Semin Cell Dev Biol,
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D.Auguin,
P.Barthe,
C.Royer,
M.H.Stern,
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S.T.Arold,
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C.Roumestand
(2004).
Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins.
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J Biol Chem,
279,
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D.Komander,
A.Fairservice,
M.Deak,
G.S.Kular,
A.R.Prescott,
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S.T.Safrany,
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(2004).
Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates.
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| |
EMBO J,
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PDB codes:
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D.Komander,
M.Deak,
N.Morrice,
and
D.M.van Aalten
(2004).
Purification, crystallization and preliminary X-ray diffraction of a proteolytic fragment of PDK1 containing the pleckstrin homology domain.
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Acta Crystallogr D Biol Crystallogr,
60,
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E.J.McManus,
B.J.Collins,
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L.J.Armit,
J.S.Arthur,
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(2004).
The in vivo role of PtdIns(3,4,5)P3 binding to PDK1 PH domain defined by knockin mutation.
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EMBO J,
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J.J.Gills,
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Inhibition of Akt kinase activity by a peptide spanning the betaA strand of the proto-oncogene TCL1.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
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only a partial list as not all journals are covered by
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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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