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PDBsum entry 2uzr
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References listed in PDB file
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Key reference
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Title
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A transforming mutation in the pleckstrin homology domain of akt1 in cancer.
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Authors
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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,
J.E.Thomas.
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Ref.
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Nature, 2007,
448,
439-444.
[DOI no: ]
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PubMed id
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Abstract
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Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a
central member of possibly the most frequently activated proliferation and
survival pathway in cancer, mutation of AKT1 has not been widely reported. Here
we report the identification of a somatic mutation in human breast, colorectal
and ovarian cancers that results in a glutamic acid to lysine substitution at
amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the
electrostatic interactions of the pocket and forms new hydrogen bonds with a
phosphoinositide ligand. This mutation activates AKT1 by means of pathological
localization to the plasma membrane, stimulates downstream signalling,
transforms cells and induces leukaemia in mice. This mechanism indicates a
direct role of AKT1 in human cancer, and adds to the known genetic alterations
that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT
pathway. Furthermore, the E17K substitution decreases the sensitivity to an
allosteric kinase inhibitor, so this mutation may have important clinical
utility for AKT drug development.
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Figure 1.
Figure 1: Lys 17 alters the apo and Ins(1,3,4,5)P[4]-complexed
AKT1 PHD structure. a, In apo wild-type PHD, an ionic
interaction between Glu 17 and Lys 14 (line) fills the binding
pocket. b, E17K PHD apo with Lys 17 turned away from Lys 14. c,
E17K PHD with Lys 17 involved in new hydrogen bonds (dashed
lines) with a water molecule (orange sphere), interposed with
the D6-hydroxyl group, and the D5-phosphate of Ins(1,3,4,5)P[4]
(orange). Lys 17 also forms a new hydrogen bond with the
hydroxyl of Tyr 18. The D1-phosphate forms a hydrogen bond with
the amide of Tyr 18, similar to the wild-type PHD. Distances
shown are in angstroms.
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Figure 5.
Figure 5: Timing and signature of AKT1(E17K)-driven leukaemia.
a, Timing of leukaemia onset as determined by the appearance of
discernible P-AKT(Ser 473)–GFP cells in blood of rescued
lethally irradiated host animals. Myr–AKT1 (n = 12, solid
circles), AKT1(E17K) (n = 10, filled triangles), AKT1(WT) (n =
10, open squares) and mock transduction (n = 3, X) is shown. b,
Representative flow cytometry results from leukaemic mice
(AKT1(E17K) and Myr–AKT1) and non-leukaemic mice (Mock and
AKT1(WT)) after staining for P-AKT(Ser 473). c, Stained blood
smear from a representative AKT1(E17K) animal showing leukaemic
blasts (  100
magnification).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2007,
448,
439-444)
copyright 2007.
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