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PDBsum entry 1e90
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Phosphoinositide 3-kinase gamma
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PDB id
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1e90
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural determinants of phosphoinositide 3-Kinase inhibition by wortmannin, Ly294002, Quercetin, Myricetin, And staurosporine.
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Authors
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E.H.Walker,
M.E.Pacold,
O.Perisic,
L.Stephens,
P.T.Hawkins,
M.P.Wymann,
R.L.Williams.
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Ref.
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Mol Cell, 2000,
6,
909-919.
[DOI no: ]
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PubMed id
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Abstract
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The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002
have been invaluable tools for elucidating the roles of these enzymes in signal
transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound
to these lipid kinase inhibitors and to the broad-spectrum protein kinase
inhibitors quercetin, myricetin, and staurosporine reveal how these compounds
fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely
fits and fills the active site and induces a conformational change in the
catalytic domain. Surprisingly, LY294002 and the lead compound on which it was
designed, quercetin, as well as the closely related flavonoid myricetin bind
PI3K in remarkably different orientations that are related to each other by 180
degrees rotations. Staurosporine/PI3K interactions are reminiscent of
low-affinity protein kinase/staurosporine complexes. These results provide a
rich basis for development of isoform-specific PI3K inhibitors with therapeutic
potential.
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Figure 4.
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Figure 5.
Figure 5. Stereoplots of the Active Sites of the PI3K
Inhibitor ComplexesHydrogen bonds are shown as red dotted lines.
(A) ATP, (B) Wortmannin, (C) LY294002, (D) Quercetin, (E)
Myricetin, (F) Staurosporine.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2000,
6,
909-919)
copyright 2000.
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Secondary reference #1
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Title
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Structural insights into phosphoinositide 3-Kinase catalysis and signalling.
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Authors
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E.H.Walker,
O.Perisic,
C.Ried,
L.Stephens,
R.L.Williams.
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Ref.
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Nature, 1999,
402,
313-320.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1 Overall structure of PI3K  .
a, Ribbon diagram of PI3K (prepared
with MOLSCRIPT31) showing the four domains: RBD (magenta), C2
(blue), helical (green) and catalytic with N-lobe (red) and
C-lobe (yellow). The N-terminal region preceding the RBD and the
ordered portion between the RBD and C2 domain are white. b, The
solvent-accessible surface of the enzyme in the same orientation
as in a (prepared with GRASP29). c, Domain organization of the
PI3K classes.
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Figure 4.
Figure 4 Model of phospholipid headgroup interactions with
PI3K .
a, Orthogonal views of the solvent-accessible surface. The
activation loop is black. An inositol 1,4,5-trisphosphate
(InsP[3]) molecule (white ball-and-stick) is modelled in the
active site with the 3-OH near the -phosphate
of the bound ATP. b, The same views in ribbon representation
showing the activation loop (magenta) and InsP[3] (blue). The
right panel is expanded to show features of the putative
headgroup interaction.
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The above figures are
reproduced from the cited reference
with permission from Macmillan Publishers Ltd
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