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PDBsum entry 2rd0
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Transferase/oncoprotein
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PDB id
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2rd0
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References listed in PDB file
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Key reference
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Title
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The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic pi3kalpha mutations.
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Authors
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C.H.Huang,
D.Mandelker,
O.Schmidt-Kittler,
Y.Samuels,
V.E.Velculescu,
K.W.Kinzler,
B.Vogelstein,
S.B.Gabelli,
L.M.Amzel.
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Ref.
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Science, 2007,
318,
1744-1748.
[DOI no: ]
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PubMed id
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Abstract
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PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes
for p110alpha, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform
alpha (PI3Kalpha, p110alpha/p85). Here, we report a 3.0 angstrom resolution
structure of a complex between p110alpha and a polypeptide containing the
p110alpha-binding domains of p85alpha, a protein required for its enzymatic
activity. The structure shows that many of the mutations occur at residues lying
at the interfaces between p110alpha and p85alpha or between the kinase domain of
p110alpha and other domains within the catalytic subunit. Disruptions of these
interactions are likely to affect the regulation of kinase activity by p85 or
the catalytic activity of the enzyme, respectively. In addition to providing new
insights about the structure of PI3Kalpha, these results suggest specific
mechanisms for the effect of oncogenic mutations in p110alpha and p85alpha.
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Figure 2.
Fig. 2. Mutations in PIK3CA identified in human cancers. (A)
Distribution of representative mutations within p110  .
Residues mutated in cancers are shown as CPK models. The start
of the cancer-associated truncation (residue 571 of p85) is
shown by the red arrowhead. (B) Electron density map of Arg^38
and Arg^88 cancer mutations shown at the interface between the
ABD and the kinase domains. (C) Close-up view of the interface
of the C2 domain of p110 with iSH2 of p85. The stick
representation of the Asn^345 mutation of C2 and the residues
within iSH2 (Asp^560 and Asn^564) with which it may interact are
shown. (D) Mutations in the helical domain (Glu^542, Glu^545,
and Gln^546), located at the interface with nSH2 (orange
surface). (E) Mutations of the kinase domain (Met^1043 and
His^1047), located near the C-terminal end of the activation
loop, are shown in light green. The part of the activation loop
between residues 941 and 950 could not be traced (see text).
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Figure 3.
Fig. 3. Model of membrane interaction. (A) Positively charged
residues on the surface of iSH2 domain of p85 (red) and loops
of the C2 and kinase domains of p110 (black) are
proposed to contact the negatively charged phospholipid bilayer.
(B) Model of p110 /niSH2 bound to
Ras and its proposed orientation with respect to the lipid
membrane.
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The above figures are
reprinted
by permission from the AAAs:
Science
(2007,
318,
1744-1748)
copyright 2007.
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