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Review
. 2008 Sep;8(9):665-9.
doi: 10.1038/nrc2443.

Structural comparisons of class I phosphoinositide 3-kinases

L Mario Amzel  1 , Chuan-Hsiang Huang, Diana Mandelker, Christoph Lengauer, Sandra B Gabelli, Bert Vogelstein
Affiliations
Review

Structural comparisons of class I phosphoinositide 3-kinases

L Mario Amzel et al. Nat Rev Cancer. 2008 Sep.

Abstract

Class I phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate cell growth. One of these kinases, PI3Kalpha, is frequently mutated in diverse tumour types. The recently determined structure of PI3Kalpha reveals features that distinguish this enzyme from related lipid kinases. In addition, wild-type PI3Kgamma differs from PI3Kalpha by a substitution identical to a PI3Kalpha oncogenic mutant (His1047Arg) that might explain the differences in the enzymatic activities of the normal and mutant PI3Kalpha. Comparison of the PI3K structures also identified structural features that could potentially be exploited for the design of isoform-specific inhibitors.

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Figures

Fig. 1
Fig. 1
Comparison of the RBDs (Ras-binding domains) of p110α and p110γ A. Comparison of the RBDs of p110α (blue) and free p110γ (gold). The blue arrow shows the ordering of residues 227–247 in p110α. B. Comparison of the RBDs of p110α and Ras/p110γ complex. The red arrow indicates the position of residues 255–267 in p110γ that become ordered by the binding of Ras. C. Interaction between p110α molecules in the crystal structure. The RBD (blue, molecule B) is locked in the ATP binding pocket of the kinase domain from a neighboring molecule (magenta, molecule A)
Fig. 2
Fig. 2
Comparison between the C2 domains of p110α and p110γ The C2 domains from p110α (cyan) and p110γ (pink) are aligned. The incompatibility between CBR1 of p110γ and iSH2 binding is indicated by red arrow (see text)
Fig. 3
Fig. 3
Comparison between the Kinase domains of p110α and p110γ A. The two equivalent helices, αK12 of p110α and kα11 of p110γ, are shown in magenta and orange, respectively. The positions of the helices in each of the structures are shown by the arrows. B. The interaction between His1047 and Leu956 in p110α is shown. C. The interaction between Arg1076 and Lys1000 in p110γ is shown. Superposition of the p110α shows the different position of αK12 helix compared with kα11 helix of p110γ. D. Conformations of the activation and catalytic loops of p110α and p110γ.
See this image and copyright information in PMC

References

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