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. 2000 Dec 8;103(6):931-43.
doi: 10.1016/s0092-8674(00)00196-3.

Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma

M E Pacold  1 , S Suire, O Perisic, S Lara-Gonzalez, C T Davis, E H Walker, P T Hawkins, L Stephens, J F Eccleston, R L Williams
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Free article

Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma

M E Pacold et al. Cell. .
Free article

Abstract

Ras activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. We find that PI3Kgamma is strongly and directly activated by H-Ras G12V in vivo or by GTPgammaS-loaded H-Ras in vitro. We have determined a crystal structure of a PI3Kgamma/Ras.GMPPNP complex. A critical loop in the Ras binding domain positions Ras so that it uses its switch I and switch II regions to bind PI3Kgamma. Mutagenesis shows that interactions with both regions are essential for binding PI3Kgamma. Ras also forms a direct contact with the PI3Kgamma catalytic domain. These unique Ras/PI3Kgamma interactions are likely to be shared by PI3Kalpha. The complex with Ras shows a change in the PI3K conformation that may represent an allosteric component of Ras activation.

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