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

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Abstract

Ras activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. We find that PI3Kγ, is strongly and directly activated by H-Ras G12V in vivo or by GTPγS-loaded H-Ras in vitro. We have determined a crystal structure of a PI3K-γ/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 PI3Kγ. Mutagenesis shows that interactions with both regions are essential for binding PI3Kγ Ras also forms a direct contact with the PI3Kγ catalytic domain. These unique Ras/PI3Kγ interactions are likely to be shared by PI3Kα. The complex with Ras shows a change in the PI3K conformation that may represent an allosteric component of Ras activation.

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Pacold, M. E., Suire, S., Perisic, O., Lara-Gonzalez, S., Davis, C. T., Walker, E. H., … Williams, R. L. (2000). Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell, 103(6), 931–944. https://doi.org/10.1016/s0092-8674(00)00196-3

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