Editors' ChoiceStructural Biology

Crystallized Kinase Regulation

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Science's STKE  17 Jul 2007:
Vol. 2007, Issue 395, pp. tw255
DOI: 10.1126/stke.3952007tw255

Many human cancers involve gain-of-function mutations in the phosphoinositide 3-kinase PI3Kα. The kinase is a heterodimer of a catalytic subunit (p110α) and a regulatory subunit (p85α), with both subunits comprising multiple domains. Miled et al. (see the Perspective by Lee et al.) have determined the crystal structure of the adaptor binding domain of p110α bound to the inter-SH2 domain of p85α at 2.4 angstrom resolution and have performed functional studies to investigate the effect of oncogenic mutations in the helical domain of p110α on its interaction with the N-terminal SH2 domain of p85α. The studies suggest how these two classes of mutations cause the up-regulation of PI3Kα that can lead to cancer.

N. Miled, Y. Yan, W.-C. Hon, O. Perisic, M. Zvelebil, Y. Inbar, D. Schneidman-Duhovny, H. J. Wolfson, J. M. Backer, R. L. Williams, Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239-242 (2007). [Abstract] [Full Text]

J. Y. Lee, J. A. Engelman, L. C. Cantley, PI3K charges ahead. Science 317, 206-207 (2007). [Summary] [Full Text]