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      Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.

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          Abstract

          The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.

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          Author and article information

          Journal
          Mol Cell
          Molecular cell
          Elsevier BV
          1097-2765
          1097-2765
          Oct 2000
          : 6
          : 4
          Affiliations
          [1 ] MRC Laboratory of Molecular Biology, MRC Centre, Cambridge, United Kingdom.
          Article
          S1097-2765(05)00089-4
          10.1016/s1097-2765(05)00089-4
          11090628
          e0f99c68-955e-4168-8190-9d80bcddf83f
          History

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