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

The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY2 94002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3K gamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal h ow these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a confor mational change in the catalytic domain. Surprisingly, LY294002 and the lea d compound on which it was designed, quercetin, as well as the closely rela ted flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K int eractions are reminiscent of low-affinity protein kinase/staurosporine comp lexes. These results provide a rich basis for development of isoform-specif ic PI3K inhibitors with therapeutic potential.