1e7u: Difference between revisions
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==Overview== | ==Overview== | ||
The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and | 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Ried, C.]] | [[Category: Ried, C.]] | ||
[[Category: Stephens, L.]] | [[Category: Stephens, L.]] | ||
[[Category: Walker, E | [[Category: Walker, E H.]] | ||
[[Category: Williams, R | [[Category: Williams, R L.]] | ||
[[Category: KWT]] | [[Category: KWT]] | ||
[[Category: phosphoinositide 3-kinase gamma]] | [[Category: phosphoinositide 3-kinase gamma]] | ||
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[[Category: wortmannin]] | [[Category: wortmannin]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:24:50 2008'' | ||
Revision as of 13:24, 21 February 2008
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STRUCTURE DETERMINANTS OF PHOSPHOINOSITIDE 3-KINASE INHIBITION BY WORTMANNIN, LY294002, QUERCETIN, MYRICETIN AND STAUROSPORINE
OverviewOverview
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.
About this StructureAbout this Structure
1E7U is a Single protein structure of sequence from Sus scrofa with as ligand. Active as Phosphatidylinositol 3-kinase, with EC number 2.7.1.137 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine., Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL, Mol Cell. 2000 Oct;6(4):909-19. PMID:11090628
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