1e7u
From Proteopedia
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==Overview== | ==Overview== | ||
| - | 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, . | + | 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== | ||
| - | 1E7U is a | + | 1E7U is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with KWT as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase Phosphatidylinositol 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.137 2.7.1.137] Structure known Active Site: KWT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1E7U OCA]. |
==Reference== | ==Reference== | ||
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[[Category: wortmannin]] | [[Category: wortmannin]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 12:58:17 2007'' |
Revision as of 10:52, 5 November 2007
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STRUCTURE DETERMINANTS OF PHOSPHOINOSITIDE 3-KINASE INHIBITION BY WORTMANNIN, LY294002, QUERCETIN, MYRICETIN AND STAUROSPORINE
Overview
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
1E7U is a Single protein structure of sequence from Sus scrofa with KWT as ligand. Active as Phosphatidylinositol 3-kinase, with EC number 2.7.1.137 Structure known Active Site: KWT. Full crystallographic information is available from OCA.
Reference
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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