1E7V

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

1E7V の概要

• エントリーDOI: 10.2210/pdb1e7v/pdb
• 分子名称: PHOSPHATIDYLINOSITOL 3-KINASE CATALYTIC SUBUNIT, 2-MORPHOLIN-4-YL-7-PHENYL-4H-CHROMEN-4-ONE (3 entities in total)
• 機能のキーワード: transferase, secondary messenger generation pi3k, pi 3k, ly294002
• 由来する生物種: SUS SCROFA (WILD BOAR)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110259.90

構造登録者

Walker, E.H.,Pacold, M.E.,Perisic, O.,Stephens, L.,Hawkins, P.T.,Wymann, M.P.,Williams, R.L. (登録日: 2000-09-08, 公開日: 2000-11-17, 最終更新日: 2023-12-13)

主引用文献

Walker, E.H.,Pacold, M.E.,Perisic, O.,Stephens, L.,Hawkins, P.T.,Wymann, M.P.,Williams, R.L.
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.
Mol.Cell, 6:909-919, 2000

PubMed 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.

PubMed: 11090628
DOI: 10.1016/s1097-2765(05)00089-4

実験手法

X-RAY DIFFRACTION (2.4 Å)