1e90: Difference between revisions

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==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.

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==

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[[Category: Single protein]]

[[Category: Sus scrofa]]

[[Category: Hawkins, P.T.]]

[[Category: Hawkins, P T.]]

[[Category: Pacold, M.E.]]

[[Category: Pacold, M E.]]

[[Category: Perisic, O.]]

[[Category: Stephens, L.]]

[[Category: Walker, E.H.]]

[[Category: Walker, E H.]]

[[Category: Williams, R.L.]]

[[Category: Williams, R L.]]

[[Category: Wymann, M.P.]]

[[Category: Wymann, M P.]]

[[Category: MYC]]

[[Category: myricetin]]

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[[Category: secondary messenger generation]]

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@@ Line 4: / Line 4: @@
 ==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.
+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==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Sus scrofa]]
-[[Category: Hawkins, P.T.]]
+[[Category: Hawkins, P T.]]
-[[Category: Pacold, M.E.]]
+[[Category: Pacold, M E.]]
 [[Category: Perisic, O.]]
 [[Category: Stephens, L.]]
-[[Category: Walker, E.H.]]
+[[Category: Walker, E H.]]
-[[Category: Williams, R.L.]]
+[[Category: Williams, R L.]]
-[[Category: Wymann, M.P.]]
+[[Category: Wymann, M P.]]
 [[Category: MYC]]
 [[Category: myricetin]]
@@ Line 28: / Line 28: @@
 [[Category: secondary messenger generation]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Feb  3 09:38:20 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:25:11 2008''