1uvr
From Proteopedia
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==Overview== | ==Overview== | ||
| - | LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific | + | LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 | + | [[Category: Transferred entry: 2 7.11 1]] |
| - | [[Category: Aalten, D | + | [[Category: Aalten, D M.F Van.]] |
| - | [[Category: Alessi, D | + | [[Category: Alessi, D R.]] |
[[Category: Bain, J.]] | [[Category: Bain, J.]] | ||
[[Category: Deak, M.]] | [[Category: Deak, M.]] | ||
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[[Category: Garrido-Franco, M.]] | [[Category: Garrido-Franco, M.]] | ||
[[Category: Komander, D.]] | [[Category: Komander, D.]] | ||
| - | [[Category: Kozikowski, A | + | [[Category: Kozikowski, A P.]] |
| - | [[Category: Kular, G | + | [[Category: Kular, G S.]] |
| - | [[Category: Prakash, K | + | [[Category: Prakash, K R.]] |
| - | [[Category: Schuttelkopf, A | + | [[Category: Schuttelkopf, A W.]] |
[[Category: BI8]] | [[Category: BI8]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''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 15:28:49 2008'' |
Revision as of 13:28, 21 February 2008
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STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH BIM-8
Overview
LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.
About this Structure
1UVR is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1., Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM, Structure. 2004 Feb;12(2):215-26. PMID:14962382
Page seeded by OCA on Thu Feb 21 15:28:49 2008
Categories: Homo sapiens | Single protein | Transferred entry: 2 7.11 1 | Aalten, D M.F Van. | Alessi, D R. | Bain, J. | Deak, M. | Elliot, M. | Garrido-Franco, M. | Komander, D. | Kozikowski, A P. | Kular, G S. | Prakash, K R. | Schuttelkopf, A W. | BI8 | GOL | SO4 | Bim-8 | Bisindolyl maleimide | Cancer | Diabetes | Inhibitor | Ly333531 | Pdk1 | Pkb | Protein kinase | Transferase
