2jdo
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Although the crystal structure of the anti-cancer target protein kinase B | + | Although the crystal structure of the anti-cancer target protein kinase B (PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related kinase PKA has generally been used as a structural mimic due to its facile crystallization with a range of ligands. The use of PKB-inhibitor crystallography would bring important benefits, including a more rigorous understanding of factors dictating PKA/PKB selectivity, and the opportunity to validate the utility of PKA-based surrogates. We present a "back-soaking" method for obtaining PKBbeta-ligand crystal structures, and provide a structural comparison of inhibitor binding to PKB, PKA, and PKA-PKB chimera. One inhibitor presented here exhibits no PKB/PKA selectivity, and the compound adopts a similar binding mode in all three systems. By contrast, the PKB-selective inhibitor A-443654 adopts a conformation in PKB and PKA-PKB that differs from that with PKA. We provide a structural explanation for this difference, and highlight the ability of PKA-PKB to mimic the true PKB binding mode in this case. |
==Disease== | ==Disease== | ||
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[[Category: Barford, D.]] | [[Category: Barford, D.]] | ||
[[Category: Collins, I.]] | [[Category: Collins, I.]] | ||
| - | [[Category: Davies, T | + | [[Category: Davies, T G.]] |
| - | [[Category: Garrett, M | + | [[Category: Garrett, M D.]] |
[[Category: Graham, B.]] | [[Category: Graham, B.]] | ||
| - | [[Category: Hamlett, C | + | [[Category: Hamlett, C C.F.]] |
[[Category: Jhoti, H.]] | [[Category: Jhoti, H.]] | ||
[[Category: Mchardy, T.]] | [[Category: Mchardy, T.]] | ||
[[Category: Saalau-Bethell, S.]] | [[Category: Saalau-Bethell, S.]] | ||
| - | [[Category: Verdonk, M | + | [[Category: Verdonk, M L.]] |
| - | [[Category: Woodhead, S | + | [[Category: Woodhead, S J.]] |
[[Category: Workman, P.]] | [[Category: Workman, P.]] | ||
[[Category: EDO]] | [[Category: EDO]] | ||
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[[Category: wnt signaling pathway]] | [[Category: wnt signaling pathway]] | ||
| - | ''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 18:02:07 2008'' |
Revision as of 16:02, 21 February 2008
|
STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH ISOQUINOLINE-5-SULFONIC ACID (2-(2-(4-CHLOROBENZYLOXY) ETHYLAMINO)ETHYL) AMIDE
Contents |
Overview
Although the crystal structure of the anti-cancer target protein kinase B (PKBbeta/Akt-2) has been useful in guiding inhibitor design, the closely related kinase PKA has generally been used as a structural mimic due to its facile crystallization with a range of ligands. The use of PKB-inhibitor crystallography would bring important benefits, including a more rigorous understanding of factors dictating PKA/PKB selectivity, and the opportunity to validate the utility of PKA-based surrogates. We present a "back-soaking" method for obtaining PKBbeta-ligand crystal structures, and provide a structural comparison of inhibitor binding to PKB, PKA, and PKA-PKB chimera. One inhibitor presented here exhibits no PKB/PKA selectivity, and the compound adopts a similar binding mode in all three systems. By contrast, the PKB-selective inhibitor A-443654 adopts a conformation in PKB and PKA-PKB that differs from that with PKA. We provide a structural explanation for this difference, and highlight the ability of PKA-PKB to mimic the true PKB binding mode in this case.
Disease
Known disease associated with this structure: Diabetes mellitus, type II OMIM:[164731]
About this Structure
2JDO is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera., Davies TG, Verdonk ML, Graham B, Saalau-Bethell S, Hamlett CC, McHardy T, Collins I, Garrett MD, Workman P, Woodhead SJ, Jhoti H, Barford D, J Mol Biol. 2007 Mar 30;367(3):882-94. Epub 2007 Jan 9. PMID:17275837
Page seeded by OCA on Thu Feb 21 18:02:07 2008
Categories: Homo sapiens | Non-specific serine/threonine protein kinase | Protein complex | Barford, D. | Collins, I. | Davies, T G. | Garrett, M D. | Graham, B. | Hamlett, C C.F. | Jhoti, H. | Mchardy, T. | Saalau-Bethell, S. | Verdonk, M L. | Woodhead, S J. | Workman, P. | EDO | I5S | Alternative splicing | Atp-binding | Kinase | Nucleotide-binding | Phosphorylation | Serine/threonine-protein kinase | Transferase | Wnt signaling pathway
