2JDR

STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH THE INHIBITOR A-443654

Summary for 2JDR

• Entry DOI: 10.2210/pdb2jdr/pdb
• Related: 1GZK 1GZN 1GZO 1MRV 1MRY 1O6K 1O6L 1P6S 2JDO
• Descriptor: RAC-BETA SERINE/THREONINE-PROTEIN KINASE, GLYCOGEN SYNTHASE KINASE-3 BETA, (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE, ... (4 entities in total)
• Functional Keywords: wnt signaling pathway, serine/threonine-protein kinase, kinase, transferase, atp-binding, phosphorylation, nucleotide-binding, alternative splicing
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 41381.08

Authors

Davies, T.G.,Verdonk, M.L.,Graham, B.,Saalau-Bethell, S.,Hamlett, C.C.F.,McHardy, T.,Collins, I.,Garrett, M.D.,Workman, P.,Woodhead, S.J.,Jhoti, H.,Barford, D. (deposition date: 2007-01-12, release date: 2007-02-13, Last modification date: 2024-11-13)

Primary citation

Davies, T.G.,Verdonk, M.L.,Graham, B.,Saalau-Bethell, S.,Hamlett, C.C.F.,Mchardy, T.,Collins, I.,Garrett, M.D.,Workman, P.,Woodhead, S.J.,Jhoti, H.,Barford, D.
A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-Pkb Chimera
J.Mol.Biol., 367:882-, 2007

PubMed Abstract: 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.

PubMed: 17275837
DOI: 10.1016/J.JMB.2007.01.004

Experimental method

X-RAY DIFFRACTION (2.3 Å)