Journal of molecular biology, 2007-03, Vol.367 (3), p.882-894
2007
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Details
- Autor(en) / Beteiligte
- Titel
- A Structural Comparison of Inhibitor Binding to PKB, PKA and PKA-PKB Chimera
- Ist Teil von
- Journal of molecular biology, 2007-03, Vol.367 (3), p.882-894
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2007
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Although the crystal structure of the anti-cancer target protein kinase B (PKBβ/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 PKBβ-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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2836eISSN: 1089-8638DOI: 10.1016/j.jmb.2007.01.004Titel-ID: cdi_proquest_miscellaneous_70236467
- Format
- –
- Schlagworte
- Akt, Animals, Binding Sites, cancer, Cattle, Crystallography, X-Ray, Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors, Cyclic AMP-Dependent Protein Kinases - chemistry, Cyclic AMP-Dependent Protein Kinases - genetics, Cyclic AMP-Dependent Protein Kinases - metabolism, Humans, In Vitro Techniques, inhibitor, kinase, Models, Molecular, Protein Conformation, Proto-Oncogene Proteins c-akt - antagonists & inhibitors, Proto-Oncogene Proteins c-akt - chemistry, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, Recombinant Fusion Proteins - antagonists & inhibitors, Recombinant Fusion Proteins - chemistry, Recombinant Fusion Proteins - genetics, Recombinant Fusion Proteins - metabolism, Static Electricity, structure-based drug design