A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-pkb Chimera.
From: Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. t.davies@astex-therapeutics.com
Journal of molecular biology
- Publish Date: Mar 2007
- ISSN: 0022-2836
- Volume: 367
- Issue: 3
- Pages: 882-94
- Medium: Print
- Language: English
- Citation (JAMA): Davies Thomas G, Verdonk Marcel L, Graham Brent, et al. A Structural Comparison of Inhibitor Binding to Pkb, Pka and Pka-pkb Chimera.. J. Mol. Biol. Mar 2007;367:882-94
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.
Mesh Headings (Keywords): Animals, Binding Sites, Cattle, Crystallography, X-Ray, Cyclic AMP-Dependent Protein Kinases, Electrostatics, Humans, Models, Molecular, Protein Conformation, Proto-Oncogene Proteins c-akt, Recombinant Fusion Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 17275837
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.