2jdr Citations

A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera.

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.

Reviews - 2jdr mentioned but not cited (2)

  1. Chiral kinase inhibitors. Jiang JK, Shen M, Thomas CJ, Boxer MB. Curr Top Med Chem 11 800-809 (2011)
  2. Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein. Primavera E, Palazzotti D, Barreca ML, Astolfi A. Pharmaceuticals (Basel) 16 993 (2023)

Articles - 2jdr mentioned but not cited (13)



Reviews citing this publication (5)

  1. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Garcia-Echeverria C, Sellers WR. Oncogene 27 5511-5526 (2008)
  2. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. Miller TW, Balko JM, Arteaga CL. J Clin Oncol 29 4452-4461 (2011)
  3. Structure-based design of molecular cancer therapeutics. van Montfort RL, Workman P. Trends Biotechnol 27 315-328 (2009)
  4. Clinical development of phosphatidylinositol-3 kinase pathway inhibitors. Arteaga CL. Curr Top Microbiol Immunol 347 189-208 (2010)
  5. Autoregulation of kinase dephosphorylation by ATP binding in AGC protein kinases. Chan TO, Pascal JM, Armen RS, Rodeck U. Cell Cycle 11 475-478 (2012)

Articles citing this publication (36)