Article
- The EMBO Journal (2006) 25, 5469 - 5480
- doi:10.1038/sj.emboj.7601416
Published online: 16 November 2006
Subject Category:
Allosteric activation of the protein kinase PDK1 with low molecular weight compounds
Matthias Engel1,a, Valerie Hindie2,3,a, Laura A Lopez-Garcia2, Adriana Stroba1, Francis Schaeffer3, Iris Adrian2, Jochen Imig2, Leila Idrissova2, Wolfgang Nastainczyk4, Stefan Zeuzem2, Pedro M Alzari3, Rolf W Hartmann1, Albrecht Piiper2 and Ricardo M Biondi2
- Research Group PhosphoSites, Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, Saarbrücken, Germany
- Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg, Germany
- Structural Biochemistry Unit, Pasteur Institute, Paris, France
- Department of Medicinal Biochemistry, University of Saarland, Homburg, Germany
Correspondence to:
Ricardo M Biondi, Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Kirrbergerstr., Homburg 66421, Germany. Tel.: +49 6841 16 23263; Fax: +49 6841 16 23570; E-mail: r.m.biondi@uniklinik-saarland.de
aThese authors contributed equally to this work
Received 24 April 2006; Accepted 10 October 2006
Abstract
Organisms rely heavily on protein phosphorylation to transduce intracellular signals. The phosphorylation of a protein often induces conformational changes, which are responsible for triggering downstream cellular events. Protein kinases are themselves frequently regulated by phosphorylation. Recently, we and others proposed the molecular mechanism by which phosphorylation at a hydrophobic motif (HM) regulates the conformation and activity of many members of the AGC group of protein kinases. Here we have developed specific, low molecular weight compounds, which target the HM/PIF-pocket and have the ability to allosterically activate phosphoinositide-dependent protein kinase 1 (PDK1) by modulating the phosphorylation-dependent conformational transition. The mechanism of action of these compounds was characterized by mutagenesis of PDK1, synthesis of compound analogs, interaction-displacement studies and isothermal titration calorimetry experiments. Our results raise the possibility of developing drugs that target the AGC kinases via a novel mode of action and may inspire future rational development of compounds with the ability to modulate phosphorylation-dependent conformational transitions in other proteins.
Keywords:
- AGC kinase,
- PDK1,
- PIF-pocket,
- protein conformation,
- protein phosphorylation
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