1. Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase.
- Author
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Schulze JO, Saladino G, Busschots K, Neimanis S, Süß E, Odadzic D, Zeuzem S, Hindie V, Herbrand AK, Lisa MN, Alzari PM, Gervasio FL, and Biondi RM
- Subjects
- Allosteric Site drug effects, Aurora Kinases antagonists & inhibitors, Aurora Kinases chemistry, Aurora Kinases metabolism, Binding Sites drug effects, HEK293 Cells, Humans, Indazoles chemistry, Molecular Docking Simulation, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases chemistry, Protein Serine-Threonine Kinases metabolism, Pyrimidines chemistry, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Adenosine Triphosphate metabolism, Allosteric Regulation drug effects, Indazoles pharmacology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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