Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase

• Published in: Cell chemical biology Vol. 23; no. 10; pp. 1193 - 1205
• Main Authors: Schulze, Jörg O., Saladino, Giorgio, Busschots, Katrien, Neimanis, Sonja, Süß, Evelyn, Odadzic, Dalibor, Zeuzem, Stefan, Hindie, Valerie, Herbrand, Amanda K., Lisa, María-Natalia, Alzari, Pedro M., Gervasio, Francesco L., Biondi, Ricardo M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 20.10.2016; Cell Press
• Subjects: adenosine; Adenosine Triphosphate; Adenosine Triphosphate - metabolism; AGC kinase; Allosteric Regulation; Allosteric Regulation - drug effects; Allosteric Site; Allosteric Site - drug effects; Aurora; Aurora Kinases; Aurora Kinases - antagonists & inhibitors; Aurora Kinases - chemistry; Aurora Kinases - metabolism; Binding Sites; Binding Sites - drug effects; Biochemistry, Molecular Biology; Bioinformatics; Biological Physics; Cellular Biology; Chemical Sciences; Computer Science; Cristallography; GSK2334470; HEK293 Cells; Humans; Indazoles; Indazoles - chemistry; Indazoles - pharmacology; Life Sciences; Molecular Docking Simulation; molecular dynamics; PDK1; Physics; PIF pocket; protein kinase; Protein Kinase Inhibitors; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - metabolism; Pyrimidines; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; small compounds; Structural Biology; adenosine; GSK2334470; Aurora; PIF pocket; allosteric regulation; molecular dynamics; small compounds; protein kinase; AGC kinase; PDK1
• ISSN: 2451-9456; 2451-9456
• DOI: 10.1016/j.chembiol.2016.06.017

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. •PS653 inhibits the binding of PIFtide by interaction with the ATP-binding site•Adenosine binds at the ATP-binding site and enhances the binding of PIFtide•Molecular dynamics simulations describe the conformational changes of PDK1•Potent drugs to the ATP site of PDK1 have different effects on the PIF pocket Schulze et al. show that compounds binding to the ATP-binding site of a kinase can produce profound effects on a distant site, enhancing or inhibiting the interaction with allosteric regulators. The principle can be exploited in drug discovery and development.