title: Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site.
abstract: The PIF-pocket of AGC protein kinases participates in the physiologic mechanism of regulation by acting as a docking site for substrates and as a switch for the transduction of the conformational changes needed for activation or inhibition. We describe the effects of compounds that bind to the PIF-pocket of PDK1. In vitro, PS210 is a potent activator of PDK1, and the crystal structure of the PDK1-ATP-PS210 complex shows that PS210 stimulates the closure of the kinase domain. However, in cells, the prodrug of PS210 (PS423) acts as a substrate-selective inhibitor of PDK1, inhibiting the phosphorylation and activation of S6K, which requires docking to the PIF-pocket, but not affecting PKB/Akt. This work describes a tool to study the dynamics of PDK1 activity and a potential approach for drug discovery.
authors.affiliation: Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Katrien
authors.initials: K
authors.lastname: Busschots
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lopez-Garcia
authors.forename: Carmen
authors.initials: C
authors.lastname: Lammi
authors.forename: Adriana
authors.initials: A
authors.lastname: Stroba
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Albrecht
authors.initials: A
authors.lastname: Piiper
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Alzari
authors.forename: Sonja
authors.initials: S
authors.lastname: Neimanis
authors.forename: Jose M
authors.initials: JM
authors.lastname: Arencibia
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
authors.forename: Jörg O
authors.initials: JO
authors.lastname: Schulze
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
mesh_terms: D000495:Allosteric Site / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047188:Chalcones; D003998:Dicarboxylic Acids; C000631429:PDK1 protein, human; C000589383:PS210; C000631433:Pdk1 protein, mouse; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases