Author/Authors :
Katrien Busschots، نويسنده , , Laura A. Lopez-Garcia، نويسنده , , Carmen Lammi، نويسنده , , Adriana Stroba، نويسنده , , Stefan Zeuzem، نويسنده , , Albrecht Piiper، نويسنده , , Pedro M. Alzari، نويسنده , , Sonja Neimanis، نويسنده , , Jose M. Arencibia، نويسنده , , Matthias Engel، نويسنده , , J?rg O. Schulze، نويسنده , , Ricardo M. Biondi، نويسنده ,
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.
