National Center for
4AW1: Human PDK1 Kinase Domain in Complex with Allosteric Compound PS210 Bound to the PIF-Pocket
Substrate-selective inhibition of protein kinase PDK1 by small compounds that bind to the PIF-pocket allosteric docking site
Chem. Biol. (2012) 19 p.1152-1163
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.
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