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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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03137915
Contributor : Marie de Tarragon <>
Submitted on : Wednesday, February 10, 2021 - 5:41:08 PM
Last modification on : Wednesday, March 31, 2021 - 3:23:46 AM

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Katrien Busschots, Laura Lopez-Garcia, Carmen Lammi, Adriana Stroba, Stefan Zeuzem, et al.. Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF-Pocket Allosteric Docking Site. Chemistry and Biology, Elsevier, 2012, 19 (9), pp.1152-1163. ⟨10.1016/j.chembiol.2012.07.017⟩. ⟨pasteur-03137915⟩

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