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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Site / drug effects*
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Animals
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Cell Line
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Chalcones / chemistry
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Chalcones / pharmacology*
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Dicarboxylic Acids / chemistry
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Dicarboxylic Acids / pharmacology*
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HEK293 Cells
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Humans
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Mice
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Models, Biological
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Models, Molecular
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Molecular Structure
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Molecular Weight
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Prodrugs / chemistry
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Prodrugs / pharmacology*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Chalcones
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Dicarboxylic Acids
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PDK1 protein, human
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PS210
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Pdk1 protein, mouse
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Prodrugs
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Protein Kinase Inhibitors
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Protein Serine-Threonine Kinases