Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling

  • Alejandro E. Leroux
  • Lissy Z. F. Gross
  • Mariana Sacerdoti
  • Ricardo M. BiondiEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)


Allostery is a basic principle that enables proteins to process and transmit cellular information. Protein kinases evolved allosteric mechanisms to transduce cellular signals to downstream signalling components or effector molecules. Protein kinases catalyse the transfer of the terminal phosphate from ATP to protein substrates upon specific stimuli. Protein kinases are targets for the development of small molecule inhibitors for the treatment of human diseases. Drug development has focussed on ATP-binding site, while there is increase interest in the development of drugs targeting alternative sites, i.e. allosteric sites. Here, we review the mechanism of regulation of protein kinases, which often involve the allosteric modulation of the ATP-binding site, enhancing or inhibiting activity. We exemplify the molecular mechanism of allostery in protein kinases downstream of PI3-kinase signalling with a focus on phosphoinositide-dependent protein kinase 1 (PDK1), a model kinase where small compounds can allosterically modulate the conformation of the kinase bidirectionally.


Allostery Kinase PDK1 PIF pocket Small molecules AGC kinase Allosteric drug Bidirectional allostery ATP binding site 



The work was supported by DFG BI 1044/12-1, CONICET (subsidio P. UE.); ANPCyT (subsidio PICT PRH-2016-4835), ANPCyT (subsidio PICT -2016-3525), FOCEM-Mercosur (COF 03/11) and CONICET.


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Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Alejandro E. Leroux
    • 1
  • Lissy Z. F. Gross
    • 1
  • Mariana Sacerdoti
    • 1
  • Ricardo M. Biondi
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) – CONICET – Partner Institute of the Max Planck SocietyBuenos AiresArgentina
  2. 2.Department of Internal Medicine IUniversitätsklinikum FrankfurtFrankfurtGermany
  3. 3.DKTK German Cancer Consortium (DKTK)FrankfurtGermany
  4. 4.German Cancer Research Center (DKFZ)HeidelbergGermany

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