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Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling

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Protein Allostery in Drug Discovery

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1163))

Abstract

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.

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Acknowledgements

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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Authors and Affiliations

  1. Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) – CONICET – Partner Institute of the Max Planck Society, Buenos Aires, Argentina

    Alejandro E. Leroux, Lissy Z. F. Gross, Mariana Sacerdoti & Ricardo M. Biondi

  2. Department of Internal Medicine I, Universitätsklinikum Frankfurt, Frankfurt, Germany

    Ricardo M. Biondi

  3. DKTK German Cancer Consortium (DKTK), Frankfurt, Germany

    Ricardo M. Biondi

  4. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Ricardo M. Biondi

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  1. Alejandro E. Leroux
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  2. Lissy Z. F. Gross
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  3. Mariana Sacerdoti
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  4. Ricardo M. Biondi
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Correspondence to Ricardo M. Biondi .

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  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Jian Zhang

  2. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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Leroux, A.E., Gross, L.Z.F., Sacerdoti, M., Biondi, R.M. (2019). Allosteric Regulation of Protein Kinases Downstream of PI3-Kinase Signalling. In: Zhang, J., Nussinov, R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore. https://doi.org/10.1007/978-981-13-8719-7_12

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