Chemical Biology of regulatory mechanisms

Group Leader

Dr. Ricardo Miguel Biondi
See CV

Researchers

Alejandro E. Leroux.

PhD Students

Mariana Sacerdoti, Lissy Gross.

Students

Marina Taylor.

Protein kinases are a large group of proteins in the human genome. Protein kinases are central to the mechanisms by which the cells transmit messages. Deregulation of protein kinases often lead to diseases, like cancer, neurological disorders or diabetes. Over the years we employed an interdisciplinary chemical biology approach (i.e. molecular biology, biochemistry, screening of libraries of compounds, structural biology, medicinal chemistry and computational biophysics) to understand the allosteric mechanisms of regulation and to identify and develop new small molecules that bind to a regulatory site and can turn the activity of a protein kinase ON or OFF.

We also describe a metabolite and synthetic compounds that bind to the active site and can modulate the function of the regulatory site. An innovative allosteric drug in clinical trials against cancers developed by Merck AG, MK-2206, binds to the inactive conformation of a regulatory site that we characterized around 18 years ago. Allosteric drug developments to protein kinases have more recently gained force as promising source of innovative drugs for the treatment of human diseases. Our studies of the mechanisms of regulation of protein kinases help to better understand the mechanisms of cellular regulation and facilitate the drug discovery and drug development process of innovative allosteric drugs.

Our research group investigates the complex mechanisms of regulation of protein kinases in vitro and in vivo and extends our studies into different groups of proteins involved in diseases with important medical need. We continue a collaboration with the Department of Internal Medicine, University of Frankfurt, were we keep a small research group.

Publications related to this project

  • Raab M, Sanhaji M, Pietsch L, Béquignon I, Herbrand AK, Süß E, Gande SL, Caspar B, Kudlinzki D, Saxena K, Sreeramulu S, Schwalbe H, Strebhardt K, Biondi RM.
    Modulation of the Allosteric Communication between the Polo-Box Domain and the Catalytic Domain in Plk1 by Small Compounds.
    ACS Chem Biol. 13(8):1921-1931 (2018).
  • Leroux AE, Schulze JO, Biondi RM.
    AGC kinases, mechanisms of regulation ‎and innovative drug development.
    Semin Cancer Biol. 48:1-17 (2018)
  • Schulze JO, Saladino G, Busschots K, Neimanis S, Süß E, Odadzic D, Zeuzem S, Hindie V, Herbrand AK, Lisa MN, Alzari PM, Gervasio FL, Biondi RM.
    Bidirectional Allosteric Communication between the ATP-Binding Site and the Regulatory PIF Pocket in PDK1 Protein Kinase.
    Cell Chemical Biology 23, 1193–1205 (2016)
  • Zhang H, Neimanis S, Lopez-Garcia LA, Arencibia JM, Amon S, Stroba A, Zeuzem S, Proschak E, Stark H, Bauer AF, Busschots K, Jørgensen TJ, Engel M, Schulze JO, Biondi RM.
    Molecular Mechanism of Regulation of the Atypical Protein Kinase C by N-terminal Domains and an Allosteric Small Compound.
    Chem. Biol. 21:754-65 (2014)
  • Busschots K, Lopez-Garcia LA, Lammi C, Stroba A, Zeuzem S, Piiper A, Alzari PM, Neimanis S, Arencibia JM, Engel M, Schulze JO, Biondi RM
    Substrate-Selective Inhibition of Protein Kinase PDK1 by Small Compounds that Bind to the PIF- Pocket Allosteric Docking Site.
    Chem. Biol. 19:1152-63 (2012)
  • Hindie, Stroba, Zhang, Lopez-Garcia, Idrissova, Zeuzem, Hirschberg, Schaeffer, Jorgensen, Engel, Alzari, Biondi RM.
    High resolution complex structure and allosteric effects of low molecular weight activators on the protein kinase PDK1.
    Nat. Chem. Biol. 5, 758-64. (2009)
  • Engel M, Hindie V, Lopez-Garcia LA, Stroba A, Schaeffer F, Adrian I, Imig J, Idrissova L, Nastainczyk W, Zeuzem S, Alzari PM, Hartmann RW, Piiper A, Biondi RM.
    Allosteric activation of protein kinase PDK1 with low molecular weight compounds.
    EMBO J. 25:5469-80. (2006)
  • Frodin M, Antal TL, Dummler BA, Jensen CJ, Deak M, Gammeltoft S, Biondi RM.
    AGC kinases and PDK1 contain a phospho-Ser/Thr binding pocket that mediates activation by hydrophobic motif phosphorylation.
    EMBO J. 21, 5396-5407. (2002)
  • Frame SM, Cohen P, Biondi RM.
    A common phosphate binding site explains the substrate specificity of GSK3 and its inactivation by phosphorylation.
    Mol. Cell. 7, 1321-1327. (2001)
  • Biondi RM, Kieloch, A, Currie R, Deak M, Alessi DR.
    The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK but not PKB.
    EMBO J. 20, 4380-4390. (2001)