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Marko Hyvönen

Specificity, regulation and inhibition of protein-protein interactions in cellular signalling

Summary:

Our research is aiming to understand how cells in humans communicate with each other, how signals are transmitted from one cell to anotherm and how cells interpret these signals at atomic level detail. Many disease states are affects by errors in communication between and within cells, and we hope to elucidate these details in order to understand how complex organisms work and what causes these diseases. Using this information we aim to develop novel drugs that will act against these signalling molecules and correct the problems associated with them.

We are interested in understanding how various signalling proteins interact with other signalling molecules. We use biochemical, biophysical and structural techniques to study these molecules, and try to understand how their interactions are regulated and how we could manipulate these interactions in vivo and in vitro.

One of the system we have studied in detail is the extracellular regulation of TGFβ family growth factors. This is a large family of related proteins with over thirty members in humans and we are interested in the determinants of signalling specificity and interactions with inhibitor proteins. Many of our projects are in collaboration with developmental and stem cell biologists.

We are members of an interdisplinary research consortium in Cambridge applying novel methods to the development of inhibitors against clinically relevant targets. Our particular aim is to  inhibit specific protein-protein interactions. These are traditionally seen as very difficult targets for chemical intervention but hold great promise for therapeutic use and as chemical tools.

One of the targets in this programme is the interaction between RAD51, a human recombinase required for repair of damaged DNA, and its interaction partner BRCA2. We use fragment-based drug discovery methods to develop inhibitors against this interaction, and employ calorimetry, X-ray crystallography and protein engineering amongst other techniques to guide the development process.

Lab members: Cat Donaldson, Gerhard Fischer, Clare Henry, Tommaso Moschetti, Mariana Rangel Pereira, Maxim Rossmann, Katharina Ravn, Agata Sienkiewitz-Porzucek, Xuelu Wang, Emma Xu

Collaborators:  Chris Abell, Tom Blundell, David Spring, Ashok Venkitaraman, Florian HollfelderMorten Grøtli, Andrea Balan, Laura Itzhaki, Olli Ritvos,

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Key publications:

1. Innis, C.A. & Hyvönen, M. (2003) Crystal structures of the heparan sulfate-binding domain of follistatin. Insights into ligand binding. J. Biol. Chem. 278, 39969.39977.

2. Hyvönen, M. (2003) CHRD, a novel domain in the bone morphogenetic protein inhibitor chordin, is also found in microbial proteins. Trends Biochem. Sci. 28, 470.473.

3. Harrington, A.E., Morris-Triggs, S.A., Ruotolo B.T., Robinson, C.V., Ohnuma, S. and Hyvönen, M (2006) Structural basis for the inhibition of activin signalling by follistatin The EMBO Journal 25, 1035-1045

4. Ludlow, H., Muttukrishna, S., Hyvonen, M., Groome, N.G (2008) Development of a new antibody to the human inhibin/activin betaB subunit and its application to improved inhibin B ELISAs. J Immunol Methods 329:102-11

5. Valkov, E., Sharpe, T., Marsh, M., Greive S., and Hyvönen, M. Targeting protein-protein interactions and fragment-based drug discovery (2012)  in Topics in Current Chemistry: “Fragment- based drig discovery and X-ray crystallography” 317:145-79. ed. T. Davies and M. Hyvönen.

6. Scott, D.E. , Ehebauer, M.T., Pukala, T., Marsh,M,  Blundell, T.L., Venkitaraman, A.R., Abell, C., Hyvönen, M. (2013) Targeting the RAD51:BRCA2 Protein-Protein Interaction using Fragment-based methods. ChemBioChem 14(3):332-42.