Understanding structure, function and modulation of proteins
Summary:
Our research is aiming to understand how protein work and how their structures contribute to their function. With that understanding in mind, we try to modulate the proteins in different ways, including by protein engineering and by developing small molecule modulators that can alter the function of the target proteins, typically inhibiting 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 with other molecules are regulated and how we could manipulate these interactions in vivo and in vitro.
One of the systems we have studied in detail is the extracellular regulation of TGF-β 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.
For over 15 years we have been heavily engaged in the development of inhibitors against clinically relevant target proteins. In doing so, we are usually working either on entirely novel, unexplored protein targets or developing new approaches to target known and validated targets. We try to use approaches that are more speculative and risky than industry would use, with an aim of providing proof-of-concept data and results that enable further development of the inhibitors into drug candidates. Our molecular targets are involved in variety of different disease processes, from cancer, infectious diseases, metabolic diseases and neurodegeneration.
Together with the group of Florian Hollfelder, we have worked on various enzyme families for over 15 years and we have now a joint BBSRC sLoLa grant for isolation and development of novel plastic degrading enzymes, plastizymes.
Marko is a visiting professor at the Department of Microbiology, University of São Paulo, where he is setting up a satellite lab to study mechanisms of efflux pumps in antimicrobial resistance.
Qkine is a Cambridge-based biotechnology company that was founded by Marko in 2016. The company is translating the group’s expertise in producing difficult to make proteins in high quality to commercial setting, serving a worldwide customer base with their growth factors and cytokines.
Lab members: Paul Brear, Nicola Coker Gordon, Emma Belcher, Gwen Pyeatt, Lena Quambusch, Caio dos Reis, Attila Tököli, Lení Jodaitis, Archie Coombs, Flora Foltanyi.
Collaborators: Florian Hollfelder, Morten Grotli, David Spring, Andrea Balan, Sheena D’Arcy, Deborah Schechtman, Caroline Hill
Industrial collaborations: AstraZeneca, Apollo Therapeutics, Bicycle Therapeutics, Qkine.
Key publications:
S. R. Stockwell, D. E. Scott, G. Fischer, E. Guarino, T. P. C. Rooney, T. Feng, T. Moschetti, R. Srinivasan, E. Alza, A. Asteian, C. Dagostin, A. Alcaide, M. Rocaboy, B. Blaszczyk, A. Higueruelo, X. Wang, M. Rossmann, T. R. Perrior, T. L. Blundell, D. R. Spring, G. McKenzie, C. Abell, J. Skidmore, M. Hyvönen, A. R. Venkitaraman. Selective inhibitors of the Aurora A-TPX2 protein-protein interaction exhibit in vivo efficacy as targeted anti-mitotic agents. Journal of Medicinal Chemistry, 17:15521–15536 (2024). https://doi.org/10.1021/acs.jmedchem.4c01165
T. Pantelejevs, P. Zuazua-Villar, O. Koczy, A. Counsell, S. J. Walsh, N. S. Robertson, D. R. Spring, J. Downs, M. Hyvönen. A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase. Chemical Biology, 4:13915-13923 (2023). https://doi.org/10.1039/D3SC03331G
L. H. Lindenburg, T. Pantelejevs, F. Gielen, P. Zuazua-Villar, M. Butz, E. Rees, C. F. Kaminski, J. A. Downs, M. Hyvönen, F. Hollfelder. Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats. Proceedings of the National Academy of Sciences of the USA, 118:e2017708118, 2021 https://doi.org/10.1073/pnas.2017708118
D. E. Scott, N. J. Francis-Newton, M. E. Marsh, A. G. Coyne, G. Fischer, T. Moschetti, A. R. Bayly, T. D. Sharpe, K. T. Haas, L. Barber, C. R. Valenzano, R. Srinivasan, D. J. Huggins, M. Lee, A. Emery, B. Hardwick, M. Ehebauer, C. Dagostin, A. Esposito, L. Pellegrini, T. Perrior, G. McKenzie, T. L. Blundell, M. Hyvönen, J. Skidmore, A. R. Venkitaraman, C. Abell. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death. Cell Chemical Biology, 28: 1–13, 2020. https://doi.org/10.1016/j.chembiol.2021.02.006
T. Cotton, G. Fischer, X. Wang, J. McCoy, M. Czepnik, T. B. Thompson, M. Hyvӧnen. Structure of the human pro-myostatin precursor and determinants of growth factor latency. EMBO Journal 37:367-383, 2018. https://doi.org/10.15252/embj.201797883. PMCID:PMC5793801
X. Wang, G. Fischer and M. Hyvönen. Structure and activation of pro-activin A. Nature Communications, 7:12052. doi: 10.1038/ncomms12052, 2016
P. Brear, C. De Fusco, K. Hadje Georgiou, N. J. Francis-Newton, C. J. Stubbs, H. F. Sore, A. R. Venkitaraman, C. Abell, D. R. Spring, M. Hyvönen. Specific inhibition of CK2α from an anchor outside the active site. Chemical Science,7, 6839-6845 doi: 10.1039/C6SC02335E, 2016