Structure, Function and Inhibition of Human ADP-ribosyltransferases

This project will address key differences in human ARTD enzymes and elucidate the structures of macromolecular complexes at atomic resolution with protein crystallography, cryo-EM and NMR, and complementing this with biochemical methods.

Project information

Project duration

-

Funded by

Multiple sources (Focus area spearhead projects)

Project coordinator

University of Oulu

Contact information

Contact person

  • Lari Lehtiö

    Professor
    Lari
    Lehtiö
    lari.lehtio@oulu.fi
    +358 294 481169

Researchers

Project description

Human ADP-ribosyltransferases (ARTDs, PARPs) catalyze a transfer of ADP-ribose from NAD+ to target proteins. Structures of ARTD catalytic domains have been elucidated by protein crystallography facilitating the development of small molecule inhibitors some of which have entered the clinics. We are now reaching towards understanding how the multidomain ARTDs function by addressing several key questions in ARTD oligomerization, protein-protein and DNA-protein interactions. The project will address key differences in human ARTD enzymes and elucidate the structures of macromolecular complexes at atomic resolution with protein crystallography, cryo-EM and NMR, and complementing this with biochemical methods. We will study structural changes during activation of the catalytic ADP-ribosyltransferase domain upon formation of macromolecular complexes and use a range of biophysical techniques to combine information into a functional models of the enzymes.

ARTD complexes control key signalling events of the cell through interactions and posttranslational modifications, which modulate stability of macromolecular assemblies in the cytoplasm and in the nucleus. ADP-ribosylation signaling is often misregulated in diseases like cancer or ARTDs promote proliferation and survival of cancer cells. Small molecule inhibitors interfering with the catalytic activity or with protein-protein interactions could provide new tools to and enable development of novel therapies.

Selected publications

  1. Leenders, R., Brinch, S., Sowa, S.T., Amundsen-Isaksen, E., Galera-Prat, A., Murthy, S., Aertssen, S., Smits, J., Nieczypor, P., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L., Waaler, J., & Krauss, S. (2021) Development of a 1,2,4-Triazole Based Lead Tankyrase Inhibitor. J. Med. Chem. In press https://doi.org/10.1021/acs.jmedchem.1c01264
  2. Glumoff, T., Sowa, S.T. & Lehtiö, L. (2021) Assay technologies facilitating drug discovery for ADP-ribosyl writers, readers and erasers. BioEssays In press https://doi.org/10.1002/bies.202100240
  3. Sowa, S.T., Galera-Prat, A., Wazir, S., Alanen, H.I., Maksimainen, M.M. & Lehtiö, L. (2021) A molecular toolbox for ADP-ribosyl binding proteins. Cell Reports Methods In press https://doi.org/10.1016/j.crmeth.2021.100121
  4. Maksimainen, M.M., Murthy, S., Sowa, S.T., Galera-Prat, A., Rolina, E., Heiskanen, J.P. & Lehtiö, L. (2021) Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs. Bioorg. Med. Chem. 52:116511
  5. Mattila, S., Merilahti, P., Quirin, T., Wazir, S., Maksimainen, M.M., Zhang, Y., Xhaard, H., Lehtiö, L. & Ahola, T. (2021) Macrodomain binding compound MRS 2578 inhibits alphavirus replication. Antimicrob. Agents Chemother. 65:e0139821.
  6. Obaji, E., Maksimainen M.M., Galera-Prat, A. & Lehtiö, L. (2021) Activation of ARTD2/PARP2 by DNA damage induces conformational changes relieving enzyme autoinhibition. Nat. Comm. 12:3479.
  7. Sowa, S.T., Vela-Rodríguez, C., Galera-Prat, A, Cázares-Olivera, M., Prunskaite-Hyyryläinen, R., Ignatev, A. & Lehtiö, L. (2020) A FRET-based high throughput screening platform for the discovery of chemical probes targeting the scaffolding functions of human tankyrases. Sci. Rep. 10:12357.
  8. Waaler, J., Leenders, R.G.G., Sowa, S.T., Brinch, S.A., Lycke, M., Nieczypor, P., Aertssen, S., Murthy, S., Galera-Prat, A., Damen, E., Wegert, A., Nazaré, M., Lehtiö, L. & Krauss, S. (2020) Pre-clinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor. J. Med. Chem. 63:6834-6846.