Structure, Function and Inhibition of Human ADP-ribosyltransferases - Lari Lehtiö

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. Daniel, E., Maksimainen, M.M., Smith, N., Ratas, V., Biterova, E., Murthy, S.N., Rahman, M.T., Kiema, T.-R., Sridhar, S., Cordara, G., Subhadra, D., Venkatesan, R., Prilusky, J., Dym, O., Lehtiö, L., Koski, M.K., Ashton, A.W:, Sussman, J.L, & Wierenga, R.K. (2020) IceBear: An intuitive and versatile web application for research data tracking from crystallization experiment to PDB deposition. Acta Cryst. F In press 
  2. Wazir, S., Maksimainen, M.M. & Lehtiö, L. (2020) Multiple crystal forms of human MacroD2. Acta Cryst. F 76:477-482.
  3. 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.
  4. 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.
  5. Maksimainen, M.M., Nurmesjärvi, A., Terho, R.A., Threadgill, M.D, Lehtiö, L. & Heiskanen, J.P. (2020) Synthesis of 8-alkoxythieno[2,3-c]isoquinolin-5(4H)-ones. ACS Omega 28:13447-13453.
  6. Wazir, S., Maksimainen, M.M., Alanen, H.I., Galera-Prat, A. & Lehtiö, L. (2020) Activity-based Screening Assay for Mono-ADP-ribosylhydrolases. SLAS Disc. In press
  7. Ashok, Y., Maksimainen, M.M., Kallio, T., Kilpeläinen, P. & Lehtiö, L. (2020) FMN-dependent oligomerization of putative lactate oxidase from Pediococcus acidilactici. PloS One 15:e0223870.
  8. Ashok, Y., Miettinen, M., Oliveira, D.K.H., Tamirat, M.Z., Näreoja, K., Tiwari, A., Hottiger, M.O., Johnson, M.S., Lehtiö, L. & Pulliainen, A.T. (2020) Discovery of Compounds Inhibiting the ADP-Ribosyltransferase Activity of Pertussis Toxin. ACS Infect Dis. 6:588-602.


Lari Lehtiö

Lari Lehtiö

Professor of Structural Biology