Protein lysine methylation is a post-translational modification which is introduced by protein lysine methyltransferases (PKMTs). Currently the rules determining the substrate selection of PKMTs are not well understood. The Jeltsch group has developed a unique and powerful approach to study PKMT specificity based on peptide SPOT synthesis, which we aim to apply here to novel PKMTs. In collaboration with the Jeltsch group, we conduct large-scale MD simulations of PKMT-peptide complexes to understand the experimental data in the context of available protein structural data, This will lead to the identification of critical contacts which afterwards will be studied experimentally. Our project will include advanced questions like the investigation of coupled interactions, binding of novel and optimized substrates and the analysis of the effects of somatic mutations in PKMTs observed in cancer cells. The project will adapt and currently established workflows to perform and analyse of many hundred simulations and report the simulation results and further develop data management and data structure.
This research project is funded in the framework of the Stuttgart Cluster of Excellence SimTech.
Publications
- Schnee, P., Pleiss, J., Jeltsch, A.: Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques. Critical Reviews in Biochemistry and Molecular Biology. 59, 20–68 (2024). https://doi.org/10.1080/10409238.2024.2318547.
- Khella, M.S., Schnee, P., Weirich, S., Bui, T., Bröhm, A., Bashtrykov, P., Pleiss, J., Jeltsch, A.: The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation. Journal of Biological Chemistry. 299, 104796-- (2023). https://doi.org/10.1016/j.jbc.2023.104796.
- Mack, A., Emperle, M., Schnee, P., Adam, S., Pleiss, J., Bashtrykov, P., Jeltsch, A.: Preferential Self-interaction of DNA Methyltransferase DNMT3A Subunits Containing the R882H Cancer Mutation Leads to Dominant Changes of Flanking Sequence Preferences. Journal of Molecular Biology. 434, 167482 (2022). https://doi.org/10.1016/j.jmb.2022.167482.
- Schnee, P., Choudalakis, M., Weirich, S., Khella, M.S., Carvalho, H., Pleiss, J., Jeltsch, A.: Mechanistic basis of the increased methylation activity of the SETD2 protein lysine methyltransferase towards a designed super-substrate peptide. Communications Chemistry. 5, 139-- (2022). https://doi.org/10.1038/s42004-022-00753-w.
Members
Dr. Philipp Schnee
Bioinformatik