Molecular dynamics simulations of the substrate recognition of protein lysine methyltransferases

PN 2-5

Project description

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 ap-proach to study PKMT specificity based on peptide SPOT synthesis, which we aim to apply here to novel PKMTs. To understand the experimental data in the context of available protein structural data, we will to conduct high-end MD simulations of PKMT-peptide complexes. 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.

Project information

Poject title Molecular dynamics simulations of the substrate recognition of protein lysine methyltransferases
Project leaders Albert Jeltsch (Jürgen Pleiss)
Project duration November 2020 - June 2023
Project number PN 2-5
  • Follow-up project 2-5 (II)
    Molecular dynamics simulations of the substrate recognition and specificity of protein and DNA methyltransferases

Publications PN 2-5 and PN 2-5 (II)

  1. 2024

    1. S. Weirich, D. Kusevic, P. Schnee, J. Reiter, J. Pleiss, and A. Jeltsch, “Discovery of NSD2 non-histone substrates and design of a super-substrate,” Communications Biology, vol. 7, Art. no. 1, 2024, doi: 10.1038/s42003-024-06395-z.
    2. P. Schnee, J. Pleiss, and A. Jeltsch, “Approaching the catalytic mechanism of protein lysine methyltransferases by biochemical and simulation techniques,” Critical Reviews in Biochemistry and Molecular Biology, vol. 59, Art. no. 1–2, 2024, doi: 10.1080/10409238.2024.2318547.

  2. 2023

    1. M. S. Khella et al., “The T1150A cancer mutant of the protein lysine dimethyltransferase NSD2 can introduce H3K36 trimethylation,” Journal of Biological Chemistry, vol. 299, Art. no. 6, 2023, doi: https://doi.org/10.1016/j.jbc.2023.104796.

  3. 2022

    1. A. Mack et al., “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, vol. 434, Art. no. 7, 2022, doi: 10.1016/j.jmb.2022.167482.
    2. P. Schnee et al., “Mechanistic basis of the increased methylation activity of the SETD2 protein lysine methyltransferase towards a designed super-substrate peptide,” Communications Chemistry, vol. 5, Art. no. 1, 2022, doi: 10.1038/s42004-022-00753-w.
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