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Jan Kosinski

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Integrative Modeling of Infection Cycles

"In infection disease, pathogens attack at the molecular level but break the workings of entire cellular and organismal systems. To explain how this happens and rationally design new treatments, we need to understand how interactions between molecular structures of the pathogen and the host translate to dysfunction at the system level. At CSSB we can achieve this using cutting-edge technologies and state-of-the-art methods in both structural and systems biology."

Jan Kosinski, CSSB Group Leader

Previous and current research

During infection, pathogens undergo complex life cycles, interact with molecular systems of their hosts, and disturb and hijack host molecular machines for their own purposes. In our lab, we aim at creating comprehensive multi-scale models of entire infection cycles to discover host-pathogen interactions and identify which of them are the most crucial for infection. To this end, we integrate systems biology data with structural information using novel systems biology and structural modeling methods. We then characterize the most promising interactions using bioinformatics and wet-lab experiments

Integrative modeling of infection cycles

Recently, we have made significant contributions to developing and applying methods for integrative structural modeling. For example, we applied our methods to build a near-atomic model of one of the largest complexes in the cell - the human nuclear pore complex, based on data from electron tomography and crosslinking mass spectrometry. We will now apply the experience and methods of modeling molecular structures to modeling entire molecular processes and systems.

Our research is highly collaborative and will involve common projects with other EMBL and CSSB groups, CSSB partners, and external groups. We are just starting building our research group and aim at assembling an interdisciplinary team of scientists who combine bioinformatics with wet-lab experimentation.

The structure of the nuclear pore complex obtained by integrative modeling

Future projects and goals
- Development and application of methods for integrative modeling of infection cycles
- Mechanisms of subversion of the nuclear pore complex by pathogens
- Identification and characterization of host-pathogen interactions most promising for therapeutic intervention
- Integrative structural modeling of macromolecular complexes and cellular landscapes

Selected Publications

Ferber M, Kosinski J, Ori A, Rashid UJ, Moreno-Morcillo M, Simon B, Bouvier G, Batista PR, Müller CW, Beck M, Nilges M. (2016) Automated structure modeling of large protein assemblies using crosslinks as distance restraints. Nat. Methods doi: 10.1038/nmeth.3838. PMID: 27111507

Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M. (2016) Molecular architecture of the inner ring scaffold of the human nuclear pore complex. Science 352(6283):363-365. doi: 10.1126/science.aaf0643. PMID: 27081072

Thierry E, Guilligay D, Kosinski J, Bock T, Gaudon S, Round A, Pflug A, Hengrung N, El Omari K, Baudin F, Hart DJ, Beck M, Cusack S. (2016) Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains. Mol. Cell 61(1):125-137. doi: 10.1016/j.molcel.2015.11.016. PMID: 26711008

Kosinski J, von Appen A, Ori A, Karius K, Müller CW, Beck M. (2015) Xlink Analyzer: Software for analysis and visualization of cross-linking data in the context of three-dimensional structures. J. Struct. Biol. 189(3):177-183. doi: 10.1016/j.jsb.2015.01.014. PMID: 25661704

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