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Efficient High Resolution Cryo EM Microscopy of large assemblies, membrane proteins and cellular structures

Research Project
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01.11.2017
 - 31.10.2018

Novel developments in instrumentation and software for cryo electron microscopy have resulted in a "resolution revolution" and have transformed this technique into the most efficient method for high-resolution structure determination of larger biological macromolecules. We are applying cryo electron microscopy to study biological macromolecular assemblies, such as mTOR complexes, highly-regulated multienzymes of human metabolism, polyketide synthases and bacterial Type 6 secretion systems as well as membrane proteins. Understanding the architecture, dynamics and functional mechanisms of these complex target molecules is of highest relevance for fundamental molecular biology, with direct relevance also for cancer therapy and the fight against antibiotic resistance. Despite all progress in electron microscopy methods, extensive sample screening is required for highest resolution analysis. In particular, highly dynamic assemblies and transient complexes affected by conformational and compositional heterogeneity remain a challenge for structural analysis. Here, sample quality often limits the final resolution of structure determination and consequently the quality of mechanistic insights. Often, careful sample stability assays, stabilization by specific or unspecific crosslinking and exhaustive testing of sample vitrification and grid preparation are required to obtain useful results. Here, we request funding for a highly efficient FEG electron microscope with direct electron detector and multi-sample loader for sample screening and analysis. This instrument shall permit high-resolution sample analysis and characterization crucial for the detection of e.g. presence of small protein binding partners, conformational homogeneity, as well as successful trapping and stabilization of specific biological states of the target molecules. Overall, this instrument will uniquely contribute to moving cellular biology analysis to molecular resolution.

Funding

Efficient High Resolution Cryo EM Microscopy of large assmeblies, membrane proteins and cellular structures

SNF Projekt (GrantsTool), 11.2017-10.2018 (12)
PI : Maier, Timm.
CI : Basler, Marek,Perez, Camilo.

Members (3)

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Timm Maier

Principal Investigator
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Marek Basler

Co-Investigator
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Camilo Perez

Co-Investigator