Helmholtz Munich etabliert modernste Cryo-Elektronenmikroskopie-Technologie
Diese ermöglicht Durchbrüche für die hochauflösende Strukturanalyse von therapeutischen Zielmolekülen und die Visualisierung in ihrer natürlichen zellulären Umgebung
Strukturbiologische Techniken wie die Röntgenkristallographie, die Kernspinresonanzspektroskopie (NMR)-Spektroskopie und die Cryo-Elektronenmikroskopie Einzelpartikelanalyse (Cryo-EM SPA) bieten einzigartige Einblicke in die molekularen Mechanismen von biologischen Prozessen und ermöglichen strukturbasierte Medikamentenentwicklung zur Behandlung von menschlichen Krankheiten. Hochauflösende Strukturen biologischer Moleküle werden an isolierten in vitro aufgereinigten Biomoleküle durchgeführt. Bis vor Kurzem war es schwierig, subzelluläre Kompartimente in ihrer natürlichen zellulären Umgebung zu untersuchen.
Ein weiterer Schritt, gestützt durch die fachübergreifende Zusammenarbeit zwischen dem Helmholtz Pioneer Campus und dem Molecular Targets and Therapeutics Center (MTTC) ist die Implementierung einer weltweit aufstrebenden, neuartigen Technologie namens in-situ Cryo-Elektronentomographie (Cryo-ET) bei Helmholtz Munich Cryo-ET ermöglicht die Visualisierung zellulärer Strukturen in ihrer natürlichen und funktionalen Umgebung mit molekularer Auflösung. Diese Technologie bildet das Herzstück der neuen Helmholtz Munich Cryo-EM-Plattform (CEMP), die modernste Cryo-EM-Infrastrukturen für sowohl In-situ Cryo-ET als auch Cryo-EM-SPA bereitstellt. Die neue multimillionenschwere Ausstattung deckt alle Arbeitsabläufe fortgeschrittener Cryo-EM-Anwendungen ab und kann für eine Vielzahl von Forschungsthemen eingesetzt werden - angefangen von der Aufklärung molekularer Mechanismen bis hin zur Beschleunigung neuer therapeutischer Ansätze. Helmholtz Munich ist somit einer der wenigen Standorte weltweit, die das gesamte Spektrum der strukturellen Technologien mit atomarer Auflösung nutzen und anbieten, einschließlich hochmoderner Cryo-EM und 1,2 GHz Ultrahochfeld-NMR-Spektroskopie. (Quelle: https://www.bnmrz.org/)
Prof. Michael Sattler, Leiter des Molecular Targets and Therapeutics Center und Direktor des Instituts für Strukturbiologie bei Helmholtz Munich, kommentiert: " Wir erwarten beispiellose Einblicke in biomolekularen Strukturen in ihrer natürlichen Umgebung in gesunden und krankheitsverknüpften Zuständen und ermöglichen damit die Entwicklung neuartiger therapeutischer Ansätze.“
Helmholtz Munich | ©Almut BardenHow will the Helmholtz Munich Cryo-EM Platform be used?
The Helmholtz Munich CEMP provides unique access and expertise to cryo-EM SPA as well as cryo-ET workflows. The former enables high-resolution structural analysis of biomolecular complexes that are of the highest biomedical importance and thus enable structure-guided drug discovery on challenging targets, such as signaling receptors, membrane-associated protein complexes, and large protein-RNA complexes in gene regulation, enabling structure-based drug discovery efforts of Michael Sattler and team.
Dr. Marion Jasnin, Principal Investigator of the Cryoskeleton Lab at the Helmholtz Pioneer Campus leads the implementation of the cryo-ET workflow. She was only recently recruited from Prof. Baumeister’s lab (MPI Martinsried), one of the globally recognized pioneers of cryo-ET. Marion also accelerates her own research program that investigates actin, a small globular protein, and its associated cytoskeletal proteins in their native cellular environment to advance our understanding of cellular structure, the underlying biology and disease mechanisms, in particular tumor cell invasion.
Together, the integration of scientific expertise of cryo-EM SPA, NMR spectroscopy, X-ray crystallography, in situ cryo-ET, optical imaging and artificial intelligence (AI) at Helmholtz Munich will ultimately lead to a better understanding of cellular structures, dynamics and mechanisms across scales, from individual macromolecules to whole organisms.
Who utilizes the Helmholtz Munich Cryo-EM Platform?
Many research groups at Helmholtz Munich have already established collaborations and have access to the cryo-EM technologies at the Helmholtz Munich CEMP. A cooperation on structural biology applications is currently being established with the Technical University of Munich (TUM School of Natural Sciences, Department of Bioscience, and Center for functional Protein Assemblies (CPA)). The Helmholtz Munich CEMP, managed by Dr. Stefan Bohn, will be used to study emerging topics in biomedical research, ranging from stem cell, diabetes and environmental health to molecular targets and therapeutics. In addition, the unique expertise in AI-based computational tools for image analysis available at the Computational Health Center and Helmholtz AI at Helmholtz Munich is expected to significantly advance the application of cryo-ET technology for in-cell structural biology to understand physiological and pathological pathways and enable the development of new therapeutic concepts to treat human diseases.
About the scientists
Prof. Dr. Michael Sattler, Head of the Molecular Targets & Therapeutics Center, Director of the Institute of Structural Biology and the Bavarian NMR Center (Helmholtz Munich & TUM)
Dr. Marion Jasnin, Principal investigator of the Cryoskeleton Lab at the Helmholtz Munich Pioneer Campus
Dr. Stefan Bohn, CEMP Facility Manager and Staff Scientist at the Institute of Structural Biology at the Molecular Targets & Therapeutics Center at Helmholtz Munich
How does cryo-ET work and what can be analyzed?
During cryo-ET acquisition, 2D images of a vitrified sample are taken at different angles (typically from -60 to +60 degrees), which can then be reconstructed into a 3D volume called a tomogram. The tomogram shows not only the macromolecule of interest, but also its location and spatial arrangement within the cellular environment, from which the biological function can be inferred. Although cryo-ET provides lower (nanometer to subnanometer) resolutions than cryo-EM SPA, where single atoms can be resolved, cryo-ET has a decisive advantage in revealing spatial information. Cryo-ET already facilitates the analysis of samples such as cellular organelles, membrane structures with membrane proteins, bacteria, viruses and large molecular machineries. In addition, dynamic organelles such as cilia or other structures associated with cell mobility, signal transport or transmission have been visualized so far. Furthermore, recent progress in the field demonstrates that structural analysis of organoids, large mammalian cells, and even whole organisms such as the nematode C. elegans is feasible. The only limitation is the crystal-free freezing of the biological sample. In situ cryo-ET is a rapidly emerging technique, with many breakthroughs still to come.
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