Tomographic reconstruction of frozen-hydrated specimens followed by extraction and averaging of sub-tomograms has successfully been used to determine the structure of macromolecules in their native environment at resolutions that are high enough to reveal molecular level interactions.
The advent of high-throughput methods for data acquisition that can produce thousands of high-quality tilt series during a single microscope session, however, has uncovered bottlenecks in the downstream data analysis which has so far relied on supervised, user-driven pipelines.
In this talk, I will present recent advances in high-throughput tomography that have allowed us to streamline the cryo-ET structure-determination process and improve the resolution of structures using the "constrained single-particle tomography" paradigm. The combination of strategies for accelerated tilt-series acquisition together with data-driven techniques for high-resolution image analysis, will pave the way for cryo-ET to become the technique of choice to determine protein structures in their native environment.
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