Electron cryo-tomography for observation of macromolecular changes induced by test compound within a cell

Structures obtained by NMR, X-ray diffraction and single particle cryo-electron microscopy lack the cellular context. In the cell, quite often chemicals that are supposed to bind a specific target show lower affinity and are not delivered to the target or they interact with unpredicted cellular components with possible toxic side effects.

Cryo-electron tomography is an emerging tool that allows us to visualize macromolecular complexes within high pressure frozen cells (1) With novel methods for generating vitreous cryo-sections and iterative reconstruction techniques, developed within the project, we push forward the resolution to the point of being able to identify structural changes induced by drugs on macromolecular complexes in a native cellular context (2).

The implementation of this technology will bring additional dimension to our understanding of the toxic effect of chemicals in the cell.