High-resolution structure determination of dynamic macromolecular complexes

Holger Stark

Single particle cryo electron microscopy (cryo-EM) has developed into a powerful technique to determine 3D structures of large macromolecular complexes. Due to improvements in instrumentation and computational image analysis, the number of high-resolution structures is steadily increasing. The method cannot only be used to determine high-resolution structures but also to study the dynamic behavior of macromolecular complexes and thus represents a very complementary method to X-ray crystallography. We have recently determined the structure of human proteasomes and their inhibition by anti-cancer drugs using X-ray crystallography to visualize the chemistry of inhibition at unprecedented resolution of 1.8 Å. By cryo-EM we were able to visualize the long-range allosteric conformational changes induced by the drug binding and visualized the effects of drug binding in terms of restrictions in the free-energy landscape of the human 26S proteasome. More examples of cryo-EM studies of dynamic processes in large macromolecular complexes will be presented at the conference.

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