Biological macromolecules adopt complicated three-dimensional (3D) structures that are critical to their function. We want to learn how these complicated structures help macromolecules perform particular tasks. To do this we use a visualization technique called electron cryomicroscopy (cryo-EM), which involves firing a beam of high-energy electrons at a biological sample at cryogenic temperatures. Some of these electrons interact with the sample and when recorded form a 2D image of the sample. A 3D density map can then be formed from a series of these 2D images. In recent years the quality of these maps has improved rapidly and often have sufficient detail (resolution) to build an atomic model of the structure. This “resolution revolution” is the result of better microscopes, advances in electron detection, and new mathematical models for interpreting the raw images.

Cryo-EM has made the impossible possible. We can now visualize macromolecules that are structurally heterogeneous, produced at low yield, and, perhaps most excitingly, directly in their native environment.

Visualizing ribosomes

In the past, we made use of the developments in cryo-EM to solve the structures of the specialized ribosomes of both human and yeast mitochondria. These structures improved our understanding of mitochondrial translation, but also revealed the amazing diversity of mitochondrial ribosomes.

We also solved structures of bacterial and eukaryotic ribosomes nearing the end of translation. A particular highlight was revealing the molecular basis by which the eukaryotic release factor (eRF1) recognizes stop codons, which was done in collaboration with Sichen Shao. Work on ribosome structure and function continues in the Shao lab, our close neighbors on the quad. 

Molecular transport complexes from native sources

Our long-term goal is to understand transport mechanisms in the cell. We are particularly interested in the interplay between microtubules, motor proteins, adaptor complexes and their cargoes, and the role of these processes in signalling pathways. To do this we use a combination of structural, biophysical and biochemical techniques with an emphasis on high-resolution electron microscopy.

Methods for interpreting cryo-EM maps

We are also interested in developing new methods to accelerate and improve cryo-EM structure determination. In particular how we can improve the interpretation of cryo-EM density maps with all-atom models and make these models as accurate as possible.

Some useful tools that we helped develop for cryo-EM can be found here.