Fragment screening in cells with cryo-EM

Of all the biophysical advances so far this century, cryogenic electron microscopy (cryo-EM) has probably made the most impressive strides. Frequently dismissed as “blobology” just a few years ago, the technique now regularly produces three-dimensional structural models that rival those from X-ray crystallography. Indeed, it is rare to pick up an issue of Science or Nature that doesn’t contain a cryo-EM structure. Earlier this year, researchers from Astex described the structures of fragment hits against two proteins determined using cryo-EM. Now, the boffins from DREADCO (who previously brought us universal crystallography) have begun fragment screening in cells using cryo-EM.

Fragment screening in cells is not new: we previously highlighted work using either covalent or non-covalent fragments. However, figuring out which proteins the fragments bind can be challenging, which is one of the reasons structural information is so useful.

The researchers from DREADCO incubate their fragment library against cells – human or otherwise – for varying lengths of time. They then flash-freeze the cells in liquid ethane, collect, and process the data, using standard cryo-EM workflows. Of course, given the complexity of cells, the computational processing power needed is enormous – but nothing their SkyFragNet platform can’t handle.

One of the advantages of cryo-EM is that larger structures are more easily solved, so the researchers are focusing on organelles such as mitochondria, as well as ribosomes. Already they’ve found dozens of hits that resolve to high resolution, and they are in active fragment-to-lead optimization. Surely it is only a matter of time before our list of fragment-derived drugs includes one discovered with the aid of cryo-EM.