Once considered the poor cousin in structural biology, cryo-electron microscopy (cryo-EM) has found new favor in industry, after technical improvements have broken barriers in molecular size and resolution, resulting in floods of data that can support better drug design. Now, close collaboration between academics and companies, including hardware and software developers, promises to unlock a wide array of therapeutically relevant structures that have eluded other approaches.
Cryo-EM involves firing electrons at flash-frozen molecules. Those electrons pass through a molecule's empty spaces and bounce off its dense areas, producing a scattering pattern that is used to deduce the molecule's structure.
Until about four years ago, lower-resolution outputs and cumbersome protocols prevented widespread adoption of the technique.
"With cryo-EM, it was generally considered that you could get structures that looked like 'blobs', but you would never get to atomic resolution structures," said Sriram Subramaniam, a senior investigator of cell biology at the National Cancer Institute (NCI).
That changed when improvements in instrumentation and data analysis enabled characterization of smaller structures at better resolution, leading to a surge in published structures. Subramaniam's team has broken multiple technical barriers of cryo-EM, including recently using it to solve the structure of a protein smaller than 100 kDa (see "Box: New resolutions").
Richard Henderson, a pioneer in cryo-EM, who is programme leader in structural studies at the Medical Research