Imaging small proteins for drug discovery

One approach to treating cancer is to identify biomolecular processes that occur only in cancer cells and design drugs to disrupt them. For example, in some cancers, the enzyme isocitrate dehydrogenase (IDH) contains a mutation that causes it to affect cellular metabolism in cancer cells than it does in healthy cells, but a chemical called ML309 can bind to the mutant IDH and render it nonfunctional. Imaging that and other drug–protein complexes could make it easier to identify the most effective drugs. Now Sriram Subramaniam of the National Institutes of Health in Bethesda, Maryland, and his colleagues have shown that cryo-electron microscopy may be up to the job.

To determine a biomolecule’s structure with cryo-EM, embed thousands of copies of the molecule in a thin sheet of amorphous ice and scan them with an electron beam. Each image of an individual copy is incomplete and noisy, but aligning and averaging them produces a complete, high-resolution image. Spurred by the advent of faster electron detectors, the technique has seen rapid progress over the past few years. Yet researchers have struggled to image relatively small proteins like IDH (a mere 93 000 atomic mass units), largely because of the difficulty of aligning the individual images.

Subramaniam and colleagues showed that it can be done through a combination of tricks, including using thinner ice sheets and performing algorithms to discard data from molecules damaged by the electron beam. Their structure of the IDH–ML309 complex (shown in the figure with ML309 in red) isn’t quite crisp enough to resolve individual atoms. Even so, it yielded new insights into how the molecules interact: The IDH molecule’s two subunits, shown in yellow and blue, are wedged apart by the ML309 molecule. (A. Merk et al., Cell 165, 1698, 2016 .)