Moving beyond protein structure

It’s a bit ironic that, just as methods for deducing the crystal structures of protein molecules have become supercharged, we’ve started to discover they might not always help very much for developing drugs that target proteins. First there was synchrotron radiation, and now free-electron lasers, as sources of ultrabright x-ray beams that can reduce data collection times and crystal sizes for crystallography. Meanwhile, AlphaFold can predict the structures of many proteins with impressive accuracy from sequence data alone.

Yet it’s not always a question of structure. Take a recent study by a team at University College London, UK, revealing the crucial role of dynamics and of the ability of enzymes to explore their conformational landscape. The researchers point out that some single-residue mutations of proteins can significantly change their activity while barely impacting their crystal structure, because the active conformations are only sparsely represented in the distribution of dynamical states.