An unstructured proteasome inhibitor comes into focus.

The inhibitory mechanism of an intrinsically disordered proteasome inhibitor identified over 30 years ago has finally been revealed by cryo-electron microscopy by Hsu et al. in a recent report in the Journal of Biological Chemistry. The structure, coupled with biochemical and cell-based experiments, resolves lingering questions about how the inhibitor achieves multisite inhibition of proteasomal protease activity, while raising several exciting new questions on the nature of proteasome subpopulations in the process.