γ-Secretase is a highly regulated allosteric enzyme. This multisubunit complex can cleave integral membrane proteins within the lipid bilayer. Aberrant cleavage of one such protein, amyloid precursor protein, results in Alzheimer disease, but γ-secretase has also been linked to other cellular and disease processes. Divergent views about the enzyme complex exist, based on either functional studies or static views, so here (p. 589), Bart De Strooper, Lucia Chavez-Gutierrez and colleagues use single-particle electron microscopy (EM) to analyse the conformational landscape of the γ-secretase complex. They established a novel purification protocol for the complex, which yielded highly pure and active enzyme. Single-particle EM revealed that wild-type γ-secretase exists in three different structural states: extended, intermediate and compact. These states differ in their overall compactness and relative position of the nicastrin ectodomain. The authors show that the equilibrium that exists between the different conformers can be shifted by the binding of inhibitors to the protease's active or substrate-binding sites. Interestingly, a mutation linked to familial Alzheimer disease resulted in the enrichment of complexes with the extended conformation and increased flexibility. This study shows, for the first time, a dynamic structural–functional interplay in which significant conformational rearrangements dictate protease function.