Open Sesame The proteosome plays a key role in cellular homeostasis through catalyzing protein degradation. It is a barrel-shaped nanomachine whose activity is regulated through gating substrate entry. Religa et al. (p. 98 ) now show that N-terminal gating residues in the proteasome interconvert on a second's time-scale between conformations that place them either outside or inside the proteasomal antechamber. An increase in the number of termini occupying the “in” state decreased rates of hydrolysis. Furthermore, proteasome activators known to increase the proteolysis rate lead to an increase in the number of termini in the “out” state.