Figure 5. Proposed model for Sec61 inhibition.

a, General model for the mechanism of Sec61 inhibitors. Inhibitors bind to Sec61 in a partially open conformation and preclude the plug from opening. This prevents substrate polypeptide insertion. b, A proposed model for client-specific inhibition. Certain client-specific inhibitors may allow an interaction between strong signals (e.g., TM signal anchors) and the channel such that the signal sequence/anchor is wedged into the partially open lateral gate. This would further open the lateral gate to cause release of the inhibitor. Inhibitors forming less interactions with the pore and plug, rendering the lateral gate into a more open conformation, and/or displaying a weaker overall affinity are likely to be overcome by this manner.