Figure 7.

Discovery of structural probes for γ-secretase. Schematic shows the design concept. Helical peptide inhibitors (HPIs) directed to the substrate docking exosite were conjugated through a variable linker to transition-state analogue inhibitors (TSAs) directed to the active site. Presenilin (blue-grey) and other components of the γ-secretase complex (outlined) are shown schematically in the absence and presence of a hybrid HPI-TSA inhibitor. The active site contains two catalytic transmembrane aspartates and three hydrophobic pockets S1′, S2′ and S3′ that must be engaged for intramembrane proteolysis. Linking TSA 10 to HPI 11 through a 10-atom linker led to stoichiometric inhibitor 15.