Journal
CELL CHEMICAL BIOLOGY
Volume 24, Issue 1, Pages 3-8Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2016.12.006
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Funding
- NIH [R01AG026660, R01NS076117, R01NS096275]
- Alzheimer Association [IIRG-12-242137]
- JPB Foundation
- MetLife Foundation
- MSK Cancer Center Support Grant/Core Grant [P30 CA008748]
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gamma-Secretase, a four-subunit transmembrane aspartic proteinase, is a highly valued drug target in Alzheimer's disease and cancer. Despite significant progress in structural studies, the respective molecular mechanisms and binding modes of gamma-secretase inhibitors (GSIs) and modulators (GSMs) remain uncertain. Here, we developed biotinylated cleavable-linker photoprobes based on the BMS-708163 GSI to study its interaction with gamma-secretase. Comparison of four cleavable linkers indicated that the hydrazinelabile N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl (Dde) linker was cleaved most efficiently to release photolabeled and affinity-captured presenilin- 1 (PS1), the catalytic subunit of gamma-secretase. Peptide mapping showed that the BMS-708163-based probe photoinserted at L282 of PS1. This insertion site was consistent with the results of molecular dynamics simulations of the gamma-secretase complex with inhibitor. Taken together, this work reveals the binding site of a GSI and offers insights into the mechanism of action of this class of inhibitors.
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