AI Article Synopsis
- γ-Secretase is a key target for drugs in treating Alzheimer's and cancer, but the specific workings of its inhibitors (GSIs) and modulators (GSMs) are still not fully understood.
- Researchers created a special probe based on the GSI BMS-708163 to explore how it interacts with the γ-secretase enzyme.
- The study found that the most effective probe linked to a specific site on the catalytic subunit of γ-secretase, providing new knowledge about how these inhibitors function.
Article Abstract
γ-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 γ-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 γ-secretase. Comparison of four cleavable linkers indicated that the hydrazine-labile 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 γ-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 γ-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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516958 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2016.12.006 | DOI Listing |
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