Gamma secretase cleaves the amyloid precursor protein, which results in the formation of neurotoxic Aβ42 peptides that have been implicated in the pathogenesis of Alzheimer's disease. Gamma<i> s</i>ecretase inhibitors (GSIs) have been unsuccessful in clinical trials, likely due to toxicity related to the inhibition of the NOTCH signaling pathway. Therefore, gamma secretase modulators (GSMs) have been developed to reduce the production of the Aβ42 peptides without inhibiting the processing of gamma secretase substrates. Utilizing clickable photoprobes, we have shown that GSIs and GSMs have distinct binding sites on gamma secretase, although the precise binding sites have remained elusive. In this presentation, we demonstrate a cleavable photoprobe of BMS-708163 labels the intracellular inhibitory loop of presenilin-1 within the gamma secretase complex, revealing the binding site of this class of GSIs. Furthermore, modeling of gamma secretase and the photoprobe inhibitor using molecular dynamic simulations corroborates photolabeling experiments.

Cleavable photoprobes enable binding site identification of a gamma secretase inhibitor

254th National Meeting (2017)

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