ArticleCell chemical biology2017
Mapping the Binding Site of BMS-708163 on γ-Secretase with Cleavable Photoprobes.
Article in Cell chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 41 citations in OpenAlex.
- Covalent Chemical Tagging of Transmembrane Transport Proteins Illuminates the Internalization Pathways of Xenosiderophores.Journal of the American Chemical Society · 2026Article
- Chemical proteomic mapping of reversible small molecule binding sites in native systems.Trends in pharmacological sciences · 2024Review
- Solid-Phase Compatible Silane-Based Cleavable Linker Enables Custom Isobaric Quantitative Chemoproteomics.Journal of the American Chemical Society · 2023Article
- An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.Biophysical journal · 2022Article
- Structure and mechanism of the γ-secretase intramembrane protease complex.Current opinion in structural biology · 2022Review
- Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase.Journal of the American Chemical Society · 2022Article
- Turning the tide on Alzheimer's disease: modulation of γ-secretase.Cell & bioscience · 2022Review
- Improved Handling of Peptide Segments Using Side Chain-Based "Helping Hand" Solubilizing Tools.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Labeling Preferences of Diazirines with Protein Biomolecules.Journal of the American Chemical Society · 2021Article
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- Bioorthogonal Reactions in Activity-Based Protein Profiling.Molecules (Basel, Switzerland) · 2020Review
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Bioorthogonal Ligations and Cleavages in Chemical Biology.ChemistryOpen · 2020Review
- Mechanisms of γ-Secretase Activation and Substrate Processing.ACS central science · 2020Article
- Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer's Therapeutics.International journal of molecular sciences · 2020Review
- Small Molecule Interactome Mapping by Photo-Affinity Labeling (SIM-PAL) to Identify Binding Sites of Small Molecules on a Proteome-Wide Scale.Current protocols in chemical biology · 2019Article
- Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.