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Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2020 Feb 19; Vol. 142 (7), pp. 3351-3355. Date of Electronic Publication: 2020 Feb 04. - Publication Year :
- 2020
-
Abstract
- γ-Secretase is a membrane-embedded aspartyl protease complex central in biology and medicine. How this enzyme recognizes transmembrane substrates and catalyzes hydrolysis in the lipid bilayer is unclear. Inhibitors that mimic the entire substrate transmembrane domain and engage the active site should provide important tools for structural biology, yielding insight into substrate gating and trapping the protease in the active state. Here, we report transmembrane peptidomimetic inhibitors of the γ-secretase complex that contain an N-terminal helical peptide region that engages a substrate docking exosite and a C-terminal transition-state analog moiety targeted to the active site. Both regions are required for stoichiometric inhibition of γ-secretase. Moreover, enzyme inhibition kinetics and photoaffinity probe displacement experiments demonstrate that both the docking exosite and the active site are engaged by the bipartite inhibitors. The solution conformations of these potent transmembrane-mimetic inhibitors are similar to those of bound natural substrates, suggesting these probes are preorganized for high-affinity binding and should allow visualization of the active γ-secretase complex, poised for intramembrane proteolysis, by cryo-electron microscopy.
- Subjects :
- Amyloid Precursor Protein Secretases metabolism
Catalytic Domain
HEK293 Cells
Humans
Kinetics
Molecular Docking Simulation
Peptidomimetics metabolism
Protease Inhibitors metabolism
Protein Binding
Protein Conformation, alpha-Helical
Amyloid Precursor Protein Secretases antagonists & inhibitors
Peptidomimetics chemistry
Protease Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 142
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 31999444
- Full Text :
- https://doi.org/10.1021/jacs.9b13405